THE CHEMICAL COMPONENTS

OF TOBACCO
AND TOBACCO SMOKE

© 2009 by Taylor & Francis Group, LLC

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 THE CHEMICAL COMPONENTS
OF TOBACCO
AND TOBACCO SMOKE

Alan Rodgman
Thomas A. Perfetti

Boca Raton London New York

CRC Press is an imprint of the

Taylor & Francis Group, an informa business

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 CRC Press
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Library of Congress Cataloging-in-Publication Data

Rodgman, Alan.
The chemical components of tobacco and tobacco smoke / Alan Rodgman and Thomas A. Perfetti.
p. ; cm.
“A CRC title.”
Includes bibliographical references and index.
ISBN 978-1-4200-7883-1 (hardcover : alk. paper) 1. Tobacco--Composition. 2. Tobacco smoke--Composition. I. Perfetti, Thomas
Albert, 1952- II. Title.
[DNLM: 1. Smoke--adverse effects. 2. Tobacco--chemistry. 3. Smoking--adverse effects. 4. Tobacco--adverse effects. WA 754 R691c
2009]

SB275.R63 2009
613.85--dc22 2008018913

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 Table of Contents
Foreword ...................................................................................................................................................................................... ix
Acknowledgments........................................................................................................................................................................ xi
The Authors ...............................................................................................................................................................................xiii
List of Tables.............................................................................................................................................................................xvii
List of Figures ........................................................................................................................................................................... xxv
Introduction.............................................................................................................................................................................xxvii

Chapter 1 The Hydrocarbons ................................................................................................................................................. 1

I.A The Alkanes......................................................................................................................................................................... 1
I.B The Alkenes and Alkynes ................................................................................................................................................... 7
I.C The Alicyclic Hydrocarbons.............................................................................................................................................. 36
I.D The Monocyclic Aromatic Hydrocarbons ......................................................................................................................... 47
I.E The Polycyclic Aromatic Hydrocarbons............................................................................................................................ 55
I.F Summary ......................................................................................................................................................................... 102

Chapter 2 Alcohols and Phytosterols ..................................................................................................................................111

II.A Alcohols............................................................................................................................................................................111
II.B Phytosterols.......................................................................................................................................................................115

Chapter 3 Aldehydes and Ketones ..................................................................................................................................... 215

The Assertion of Aldehydes and Ketones as Ciliastatic Tobacco Smoke Components ........................................................... 221
Ciliastasis Studies with Cigarette Smoke Condensate Fractions.............................................................................................. 226
Ciliastasis Studies With Individual Cigarette Mainstream Smoke Components ..................................................................... 226
Nose Inhalation of Environmental Tobacco Smoke vs. Mouth Inhalation of Mainstream Smoke .......................................... 227

Chapter 4 Carboxylic Acids .................................................................................................................................................317

IV.A The Carboxylic Acids .......................................................................................................................................................317
IV.B The Amino Acids and Related Compounds .....................................................................................................................318

Chapter 5 The Esters........................................................................................................................................................... 381

Chapter 6 The Lactones ...................................................................................................................................................... 439

Chapter 7 Anhydrides ......................................................................................................................................................... 461

Chapter 8 Carbohydrates and Their Derivatives ............................................................................................................. 465

Chapter 9 Phenols and Quinones ....................................................................................................................................... 487

IX.A Phenols .......................................................................................................................................................................... 487
IX.A.1 Identification and Quantitation of Phenols in Cigarette MSS ....................................................................... 492
IX.A.2 Bioassays to Determine the Contribution of Phenols to Cigarette Smoke
Condensate Tumorigenicity ........................................................................................................................... 495
IX.A.3 Determination of the Nature of the Precursors in Tobacco of the Phenols
in Mainstream Smoke.................................................................................................................................... 501
IX.A.4 The Effect of Cigarette Design Parameters on Yield of Mainstream Smoke Phenols .................................. 507
IX.B Quinones ....................................................................................................................................................................... 547

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 Chapter 10 The Ethers ........................................................................................................................................................ 555
Overall Summary of Oxygen-Containing Components of Tobacco and/or Smoke: Chapters 2 through 10 ........................... 555

Chapter 11 Nitriles................................................................................................................................................................615

Chapter 12 Acyclic Amines ................................................................................................................................................. 627

Chapter 13 Amides .............................................................................................................................................................. 663

Chapter 14 Imides................................................................................................................................................................ 679

Chapter 15 N-Nitrosamines ................................................................................................................................................ 687

XV.A Volatile N-Nitrosamines........................................................................................................................................... 691
XV.B Nonvolatile N-Nitrosamines..................................................................................................................................... 691
XV.C Tobacco-Specific N-Nitrosamines ........................................................................................................................... 699
XV.D N-Nitrosamino Acids ............................................................................................................................................... 704
XV.E Tobacco-Specific N-Nitrosamines: An Exception among the Major MSS Toxicants ............................................. 707
XV.F Direct Transfer of TSNAs from Tobacco vs. Their Formation during the Smoking Process ................................. 708
XV.G Infrequently Studied Tobacco and/or Smoke Secondary Amines and Their N-Nitrosamines................................ 708
XV.H Flue-Curing and Tobacco-Specific N-Nitrosamines................................................................................................ 712

Chapter 16 Nitroalkanes, Nitroarenes, and Nitrophenols ............................................................................................... 721

Chapter 17 Nitrogen Heterocyclic Components................................................................................................................ 727

XVII.A Monocyclic Four- and Five-Membered N-Containing Ring Compounds ............................................................... 727
XVII.A.1 Background........................................................................................................................................... 727
XVII.A.2 Four-Membered N-Containing Rings................................................................................................... 727
XVII.A.3 Five-Membered N-Containing Rings ................................................................................................... 727
XVII.A.4 Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke With Multiple
Five-Membered N-Containing Rings ................................................................................................... 732
XVII.B Monocyclic Six-Membered N-Containing Ring Compounds.................................................................................. 747
XVII.B.1 Introduction .......................................................................................................................................... 747
XVII.B.2 Biosynthesis of Six-Membered N-Containing Ring Compounds and the
Five- and Six-Membered and Multiple Six-Membered Nitrogen Heterocycles of Tobacco................. 748
XVII.B.3 Other Means for the Formation of the Six-Membered N-Containing Ring Compounds
Found in Tobacco ................................................................................................................................. 750
XVII.B.4 Six-Membered N-Containing Ring Compounds in Tobacco and Tobacco Smoke................................751
XVII.B.4.1 Piperidine and the Tetra- and Dihydropyridines ............................................................ 752
XVII.B.4.2 Pyridines ......................................................................................................................... 752
XVII.B.4.3 Pyrazines..........................................................................................................................753
XVII.B.4.4 Pyrimidines..................................................................................................................... 754
XVII.B.5 Compounds in Tobacco and Tobacco Smoke Containing a Five-Membered
and a Six-Membered N-Containing Ring............................................................................................. 779
XVII.B.5.1 Nicotine and Tobacco Alkaloids with a Six-Membered N-Containing Ring
and a Second Five-Membered N-Containing Ring ........................................................ 780
XVII.B.5.2 Compounds in Tobacco and Tobacco Smoke with Two or More Six-Membered
N-Containing Rings ........................................................................................................ 790
XVII.C Lactams .................................................................................................................................................................... 798
XVII.D Oxazoles and Oxazines............................................................................................................................................ 798

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 XVII.E Aza-Arenes............................................................................................................................................................... 806
XVII.E.1 Alternate Exposures to Aza-Arenes ......................................................................................................818
XVII.F N-Heterocyclic Amines............................................................................................................................................ 834

Chapter 18 Miscellaneous Components............................................................................................................................. 855

XVIII.A Sulfur-Containing Components ............................................................................................................................... 855
XVIII.B Halogenated Components ........................................................................................................................................ 857

Chapter 19 Fixed and Variable Gases................................................................................................................................ 893

XIX.A Analytical Methods.................................................................................................................................................. 895
XIX.A.1 Carbon Dioxide (CO2) and Carbon Monoxide (CO) ............................................................................ 896
XIX.A.2 Nitrogen Oxides (NO, NO2, N2O, NOx) ............................................................................................... 896
XIX.A.3 Hydrogen Cyanide (HCN).................................................................................................................... 896
XIX.A.4 Ammonia (NH3) ................................................................................................................................... 897

Chapter 20 Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts.................................................................... 907
XX.A Elements, Isotopes, and Ions in Plants..................................................................................................................... 907
XX.A.1 Elements, Isotopes, and Ions in Tobacco.............................................................................................. 907
XX.A.2 Elements, Isotopes, and Ions in Tobacco Smoke...................................................................................910
XX.B Methods for the Detection and Identification of Metals, Ions, and Isotopes in Tobacco
and Tobacco Smoke ..................................................................................................................................................911
XX.C The Transference of Elements, Isotopes, and Ions from Tobacco to Tobacco Smoke............................................. 912
XX.C.1 Elements in Tobacco Smoke of Special Interest................................................................................... 912
XX.C.1.a Arsenic (As) .................................................................................................................... 913
XX.C.1.b Beryllium (Be) ................................................................................................................ 915
XX.C.1.c Chromium (Cr), Cadmium (Cd), and Lead (Pb) ............................................................. 915
XX.C.1.d Chromium VI [Cr (VI)] .................................................................................................. 915
XX.C.1.e Nickel (Ni) ...................................................................................................................... 915
XX.C.1.f Cobalt (Co) ...................................................................................................................... 915
XX.C.1.g Mercury (Hg) ...................................................................................................................916
XX.C.1.h Selenium (Se) ...................................................................................................................916
XX.C.1.i 210Polonium (210Po) ...........................................................................................................916

XX.D Summary...................................................................................................................................................................916

Chapter 21 Pesticides and Growth Regulators ................................................................................................................. 933

XXI.A Synthetic Pesticides and Plant Growth Regulator Residues on Tobacco................................................................. 934
XXI.B Naturally Occurring Plant Growth Regulators and Pesticides in Tobacco.............................................................. 935
XXI.C Transfer Rates of Pesticides and Plant Growth Regulators to MSS ........................................................................ 936
XXI.D Decomposition Products of Agrochemicals in Mainstream Smoke ........................................................................ 937
XXI.E Methods for Analysis of Pesticides and Plant Growth Regulators .......................................................................... 938
XXI.F Residues of Synthetic Pesticides and Plant Growth Regulators Identified
in Tobacco and Tobacco Smoke............................................................................................................................... 938

Chapter 22 Genes, Nucleotides, and Enzymes.................................................................................................................. 977

XXII.A General Discussion of Genetics ............................................................................................................................... 977
XXII.B Tobacco Genetics ..................................................................................................................................................... 978
XXII.C Genes, Nucleotides, and Enzymes Identified in Tobacco ........................................................................................ 979
Acknowledgments .................................................................................................................................................... 982

Chapter 23 “Hoffmann Analytes” ................................................................................................................................... 1001

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 Chapter 24 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients ...........................................1053
Acknowledgment.....................................................................................................................................................1106
Chapter 25 Pyrolysis...........................................................................................................................................................1107
XXV.A Individual Tobacco Types ....................................................................................................................................... 1111
XXV.B Extracts from Tobacco ............................................................................................................................................1112
XXV.C Individual Tobacco Components.............................................................................................................................1115
XXV.C.1 Nicotine ...............................................................................................................................................1116
XXV.C.2 Organic Solvent-Soluble Components (Long-Chained Aliphatic Hydrocarbons,
Phytosterols, Solanesol, High Molecular Weight Esters, etc.) ............................................................1118
XXV.C.3 Structural Components of Tobacco (Cellulose, Lignin, Pectins, etc.)................................................ 1124
XXV.C.4 Acids....................................................................................................................................................1129
XXV.C.5 Proteins and Amino Acids ..................................................................................................................1130
XXV.D Tobacco Additives ...................................................................................................................................................1134
XXV.D.1. Additives Used in Tobacco Production ...............................................................................................1134
XXV.D.1.a Sucker Growth Inhibitors...............................................................................................1134
XXV.D.1.b Pesticides........................................................................................................................1137
XXV.D.2 Additives Used in Cigarette Manufacture ...........................................................................................1139
XXV.D.2.a Casing Materials (Sugars, Cocoa, Licorice)..................................................................1139
XXV.D.2.b Humectants (Glycerol, Propylene Glycol).....................................................................1140
XXV.E Cigarette Construction Materials (Paper, Adhesives, etc.) .....................................................................................1141
XXV.F Flavoring Ingredients ..............................................................................................................................................1142

Chapter 26 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens.............1173
XXVI.A Carcinogens, Tumorigens, and Mutagens ...............................................................................................................1173
XXVI.A.1 The Polycyclic Aromatic Hydrocarbons .............................................................................................1182
XXVI.A.2 Other Classes of Carcinogens, Tumorigens, and Mutagens ................................................................1183
XXVI.A.2.a Aza-Arenes..................................................................................................................1183
XXVI.A.2.b N-Nitrosamines............................................................................................................1189
XXVI.A.2.c N-Heterocyclic Amines ...............................................................................................1190
XXVI.B Anticarcinogens, Inhibitors, and Antimutagens .....................................................................................................1193
XXVI.B.1 Alternate Exposures to Carcinogens, Tumorigens, and Mutagens......................................................1218
XXVI.B.1.a Alternate Exposures to Polycyclic Aromatic Hydrocarbons.......................................1219
XXVI.B.1.b Alternate Exposures to Aza-Arenes ........................................................................... 1223
XXVI.B.1.c Alternate Exposures to N-Nitrosamines..................................................................... 1223
XXVI.B.1.d Alternate Exposures to N-Heterocyclic Amines .........................................................1231
XXVI.C Summary................................................................................................................................................................ 1233

Chapter 27 Free Radicals.................................................................................................................................................. 1235

XXVII.A Introduction ......................................................................................................................................................... 1235
XXVII.B Analytical Methods for Determination of Free Radicals .................................................................................... 1236
XXVII.C Free Radicals in Tobacco Smoke......................................................................................................................... 1237
XXVII.D Historical Review of Free Radical Research on Cigarette Smoke ...................................................................... 1238
XXVII.E Proposed Mechanisms for the Generation of Free Radicals in MSS .................................................................. 1250

Chapter 28 Summary ........................................................................................................................................................ 1257

Bibliography ...........................................................................................................................................................................1261

Alphabetical Component Index ........................................................................................................................................... 1483

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 Foreword
The following pages are an attempt to update a situation with
regard to the composition of tobacco and tobacco smoke that
has existed for almost four decades. Although it is suspected
that the chemical components of tobacco and tobacco smoke
may have been cataloged in-house at various U.S. and foreign
tobacco companies as well as by various governmental agen-
cies, no such catalog has been published since the 1968 review
by the highly competent tobacco scientist R.L. Stedman of the
U.S. Department of Agriculture (3797). One article published
by a tobacco company prior to that of Stedman was a 1963
referenced monograph on tobacco and tobacco smoke compo-
nents by Philip Morris, Inc. (2939). Its monograph was sub-
mitted to the 1964 Advisory Committee for use in preparation
of its 1964 report to the U.S. Surgeon General. The Philip
Morris monograph had been preceded by the 1959 published
review by Johnstone and Plimmer (1971). In subsequent years,
several tobacco and tobacco smoke publications dealt with
specific types or classes of components, for example, the 1964
compilation of the polycyclic aromatic hydrocarbons (PAHs)
in tobacco smoke by Elmenhorst and Reckzeh (1139), the 1969
review by Neurath on the nitrogen-containing components
identified in tobacco smoke (2724), and the 1977 review by
Schmeltz and Hoffmann on the nitrogen-containing compo-
nents in both tobacco and tobacco smoke (3491). Several cata-
logs of the chemical components of only tobacco smoke have
been published, for example, the 1954 article by Kosak (2170),
but the most recent one was that of Ishiguro and Sugawara
(1884) in 1980. Since the 1968 Stedman article in which about
1200 tobacco and smoke components were listed, the num-
ber of identified tobacco and tobacco smoke components has
increased sevenfold to almost 8400, a number that includes
only about 500 of the many thousands of enzymes identified
in the tobacco plant.
The references cited for a particular tobacco and/or
tobacco smoke component may deal with its identification
or with a variety of topics pertinent to the particular com-
ponent. Topics may include such simple items as the isola-
tion and identification of a component, its characterization
by classical chemical means, for example, the definition of
the structure of solanesol isolated from flue-cured tobacco
by Rowland et al. (3359), or the characterization of a compo-
nent by spectrographic means, for example, UV, IR, NMR,
MS, and chromatographic retention time. One example is
the identification by Snook et al. of many PAHs (3756–3758)
and aza-arenes (3750) in cigarette mainstream smoke (MSS).
Many references cited herein describe the search for and
elucidation of the precursor in tobacco of a particular com-
ponent in cigarette MSS (3616), for example, the saturated
aliphatic hydrocarbon precursors of the PAHs, including
benzo[a]pyrene (B[a]P); the quantitation of the component
on a per gram of tobacco basis or on its per cigarette MSS
© 2009 by Taylor & Francis Group, LLC
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yield, particularly if the component is considered a health
problem; the improvements/developments in analytical tech-
nology to determine the per cigarette MSS and/or sidestream
smoke (SSS) yield of the component. Also included in cita-
tions for a particular MSS, SSS, and environmental tobacco
smoke (ETS) component are the publications of results of
experimental studies on its biological activity plus discus-
sions and/or assertions of its toxicity and/or tumorigenicity.
While their number is much fewer than the opposite point of
view, included are references to studies on the inhibition of
adverse biological activity of a tobacco smoke component
by another smoke component, for example, the inhibition
of mouse-skin tumorigenicity of B[a]P by n-hentriacon-
tane and n-pentatriacontane (4314, 4336), the inhibition of
N-nitrosodimethylamine (NDMA) mutagenicity by nicotine
(2327a, 2327b), the inhibition of mouse-skin tumorigenicity
of dibenz[a,h]anthracene (DB[a,h]A) by benz[a]anthracene
(B[a]A) (3814), both classified as significant tobacco smoke
tumorigens. Also cited are reports on the controversies over
the extrapolation of the biological effect of a specific com-
ponent administered individually vs. its biological effect
when it is the component in a highly complex mixture such
as MSS and is administered to a different species, by a dif-
ferent route, and at a dose level far in excess of its level in the
complex mixture (1318a, 3300, 3627). Lastly, many studies
are cited in which cigarette design technologies were gener-
ated to control the per cigarette MSS yield of Federal Trade
Commission (FTC)-defined “tar” and one or more specific
components of concern, for example, reconstituted tobacco
sheet, expanded tobacco, ventilated filters, filter-tip and cig-
arette paper additives.
While some of the citations may seem obscure to a
reader newly involved in tobacco and/or smoke research,
they are included to elucidate the historical background and
relationship to more recent studies, for example, publica-
tions pertinent to 2-methyl-1,3-butadiene (isoprene), a fairly
plentiful component of the vapor phase of cigarette smoke.
The publications include the 1913 report by Staudinger
et al. (25A68) that pyrolysis of isoprene yielded a “tar.”
In 1918, the procedure to successfully generate tumors by
animal skin painting was described (4361). Five years later,
Kennaway (2073–2076) demonstrated the tumorigenic-
ity of the pyrolysate “tar” from isoprene, and much later,
Badger et al. (143) recorded the PAH content of an isoprene
pyrolysate. Another example includes a series of references
to the research results reported by Roffo that a tobacco
“destructive distillate” was tumorigenic (3322, 3325),
contained B[a]P (3316), and the B[a]P content and tum-
origenicity of the “destructive distillate” were reduced by
organic-solvent extraction of the tobacco prior to destruc-
tive distillation (3327).
11/24/08 3:16:30 PM
 Our goal was to present to the reader as many pertinent
references as we could find for a particular component and
permit the reader to decide which references to study. For
some components, dozens of references are available, for
other components only one or two. The multi-referenced
components are usually those considered to be involved in
the health problems connected to tobacco smoking.
We express our deep appreciation to several scientific staff
members of the Verband der Cigaretten-Industrie and the
Beiträge zur Tabakforschung International. They reviewed
the initial chapter of our opus and made many meaningful
suggestions and pointed out the need for several corrections.
Most of their input was applied to that chapter and eventu-
ally extended to subsequent chapters as we wrote them. One
needed correction that was described was a problem with
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78836_C000.indd 10
the electronic address for a specific reference. It was found
to be inaccessible at the time of the review. That was cor-
rected since the reference had multiple electronic addresses
so the inaccessible one was replaced with an accessible and
operative one. However, the finding triggered an examination
of all the electronic addresses cited in the Bibliography. Of
the nearly 900 such addresses, three more were found to be
inaccessible. Fortunately, each was part of a reference with
multiple electronic addresses and the inaccessible address for
each was replaced with an accessible one.
We apologize to the reader for the omission not only of any
tobacco or tobacco smoke component from the catalog but also
any significant reference by one or more competent investiga-
tors who provided information pertinent to one or more specific
components.
11/24/08 3:16:31 PM
 Acknowledgments
During the many years that this tobacco and tobacco
smoke component catalog was being prepared, numer-
ous components were discussed with colleagues, many of
whom were involved either in tobacco or tobacco smoke
research within the tobacco industry or outside of it. Much
meaningful information was obtained during the many
discussions and such information has been incorporated
into our effort. We greatly appreciate the input not only
from those colleagues who are still with us but also from
those who are not.
In the first group, we are extremely grateful to J. Gilbert
Ashburn, Edward Bernasek, Fred W. Best, Michael F.
Borgerding, N.M. Chopra, Christopher R.E. Coggins, William
M. Coleman III, Lawrence C. Cook, James T. Dobbins, Jr.,
Michael F. Dube, Curt R. Enzell, Charles R. Green, Dietrich
Hoffmann, Paul Kotin, Brian M. Lawrence, Chin K. Lee, John
C. Leffingwell, Chuan Liu, Robert A. Lloyd, Jr., William C.
Luffman, Dwo Lynm, C.D. McGee, Alan B. Norman, Charles
W. Nystrom, Michael W. Ogden, John H. Reynolds IV, Charles
H. Risner, Charles E. Rix, Joseph N. Schumacher, Stephen B.
Sears, Jeffery I. Seeman, Carr J. Smith, Thomas W. Stamey,
Jr., David E. Townsend, and Jack L. White.
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78836_C000.indd 11
In the second group, we are grateful for the contributions
of the following late colleagues: Richard R. Baker, Stuart
A. Bellin, Herbert R. Bentley, Robert H. Cundiff, Wilbur R.
Franks, James D. Fredrickson, Jesse A. Giles, Kurt Grob,
Robert A. Heckman, Charles H. Keith, Philip H. Latimer, Jr.,
Anders H. Laurene, Jerry W. Lawson, Larry A. Lyerly, John
G. Mason, Marjorie P. Newell, Thomas S. Osdene, Donald
L. Roberts, Ralph L. Rowland, Alex W. Spears, William A.
Rohde, Fredrick A. Thome, George P. Touey, John J. Whalen,
George F Wright, Ernst L. Wynder, and George W. Young.
We also wish to express our gratitude to those who, over
the years, have provided us with much information on scien-
tific publications and presentations. They include Frank G.
Colby, Charles W. Nystrom, Nell W. Sizemore, and the late
William W. Menz and John J. Whalen. Particularly meaning-
ful over the past decade has been the information provided by
the extremely diligent Helen S. Chung of the R.J. Reynolds
R&D Scientific Information Division.
One of us (T.A.P.) wishes to especially thank Patricia F.
Perfetti for the encouragement and faith she has shown me
as my wife, best friend, faithful colleague, and my partner in
many happy and productive years of scientific research.
11/24/08 3:16:31 PM
 The Authors
Thomas A. Perfetti, Ph.D. was born in 1952 in Jeannette,
Pennsylvania, the second son of Ruth Peters and Bruno
Massimo Perfetti. He was one of five children. Perfetti
received his elementary education in several schools in the
Pittsburgh area. In 1970, he entered Indiana University of
Pennsylvania (IUP). He earned a Bachelor of Science degree
in Chemistry in 1974. During his stay at IUP he conducted
cell transport research with Dr. Richard Hartline and synthe-
sized numerous radiopharmaceuticals. Perfetti’s first publica-
tion was on the preferential uptake of d-A-amino adipate by
Alcaligens denitrificans in 1975.
In 1974, he entered the Virginia Polytechnic Institute and
State University (VPI-SU), Blacksburg, VA. His doctoral
thesis (1977), under Dr. Michael Ogliaruso, was on the elec-
tronic effects associated with the Woodward-Hoffman Rules.
While pursuing his doctoral degree in physical organic
chemistry, Perfetti worked as a Research Fellow for NASA,
taught organic chemistry labs, and tutored undergraduates.
In 1976, Perfetti won the President’s Award for Distinguished
Teaching at VPI-SU.
Perfetti married Patricia Ann Finley, who graduated with
him from the Chemistry Department at IUP in 1975. They
have two sons, Michael and David. The family now resides
in Winston-Salem, North Carolina.
In late 1977, Dr. Perfetti joined the R.J. Reynolds Tobacco
Company (RJRT) as a research chemist. There, he initiated
several research programs on tobacco and smoke chemistry,
cigarette design, sensory science, flavor chemistry, and ana-
lytical method development. Perfetti was promoted to Senior
Research Chemist (1979), to Senior Staff Scientist (1984),
then to Master Scientist (1986), and finally to Principal
Scientist (1991). Perfetti is a recognized expert in the areas of
nicotine and menthol chemistry and in the area of innovation.
As Principal Scientist he worked with R.J. Reynolds-Nabisco
and R.J. Reynolds International on corporate program devel-
opment and program management issues. He also acted as
a liaison on patent acquisitions, patent applications, and
consulting activities on the scientific aspects of litigation
against RJRT. Much of his career was spent in the labora-
tory, although he served as the manager of several divisions.
Dr. Perfetti retired from RJRT in 2003. In that same year,
he and his wife started Perfetti & Perfetti, LLC, a scientific
consulting firm in Winston-Salem, North Carolina. Their
company has done quite well, with numerous national and
international clients.
Perfetti has served as a reviewer for Tobacco Science,
the Journal of Food and Chemical Toxicology, and Beiträge
zur Tabakforschung International. He has served on several
Tobacco Chemists’ Research Conference committees and
contributed to two of its symposia (1987, 1993), one of which
he chaired (1993).
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78836_C000.indd 13
Perfetti is a member of the American Chemical Society
(ACS). He has served as assistant historian to the Division of
the History of Chemistry. He is a member and Fellow of the
American Institute of Chemists and is a Certified Professional
Chemist. He was a co-founder and past president of the
North Carolina Chromatography Discussion Group and for-
mer chairman of the Education Committee of the Central
North Carolina Section of the ACS. Dr. Perfetti has been
cited in Who’s Who in America, Who’s Who in Science and
Technology, in the International Directory of Distinguished
Leadership and Who’s Who in American Leaders in America.
In 1993, Dr. Perfetti was presented with the Distinguished
Alumni Award, Indiana University of Pennsylvania. In 1995,
he and several other RJRT scientists were given the George
Land World-Class Innovator Award for outstanding work in
instilling the principles of innovation at RJRT Research and
Development.
Over the last 32 years Perfetti has made over 60 presen-
tations and published numerous papers in peer-reviewed
journals in the areas of biochemistry, tobacco and smoke
chemistry, sensory perception, mathematics, and innovation.
During his career at RJRT he prepared more than 250 formal
company research reports. He has written chapters for two
books and has developed and presented five courses in the
areas of cigarette design and innovation. Dr. Perfetti has 38
U.S. patents and hundreds of foreign patents.
Alan Rodgman, M.A., Ph.D. Most of the original text
of the following biography was written in 2003 for Alan
Rodgman’s nomination for the Tobacco Science Research
Conference Lifetime Achievement Award. He was recipient
of the 2003 award. In several places, the nominator’s para-
graphs have been slightly modified to include additional,
more recent information. The author of the 2003 nomina-
tion wrote:
For here we are not afraid to follow truth wherever it may
lead, nor to tolerate any error so long as reason is left free to
combat it.——Thomas Jefferson, 1820
The words penned long ago by Mr. Jefferson epitomize the
life and professional career of Alan Rodgman.
For one year short of a half century Dr. Rodgman has
been at the forefront of tobacco science. His increasingly
rare combination of keen scientific intellect, unceasing
productivity, sense of tobacco science history, and unfail-
ing attention to clear, concise, timely communication make
him an ideal choice for the Tobacco Science Research
Conference’s (TSRC’s) Lifetime Achievement Award. Not
only has Dr. Rodgman made his own prodigious, personal
scientific contributions to tobacco and smoke chemistry and
their related toxicology, but his mentoring of associates and
many other tobacco scientists has allowed him to amplify
11/24/08 3:16:31 PM
 his contributions far beyond those capable of any one man.
Dr. Rodgman’s professional “family tree” reads as a “Who’s
Who” in tobacco science.
Alan Rodgman was born in 1924 in Aberdare, Glamorgan
County, Wales, to Arch and Margaret Llewellyn Rodgman.
The family moved to Toronto, Ontario, Canada, in 1928.
There he was educated at the grade and collegiate levels.
Because of the early death of his father when Rodgman was
ten years old, he worked after school and on Saturdays at
the children’s and adult department of a local branch of the
Toronto Public Library from 1937 to 1942. In 1945, Rodgman
entered the University of Toronto as recipient of the two
highest mathematics, physics, and chemistry scholarships
awarded in competition in 1942. Because of a University
of Toronto rule on retaining no more than two competi-
tive scholarships, a third chemistry and physics scholarship
awarded to Rodgman reverted to the next highest candidate.
The 3-year period between earning the scholarships and their
implementation was spent on active duty as a volunteer in
the Royal Canadian Navy during WWII, with service on the
North Atlantic Ocean.
Between 1945 and 1949 at the University of Toronto,
Rodgman was awarded eight additional scholarships, one
in mathematics, physics, and chemistry in 1946; seven in
chemistry in 1947, 1948, and 1949. His bachelor’s thesis on
N-nitrosamines (1949), master’s thesis on kinetics of the orig-
inal Diels-Alder reaction (1951), and doctoral thesis on oxy-
mercuration-deoxymercuration (1953) were conducted with
Dr. George F Wright* as his advisor. He taught the labora-
tory aspect of analytical chemistry during the first year of his
master’s period. His master’s and doctoral research formed
part of eleven publications co-authored between 1952 and
1959 with Dr. Wright who, by the way, from 1954 to 1959,
preceded Dr. Dietrich Hoffmann as Dr. Ernst L. Wynder’s
tobacco smoke chemistry colleague.
Rodgman married Doris Curley in June 1947. They have
three sons, Eric, Paul, and Mark, three daughters-in-law,
Melody, Ella, and Sara, and seven grandchildren.
While pursuing his chemistry degrees, Rodgman con-
ducted carcinogenesis and anticarcinogenesis research from
1947 to 1953 during summers, winter evenings, and week-
ends with Dr. Wilbur R. Franks, Cancer Research Professor
at the Banting and Best Department of Medical Research,
University of Toronto. He conducted such research full-
time to mid-1954 after receiving his doctorate in June 1953.
Rodgman’s first three scientific publications (on anticarcino-
genesis) in 1947 and 1948 preceded the receipt of his bache-
lor’s degree in chemistry in 1949. From 1951 to mid-1954, he
also taught organic and physical chemistry plus mathematics
for physical chemistry in evening courses sponsored by the
Chemical Institute of Canada.
In mid-1954, Rodgman joined the Research Department
of the R.J. Reynolds Tobacco Company as a senior research
chemist. In October 1954, he initiated its program on
* The lack of a period after Dr. Wright’s middle initial is not a typographi-
cal error.
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78836_C000.indd 14
cigarette smoke composition, personally conducting the
laboratory research until 1967 and actively directing it and
environmental tobacco smoke studies thereafter until 1987.
Following successive promotions from senior research chem-
ist to section head to division manager, he became director of
research in 1976, and after an R&D reorganization in 1980,
he was appointed director of fundamental research. Rodgman
became a U.S. citizen in 1961.
After more than 60 years, Rodgman is still a member of
the American Chemical Society and the Chemical Institute
of Canada. Until 2006, he had been a member of the New
York Academy of Sciences for over 40 years and also a
member of Sigma Xi. He served on the editorial board of
Tobacco Science as member and Vice-Chairman (1963–
1967); on the editorial board of Beiträge zur Tabakforschung
International (1976–1987); on the Industry Technical
Committee, Council for Tobacco Research (1955–1960);
on the CORESTA Scientific Commission (1982–1985);
and on several U.S. government committees, including, the
Tobacco Working Group of the National Cancer Institute’s
Smoking and Health Program on the Less Hazardous
Cigarette (1976–1977) and the U.S. Technical Study Group
of the Cigarette Safety Act of 1984 (1984–1987). From 1960
to 1987, Rodgman served on numerous Tobacco Chemists’
Research Conference (TCRC) committees. In 1972, he
was involved in various aspects of the joint CORESTA/
TCRC Conference in Williamsburg, Virginia. In 1976,
he persuaded his company’s management to continue its
CORESTA membership. In the early 1980s, when a host
site for the 1982 CORESTA Symposium did not material-
ize, Rodgman was instrumental in arranging for his com-
pany to sponsor the symposium in Winston-Salem, North
Carolina. He served as its vice chairman.
Rodgman was the chairman for the 1984, 38th TCRC
symposium entitled “Design of Low-‘Tar’ Cigarettes.” On
the occasion of TCRC’s 50th Conference in 1996, he co-
authored with Charles R. Green a comprehensive review
and presentation entitled “The Tobacco Chemists’ Research
Conference: A Half Century Forum for Advances in
Analytical Methodology of Tobacco and its Products.” The
following year at the 51st Conference, he prepared a sympo-
sium paper and presentation on “FTC ‘Tar’ and Nicotine in
Cigarette Mainstream Smoke: A Retrospective.” In addition,
Rodgman has presented many other original research papers
at the conference.
In the journal Tobacco Science, he has published thirteen
scientific papers on tobacco smoke composition. Additionally,
the 1986 volume of Tobacco Science was dedicated to Dr.
Rodgman to honor his prolific career. In addition to serving
as a reviewer for manuscripts submitted to Tobacco Science
and Beiträge zur Tabakforschung International, Rodgman
has served as a reviewer not only for manuscripts submit-
ted to several other journals, including Recent Advances
in Tobacco Science, Journal of Analytical and Applied
Pyrolysis, Food and Chemical Toxicology and the Journal
of Organic Chemistry but also for the page proofs of several
well-known books on tobacco-related topics.
11/24/08 3:16:31 PM
 From 1954 to retirement and from retirement to 2004,
Rodgman was involved in consulting activities on the sci-
entific aspects of litigation against R.J. Reynolds Tobacco
Company. Over 13,000 pages of his contributions are avail-
able at http://tobaccodocuments.org/bliley_rjr/list. Many of
the more recent contributions were the consequence of the
“Master Settlement” between the states and tobacco compa-
nies. Additionally, he has been a major contributor to the sci-
entific content of Beiträge zur Tabakforschung International
both through submitted papers and as a volunteer editor. Dr.
Rodgman has mined the wealth of documents previously
considered proprietary to clarify the intent and content of
tobacco and smoke research conducted by himself, his col-
leagues, and other scientists. The published papers authored/
co-authored by Rodgman during the last decade and a half
include the following: Environmental Tobacco Smoke (1992);
FTC “Tar” and Nicotine in Cigarette Mainstream Smoke: A
Retrospective (1997); Tobacco Smoke Components (1998);
The Composition of Cigarette Smoke: A Retrospective, With
Emphasis on Polycyclic Components (2000); “Smoke pH”: A
Review (2000); “IARC Group 2A Carcinogens” Reported in
Cigarette Mainstream Smoke (2000); Studies of Polycyclic
Aromatic Hydrocarbons in Cigarette Mainstream Smoke:
Identification, Tobacco Precursors, Control of Levels: A
Review (2001); “IARC Group 2B Carcinogens” Reported
in Cigarette Mainstream Smoke (2001); Some Studies of
the Effects of Additives on Cigarette Mainstream Smoke
Properties. I. Flavorants (2002); Some Studies of the Effects
of Additives on Cigarette Mainstream Smoke Properties.
II. Casing Materials and Humectants (2002); The Relative
Toxicity of Substituted Phenols Reported in Cigarette
Mainstream Smoke (2002); The Composition of Cigarette
Smoke: Problems With Lists of Tumorigens (2003); Toxic
Chemicals in Cigarette Mainstream Smoke: Hazard and
Hoopla (2002, 2003); Some Studies of the Effects of Additives
on Cigarette Mainstream Smoke Properties. III. Ingredients
Reportedly Used in Various Commercial Cigarette Products
in the USA and Elsewhere (2004); The Composition of
Cigarette Smoke: A Catalogue of the Polycyclic Aromatic
Hydrocarbons (2006); The Composition of Cigarette Smoke:
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78836_C000.indd 15
A Chronology of the Studies of Four Polycyclic Aromatic
Hydrocarbons (2006); Comparisons of the Composition
of Tobacco Smoke and the Smokes from Various Tobacco
Substitutes (2007); The Expansion of Tobacco and its Effect
on Cigarette Mainstream Smoke Properties (2007).
At the 2002 CORESTA Congress held in New Orleans, Dr.
Rodgman co-authored with Charles R. Green an invited speaker
symposium paper entitled “Toxic Chemicals in Cigarette
Mainstream Smoke: Hazard or Hoopla.” In this paper the
authors critically examined the proper listing and prioritizing
of toxic chemicals in cigarette mainstream smoke. Moreover,
the authors pointed to a number of disconcerting chemical and
biological limitations in existing knowledge which calls into
question the veracity of such listing strategies for their oft-stated
purposes. This example is included in Alan Rodgman’s nomina-
tion to illustrate his lifelong pursuit of the truth.
In summary, there is no question that Alan Rodgman has
dedicated his professional life to the achievement of the high-
est standards for tobacco science. Even with this nomination
and the accompanying materials, it is impossible to convey
to an outsider the tremendous impact that this person has had
on our knowledge of tobacco and its smoke. Although his
own personal scientific accomplishments are by themselves
worthy of TSRC’s Lifetime Achievement Award, the ampli-
fication of his life’s work through influence on many other
tobacco scientists is difficult to quantify. Beyond his many
professional achievements is a man who is widely respected
and personally liked both within and outside the tobacco sci-
ence community.
Because his philosophy on publication authorship dif-
fered substantially from that of many academic, government
agency, and health organization investigators, Rodgman did
not insert his name as co-author on the many articles on
tobacco and smoke composition presented at conferences
and/or published in peer-reviewed journals by his staff mem-
bers. If he had done what many supervisors do, his list of
publications between 1960 and 1987 would be increased by
almost 200. However, his contributions to many of the stud-
ies are described in the Acknowledgment section of many of
his staff/colleagues’ publications.
11/24/08 3:16:32 PM
 List of Tables
Chapter 1 The Hydrocarbons
I.A-1 Relative percentage composition of tobacco alkanes in tobacco and cigarette smoke,
based on mass spectroscopic analysis ...................................................................................................................... 2
I.A-2 Relative percentage composition of n-alkanes in tobacco and cigarette smoke, based on gas-liquid
chromatographic analysis ......................................................................................................................................... 2
I.A-3 Alkane content of cigarette mainstream smoke ....................................................................................................... 2
I.A-4 Relative percentage composition of tobacco alkanes based on gas-liquid chromatographic data
(Figures rounded from those provided by Mold et al.) ............................................................................................ 3
I.A-5 Alkane isomers identified in cigarette mainstream smoke, 1968 vs. 1992 .............................................................. 3
I.A-6 Melting point and boiling point data for n-alkanes.................................................................................................. 3
I.A-7 Chronology of studies on alkanes in tobacco and tobacco smoke ........................................................................... 4
I.A-8 Polycyclic aromatic hydrocarbons from tobacco aliphatic hydrocarbons pyrolyzed in air
at various temperatures ............................................................................................................................................ 5
I.A-9 Ratios for individual polycyclic aromatic hydrocarbons in gasoline engine exhaust “tar” (EET)
and cigarette smoke condensate (CSC) .................................................................................................................... 6
I.A-10 Alkanes in tobacco, tobacco smoke, and tobacco substitute smoke .................................................................. 8–16
I.B-1 Alkenes and alkynes in tobacco, tobacco smoke, and tobacco substitute smoke .............................................17–33
I.C-1 Alicyclic hydrocarbons in tobacco, tobacco smoke, and tobacco substitute smoke......................................... 37–45
I.D-1 Monocyclic aromatic hydrocarbons in tobacco, tobacco smoke, and tobacco substitute smoke ..................... 48–54
I.E-1 Chronology of catalogs of PAHs in MSS............................................................................................................... 56
I.E-2 Benzenoid hydrocarbons discussed by Pullman and Pullman......................................................................... 62–63
I.E-3 Polycyclic hydrocarbons reported in tobacco smoke by year-end 1955 ................................................................. 63
I.E-4 Inhibition of tumorigenicity of potently tumorigenic PAHs by non-tumorigenic or weakly
tumorigenic PAHs .................................................................................................................................................. 65
I.E-5 Levels of PAH classes in cigarette mainstream smoke .......................................................................................... 65
I.E-6 Polycyclic aromatic hydrocarbons in tobacco, tobacco smoke, and tobacco substitute smoke.......................67–102
I.E-7 Tobacco smoke PAHs discussed in various publications on the relationship between PAH structure
and tumorigenicity......................................................................................................................................... 103-109
I.E-8 Distribution of identified hydrocarbons between tobacco and tobacco smoke .....................................................110

Chapter 2 Alcohols and Phytosterols

II.A-1 Tobacco and tobacco smoke components identified by classical chemical methods ............................................112
II.A-2 Tobacco and tobacco smoke studies in which components were identified by a combination of spectral
technologies ...........................................................................................................................................................113
II.A-3 Tobacco components identified post-1975 .............................................................................................................114
II.A-4 Tobacco and/or smoke alcohols used in flavor formulations.................................................................................116
II.A-5 Alcohols in tobacco, tobacco smoke, and tobacco substitute smoke ............................................................117–204
II.B-1 Studies on identification of phytosterols and phytosteryl derivatives in tobacco and tobacco smoke ................. 207
II.B-2 Phytosterols, their derivatives, and related compounds in tobacco, tobacco smoke, and tobacco
substitute smoke.............................................................................................................................................208–214

Chapter 3 Aldehydes and Ketones

III-1 Tobacco smoke components listed by Kosak ........................................................................................................216
III-2 Studies on low molecular weight carbonyls in tobacco and tobacco smoke: Derivatizing agents........................217
III-3 Analysis of cigarette mainstream smoke by gas chromatography ........................................................................218
III-4 Precursors in tobacco of aldehydes and ketones in tobacco................................................................................. 220
III-5 Aldehydes and ketones in mainstream smoke from all lamina and all-midrib cigarette..................................... 221
III-6 In vitro ciliary activity, cigarette smoke fractions, and dose level ....................................................................... 226
III-7 Lowest concentrations in Ringer solution leading to ciliastasis in ciliated rat trachea........................................ 226
III-8 Lung retention and mouth absorption of several cigarette mainstream smoke components ............................... 228

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 III-9 Difference between composition of inhaled and exhaled mainstream smoke and between mouth-held
and exhaled mainstream smoke ........................................................................................................................... 228
III-10 Lung retention and mouth absorption data........................................................................................................... 229
III-11 Tobacco and/or tobacco smoke aldehydes and ketones used in flavor
formulations.................................................................................................................................................. 230–231
III-12 Aldehydes in tobacco, tobacco smoke, and tobacco substitute smoke ......................................................... 232–248
III-13 Ketones in tobacco, tobacco smoke, and tobacco substitute smoke..............................................................249–311
III-14 Chronology of studies on aldehydes and ketones in tobacco smoke............................................................. 311–315

Chapter 4 Carboxylic Acids

IV.A-1 Acids identified in tobacco and tobacco smoke to date.........................................................................................318
IV.A-2 Tobacco and/or tobacco smoke carboxylic acids used in flavor formulations.......................................................319
IV.A-3 Carboxylic acids in tobacco, tobacco smoke, and tobacco substitute smoke ............................................... 320–365
IV.B-1 Components in pyrolysates from the amino acids lysine, leucine, and tryptophan ............................................. 366
IV.B-2 Pyrolysis of phenylalanine. A. Effect of pyrolysis temperature. B. Effect of equimolar addition
of tryptophan or pyrrole ....................................................................................................................................... 367
IV.B-3 Components in pyrolysates from amino acids (proline and glycine) and proteins (casein and collagen) ........... 368
IV.B-4 Amino acid-derived N-heterocyclic amines......................................................................................................... 369
IV.B-5 Summary of lists of tumorigenic N-heterocyclic amines in tobacco smoke........................................................ 369
IV.B-6 Tobacco and/or tobacco smoke amino acids used in flavor formulations ............................................................ 369
IV.B-7 Amino acids and related compounds in tobacco, tobacco smoke, and tobacco substitute smoke ............... 370–379

Chapter 5 The Esters

V-1 Esters used as tobacco ingredients by U.S. tobacco product manufacturers................................................ 383–385
V-2 Esters used as tobacco ingredients by tobacco product manufacturers outside of the U.S.................................. 385
V-3 Esters in tobacco, tobacco smoke, and tobacco substitute smoke ................................................................ 386–438

Chapter 6 The Lactones

VI-1 Some biological properties of lactones used as additives in foodstuffs as well as in tobacco products ............. 442
VI-2 Tobacco and/or smoke lactones used in flavor formulations ................................................................................ 443
VI-3 Lactones identified in tobacco, tobacco smoke, and tobacco substitute smoke ...........................................444–460

Chapter 7 Anhydrides
VII-1 Anhydrides in tobacco, tobacco smoke, and tobacco substitute smoke .......................................................462–463

Chapter 8 Carbohydrates and Their Derivatives

VIII-1 Tobacco and/or smoke carbohydrates used in flavor formulations....................................................................... 466
VIII-2 Effect of sugars added to burley tobacco on mainstream smoke aldehyde and ketone yields ............................. 466
VIII-3 Carbohydrates in tobacco, tobacco smoke, and tobacco substitute smoke ..................................................468–486

Chapter 9 Phenols and Quinones

IX.A-1 Dibenz[a,h]acridine (I), dibenz[a,j]acridine (II), and 7H-dibenzo[c,g]carbazole (III) in nicotine pyrolysates
(Pyr) and mainstream cigarette smoke condensate .............................................................................................. 488
IX.A-2 Tobacco smoke components listed by Kosak ....................................................................................................... 490
IX.A-3 Phenolic components of tobacco smoke listed by Kosak..................................................................................... 491
IX.A-4 Studies of phenolic components of tobacco smoke omitted from the 1954 listing by Kosak.............................. 491
IX.A-5 Tobacco smoke phenols catalogued by Johnstone and Plimmer.......................................................................... 493
IX.A-6 Publications/presentations (1952–1964) pertinent to identification of phenolic
components of tobacco smoke.............................................................................................................................. 493
IX.A-7 Tobacco smoke phenols catalogued by Stedman (3797) ...................................................................................... 494
IX.A-8 Presentations at Tobacco Chemists’ Research (TCRC) and Tobacco Science Research Conferences
(TSRC) on phenolic components of tobacco products ......................................................................................... 495
IX.A-9 Reports of research pertinent to phenolic compounds in tobacco and tobacco smoke
1964 to 2005 .................................................................................................................................................496–497
IX.A-10 Variation in bioassay results with phenols or phenol-containing materials ......................................................... 498
IX.A-11 Inhibitors and anticarcinogens in tobacco smoke ................................................................................................ 500
IX.A-12 Tobacco smoke phenols with anticarcinogenic or antipromoting properties ....................................................... 501

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 IX.A-13 Precursors in tobacco of phenols in tobacco smoke............................................................................................. 503
IX.A-14 Pyrolysis of tobacco, tobacco components, and spinach: Phenol content of pyrolysate ...................................... 504
IX.A-15 Pyrolysis of tobacco components: Generation of phenols.................................................................................... 505
IX.A-16 Smoke chemistry data: NCI study of cocoa addition ........................................................................................... 506
IX.A-17 Studies on the selective filtration of phenolic compounds in cigarette mainstream smoke................................. 508
IX.A-18 Effect of tobacco expansion on levels of mainstream smoke phenols.................................................................. 509
IX.A-19 Studies involving nitrate addition to tobacco ................................................................................................ 511–512
IX.A-20 Effect of cut width on mainstream smoke properties............................................................................................513
IX.A-21 Theoretical relationship between phenols in tobacco and several phenols in tobacco smoke ..............................514
IX.A-22 Phenols in tobacco, tobacco smoke, and tobacco substitute smoke ............................................................. 515–546
IX.B-1 Comparison of the tumorigenicities of aromatic hydrocarbons, their diols (phenols),
and their diones (quinones)................................................................................................................................... 547
IX.B-2 Quinones identified in tobacco, tobacco smoke, and tobacco substitute smoke ...........................................549–551
IX.B-3 Chronology of identification of quinones in tobacco and/or smoke…..........................................................552–553

Chapter 10 The Ethers

X-1 Tobacco and/or smoke ethers used in flavor formulations ................................................................................... 556
X-2 Ethers in tobacco, tobacco smoke, and tobacco substitute smoke.................................................................557–614
X-3 Distribution of identified oxygen-containing components between tobacco and tobacco smoke.........................614

Chapter 11 Nitriles
XI-1 Nitriles identified and/or discussed in tobacco smoke by the mid-1960s..............................................................616
XI-2 Nitriles in tobacco, tobacco smoke, and tobacco substitute smoke...............................................................617–625

Chapter 12 Acyclic Amines

XII-1 IARC evaluation of carcinogenicity of various aromatic amines in tobacco smoke (1870) ................................ 628
XII-2 Amines identified in tobacco, tobacco smoke, and tobacco substitute smoke ............................................. 630–661

Chapter 13 Amides
XIII-1 Amides identified in tobacco, tobacco smoke, and tobacco substitute smoke ............................................. 665–677

Chapter 14 Imides
XIV-1 Imides identified in tobacco, tobacco smoke, and tobacco substitute smoke...............................................680–685

Chapter 15 N-Nitrosamines
XV-1 Major N-nitrosamines in tobacco and/or tobacco smoke ..................................................................................... 690
XV-2 Summary of lists of tumorigenic N-nitrosamines in tobacco and tobacco smoke............................................... 692
XV-3 A brief chronology of the research on volatile N-nitrosamines from 1937 to 1990..................................... 693–698
XV-4 A brief chronology of the research on tobacco-specific N-nitrosamines ..................................................... 700–704
XV-5 N-Nitrosamines in tobacco and/or tobacco smoke............................................................................................... 708
XV-6 Aliphatic secondary amines and volatile N-nitrosamines in tobacco and tobacco smoke .................................. 709
XV-7 Aromatic and cyclic secondary amines and N-nitrosamines in tobacco and tobacco smoke.......................710–711
XV-8 N-Nitrosamines in tobacco, tobacco smoke, and tobacco substitute smoke .................................................713–720

Chapter 16 Nitroalkanes, Nitroarenes, and Nitrophenols

XVI-1 Nitroalkanes, nitroarenes, and nitrophenols in tobacco, tobacco smoke, and tobacco substitute
smoke............................................................................................................................................................ 722–725

Chapter 17 Nitrogen Heterocyclic Components

XVII.A-1 4-Membered N-containing ring compounds in tobacco, tobacco smoke, and tobacco substitute smoke............ 728
XVII.A-2 Studies on the pyrolysis of amino acids ............................................................................................................... 730
XVII.A-3 Distribution of 5-membered N-containing ring compounds between tobacco and tobacco smoke..................... 732
XVII.A-4 5-Membered N-containing ring compounds in tobacco, tobacco smoke, and tobacco substitute
smoke.............................................................................................................................................................733–746

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 XVII.A-5 Compounds in tobacco, tobacco smoke, and tobacco substitute smoke with multiple 5-membered
N-containing rings.........................................................................................................................................746–747
XVII.B-1 Distribution of 6-membered N-containing ring compounds between tobacco and tobacco smoke…..................751
XVII.B-2 Compounds in tobacco, tobacco smoke, and tobacco substitute smoke with a 6-membered
N-containing ring ..........................................................................................................................................755–779
XVII.B-3 Distribution of components with a 6-membered N-containing ring
and a second 5-membered N-containing ring between tobacco and tobacco smoke........................................... 780
XVII.B-4 Compounds in tobacco, tobacco smoke, and tobacco substitute smoke with a 6-and a 5-membered
N-containing ring ..........................................................................................................................................781–789
XVII.B-5 Distribution of components with two or more 6-membered N-containing rings between
tobacco and tobacco smoke .................................................................................................................................. 791
XVII.B-6 Compounds in tobacco, tobacco smoke, and tobacco substitute smoke with two or more
6-membered N-containing rings .................................................................................................................. 792–797
XVII.B-7 Tobacco and tobacco smoke compounds with 6-membered rings, with a 5- and a 6-membered
ring, or with two or more 6-membered N-containing rings ................................................................................ 797
XVII.C-1 Lactams in tobacco, tobacco smoke, and tobacco substitute smoke… .........................................................799-804
XVII.D-1 The distribution of oxazole- and oxazine-related compounds identified in tobacco and tobacco smoke............ 806
XVII.D-2 Oxazole- and oxazine-related compounds in tobacco, tobacco smoke, and tobacco substitute
smoke............................................................................................................................................................ 807–809
XVII.E-1 Dibenz[a,h]acridine {I}, dibenz[a,j]acridine {II}, and 7H-dibenzo[c,g]carbazole {III}
in nicotine pyrolysates (Pyr) and mainstream cigarette smoke condensate (CSC)...............................................811
XVII.E-2 Chronology of selected aza-arenes: Dibenz[a,h]acridine, dibenz[a,j]acridine,
7H-dibenzo[c,g]carbazole, quinoline ............................................................................................................813–817
XVII.E-3 Summary of lists of tumorigenic aza-arenes in tobacco smoke............................................................................818
XVII.E-4 Tobacco smoke components related to aza-arenes in tumorigen lists...................................................................819
XVII.E-5 Aza-arene sources other than tobacco smoke… ...................................................................................................819
XVII.E-6 Aza-arenes and other polycyclic nitrogen compounds in tobacco, tobacco smoke,
and tobacco substitute smoke ....................................................................................................................... 820–833
XVII.E-7 Structures of aza-arenes in tobacco and tobacco smoke… .................................................................................. 834
XVII.E-8 Derivatives of fused N-containing-ring compounds with two or more nitrogens in the rings..................... 835–840
XVII.F-1 Mutagenic activities of N-heterocyclic amines towards Salmonella typhimurium….......................................... 840
XVII.F-2 Summary of lists of tumorigenic N-heterocyclic amines in tobacco smoke........................................................ 844
XVII.F-3 N-Heterocyclic amines: Mutagenicity of beverages, heated foods, and heated food components...............845–846
XVII.F-4 Mutagenicity of common beverages vs. cigarette smoke condensate .................................................................. 846
XVII.F-5 Benzo[a]pyrene equivalency of extracts of charred fish and meat....................................................................... 847
XVII.F-6 Components related to N-heterocyclic amines in tobacco smoke: Identification
and biological properties .............................................................................................................................. 847–848
XVII.E-7 Chronology of N-heterocyclic amine studies…………………………………………………….….. .............. 849–851
XVII.E-8 N-Heterocyclic amines in tobacco, tobacco smoke, and tobacco substitute smoke……………….….......... 852–853

Chapter 18 Miscellaneous Components

XVIII.A-1 Sulfur-containing components in tobacco, tobacco smoke, and tobacco substitute
smoke............................................................................................................................................................ 858–872
XVIII.B-1 Halogenated components identified in tobacco and tobacco smoke… ................................................................ 876
XVIII.B-2 The distribution of halogenated components identified in tobacco and tobacco smoke ...................................... 876
XVIII.B-3 Halogenated and related components in tobacco, tobacco smoke, and tobacco substitute
smoke............................................................................................................................................................ 877–892

Chapter 19 Fixed and Variable Gases

XIX-1 Volume percentages of fixed gases in the Earth’s atmosphere............................................................................. 894
XIX-2 Volume percentages of some variable gases (inorganic and organic) in the atmosphere. ................................... 894
XIX-3 Fixed gases in the vapor phase of MSS…............................................................................................................ 895
XIX-4 Major fixed and variable gases in non-filtered whole tobacco smoke… .............................................................. 895
XIX-5 Fixed and variable gases in tobacco, tobacco smoke, and tobacco substitute smoke .................................. 898–905

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 Chapter 20. Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts
XX-1 Elemental composition of a typical plant ............................................................................................................. 908
XX-2 Percent transfer of selected metallic and nonmetallic elements between tobacco and tobacco smoke ............... 913
XX-3 IARC classification and references to agents, groups of agents, mixtures and exposure
circumstances evaluated by IARC that are metals, metallic compounds, radioisotopes,
or tobacco or tobacco smoke-related materials .....................................................................................................914
XX-4 Distribution of metallic and nonmetallic elements, isotopes and ions between tobacco and tobacco smoke ......917
XX-5 Metallic and nonmetallic elements and ions in tobacco, tobacco smoke, and tobacco substitute
smoke............................................................................................................................................................ 918–926
XX-6 Various ionic and covalently bonded organic and inorganic compounds containing metals and nonmetals,
miscellaneous ions, and organometallic compounds found in tobacco, tobacco smoke, and tobacco
substitute smoke............................................................................................................................................ 927–932

Chapter 21 Pesticides and Growth Regulators

XXI-1 Percent transfer of intact agrochemicals to mainstream smoke........................................................................... 938
XXI-2 Degradation products of pesticides in mainstream smoke................................................................................... 939
XXI-3 Synthetic and natural pesticides and plant growth regulators in tobacco, tobacco smoke,
and tobacco substitute smoke ....................................................................................................................... 940–976

Chapter 22 Genes, Nucleotides, and Enzymes

XXII-1 Relative size of genomes and number of genes by species .................................................................................. 980
XXII-2 Enzymes, genes, clones in tobacco............................................................................................................... 983–999

Chapter 23 “Hoffmann Analytes”

XXIII-1 Hoffmann contributions on smoke components to the 1985 IARC Working
Group on Tobacco Smoking ............................................................................................................................... 1002
XXIII-2 Hoffmann-related lists of toxicants in tobacco and tobacco smoke................................................................... 1002
XXIII-3 The basis for the “Hoffmann Analytes”: The lists of toxicants issued by
Hoffmann et al. from 1986 to 2001.......................................................................................................... 1003–1007
XXIII-4 An abbreviated chronology of the use of the term “Hoffmann Analyte” or its equivalent in tobacco
smoke-related scientific literature .............................................................................................................1009–1011
XXIII-5 “Hoffmann analytes” in tobacco, tobacco smoke, and tobacco substitute smoke ....................................1012–1048
XXIII-6 Reported yields of “Hoffmann Analytes” in 1R4F and 2R4F mainstream
smoke; proposed MSS “Hoffmann Analyte” yield analyses.....................................................................1049–1051

Chapter 24 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

XXIV-1A As listed by Doull et al. individual ingredient components used in U.S. smoking
products.. ...................................................................................................................................................1056–1059
XXIV-1B As listed by Baker et al. individual ingredient components not used in U.S. smoking
products but used outside of the U.S .................................................................................................................. 1059
XXIV-2 Tobacco and/or tobacco smoke components used as tobacco ingredients… ............................................1060–1101
XXIV-3 A summary of tobacco ingredient studies conducted from 1997 to date.................................................. 1103–1105

Chapter 25 Pyrolysis
XXV-1 Precursor relationships between tobacco leaf components and tobacco smoke components ................... 1108–1110
XXV-2 Pyrolysis studies on n-hexane extract from tobacco ..........................................................................................1113
XXV-3 Comparison of polycyclic aromatic hydrocarbon fraction levels, phenol yields, and acid yields in
700°C pyrolysates from tobacco, petroleum ether extractables (PEE), and the tobacco residue (RES)
after extraction.....................................................................................................................................................1115
XXV-4 Dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole in nicotine pyrolysates (Pyr)
and mainstream cigarette smoke condensate (CSC) ...........................................................................................1118
XXV-5 Organic solvent-soluble components of tobacco identified post-1955.................................................................1119
XXV-6 Polycyclic aromatic hydrocarbons from aliphatic tobacco hydrocarbons pyrolyzed in air at various
temperatures ....................................................................................................................................................... 1120
XXV-7 Total, free, and bound sterols in cigarette tobacco..............................................................................................1121
XXV-8 Component distribution in eight subfractions from a petroleum ether extract of tobacco
(8% of tobacco weight) .......................................................................................................................................1123

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 XXV-9 Conversion of tobacco leaf constituents to total mainstream smoke polycyclic aromatic hydrocarbons. ..........1123
XXV-10 Polycyclic aromatic hydrocarbons from tobacco components pyrolyzed in a N2 atmosphere at 650°C.............1125
XXV-11 Conversion of components in tobacco to benzo[a]pyrene during pyrolysis........................................................1126
XXV-12 Conversion of pectins, starch, and cellulose to specific polycyclic aromatic hydrocarbons and
phenols during smoking ......................................................................................................................................1127
XXV-13 Pyrolysis vs. actual smoking conditions: Conversion of glucose, fructose, and cellulose to benzo[a]pyrene ...1129
XXV-14 Pyrolysis of leaf acids: Generation of selected phenols and polycyclic aromatic hydrocarbons ........................1130
XXV-15 Conversion of trimyristin added to tobacco to polycyclic aromatic hydrocarbons during actual
cigarette smoking ...............................................................................................................................................1131
XXV-16 Components in pyrolysates from lysine, leucine, and tryptophan ......................................................................1132
XXV-17 Pyrolysis of phenylalanine. A. Effect of pyrolysis temperature B. Effect of equimolar addition of
tryptophan (Try) or pyrrole (Pyr) .......................................................................................................................1133
XXV-18 Components in pyrolysates from amino acids (proline and glycine) and proteins (casein and collagen) ..........1134
XXV-19 Amino acid-derived N-heterocylic amines…......................................................................................................1135
XXV-20 Summary of lists of tumorigenic N-heterocyclic amines identified in tobacco smoke.......................................1135
XXV-21 Precursor relationships between N-containing tobacco leaf components and tobacco smoke components.......1136
XXV-22 NCI study (second set of experimental cigarettes): Effect of long chained alcohols sucker growth inhibitors
on cigarette smoke properties..............................................................................................................................1137
XXV-23 NCI study (fourth set of experimental cigarettes): Effect of pesticides addition on
cigarette smoke properties...................................................................................................................................1138
XXV-24 Pyrolysis of licorice vs. flue-cured tobacco: Benzo[a]pyrene generation….......................................................1139
XXV-25 NCI study (third set of experimental cigarettes): Effect of a humectant (glycerol) or casing
material (sugar or cocoa) on cigarette smoke properties.....................................................................................1140
XXV-26 Benzo[a]pyrene in the pyrolysates from various humectants used or proposed for use in cigarette
fabrication............................................................................................................................................................1140
XXV-27 Benzo[a]pyrene in the pyrolysates from various materials used or proposed for use in
cigarette fabrication ............................................................................................................................................1142
XXV-28 Pyrolysis of cellulose and starch: Comparison of benzo[a]pyrene data from Kröller with those
from Gilbert and Lindsey ....................................................................................................................................1142
XXV-29 Pyrolysis of tobacco and tobacco smoke components plus their effect on smoke composition
when added to tobacco .............................................................................................................................. 1144–1165
XXV-30 Pyrolysis of non-tobacco and non-tobacco smoke components and/or their effect on smoke
composition when added to tobacco...........................................................................................................1166-1168
XXV-31 Pyrolysis of miscellaneous tobacco product components plus their effect on smoke composition
when added to tobacco ........................................................................................................................................1169
XXV-32 Summary of tobacco ingredient studies from 1994–2005… .................................................................... 1169–1171

Chapter 26 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens
XXVI-1 Tumorigens, carcinogens, and toxicants listed by Hoffmann and colleagues............................................1174–1178
XXVI-2 The polycyclic aromatic hydrocarbon paradoxes ...................................................................................... 1184–1187
XXVI-3 Dibenz[a,h]acridine {I}, dibenz[a,j]acridine {II}, and 7H-dibenzo[c,g]carbazole {III} in nicotine
pyrolysates (Pyr) and mainstream cigarette smoke condensate (CSC) ...............................................................1188
XXVI-4 N-Nitrosamines in tobacco smoke............................................................................................................. 1190–1193
XXVI-5 Summary of tumorigenic N-heterocyclic amines in tobacco smoke...................................................................1193
XXVI-6 Chronology of N-heterocyclic amine studies ........................................................................................... 1194–1196
XXVI-7A Anticarcinogens, inhibitors, and antimutagens in tobacco and tobacco smoke........................................1199–1201
XXVI-7B Anticarcinogens, inhibitors, and antimutagens in tobacco and tobacco smoke........................................ 1202-1204
XXVI-7C Anticarcinogens, antitumorigens, inhibitors, and antimutagens in tobacco, tobacco smoke,
and tobacco substitute smoke ....................................................................................................................1205–1218
XXVI-8 Exposures to tumorigens and mutagens from sources other than mainstream and
environmental tobacco smoke .............................................................................................................................1219
XXVI-9 Personal exposure to tobacco smoke polycyclic aromatic hydrocarbons listed as
tumorigens… .............................................................................................................................................1220–1221

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 XXVI-10 Polycyclic aromatic hydrocarbon sources… ...................................................................................................... 1222
XXVI-11 Levels of benzo[a]pyrene and benz[a]anthracene in common foodstuffs…...................................................... 1223
XXVI-12 Cigarette equivalents of benzo[a]pyrene (B[a]P) and benz[a]anthracene (B[a]A) in common foodstuffs ........ 1224
XXVI-13 Comparison of daily dietary and inhalation intake of benzo[a]pyrene ............................................................. 1224
XXVI-14 Aza-arenes sources other than tobacco smoke................................................................................................... 1225
XXVI-15 N-Nitrosamines in foods and beverages (ng/g) ................................................................................................. 1226
XXVI-16 Volatile and nonvolatile N-nitrosamines in foodstuffs and beverages .....................................................1227–1228
XXVI-17 Comparison of dietary and environmental tobacco smoke................................................................................ 1229
XXVI-18 Tobacco-specific N-nitrosamines in indoor air .................................................................................................. 1229
XXVI-19 Non-tobacco exposures to tobacco/tobacco smoke N-nitrosamines .................................................................. 1230
XXVI-20 Mutagenicity of beverages, heated foods, and heated food components ..................................................1232–1233
XXVI-21 Mutagenicity of common beverages vs. cigarette smoke condensate ................................................................ 1233
XXVI-22 Benzo[a]pyrene equivalency of extracts of charred fish and meat..................................................................... 1233

Chapter 27 Free Radicals

XXVII-1 Free radicals in tobacco, tobacco smoke, and tobacco substitute smoke .................................................1253–1254

Chapter 28 Summary
XXVIII-1 Distribution of chemical components between tobacco and tobacco smoke ............................................1258–1259

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 List of Figures
I.B-1 Phytadienes with potential to yield Diels-Alder adducts and subsequently alkylanthraquinones
and anthraquinonecarboxylic acids ........................................................................................................................ 35
I.B-2 Phytadienes with little or no potential to form Diels-Alder adducts...................................................................... 35
I.C-1 Possible sterol degradation products ...................................................................................................................... 46
I.C-2 Phytadiene dimers .................................................................................................................................................. 47
I.E-1 The L region, K region, and bay region of benz[a]anthracene............................................................................... 60
II.A-1 The degradation products from ozonized solanesol..............................................................................................112
II.A-2 Tobacco and/or tobacco smoke alcohols related to cembrene...............................................................................115
II.B-1 Theoretical conversion of cholesterol to 1,2-dihydro-3-methylbenz[ j]aceanthrylene ......................................... 205
II.B-2 Possible sterol degradation products .................................................................................................................... 205
III-1 Approximate composition of cigarette mainstream smoke...................................................................................218
III-2 Cigarette mainstream smoke components: Logarithmic plot................................................................................219
III-3 Phenolic alcohol components of lignin ................................................................................................................ 221
VI-1 Relationships between coumarin, its derivatives, and dicumarol ........................................................................ 440
IX.A-1 A substituted phenol ............................................................................................................................................. 491
IX.A-2 Potential precursors in tobacco of 1,2-benzenediol (catechol) in tobacco smoke................................................ 505
X-1 Cembranoid ethers identified in tobacco and/or tobacco smoke .......................................................................... 556
XII-1 Oxygenated N-containing components of tobacco and tobacco smoke…………………… ................................. 628
XII-2 Structural similarities of alkylamines and pyrrolidines ...................................................................................... 628
XIV-1A The amide, imide, and lactam configurations ...................................................................................................... 679
XIV-1B The amide {II}, imide {III}, and lactam {IV} configurations in 1-acetyl-3-ethyl-1,5-dihydro-
4-methyl-2H-pyrrol-2-one {I} .............................................................................................................................. 679
XV-1 N-Nitrosodiethanolamine (NDELA) and N-nitrosomorpholine (NMOR)........................................................... 699
XV-2 Tobacco-specific N-nitrosamines ......................................................................................................................... 700
XV-3 References pertinent to tobacco-specific N-nitrosamines, 1983–2004 ................................................................ 704
XV-4 Relationships among amino acids, N-nitrosamino acids, their esters, and N-nitrosamines ................................ 706
XV-5 Indole {XLII}, carbazole {XLIII}, and 1H-benzimidazole {XLIV} ................................................................... 712
XVII.A-1 Representative structures of the 4- and 5-membered N-containing ring compounds in tobacco,
tobacco smoke, and tobacco substitute smoke ..................................................................................................... 728
XVII.A-2 Porphyrin .............................................................................................................................................................. 732
XVII.B-1 Proposed biosynthetic pathways for production of several pyridine alkaloids .................................................... 749
XVII.B-2 Structures of the 6-membered N-containing compounds found in tobacco and tobacco smoke......................... 752
XVII.B-3 Common tobacco alkaloids found in tobacco and tobacco smoke....................................................................... 789
XVII.B-4 Common tobacco alkaloids found in tobacco and tobacco smoke with two or more
6-membered N-containing rings .......................................................................................................................... 791
XVII.C-1A The imide and lactam configurations…………………………................................................................................... 798
XVII.C-1B The imide {II} and lactam {III} configurations in 1,7-dihydro-6H-purine-2,6-dione (xanthine) {I}.................. 798
XVII.D-1 Parent structures of the oxazoles and oxazines identified in tobacco and tobacco smoke................................... 805
XVII.E-1 Quinoline and naphthalene....................................................................................................................................810
XVII.E-2 Some polycyclic components of tobacco smoke ...................................................................................................810
XVII.E-3 Some amino acid-derived N-heterocyclics identified in tobacco smoke.............................................................. 812
XVII.F-1 Pyrocoll, norharman, and harman….................................................................................................................... 834
XVII.F-2 N-Heterocyclic amines, the “cooked food” mutagens.......................................................................................... 834
XVII.F-3 Theoretical conversion of glutamic acid {XII} to aminobutanoic acids {XIII, XIV}
and aminopyridines {XV-XVII} .......................................................................................................................... 841
XVII.F-4 Theoretical routes for conversion of glutamic acid-derived aminopyridines to possible tobacco
smoke components................................................................................................................................................ 842

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 XVII.F-5 Possible tryptophan-derived compounds in tobacco smoke................................................................................. 843
XXV-1 Possible sterol degradation products ...................................................................................................................1122
XXV-2 The picene configuration present in glycyrrhizic acid ........................................................................................1139
XXVI-1 “Tar” and nicotine deliveries, sales weighted average basis ...............................................................................1181
XXVI-2 Structural similarity of several polycyclic aromatic hydrocarbons and aza-arenes............................................1183
XXVII-1 Chemical structures of 4-POBN, PBN, MNP, PNO, 4-methyl-PNO, and DMPO spin-traps
[From McCormick et al.] ................................................................................................................................... 1237

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 Introduction
History balances the frustration of how far we have to go with
the satisfaction of how far we have come. It teaches us toler-
ance for the human shortcomings and imperfections which
are not uniquely of our generation, but of all time.
—Lewis F. Powell, Jr., Associate Justice of the Supreme Court
of the United States (1972–1987)
THE INTENT OF THE WORK
Years from now, just as we were surprised how paltry was the
number of identified tobacco smoke components cataloged
in 1954 by Kosak (2170), others will no doubt have similar
remarks concerning this catalog. We hope the reader will
be satisfied rather than frustrated with the progress that has
been made by tobacco scientists over the last fifty plus years
in furthering our knowledge base of components identified in
tobacco and tobacco smoke. It should be noted the last pub-
lished detailed catalog of tobacco and tobacco smoke compo-
nents was that of Stedman (3797) in 1968.
THE CHEMICAL COMPOSITION OF TOBACCO
The Master Catalog, collected over a fifty-year period, is our
tabulation of all the information on the components identified
in tobacco and tobacco smoke. The Master Catalog contains
all of the information on components in tobacco and tobacco
smoke that is contained in each chapter of this book as well
as the information in the Bibliography and Alphabetical
Component Index sections of the book. During the creation
of the book, the information contained in the Master Catalog
was searched to extract all of the components by functional
group (alcohols, esters, aldehydes, etc.) to be includes in the
separate tables for each chapter of the book. The Bibliography
was separated from the Master Catalog as a separate section
of the book. An Alphabetical Component Index was then
created as a ready resource for readers to access particular
information on each component and to locate the chapters and
tables in the book chapters where that class of components is
discussed. The original Master Catalog that we developed as
such is not part of this book but was subdivided into numer-
ous tables of components identified in tobacco and tobacco
smoke by chemical functionality, the Bibliography, and the
Alphabetical Component Index.
Tobacco is a fascinating organism. This plant, as all plants
do, takes the simplest of molecules (carbon dioxide, nitrogen,
and water), light, and a series of metals (as micronutrients)
and through a sophisticated internal process converts these
materials to complex molecules for plant growth, regulation,
and maintenance. Tobacco has been called a chemical factory.
It has been cultivated for the purpose of collecting nicotine for
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78836_C000.indd 27
use as an insecticide and for starting material for numerous
commercial chemicals such as the pyridines. More recently, it
has been studied as a source of plant protein [Fraction 1 (F-1)
and Fraction 2 (F-2) protein] (3974c). There are many dif-
ferent botanical classifications for tobacco plants. The genus
Nicotiana has over sixty known species; each has been exam-
ined as to its genetic, physiological, botanical, and chemical
characteristics (3972, 3973). Two tobacco species are grown
commercially: Nicotiana rustica, primarily for nicotine and
solanesol collection; and Nicotiana tabacum, for use as ciga-
rette, pipe, cigar, snuff, and chewing tobaccos.
To date, approximately 4200 components have been iden-
tified in tobacco. This number does not include the nonto-
bacco components listed as added flavorants by Doull (1053)
and Baker and Bishop (172a) or the hundreds of enzyme and
other proteinaceous components listed in our Master Catalog.
This is a tremendous achievement compared to the number
of tobacco components reported as 3044 in 1988 by Roberts
(3215), reported as 2549 tobacco compounds in 1982 by Dube
and Green (1067), the 200 identified compounds reported in
1960 (2338), the 199 organic compounds and 21 inorganic
elements reported as identified in tobacco in 1959 (1971),
and the accounting of less than 10 tobacco constituents by
Frankenburg (1221) in 1946. It should be noted that in the
classification by Frankenburg, the tobacco constituents listed
were not individual compounds but classes of compounds
such as alkaloids, proteins (soluble and insoluble fractions),
nitrate-nitrogen, amino nitrogen, etc. It is estimated that liter-
ally tens of thousands of unidentified compounds are yet to be
discovered in tobacco. This estimate is based on the assump-
tions that there have already been thousands of organic, inor-
ganic, and organometallic compounds identified in tobacco,
that each plant contains hundreds of extremely complex
compounds, for example, various types of DNA and RNA,
numerous types of complex enzymes, proteins, sugar and
amino acid oligomers, needed for plant growth, regulation,
and maintenance, and that numerous fragments of these com-
plex molecules have already been reported in tobacco.
If it were not for scientists’ curiosity and the tremendous
advances in analytical chemistry over the last fifty to sixty
years, the need for this up-to-date catalog of compounds in
tobacco and tobacco smoke would not be critical. Over the
last fifty to sixty years literally tens of thousands of scien-
tific articles on varied topics in tobacco and tobacco smoke
science have been written. Our understanding of these two
areas of science has advanced tremendously in the recent past.
As noted by Knipling [see the Preface in Tso (3974c)]:
Pioneering tobacco research was the foundation of plant
science at the dawn of modern development, in such areas
as light, nutrition, genetics, growth control, disorders and
metabolism. Tobacco research led to current advancements
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 in plant biotechnology. In addition, tobacco plant research
contributed significantly to public health research in radio-
active elements, mycotoxins, and air pollutants. However,
public support for tobacco research has today greatly declined
to almost total elimination because of a sense of political
correctness … tobacco is one of the most valuable research
tools, and is a most abundant source of scientific informa-
tion. Research with tobacco plants will contribute far beyond
the frontiers of agricultural science: tobacco can be a source
of food supply with nutrition value similar to that of milk;
tobacco can be a source of health supplies including medical
chemicals and various vaccines; tobacco can be a source of
biofuel. All we need is to treat tobacco with respect; the use
of tobacco is only in its initial stages.
For nearly fifty years, our Master Catalog of components
identified in tobacco and smoke has been in the process of
assembly. Each component has one or more corresponding
references. The tobacco literature was diligently searched
for components identified in tobacco and tobacco smoke.
As new components in tobacco and tobacco smoke were
reported by R.J. Reynolds Tobacco Co. R&D personnel and
in the published scientific literature, they were entered into
the Master Catalog. Data on components in mainstream
smoke (MSS), sidestream smoke (SSS), and environmen-
tal tobacco smoke (ETS) were collected from studies on
the smokes from a variety of tobacco types and blends and
numerous forms of smoking articles, such as cigarettes,
cigars, and cigarillos. Data on tobacco components were
collected from studies on numerous species of Nicotiana
(primarily Nicotiana tabacum). The tobacco component
data were collected from studies not only on all stages of
plant development (seed to harvested plant) but also from
tobacco processed in various ways (aged, fermented [to var-
ious degrees], steamed, cut, rolled, expanded, converted to
reconstituted sheet [by various methods], treated with addi-
tives) prior to use as a smoking material.
The Master Catalog contains an enormous variety of spe-
cies from nearly every class of chemical components. We
have separated and combined the identified components in
tobacco and tobacco smoke into classes of components, for
example, hydrocarbons, alcohols, acids, esters, aza-arenes,
and each class will be discussed in a separate chapter. For
the reader’s information, tobacco and tobacco smoke com-
ponents possessing multifunctional groups will appear
in each of the appropriate chapter lists but will be only
tallied once as a tobacco component and/or a tobacco smoke
component. For example, 2-furancarboxylic acid (2-furoic
acid) is listed in the chapter on carboxylic acids and the
chapter on ethers; 4-hydroxy-3-methoxybenzaldehyde
(vanillin) is listed in each of the chapters on aldehydes,
ethers, and phenols.
The Master Catalog and the chapters on the various classes
of tobacco components do contain some items not identified
as tobacco components per se. They include items that (1)
are not identified components of untreated tobacco and/or its
smoke but are individual compounds added to the tobacco
in a flavor formulation to improve consumer acceptability
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78836_C000.indd 28
of commercial products;* (2) are the pesticides, herbicides,
nematicides, growth control agents, etc. (or their residues)
that improve the agronomic situation for tobacco cultivation
or have been found on tobacco; (3) are mycotoxic products
of microorganisms found on tobacco plants, for example,
aflatoxins; and (4) thermal degradation products from (1),
(2), and (3) found in tobacco smoke. Many of the compo-
nents in (1) were identified as added tobacco ingredients in
the reports by Doull et al. (1053), Baker and Bishop (172a),
and Baker et al. (174b). Many of the components in (2) are
retained in the tobacco after harvesting and curing, are trans-
ferred intact to the smoke, and in some cases are degraded to
compounds not usually expected in tobacco smoke. As noted
previously, the items in (1) and (3) were not included in the
4200 identified tobacco components discussed earlier. Also
not included in our Master Catalog are the additives compris-
ing mixtures from naturally occurring products, for example,
alfalfa extract, basil oil, honey. These will be discussed in the
chapter on tobacco additives.
During the 1920s and 1930s, plant nutrition was an active
area of research and tobacco served as the model in much
of that work. The results of research on nitrogen assimila-
tion, light as a factor in nitrogen fixation, and how weather
contributed to nutrient uptake contributed greatly to our
understanding of plant science. All these advancements seem
trivial today in light of the sophisticated work in genomics,
but were nonetheless initially due to the pioneering work of
scientists working with tobacco (3972, 3973).
The presence of some micro-elements in tobacco was
reported as early as 1921. Today, nearly all of the common
elements, including alkali, alkali earth, heavy metal, and
rare elements, have been reported to be present in tobacco,
for example, Al, As, Ba, B, Cs, Cr, Co, Cu, F, Au, I, Pb, Li,
Mg, Mn, Hg, Mo, Ni, Pt, Po, Ra, Rb, Se, Si, Ag, Sr, S, Ta,
Ti, Sn, U, V, and Zn. Many heavy metal radioactive compo-
nents have been reported in tobacco, including those from the
uranium series, for example, 234U, 226Ra, 228Ra, 222Rn, 210Po,
and others, such as 38Cl, 46Sc, 134Ce, 59Fe, and 40K. The pres-
ence of such elements in tobacco may be accidental, acquired
from soil or from other sources. Scientists curious to under-
stand the role of these assorted elements conducted research
studies from the 1920s in order to understand the role of
each element in plant growth and development. The effect of
boron on plant growth was first noted in 1929, zinc in 1942,
and copper in 1942. The concept of metals as catalysts in
plant growth advanced the areas of chemical catalysis and its
use in industrial fermentation (3972, 3973). The transfer of
elements, particularly some of the metallic ones noted above,
from tobacco to its smoke has been studied since the mid-
1950s, for example, see Cogbill and Hobbs (769).
* Among the flavor formulation compounds listed as tobacco ingredients by
Baker and Bishop (172a), Baker et al. (174b), and Doull et al. (1053) was a
substantial number of compounds reported as identified components of addi-
tive-free tobacco and/or its smoke [see Tables 1, 5, and 7A in (3266)]. That
number was increased recently because of the identification of several addi-
tional listed flavor formulation compounds in flue-cured tobacco by Peng
et al. (2917a) and in Perique tobacco by Leffingwell and Alford (2339a).
11/24/08 3:16:34 PM
 Elemental isotopes have also been used in tobacco research
for over fifty years. Studies with single, double, and even tri-
ple labeled compounds incorporating 15N, 3H, and 14C were
reported by personnel at the U.S. Department of Agriculture
(USDA) in the early 1950s in their studies on plant metabo-
lism (3972, 3973).
Tobacco is a very labor-intensive and sensitive crop.
Hundreds of agronomic and physical processing steps occur
from seed planting to final use in commercial products. The
type of tobacco (flue-cured, burley, Maryland, Oriental, as
well as dark air-cured tobacco and various cigar tobaccos)
and how the tobacco is produced and cured affect the type
and level of chemical compounds in tobacco leaf and in
smoke. Among the chemicals applied to tobacco are insecti-
cides, acaricides, miticides, nematicides, and growth control
agents, for example, sucker-control and yellowing agents.
These were developed to control pests and plant growth, to
reduce labor, and ultimately produce a better, healthier, and
more profitable crop. Their number and types are large. Over
the years, new chemical agents were developed and com-
mercialized as others were either banned or found to be less
effective. Nonetheless, some pesticide residues remain in the
soil and are often transported to the plant. All the commer-
cial pesticides (as well as herbicides) are tested thoroughly
and can be safely used (822a). As an example, today the
most widely used sucker-control agents are fatty compounds,
including fatty acids, alcohols, esters, and some of their
derivatives. These sucker-control agents significantly inhibit
axillary growth without causing undesirable side effects to
the plant or the public (3972, 3973).
The genetic makeup of tobacco includes 25000 to 50000
genes. Gene mapping of tobacco is being conducted in the
Plant Pathology Department, North Carolina State University
Centennial Campus, College of Agricultural and Life
Sciences, Raleigh, North Carolina, in a project known as the
Tobacco Genome Initiative (TGI). Its goal is to sequence and
catalog more than 90% of the genome of cultivated tobacco,
Nicotiana tabacum. Although tobacco has been cultivated for
more than 500 years and is a crop of great economic signifi-
cance, relatively little information exists on its genome struc-
ture and organization.
A complete tobacco gene catalog will provide information
needed to investigate the physiological and genetic processes
in the plant kingdom, in general, and in Nicotiana tabacum
specifically. Understanding the genetic processes occurring
within the tobacco plant could potentially provide valuable
information on ways to reduce the harm associated with cig-
arette smoking and also provide information on agronomic
traits associated with disease and pest resistance genes for
use in improving traditional and molecular breeding projects
aimed at enhancing the performance of tobacco as a crop.
The plants within the agriculturally important Solanaceae
family, which includes tobacco, tomato, potato, eggplant, and
pepper crop plants, will all benefit from gene discovery in
Nicotiana tabacum.
Available for public use are additional databases that con-
tain listings of enzymes, enzymatic pathways, and reaction
© 2009 by Taylor & Francis Group, LLC
78836_C000.indd 29
products of metabolic and catabolic processes occurring in
tobacco species. Many of these are listed as references in our
chapter catalogs:
r
GenBank (tobacco): For references see, http://www.
ncbi.nlm.nih.gov/Genbank/index.html (1282a).
r
BRENDA: The Comprehensive Enzyme Infor-
mation System, Entry of hydroxymethylglutaryl-
CoA reductase (NADPH) (EC-Number 1.1.1.34)
Nicotiana, KEGG Link 00100 Steroid Biosyn-
thesis, see: http://www.genome.jp/dbget-bin/show_
pathway?map00100+1.1.1.34 (429c).
r
BRENDA: The Comprehensive Enzyme Infor-
mation System; http://www.genome.jp/dbget-bin/
show_pathway?map00500+2.4.1.35 (429b).
r
Kyoto Encyclopedia of Genes and Genomes
(KEGG); see Kanehisa, M. and S. Goto: KEGG:
Kyoto Encyclopedia of Genes and Genomes;
Nucleic Acids Res. 28 (2000) 27–30 (429b).
r
Lyon, G.D.: Host pathogen interactions and crop
protection; Metabolic pathways of the diseased
potato at: http://www.scri.sari.ac.uk/publications/
annualreports/98Indiv/21Metabo.pdf (429b).
Plant scientists have long known that all organic compo-
nents are dynamic in nature and change in numerous ways
when present in biological systems. Chemical, catalytic,
enzymatic, and bacteriological processes occur continuously
during plant growth in the field and until these biological
processes are quenched at harvest and during processing.
Tobacco scientists have extensively studied the metabolism
and catabolism occurring in Nicotiana plants because the
change or formation of each compound may affect its final
quality and thus its usability. Organic compounds are formed,
transformed, and interact during plant growth in the field,
during post harvest handling processes of curing, aging, and
fermentation, and during manufacturing, including interac-
tion with additives, and during blending (3972, 3973).
The chemical composition of tobacco determines the
chemical composition and yield of components in its tobacco
smoke. For example, leaf protein (F-1 and F-2 protein) is
abundant in tobacco and turns over and decomposes con-
tinuously to produce a vast array of protein subunits, amino
acids, and amino acid oligomers (3974c).
Tobacco leaf protein by itself contributes little to smoking
quality, but it is a major precursor of hundreds of tobacco
smoke components, for example, numerous nitrogenous com-
pounds, amino acids. Similarly, other major tobacco compo-
nents, such as the carbohydrates, carboxylic acids, pigments,
polyphenols, fatty compounds, phytosterols, and many pri-
mary or secondary compounds play a significant role in pro-
ducing a myriad of tobacco smoke compounds (3972, 3973).
Tobacco has been used in one form or another in civilized
society for nearly five centuries. Eventually in the late nine-
teenth century investigations as to its composition began but
they were not particularly numerous. The major driving force
in the escalation in the mid-twentieth century of studies on
11/24/08 3:16:34 PM
 tobacco composition was the attempt to define (1) its compo-
nents that contributed to the consumer acceptability of the
taste and aroma of tobacco itself and its smoke and (2) the
precursors in tobacco of the toxicants in its smoke.
The latter investigations were triggered by the following
events: (1) The publications from 1950 to 1953 of the results
from several retrospective studies on lung cancer in smokers
and nonsmokers [Doll and Hill (1027), Mills and Porter
(2556), McConnell et al. (2515), Sadowsky et al. (3375a),
Schrek et al. (3529), Wynder and Graham (4306b)]. The
results suggested an association between cigarette smoking
and cancer of the lung, particularly the lung cancer tumor type
defined as squamous cell carcinoma. (2) The 1953 presenta-
tion and publication by Wynder et al. (4306a) of their findings
on the production of malignant tumors in a susceptible strain
of mice skin painted daily with massive doses of solutions
of cigarette smoke condensate (CSC) supposedly generated
under conditions simulating the human smoking of a ciga-
rette. These statistical and biological findings augmented by
the results of additional similar studies led to an escalation in
the research to define the composition of cigarette smoke and
to determine which of its components were responsible for
the observed biological response. When a particular class of
components — the polycyclic aromatic hydrocarbons (PAHs)
— was considered responsible, studies escalated to define the
precursors in tobacco of the PAHs in its smoke.
Previous detailed reports on the composition of tobacco
included those issued by Brückner in 1936 (451), Latimer in
1955 (2270), Johnstone and Plimmer in 1959 (1971), Shmuk
in 1961 (3657), Stedman in 1968 (3797), Roberts et al. in
1975 (3224), Schmeltz and Hoffmann on nitrogen-containing
tobacco components in 1977 (3491), Enzell and colleagues
on terpenoid-derived tobacco components between 1976 and
the late 1980s (1149, 1150, 1156, 4089, 4090). One thing has
become apparent since the mid-1950s: No other consumer
product that involves a complex mixture has been defined
in such detail as tobacco and/or its smoke, for example, the
number of components identified to date in tobacco is almost
twice that of the number identified in coffee.
IDENTIFIED COMPONENTS OF TOBACCO AND
TOBACCO SMOKE IN THE MASTER CATALOG
Many of the components identified in tobacco have also been
identified in its smoke because they transfer in part from
tobacco to its smoke during the smoking process. Many
other identified tobacco components are not found in smoke
because they decompose during the smoking process. The
level of many tobacco components considered to contribute
to the acceptable taste of its smoke are augmented by inclu-
sion in various additive formulations used in the U.S. Tobacco
Industry (1053, 3263).
Figure 0.1 illustrates the increase in number of identified
components in tobacco and its smoke. Green and Rodgman
(1373) discussed the contribution of improved analytical
technologies to the periodic escalation in the number of iden-
tified components in each.
© 2009 by Taylor & Francis Group, LLC
78836_C000.indd 30
6000
5000
E
4000
3000
2000 D
Tobacco
C Smoke
1000
B
A
0
50 55 60 65 70 75 80 85 90 95 00 05
Year
FIGURE 0.1 Number of identified tobacco and tobacco smoke
components reported since 1954: Accumulative by year: A = prior
to 1953: “classical” chemical techniques; B = 1953–1960: column
chromatography; C = 1960–1970: gas chromatography; D = 1970 to
mid-1970s: glass capillary gas chromatography coupled with mass
spectrometry; E = mid-1970s to date: derivatives for HRGC, HPLC,
mass spectrometry.
An enormous number of references exist pertinent to the
isolation, identification, and biological studies of the great
number of components in tobacco and tobacco smoke. To
avoid considerable repetition, these are presented as a unified
Bibliography which contains the references cited not only in
this Introduction but also in each chapter. It is obvious that some
references have been omitted but we assure the reader that any
omission was not by design but was done unwittingly.
The references cited for a particular tobacco and/or
tobacco smoke component may deal simply with its identi-
fication or with a variety of topics pertinent to the particular
component. Such topics may include the following:
1. The isolation and identification of the component.
2. The characterization of the component by classi-
cal chemical means, for example, the definition of
the structure of solanesol isolated from flue-cured
tobacco by Rowland et al. (3359), the character-
ization of a component by spectrographic means
such as UV, IR, NMR, MS, and chromatographic
retention time, for example, the identification by
Snook et al. of numerous PAHs (3756-3758) and
aza-arenes (3750) in cigarette MSS.
3. The search for the precursor in tobacco of a par-
ticular component in cigarette mainstream smoke
(MSS) (3616).
4. The quantitation of the component on a per gram
of tobacco basis or on its per cigarette MSS yield.
5. Improvements/developments in the analytical
technology to determine the per cigarette MSS
and/or sidestream smoke (SSS) yield of the com-
ponent, for example, see Table 6 in (3306b).
6. Studies on the biological activity of a particular
component.
7. Discussions and/or assertions of the toxicity and/or
tumorigenicity of a component in MSS, SSS, or
ETS.
11/24/08 3:16:36 PM
 8. Studies on the inhibition of adverse biological
activity of a tobacco smoke component by another TABLE 0.1
component of the smoke, for example, the inhi- Sequence of Chemical Component Categories
bition of the mouse-skin tumorigenicity of B[a]P
Chapter 1. The Hydrocarbons
by n-hentriacontane and n-pentatriacontane (4314,
I.A. The Alkanes
4336), the inhibition of the mouse-skin tumorige- I.B. The Alkenes and Alkynes
nicity of DB[a,h]A by B[a]A (3814), the inhibition I.C. The Alicyclic Hydrocarbons
of the mutagenicity of N-nitrosodimethylamine I.D. The Monocyclic Aromatic Hydrocarbons
(NDMA) by nicotine (2327a, 2327b). I.E. The Polycyclic Aromatic Hydrocarbons
I.F. Summary
9. Controversies over the extrapolation of the biolog-
ical effect of a specific component administered Oxygen-Containing Components
Chapter 2. Alcohols and Phytosterols
individually vs. its biological effect when the com- II.A. Alcohols
ponent in a highly complex mixture such as MSS II.B. Phytosterols
is administered to a different species, by a differ- Chapter 3. Aldehydes and Ketones
ent route, and at a dose level far in excess of its Chapter 4 Acids
level in the complex mixture (1318a, 3300, 3627). IV.A. Carboxylic Acids
10. Description of the design technologies to con- IV.B. Amino Acids
trol the per cigarette MSS yield of Federal Trade Chapter 5. The Esters
Chapter 6. The Lactones
Commission (FTC)-defined “tar” and a particular
Chapter 7. Anhydrides
component, for example, see Table 16 in (3300). Chapter 8. Carbohydrates and Their Derivatives
Chapter 9. Phenols and Quinones
In many instances, the references cited for a particular IX.A. Phenols
component may also contain additional references perti- IX.B. Quinones
nent to the component. Chapter 10. The Ethers
The categories of chemical components in tobacco and Nitrogen-Containing Components
tobacco smoke derived from our Master Catalog will be pre- Chapter 11. Nitriles
sented in the sequence shown in Table 0.1. These chapters Chapter 12. Acyclic Amines
Chapter 13. Amides
will be followed the Bibliography and then an Alphabetical
Chapter 14. Imides
Component Index section. Chapter 15. N-Nitrosamines
As information for the reader, Table 0.2 depicts the first Chapter 16. Nitroalkanes, Nitroarenes, and Nitrophenols
page of the catalog for the alkanes (Table I.A-10). A similar Chapter 17. Nitrogen Heterocyclic Components
component catalog is present in the chapter for each compo- XVII.A. Monocyclic Four- and Five-Membered
nent class. N-Containing Ring Compounds
XVII.B. Monocyclic Six-Membered N-Containing Ring
Tobacco smoke, particularly cigarette smoke, is an aerosol
Compounds
comprising literally millions of liquid droplets suspended in a XVII.C. Lactams
gaseous system [see Ingrebrethsen (1860)]. The liquid droplet XVII.D. Oxazoles and Oxazines
portion of this smoke is defined as the particulate phase (PP); XVII.E. Aza-arenes
the gaseous portion as the vapor phase (VP). The particulate XVII.F. N-Heterocyclic Amines
phase is also described alternatively in several ways depending Chapter 18. Miscellaneous Components
on the context of the discussion; for example, the particulate XVIII.A. Sulfur Compounds
XVIII.B. Halogenated Compounds
phase collected by a variety of collection techniques such as
Chapter 19. Fixed and Variable Gases
the Cambridge filter pad, electrostatic precipitation, jet impac- Chapter 20. Metallic and Nonmetallic Elements, Isotopes,
tion, etc. [cf. review by Dube and Green (1067)] is termed wet Ions and Salts
total particulate matter (WTPM). Correction for the water Chapter 21. Pesticides and Growth Regulators
content yields total particulate matter (TPM). Subtraction of Chapter 22. Genes, Nucleotides, and Enzymes
the nicotine level from total particulate matter gives the FTC- Chapter 23. “Hoffmann Analytes”
Chapter 24. Tobacco and/or Tobacco Smoke Components
defined “tar.” The reasons for exclusion of nicotine and water
Used as Tobacco Ingredients
to give the FTC “tar” value were the long recognized nontox-
Chapter 25. Pyrolysis
icity of water plus the low toxicity of cigarette smoke nicotine Chapter 26. Carcinogens, Tumorigens, and Mutagens vs.
as described in the 1964 report of the Advisory Committee to Anticarcinogens, Inhibitors, and Antimutagens
the U.S. Surgeon General (3999). Thus, we have the following Chapter 27. Free Radicals
relationships among these entities: Chapter 28. Summary

WTPM = TPM + H2O = FTC “tar” + nicotine + H2O

In many instances, the collected cigarette smoke particulate
The equation most frequently used in the United States since
phase is called CSC.
the late 1960s is the following:
In many countries, cigarette “tar” is determined by use
FTC “tar” = WTPM nicotine H2O of the International Organization of Standardization (ISO)

© 2009 by Taylor & Francis Group, LLC

78836_C000.indd 31 11/24/08 3:16:36 PM

 TABLE 0.2
Alkanes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

method. The “tar” yield in the ISO method ISO 4387-1991 cigarette equilibration and smoking procedure differ slightly
is calculated in the same manner as in the FTC method from those in the FTC procedure [see Table 1, p. 496 in
[Pillsbury et al. (2962)], that is, by subtraction of the water Rustemeier and Piadé (3369a)]. These differences typically
and nicotine from the WTPM collected (ISO 1991). The ISO result in slightly lower measured yields for the ISO method

© 2009 by Taylor & Francis Group, LLC

78836_C000.indd 32 11/24/08 3:16:39 PM

 vs. the FTC method. The measured values between FTC
and ISO methods are within the detection limits of the test.
They differ by no more than 0.4 mg for “tar” and no more
than 0.04 mg for nicotine for cigarettes that yield over about
10 mg of “tar.” As described by Dixon and Borgerding (988a),
under standard smoking regimes the ISO and FTC methods
give very similar results.
The physical nature of cigarette smoke is discussed
below.
Periodically during the past five decades, various reviews
and catalog on the composition of tobacco smoke, with par-
ticular emphasis on cigarette MSS, have been published.
These have dealt with the components of total MSS (the
vapor-phase and the particulate-phase components) [Kosak
(2170), Bentley and Berry (282, 283), Berry (296), Johnstone
and Plimmer (1971), Izawa (1900), Philip Morris, Inc. (2939),
Stedman (3797), Ishiguro and Sugawara (1884), IARC
(1871)], with MSS particulate-phase components only or with
MSS vapor-phase components only [Elmenhorst and Schultz
(1140)], with both MSS and SSS components [Sakuma et al.
(3394, 3397, 3398), R. J. Reynolds Tobacco Company (RJRT)
(3190), Klus (2133), Klus and Kuhn (2142)], with MSS, SSS,
and ETS components [Brunnemann et al. (462), Eatough
et al. (1099, 1100)], and with particular classes of smoke
components, for example, nitrogen-containing components
[Neurath (2724), Schmeltz and Hoffmann (3491)] or PAHs
[Elmenhorst and Reckzeh (1139)].
The majority of these reviews described the composition of
smoke from cigarettes with a filler that was primarily tobacco.
Although not published in the readily available scientific lit-
erature, substantial data are available from studies conducted
on the smoke from cigarettes whose filler was not primar-
ily tobacco but a “tobacco substitute” or a tobacco: “tobacco
substitute” mixture. Inclusion of tobacco in the filler mixture
ensures that the smoke will include the components usually
found in an all-tobacco cigarette. Such data appear not only in
documents from Celanese describing the composition of MSS
from cigarettes containing only its Cytrel® product or in docu-
ments by Imperial Tobacco and Imperial Chemical Industries
describing the MSS composition from cigarettes contain-
ing only their New Smoking Material® (NSM®) product
but also in RJRT R&D reports which outline its studies on
the composition of smoke from cigarettes made with Cytrel®
only, NSM® only, the Sutton Smoking Material (SSM) only,
or J-10 only (a tobacco substitute, comprising a puffed grain,
developed in-house at RJRT). Recently, an article by Green
et al. (1375a) on the effect of several tobacco substitutes on
cigarette MSS composition has been published.
At RJRT, all available data on the composition of MSS
from cigarettes made with various tobacco types, tobacco
blends, various “tobacco substitutes,” and/or cellulose have
been routinely cataloged by R&D personnel, including one of
the present authors (A.R.), for over five decades (2270, 2292a,
3224, 3245, 3252, 3253, 3301-3304, 3308).
Until the early 1980s, the majority of the studies on
tobacco smoke composition dealt with the composition of
cigarette MSS. Particulate-phase composition was the major
© 2009 by Taylor & Francis Group, LLC
78836_C000.indd 33
research topic throughout the 1950s with studies on vapor-
phase composition receiving increased emphasis in the early
1960s when the biological response in laboratory animals
could not be explained by nature and/or the level of any of
the particulate-phase components acting individually or in
concert.
TOBACCO SMOKE AND THE
EXAMINATION OF ITS TUMORIGENICITY
IN LABORATORY ANIMALS
The initial research efforts were directed at attempts to
identify the components in the CSC that could be respon-
sible for the observed biological response in the CSC-painted
animals. Immediately, the class of compounds selected for
intense investigation was the PAHs. Why was this class of
compounds selected? Primarily it was because of the twenty
years of research effort since the initial findings in the early
1930s (194, 2078) that had shown that many PAHs were tum-
origenic to mouse skin (1544), with several being classified
as highly potent carcinogens to mouse skin (3306b).
After more than a century of research during which inves-
tigators attempted to induce malignant tumors in laboratory
animals by administration of a variety of industrial tars, soots,
oils, etc., success was finally achieved by Yamagiwa and
Ichikawa (4361) who reported the first induction of tumors in
laboratory animals skin-painted with coal tar solutions. Their
findings, which subsequently led to extensive research on the
induction of malignant tumors by skin painting of labora-
tory animals with various tars and oils, also led to the defi-
nition in 1923 of the terms carcinogen, carcinogenesis, and
carcinogenicity. Carcinogenesis was defined as the induction
of a carcinoma by the treatment. In 1930, a synthetic pen-
tacyclic PAH, dibenz[a,h]anthracene (DB[a,h]A) {I} (760,
1184), was reported to be highly carcinogenic to mouse skin
by Kennaway and Hieger (2078). In the early 1930s, Cook
et al. (796a, 797) isolated several PAHs from two tons of coal
tar. One of the PAHs, initially unknown, was demonstrated
by characterization and synthesis to be benzo[a]pyrene
(B[a]P) {II}, another pentacyclic PAH structurally similar to
DB[a, h]A (see Figure 0.2). Subsequently it was demonstrated
by Barry et al. (194) that B[a]P was also a potent carcinogen
for the skin of susceptible mouse strains. The finding of the
carcinogenicity of these two individual compounds, DB[a,h]
A and B[a]P, was the stimulus for the synthesis and bioas-
say of literally hundreds of PAHs (and structurally similar
nitrogen analogs) and their alkyl derivatives. Many of the
PAHs with four or more fused rings were reported to be
carcinogenic to mouse skin. A wealth of data was generated
from research on attempts to correlate carcinogenic potency
with PAH structure [Coulson (829), Pullman and Pullman
(3003), Lacassagne et al. (2247a)]. The carcinogenic potency
to mouse skin is dependent on the PAH structure and its sub-
stituents; for example, benz[a]anthracene (B[a]A) {III} is a
relatively weak carcinogen to mouse skin whereas its 7,12-
dimethyl homolog (DMBA) {IV} is an extremely potent one
11/24/08 3:16:39 PM

Dibenz[a,h]anthracene {I} Benzo[a]pyrene {II}
CAS No. 53-70-3 CAS No. 50-32-8
CH3
CH3
Benz[a]anthracene {III} 7,12-Dimethylbenz[a]anthracene {IV}
CAS No. 56-55-3 CAS No. 57-97-6
CH3
H3C
H3C
CH3
Phenanthrene {V} 1,2,3,4-Tetramethylphenanthrene {VI}
CAS No. 85-01-8 CAS No. 4466-77-7
FIGURE 0.2 Polycyclic aromatic hydrocarbons.
(983). The tricyclic PAH phenanthrene {V} is noncarcino-
genic to mouse skin but its 1,2,3,4-tetramethyl homolog {VI}
is slightly carcinogenic (983).
Kennaway (2073–2076) reported that pyrolysis of a vari-
ety of organic compounds (methane, acetylene, isoprene,
cholesterol) or mixtures containing organic compounds
yielded pyrolysates which were tumorigenic to mouse skin.
Subsequently, it was reported that a variety of carcino-
genic PAHs, including B[a]P, were components of similar
pyrolysates; for example, the pyrolysates from the tobacco
smoke components methane [Burrows and Lindsey (529a)]
and isoprene [Oró et al. (2864b)], as well as the pyrolysate
from the tobacco phytosterols structurally similar to cho-
lesterol [Wynder et al. (4355), Van Duuren (4022), Schmeltz
et al. (3511), Severson et al. (3616)].
For several years in the early 1950s, whether PAHs were
present in tobacco smoke was a highly controversial subject.
The early claims of the presence of B[a]P in cigarette smoke
were criticized by Kosak et al. (2177) in 1956 and by Fieser
(1181) in 1957 because of the failure to duplicate the reported
findings when similar analytical techniques were used. Logic
dictated that the PAHs, including B[a]P, would indeed be pres-
ent because they arise pyrogenetically from organic compounds
under a variety of conditions. Several of the demonstrated
PAH precursors are known to be components of tobacco used
in a cigarette, cigar, or pipe. The smoking process involves
pyrolysis and/or combustion. The differences between the
effect of pyrolysis of an individual compound vs. the effect
of the cigarette smoking process on the same compound in
© 2009 by Taylor & Francis Group, LLC
78836_C000.indd 34
the complex tobacco mixture were discussed by Rodgman et
al. (3307) and their discussion will be summarized in a later
chapter. However, even as late as 1957, Fieser, one of the emi-
nent American authorities on tumorigenic PAHs, was not con-
vinced that the presence of B[a]P in cigarette smoke had been
demonstrated. Fieser (1181) discussed the available published
data from various laboratories as follows:
British [Cooper and Lindsey (820)] and American groups
[Lefemine et al. (2335), Alvord and Cardon (55), Cardon and
Alvord (593)] have claimed identification of benzpyrene fol-
lowing extensive chromatography of tars from cigarette smoke,
but in each case the evidence of identity is correspondence
of the smoke factor with the synthetic carcinogen in fluores-
cence spectrum, coupled with the correspondence of the two
materials in one region of the ultraviolet absorption spectrum
… In the absence of complete ultraviolet correspondence, the
smoke-factor reported by the two groups of investigators can
be described as nothing more than a benzpyrene-like sub-
stance, which may or may not be carcinogenic …
Kuratsune (2237) [examined] the smoke from cigarettes
of two Japanese brands and detected no benzpyrene … In
my laboratory 20 g of cigarette smoke tar (from 500 ciga-
rettes) to which 9.7 μg/g of benzpyrene was added was chro-
matographed … and rechromatographed … the recovery [of
benzpyrene] was 7.8 μg/g of tar (80%) … In a parallel experi-
ment with 20 g of the same tar and no additive, fractions
corresponding to the positive fractions of the control were
all negative … Our estimate was that benzpyrene could be
present in amounts no greater than 1 part in 5 million parts
of tar.
Present evidence thus indicates that benzpyrene is formed
in trace amounts on pyrolysis of constituents of tobacco
(probably cellulosic), but that no appreciable amount passes
into the smoke, and hence that this hydrocarbon is not the
agent responsible for the observed carcinogenicity to mice of
cigarette smoke tar [Wynder et al. (4306a)].
Fieser also reported that his colleagues Huang and Johnston
failed to detect B[a]P in the MSS from American cigarettes
even though they determined its level (80% recovery) in CSC
“spiked” with B[a]P (1181). In Japan, Kuratsune, unable to
demonstrate the presence of B[a]P in the CSC from Japanese
cigarettes, was able to demonstrate its presence in roasted
coffee beans and various other pyrolysates [Kuratsune (2237),
Kuratsune and Hueper (2238)]. After subsequent studies by
Orris et al. (2865) and Kiryu and Kuratsune (2099) or assess-
ment of more complete laboratory data, Fieser (1182) and other
critics reversed their earlier positions and eventually accepted
that B[a]P was indeed present in tobacco smoke. The ultimate
confirmation of the presence of B[a]P in cigarette smoke was
its isolation in crystalline form and characterization by chemi-
cal means rather than reliance solely on the correspondence of
the ultraviolet spectrum of the isolate with that of an authentic
sample. Isolation of crystalline B[a]P from the MSS of a 70-mm
nonfiltered cigarette was reported in 1956 by Rodgman (3240),
by Hoffmann [see Wynder and Hoffmann (4307)] in 1959, and
from a filtered cigarette in 1960 by Rodgman and Cook (3273).
Fieser, the major architect of the chapter on smoke composi-
tion in the 1964 report of the Advisory Committee to the U.S.
Surgeon General (3999), had access to the published data by
11/24/08 3:16:41 PM
 Wynder and Hoffmann (4307) on the isolation of crystalline
B[a]P from cigarette smoke. However, numerous proponents
of the adverse effect of cigarette smoke, for example, Wynder
and Wright (4282a, 4354) and Wynder and Hoffmann (4307,
4312) asserted that the level of B[a]P in CSC or the levels of
several tumorigenic PAHs, including B[a]P, could only account
for a few percent of the biological response observed in mouse
skin-painting studies with CSC.
Since much of the post-1950 effort on MSS composition
was directed to the definition of the cancer-causing agents in
MSS possibly responsible for the association between lung
cancer and cigarette smoke in smokers, it is a requisite that
the various terms used in laboratory studies of tumor genera-
tion be understood.
In their 1990 list, Hoffmann and Hecht (1727) cataloged
the tobacco and/or tobacco smoke components classified as
“tumorigenic agents” and the range of the per cigarette MSS
yields of each. Prior to examining the individual components
on the list, an important distinction between “tumorigenicity”
and “carcinogenicity” should be noted. In the 27th edition in
1988 of Dorland’s Medical Dictionary (1051b), the definition
of carcinogenesis, first enunciated in 1923, is the same as that
listed in the 13th edition issued in 1927 (1051b). Some inves-
tigators incorrectly use the term “carcinogenesis” for the
production of any tumor type, not just for a carcinoma. The
correct term, if used in this manner, is “tumorigenesis.” The
term “carcinogen” is often applied, again often incorrectly,
to any factor that induces any type of tumor. Common in the
past, but seldom used now, was the term “sarcogenesis” used
to describe the production of sarcoma, the endpoint obtained
in many investigations in which the mode of administration
of the compound under test, for example, a PAH, was by sub-
cutaneous injection.
Additionally, terms such as carcinogen, carcinogenicity,
and/or carcinogenesis or sarcogen, sarcogenicity, and/or
sarcogenesis should not be considered as fixed properties of
compounds. It should be noted that in several of their early
publications, Wynder and Hoffmann (4342, 4343a, 4346) and
Hoffmann and Wynder (1801) carefully differentiated among
the terms carcinogenesis, sarcogenesis, and tumorigenesis
but eventually discontinued this practice. Other investigators
have done the same.
Because of the successful induction of cancer in a labora-
tory animal by Yamagiwa and Ichikawa (4361) and the dis-
covery that several PAHs were tumorigenic when painted on
the skin of laboratory animals (194, 797, 2078), the tumori-
genicity of literally hundreds of PAHs (and structurally simi-
lar nitrogen analogs) and their alkyl derivatives was studied
from 1932 to 1941. Many of the assertions made about the
correlation between the laboratory findings and human expe-
rience were extremely farfetched and caused much confusion.
This led to the request for Shear of the U.S. National Cancer
Institute to attempt to return order to the field of carcinoge-
nicity. The result was the classical description by Shear and
Leiter (3627), a description whose pertinence is still valid.
Carcinogenicity is a variable property, depending on
a number of factors. It differs from other properties of a
© 2009 by Taylor & Francis Group, LLC
78836_C000.indd 35
compound that are fixed, for example, melting point, boiling
point, refractive index, specific gravity, crystalline form. As
noted by Shear and Leiter (3627), Hartwell (1544), and many
others, a substance or factor can show a range of effects from
carcinogenicity to noncarcinogenicity to anticarcinogenic-
ity and the response will differ in the laboratory depending
on the animal used (species, strain, sex, age), dose, route of
administration (inhalation, ingestion, injection [subcutane-
ous, intravenous, intraperitoneal], skin painting, douching),
mode of administration (single vs. multiple doses, neat, in
solution, as an aerosol, as a vapor), diet supplied the animals,
and cage care.
SMOKE-FORMATION PROCESSES,
DISTRIBUTION (MSS, SSS, ETS), CHEMICAL
COMPOSITION, AND ANALYTICAL
METHODS FOR IDENTIFICATION
Cigarette smoke composition is dependent on two major pro-
cesses occurring during the smoking of tobacco: the direct
transfer by vaporization of volatile tobacco components
directly to the smoke and the pyrogenesis of smoke compo-
nents from tobacco components. The pyrogenesis involves a
variety of reactions, including oxidation, reduction, aroma-
tization, hydration, dehydration, condensation, cyclization,
polymerization, depolymerization, etc.
Table 0.3, adapted from Kosak (2170), lists the fewer than
100 tobacco smoke components reported in the scientific lit-
erature to that date. Examination of his compilation reveals
the following:
1. Of the approximately eighty entries, the identities
of thirty-three (over 40%) of the components were
questioned by Kosak because he did not “consider
the evidence cited in the literature to be definitive
proof” of their identities.
2. Two of the listed items (B[a]P, “condensed aromat-
ics”) were reported by Roffo (3323, 3324) whose
research did not involve the study of tobacco smoke
but involved a study of material obtained by the
“destructive distillation” of tobacco.
3. Several of the alkaloid-related components (A-,
B-, and G-socratine, obelin, lohitam, anodmin,
lathraein, poikiline, and gudham) first reported
by Wenusch and Schöller (4210, 4211) and listed
under Alkaloids were subsequently demonstrated
to be mixtures or a component listed elsewhere in
Table 0.3. For example, Kuffner et al. (2224) dem-
onstrated that obelin was a salt of ammonia, A-
and B-socratine were mixtures of nicotyrine and
2,3`-bipyridine, and G-socratine was l-nornicotine.
Poikiline was characterized as 4-amino-1-(3-
pyridyl)-butanone. Many of these characteriza-
tion corrections are described in Johnstone and
Plimmer (1971).
11/24/08 3:16:41 PM
 TABLE 0.3
Tobacco Smoke Components Listed by Kosak (2170)
Class Component Class Component Class Component
Hydrocarbons Hentriacontane (?) Ketones 3-Pentanone Acids Formic acid
Acetylene 4-Heptanone Acetic acid
“Unsaturated 17-Tritriacontanone (?) Butyric acid
hydrocarbons” 2,3-Butanedione Valeric acid
Azulene “Higher” ketones (?) Caproic acid
Phenanthrene (?) C7 and C8 aliphatic acids (?)
Anthracene (?) Succinic acid (?)
Benzopyrene (?) Fumaric acid (?)
“Condensed Citric acid (?)
aromatics” (?) Benzoic acid (?)
Phenolic acids (?)
Alcohols and Methanol Alkaloids Nicotine Miscellaneous Levoglucosan d
Phenols Glycerol Pyridyl ethyl ketone Components “Phytosterol” (?)
Diethylene glycol a Myosmine C10H14O (a furan ?)
Ethylene glycol a Nicotyrine “Resins” (?)
Phenol (?) A-Socratinec “Resin acids” (?)
Catechol (?) B-Socratinec
G-Socratinec
Obelinc
Lohitamc
Anodminc
Lathraeinc
Poikilinec
Gudhamc

Aldehydes Formaldehyde Other N- Pyrrole (?) Inorganic Ammonia

Acetaldehyde containing “Pyrroles” (?) Components Carbon monoxide
Butyraldehyde components “N-Methyl- Carbon dioxide
Acrolein (?) pyrrolidines” (?) Hydrogen cyanide
Benzaldehyde Pyridine Hydrogen sulfide
2-Furaldehyde (?) b “Picoline” (?) Thiocyanic acid (?)
“Lutidine” (?) Oxygen
“Collidine” (?) Arsenic e
“Pyridine bases” (?) “Acetates” (?)
Methylamine (?) “Chlorides” (?)
“Chlorophyll “Cyanides” (?)
degradation “Nitrates” (?)
products” (?)
“Uric acids” (?)
a In smoke because of transfer of an humectant added to tobacco.
b The question mark indicates that Kosak did not consider the evidence in the literature to be definitive proof of the identity of the
component.
c Subsequent study demonstrated this component was not a well-defined compound but an artifact, a mixture, or an ammonium salt [see discus-

sion by Johnstone and Plimmer (1971)].

d 1,6-Anhydro-B-D-glucopyranose.

e Probably present as As O .
2 3.

4. Kosak listed references to phenol (1857, 4202),
catechol (2107, 4202), and “phenolic acids” (3324)
as tobacco smoke components. However, he failed
to report the 1952 presentation by Rayburn (3089)
of the unequivocal identification of phenol, guaia-
col (2-methoxyphenol), o-cresol (2-methylphenol),
and m-cresol (3-methylphenol) in the smokes from
the four major tobacco types (flue-cured, burley,
Maryland, and Oriental).
5. Azulene, a bicyclic C10H8 hydrocarbon iso-
meric with naphthalene, was first reported as
a tobacco smoke component by Ikeda (1857)
and subsequently by Gilbert and Lindsey (1287,
1288), Lindsey (2365), and Lyons (2426). Despite
improved analytical technology and hundreds of
studies on the identification of PAHs in tobacco
smoke, very few reports of its identification have
appeared since those in the 1950s. This suggests

© 2009 by Taylor & Francis Group, LLC

78836_C000.indd 36 11/24/08 3:16:41 PM

 the possibility that the azulene reported in tobacco
smoke condensate in the 1940s and 1950s may
have been formed artifactually.
In summary, Kosak’s 1954 list, shown in Table 0.3, included
only about fifty components the identities of which were
certain.
The number of identified components in cigarette tobacco
smoke has increased almost 100-fold from the fifty defini-
tively identified tobacco smoke components listed by Kosak
(2170) to the more than 5300 components identified to date
and cataloged by RJRT personnel. Components were origi-
nally included in the RJRT catalog only if their identification
criteria satisfy the identification criteria of classical organic
chemistry. Later, identification criteria from modern analyti-
cal chemistry were employed. From 1950 to 1955, the early
years of the great escalation of interest in the composition of
cigarette smoke, “isolations” were often accomplished with
no regard to the possibility of artifact formation. Also, “iden-
tifications” of tobacco smoke components were often based
on less than complete spectral data, for example, the PAHs
and their ultraviolet spectra, Rf values, color tests, and the
like. Because of the state of the art of the isolation techniques
available in the early 1950s, the level in smoke of a com-
ponent under investigation often precluded its isolation in
quantities sufficient for application of the classical chemical
techniques (melting point and mixture melting point deter-
minations, derivative preparation, elemental analysis, etc.)
used for identification.
The authors of some of the early reviews and catalogs on
tobacco smoke composition listed the smoke components
reported in the literature without regard to the analytical
validity of their identification. This problem has progres-
sively decreased over the years as analytical technology has
increased in sophistication.
Few, if any, commercial products have experienced the
analytical scrutiny that has been applied to tobacco smoke
or tobacco. The composition of coffee has been examined
but the number of components identified is less than 25% of
the number identified in tobacco smoke. Despite the identi-
fication of over 5200 additional smoke components since the
1954 listing by Kosak, various investigators have estimated
from gas chromatographic scans that for each component
identified in tobacco smoke there are five to twenty compo-
nents present at extremely low per cigarette yields that have
not yet been identified. Thus, as noted by Wakeham (4103)
when the identified tobacco smoke components numbered
about 1350: “Gas chromatographic scans indicate there are
many more, probably over ten thousand, possibly even a hun-
dred thousand [tobacco smoke components].”
Grob (1422), one of the pioneers of the use of glass capil-
lary gas chromatography in tobacco smoke composition stud-
ies, as well as other tobacco smoke investigators, also noted
that the number of peaks, each of which represented at least
one component, in the chromatographic scans far exceeded
the number of components identified.
© 2009 by Taylor & Francis Group, LLC
78836_C000.indd 37
In addition to the advancement in knowledge of the chem-
ical composition of cigarette smoke was the advancement in
the knowledge of its physical properties, that of an aerosol.
An aerosol is defined as a colloidal system of dispersed liquid
or solid material in a gaseous medium. Cigarette smoke is an
aerosol comprising liquid droplets in a gas.
For nearly two decades, investigators have accumulated
knowledge on the conditions involved in the formation of
MSS and SSS aerosols during the smoking of a cigarette
and the factors contributing to or modifying their yields
and composition. Theories on smoke formation in vogue
in the late 1950s and early 1960s were demonstrated to be
incorrect; for example, many investigators thought that all
smoke components not originally present in tobacco and
thus appearing in the MSS by pyrogenesis from the tobacco
were formed at or near the fire cone at temperatures in
excess of 900°C. New and more nearly correct theories
replaced the old ones. Advances in our knowledge of smoke
formation and transport were possible because of improved
technologies developed to accomplish the following tasks,
see Townsend (3941a):
1. Accurately measure temperatures during puffs
and during the smolder period between puffs at
various sites within the burning cigarette and its
fire cone.
2. Follow the formation of specific components and
their subsequent passage and transport, in the case
of MSS components, through the tobacco rod by
puff-driven volatilization, repetitive condensations
and revolatilizations, filtration by tobacco rod and
filter tip material, etc.
3. Follow the formation of specific components and
their subsequent emission, in the case of SSS com-
ponents, to the atmosphere.
Baker (163a, 166) has written at length on his original
research and that of others on MSS and SSS aerosols and the
conditions involved in the cigarette in their formation and
transport. He has also periodically authored or coauthored
several excellent and detailed reviews (167, 169, 170a, 171a,
171b, 174d) on this subject.
It is now known that the fire cone temperature of 900+°C
measured during the puff primarily generates gaseous com-
ponents such as the carbon oxides, water, ammonia, nitric
oxide, etc. During the puff, pyrogenesis of most MSS com-
ponents occurs in a 3- to 4-mm cylinder of the tobacco rod
a few millimeters behind the fire cone:tobacco rod interface
where the temperature ranges from 500 to 650°C. During the
smolder period, the fire cone temperature is 500 to 600°C,
and it is at this temperature range that SSS is generated from
the tobacco.
Just as profound quantitative differences exist among
the chemical compositions of fresh and aged MSS, fresh
and aged SSS, and ETS, there are several differences in the
physical properties of these smokes. One physical property
11/24/08 3:16:41 PM
 important in these various types of cigarette smoke, their
inhalation, and their retention is their particle size. There are
several ways to describe particle size. A frequently used one
is mean mass aerodynamic diameter (MMAD).
In his review of the aerosol studies on cigarette smoke,
Ingebrethsen (1860) points out that two factors are extremely
important with respect to the measured particle size of an
aerosol: (1) the time between aerosol generation and particle
size measurement, and (2) the concentration of the aerosol.
High aerosol concentration and extended time between
generation and measurement result in increased coagulation
of particles and increased particle size. Freshly generated MSS
and SSS have the major fraction of particle sizes, expressed
as MMAD, in the range 0.3 to 0.4 μm [Ingebrethsen (1860c)].
Since SSS—both intra- and inter-puff generated—is the major
contributor, estimated at 85% to 90%, to ETS, it is important to
realize that its physical properties are constantly and progres-
sively changing. These changes begin the moment it is generated
and continue during its extensive dilution as it disperses through
the room until it is eventually perceived as ETS. Depending
on the proximity of the measuring device to the source of the
SSS, it is obvious that a range of particle sizes could be found,
ranging from that measured in freshly generated SSS to that
found in essentially equilibrated ETS. The behavior of particles
in SSS under carefully controlled conditions has been studied
in detail by Ingebrethsen and Sears (1860e).
Another problem of determining the contribution of ETS
to a given air space (home, office, restaurant, aircraft, etc.) is
that other non-ETS contributors to VP and PP are measured
at the same time as the contribution of ETS to VP and PP is
measured. These include contributions from cooking oils and
foods in homes and restaurants, cleaning preparations and
furniture polishes, personal products (perfumes, after-shave
lotions, hair sprays, deodorants, etc.), and vehicular exhausts
where the air space is adjacent to much traveled roads.
Chromatographic scans of samples collected in a confer-
ence room before and after a two-hour meeting during which
smoking was permitted revealed that chromatographic peaks,
some representing compounds from nontobacco sources,
were much larger than those known to be due to ETS (1352a).
Similar findings were reported by Bayer and Black (223),
who compared volatile organic contaminants (VOCs) in the
offices of smokers and nonsmokers. The authors noted:
Building materials and furnishings are the most common
source of these VOCs. [The] VOC building background
makes it difficult to distinguish ETS contamination from the
VOCs out-gassing from other sources.
A major distinction between MSS and SSS that affects
particle size is that MSS is acidic*, with a pH ranging from
6.0 to 6.6, whereas the pH of SSS ranges from 6.7 to 7.5.
The SSS from most cigarettes is alkaline, with pH above 7.0.
Under acidic conditions (pH < 7.0), smoke amines such as
nicotine are considered to be protonated and have relatively
* The MSS from cigarettes fabricated from dark air-cured tobacco or air-
cured cigar-type tobacco shows a slightly alkaline pH.
© 2009 by Taylor & Francis Group, LLC
78836_C000.indd 38
low volatility. Under alkaline conditions (pH > 7.0), such
amines are considered to be nonprotonated, that is, “free,”
and are relatively more volatile.
The differences and similarities in the physical properties
among MSS, SSS, and ETS are summarized in Table 0.4.
When freshly generated MSS is inhaled during smoking,
the aerosol particles in the smoke are exposed in the respi-
ratory tract to an atmosphere whose temperature is 37°C
and whose relative humidity exceeds 95%. As a result, the
inhaled particles absorb water and increase in size. Those
particles that are exhaled are, on average, 20% to 25% larger
than the inhaled particles (273, 1860b, 1860d, 1860e). When
these water-saturated exhaled MSS particles (temperature
at 37°C) are released into the atmosphere (temperature gen-
erally below 30°C and relative humidity below 50%), they
cool, and immediately undergo several evaporative processes
which are completed in a few milliseconds. These processes
include the following:
1. Components, usually gaseous under ambient con-
ditions, evaporate from the particle.
2. Components with modest vapor pressures evapo-
rate from the particle.
3. Water, incorporated into the particle either during
the smoke formation process in the tobacco rod
or during its residence time in the highly humid
confines of the respiratory tract, evaporates.
SSS particles behave much differently than MSS par-
ticles. Although little research has been conducted on fresh,
undiluted SSS, it is reasonable to expect that the particles are
physically similar to those in MSS. However, the high dilu-
tion that occurs almost immediately upon generation has the
effect of preventing coagulation and promoting evaporative
losses. Also, because of the alkalinity of SSS, basic compo-
nents are nonprotonated and readily evaporate from the par-
ticle. Studies in 1985 by Eudy et al. (1169) on SSS and ETS,
both generally alkaline (pH > 7.0), indicated that little (<5%)
of the nicotine remains in the ETS particle; the bulk of it
(>95%) evaporates from the particle and appears in the VP.
As a result of these various processes, the SSS and exhaled
MSS particles, on their way to contribute to ETS, decrease
both in particle mass and in particle size to an MMAD
ranging from 0.15 to 0.20 μm for the major fraction of the
particles. Experimental data for the decrease in SSS parti-
cle size were presented by Ingebrethsen and Sears (1860e,
1860f). Ten minutes after smoke generation, a major fraction
of the SSS particles showed a particle size with an average
MMAD of 0.198 μm.
It should be noted that these various evaporative processes
involve relatively volatile smoke components. The particle
size is not diminished to any appreciable degree by evapora-
tion of nonvolatile and high molecular weight components,
such as the PAHs (B[a]P, DB[a,h]A, indeno[1,2,3-cd]pyrene,
dibenz[a,i]pyrene) listed by Hoffmann and Hecht (1727) and
Hoffmann and Hoffmann (1740, 1741), and other components
such as solanesol, the phytosterols, A-tocopherol, and the
11/24/08 3:16:42 PM
 TABLE 0.4
Physical Propertiesa of Mainstream Smoke (MSS), Sidestream Smoke (SSS), and Environmental Tobacco Smoke
(ETS)
Properties MSS
Number of identified Over 4300 in particulate phase (PP);
components about 1000 in vapor phase (VP).
Some components are present in both
the PP and VP; e.g., HCN, simple
phenols, volatile N-nitrosamines.
Approximate temperature of


r
àSF
DPOF 850-950°C


r
TNPLF
GPSNBUJPO 500-600°C
Approximate % of tobacco 30-40
rod consumedb
Particle size, μm Fresh whole MSS particles have
MMAD = 0.3-0.4 μm c contain
volatile components which readily
vaporize from the particles.
Because of coagulation, hydration,
evaporative transfer and other physical
processes, e.g., the cloud effect, MSS
particles behave as though they have a
MMAD in the micron range c.
Particle concentration, 109 to 1010
number/cm3
Retention of particulate 50 to 90%
matter in respiratory tract
Percentage retention as measured by
weight loss between time of inhalation
and exhalation due to mechanical
trapping plus loss of volatiles from
inhaled particles.
Smoke pH 6.0 to 6.6 for cigarette MSS d.
Inhalability of smoke into MSS inhalability favored by pH less
lungs than 7.0.
Nicotine behavior 99+% of nicotine in cigarette MSS is in
the PP; because the MSS pH is much
less than 7.0, amines such as nicotine
are protonated; nicotine in MSS PP is
presumed to be protonated by the low
molecular weight acids present in
MSS e
© 2009 by Taylor & Francis Group, LLC
78836_C000.indd 39
SSS ETS
Composition assumed to be qualitatively similar to that of MSS; i.e., the number
and identity of the SSS and ETS components are the same as those in MSS.
Quantitative differences in component levels are substantial. The distribution of
a component between PP and VP depends on the nature (acid, base, neutral)
and the physical properties (vapor pressure, etc.) of the particular component.
The decay (decrease) of an individual ETS component is also dependent on
numerous factors such as its nature, its physical properties, and the temperature,
relative humidity (RH), ventilation, and nature of surfaces (carpets, drapes,
upholstered furnishings, etc.) in the smoke space.
500-650°C
500-600°C
50-60
Fresh SSS particles are about the same size as During dilution to ETS,
MSS particles; within a short time (<10 min) exhaled MSS particles lose
after generation, the MMAD > 0.2 μmc for H2O and other volatile PP
SSS particles. components; particle size
decreases to a MMAD =
0.15-0.20 μmc.
SSS particles lose H2O and
other volatile PP components
such as nicotine, amines, etc.
Thus, particle size decreases
to a MMAD = 0.15-0.20 μmc.
~1-5 x 105
10 to 11%
Low percentage retention as
measured by weight loss is
due to virtual absence of
coagulation and other
physical phenomenon, e.g.,
cloud effects, and lack of
water and other volatile
components which may be
lost by inhaled ETS particles.
6.7 to 7.5 for cigarette SSS. Neutral (pH 7.0) to slightly
alkaline.
Some investigators have reported SSS pH
values as high as 8.0
Inhalability of smoke (whether cigarette SSS, pipe Because of extreme dilution by
MSS, or cigar MSS) is progressively diminished air and near neutrality (pH
as smoke pH increases above pH 7.0. close to 7.0), the inhalability of
ETS is nearly the same as that
of air.
Because of alkalinity of SSS and the high Because of the extremely high
concentration of SSS particles near the dilution of ETS and its pH at
burning cone, nicotine (and other volatile or slightly above 7.0, little
smoke components) are distributed between nicotine (or other amines) is
the SSS PP and SSS VP; PP-VP equilibrium found in ETS PP; more than
for these compounds is not attained adjacent 95% of the nicotine in ETS is
to the cigarette burning cone. in the non- protonated form
and is found in ETS VP.
(Continued)
11/24/08 3:16:42 PM
 TABLE 0.4 (CONTINUED)
Physical Propertiesa of Mainstream Smoke (MSS), Sidestream Smoke (SSS), and Environmental Tobacco Smoke
(ETS)
Properties MSS
Relationship of smoke yield MSS controllable by
to cigarette design r
UPCBDDP
SPE
MFOHUI
BOE
DJSDVNGFSFODF
r
àMUFS
UZQF
BOE
EJNFOTJPOT
r
àMUFSUJQ
BEEJUJWFT
r
UPCBDDP
CMFOE
BOE
XFJHIU
r
QSPDFTTFE
UPCBDDP
SFDPOTUJUVUJPO

which control intrapuff SSS
expansion)
r
QBQFS
BOE
QBQFS
BEEJUJWFT
r
BJS
EJMVUJPO
QBQFS
QPSPTJUZ
BOE
àMUFS

perforation)
a Properties listed are those for unaged and undiluted smoke.
b Tobacco rod not consumed during smoking estimated at 5 to 8% for filtered cigarettes; 20 to 25% for non-filtered cigarettes.
c MMAD value listed is that for a major fraction of the smoke.
d The MSS from cigarettes fabricated from dark air-cured tobacco or air-cured cigar-type tobacco shows a slightly alkaline pH.
e Protonation of nicotine in tobacco due to long-chained acids (palmitic acid, stearic acid, etc.) and polycarboxylic acids (oxalic acid, malic acid, citric
acid).
saturated aliphatic hydrocarbons. These components remain
in the particles.
In addition to the dilution that occurs when the ETS par-
ticles disperse through the room space, an additional dilu-
tion occurs by the deposition of ETS particles on the surfaces
present. These processes—evaporation, dispersion, and
deposition—decrease the concentration of ETS particles.
Ventilation, air exchanges per unit time, nature of the sur-
faces (fabric, plastic, wood, etc.), temperature, relative humid-
ity, number of cigarettes smoked per unit time, and number
of persons present are some of the known variables that will
also influence the concentration of ETS particles.
Questions are frequently raised about the particle size of
MSS, SSS, and ETS and the relationship between particle
size and retention in the respiratory tract of the inhaled
smoke. Usually, particle size plays an important role in deter-
mining mainstream particulate retention in the lungs. Based
on a comparison of particle size, one might expect ETS and
MSS to be retained similarly in human lungs on a percent-
age basis. Empirical data demonstrate that this is not the
case. In the case of MSS, other factors come into play. These
drastically alter the amount of MSS particulate matter that
is retained. Weight-loss measurements give values ranging
from 50% to 90% for the percentage retention of inhaled
MSS (1860c). The percentage retention is a characteristic of
the individual smoker. The retention of inhaled MSS is much
higher than would be predicted by the measured MMAD of
fresh smoke, 0.3 to 0.4 μm. Ingebrethsen (1860c) reviewed
the literature on the retention of MSS and identified five fac-
tors that may be responsible for increased MSS particle reten-
tion. These include coagulation, electrical charge, growth by
© 2009 by Taylor & Francis Group, LLC
78836_C000.indd 40
SSS ETS
Inter-puff SSS, the major contributor to total Since ETS comprises 85-90%
SSS, is primarily controlled by cigarette diluted and aged SSS plus
tobacco blend and weight and to a lesser 10-15% exhaled MSS, the
degree by paper properties and additives. control of ETS resides
primarily with those factors
generation.
water condensation, evaporative transfer, and cloud effects.
Evaporative transfer and cloud effects were deemed to be the
most significant factors. Recently, Moldoveanu et al. (2601b)
and Moldoveanu and St. Charles (2601a) reported on the
different degrees of retention by humans of 160 cigarette
MSS components by comparison of their levels in smoking
machine-generated MSS vs. their levels in smoker-exhaled
MSS.
ETS particles behave quite differently from MSS particles
in terms of human retention. Unlike MSS, the retention of
ETS in the lung is not affected by evaporative transfer and
cloud effects. Instead, ETS retention is influenced mainly by
particle size. Theoretical calculations indicate that the per-
centage retention of particles equivalent in size to ETS par-
ticles should vary between 10% and 20%. A value within the
theoretical range was obtained: Hiller et al. from studies with
human mouth-breathing volunteer nonsmokers who orally
inhaled polystyrene latex spheres of particle sizes similar to
those of diluted sidestream smoke (1654a) and five volunteers
who inhaled a tobacco smoke defined as “sidestream smoke
at a concentration similar to that encountered indoors with
smokers present” (1654b), estimated the percentage retention
of the smoke to be 11%.
The difference in particle retention between MSS and
ETS is due largely to the high dilution that SSS particles
experience almost upon formation. This dilution causes ETS
particles to behave as model, nonvolatile, inert particles by
preventing coagulation, obviating cloud effects, and promot-
ing evaporation prior to inhalation.
As noted earlier (Table 0.4), numerous technologies intro-
duced sequentially from the mid-1950s to the late 1960s were
11/24/08 3:16:42 PM
 Replacement of all-flue-cured or all-Oriental
1913 tobaccos with a blend of flue-cured, burley,
and Oriental tobaccos
50.0
40.0
30.0
‘TAR,’ mg
20.0
10.0
‘TAR’
0.0
1954 1958 1962
FIGURE 0.3 “Tar” and nicotine yields, sales-weighted average basis, U.S. cigarette products.
incorporated into cigarette design to control MSS yield and
composition, which some have characterized as a “less haz-
ardous” cigarette when included in cigarette design [Gori
and Bock (1334b), National Cancer Institute (2683), USPHS
(4005, 4009)]. These technologies include:
1. Tobacco blend and weight
2. Tobacco rod length and circumference
3. Filter tips (material type and additives)
4. Processed tobaccos (reconstituted tobacco sheet,
expanded tobacco)
5. Paper (type and additives)
6. Air dilution (increased paper porosity, filter tip
perforations)
The chronology of introduction of these technologies in
U.S. cigarette products is noted in Figure 0.3. Over the years,
use of these technologies in concert and to various degrees
in cigarette design has provided the consumer with a great
variety of products whose number has increased from about
a dozen in the mid-1950s to nearly 1250 in 1995 (1177c). It
should be remembered that the cigarette is a system: All
of these technologies used in cigarette design are interac-
tive, that is, inclusion of or change in the level of use of any
particular technology may require other adjustments in the
cigarette design to maintain certain attributes acceptable to
the consumer. In contrast, by current technology, SSS yield
is controlled almost totally by tobacco blend and weight.
The SSS is not subjected to filtration, the effect of filter-tip
© 2009 by Taylor & Francis Group, LLC
78836_C000.indd 41
3.00
Filter tips
Reconstituted tobacco
2.50
Paper additives
Paper porosity
Expanded tobacco 2.00
Ventilation
NICOTINE, mg
1.50
1.00
0.50
NICOTINE
0.00
1966 1970 1974 1978 1982 1986
Year
additives that specifically remove certain MSS components
from MSS (phenols, volatile N-nitrosamines), or air dilution
effects.
Adams et al. (31) reported data on MSS and SSS yields of
fourteen components in the smokes from four U.S. commercial
cigarettes of different design: a nonfilter cigarette, two filtered
cigarettes, and a perforated filter cigarette. MSS and SSS yield
data for TPM; nicotine; a PAH, (B[a]P); a phenol, catechol;
a volatile N-nitrosamine, N-nitrosodimethylamine (NDMA);
and a tobacco-specific N-nitrosamine, N-nitrosonornicotine
(NNN) are summarized in Table 0.5.
The SSS TPM yields shown in Table 0.5 for the nonfil-
tered and two filtertipped cigarettes are, on average, about
58% higher than the SSS TPM yield from the perforated-
filter cigarette. Most perforated-filter cigarettes, such as
Perforated Filter-D in Table 0.5, not only incorporate a perfo-
rated filter with a high percentage air dilution to reduce MSS
TPM but also incorporate substantial levels (30% to 50%)
of expanded tobacco in the cigarette design. The inclusion
of such a large percentage of expanded tobacco in the blend
substantially reduces the weight of tobacco in the tobacco
rod and the weight of tobacco consumed during the SSS-
generating smolder periods. Thus, these data show the SSS
TPM yield from the perforated-filter cigarette is substantially
less (37%) than the average of the SSS TPM from the other
three cigarettes.
In a more recent study on the MSS and SSS yields from
cigarettes classified as low tar, Chortyk and Schlotzhauer
(723, 724a) provided data that differ substantially from
11/24/08 3:16:43 PM
 TABLE 0.5
MSS/SSS Distribution of Selected Components Delivered by Four U.S. Commercial Cigarettes
Non-Filtered A Filtered B Filtered C Perforated Filter D
Smoke Component, Yield/cig MSS SSS MSS SSS MSS SSS MSS SSS
TPM, mg 20.1 22.6 15.6 24.4 6.8 20.0 0.9 14.1
Nicotine, mg 2.04 4.62 1.50 4.14 0.81 3.54 0.15 3.16
Catechol, mg 41.9 58.2 71.2 89.9 26.9 69.5 9.1 117
B[a]P, ng 26.2 67.0 17.8 45.7 12.2 51.7 2.2 44.8
NDMA, ng 31.1 735 4.3 597 12.1 611 4.1 685
NNN, ng 1007 857 88 307 273 185 66.3 338

the Adams et al. (31) data in Table 0.5 and from other data
(3190) reported for comparable “tar”-yield cigarettes. The
differences in the data for comparable FTC “tar”-yield ciga-
rettes were found for cigarettes delivering approximately 23,
10, and 7 mg. In their MSS and SSS collection and analy-
sis, Chortyk and Schlotzhauer (724a) used their previously
reported SSS collection procedure (723) in the generation of
their data. Green (1353) commented on several deficiencies
in the procedures used and interpretations made by Chortyk
and Schlotzhauer (724a) from their data. Examination of
their data and comparison of them with the Adams et al. (31)
and RJRT (3190) data (see Table 0.6) reveal an additional
problem: For the three cigarette categories (23-, 10-, and
7-mg FTC “tar” yields), the SSS/MSS ratios for the TPMs
in the Chortyk–Schlotzhauer study were between two and
seven times greater than those reported in the other studies.
Similarly for nicotine, the Chortyk–Schlotzhauer SSS/MSS
ratios were from about 1.5 to over seven times greater than
those reported in the other studies. This strongly suggested a
problem with their SSS collection procedure.
The escalation of the number of identified tobacco and
tobacco smoke components is depicted in Figure 0.1. This tre-
mendous increase in the number of identified tobacco smoke
(and tobacco) components was made possible by successive
advances in analytical technology, particularly the technol-
ogy pertinent to the separation of components in complex
mixtures.
It is realized that investigators who pioneered an emerg-
ing analytical technology were often involved with the devel-
opment and/or use of the technology prior to the period
indicated in Figure 0.3. No slight of their noteworthy con-
tributions is intended. The periods indicated in Figure 0.3
are those when the analytical technology in question was
sufficiently advanced and used by almost all investigators
involved in the analysis of tobacco smoke and/or definition
of its composition.
Prior to the early 1950s, the major part of tobacco smoke
component isolation effort involved so-called “classical”
chemical techniques, that is, separation of the smoke con-
densate into neutral, acidic (acids and phenols), and basic

TABLE 0.6
Comparison of SSS/MSS Ratios for Different Cigarette Types

Adams et al.(31) Chortyk and Schlotzhauer

20-mg Cigarette 23-mg Cigarette (724a) 23-mg Cigarette (723)
Analyte a MSS SSS SSS/MSS MSS SSS SSS/MSS MSS SSS SSS/MSS
TPM 20.1 22.6 1.12 21.8 56 2.57 22.9 54.9 2.40
Nicotine 2.04 4.62 2.26 1.68 9.08 5.40 1.30 5.29 4.07
R.J. Reynolds (3190) Chortyk and Schlotzhauer (724a)
1R4F 10-mg Cigarette 10-mg Cigarette
Analytea MSS SSS SSS/MSS MSS SSS SSS/MSS MSS SSS SSS/MSS
TPM 11.5 16.9 1.47 10.4 60 5.77 9.5 53 5.58
Nicotine 0.79 5.60 7.09 0.90 9.10 10.11 1.05 10.46 9.96
Adams et al. (31) Chortyk and Schlotzhauer (724a)
7-mg Cigarette 7-mg Cigarette 6-mg Cigarette 6-mg Cigarette
Analyte a MSS SSS SSS/MSS MSS SSS SSS/MSS MSS SSS SSS/MSS MSS SSS SSS/MSS
TPM 6.8 20.0 2.94 6.7 59 8.81 5.4 60 11.11 6.0 50 8.33
Nicotine 0.81 3.54 4.37 0.58 8.95 15.43 0.22 7.04 32.00 0.55 8.06 20.77
a mg/cig

© 2009 by Taylor & Francis Group, LLC

78836_C000.indd 42 11/24/08 3:16:44 PM

 fractions by partitioning between water-immiscible organic
solvents and water, aqueous basic solutions, and/or aqueous
acidic solutions, followed by crystallizations and/or distilla-
tions of the subfractions.
In the early 1950s, liquid column chromatography on col-
umn packings such as alumina, silicic acid, or Fluorosil® of
the neutral, acidic, or basic fractions, as appropriate, permit-
ted further separation of the components prior to application
of the classical chemical techniques. UV and IR spectrom-
etry were also available and used not only to combine chro-
matographic fractions rich in a specific component but also
to assist in the identification of the component. UV absorp-
tion and fluorescence spectrophotometry were extremely use-
ful in identification of the PAHs in tobacco smoke.
In the late 1950s to early 1960s, commercial equipment
for gas chromatography became available. This technique,
coupled with those mentioned previously, augmented the
investigator’s ability to separate, isolate, and identify smoke
components. Mass spectrometry and nuclear magnetic reso-
nance equipment and techniques were also more readily
available and became additional tools that facilitated compo-
nent identification. In the early days of gas chromatography,
there were fewer than a dozen chromatographic column pack-
ings commercially available and most of these did not permit
satisfactory separations above 200°C. By the late 1960s, the
number of available column packings had increased, and the
properties of newly designed column packing materials per-
mitted separations at temperatures approaching 350°C.
In the early 1960s, investigators such as Grob (1413) began
study on capillary gas chromatography and subsequently
glass capillary gas chromatography. A major contribution by
Grob was his development of methods to prepare and coat the
inner wall of a capillary tube to increase its effectiveness and
efficiency in separations. By the late 1960s to early 1970s,
this emerging technology, glass capillary gas chromatogra-
phy, had become an extremely powerful analytical tool and
was used to great advantage in the study of the complex mix-
tures tobacco smoke, see Grob (1416–1419, 1422) and Grob
and Völlmin (1426, 1427), and tobacco extracts [Lloyd et
al. (2389)]. The glass capillary column was usually a small-
diameter (about 1 mm or so) glass or quartz tube, extremely
long (50 to 300–400 m) whose interior was not packed with
a solid adsorbent or an inert material mixed with a liquid
adsorbent as in the previously used gas chromatographic
columns. The inner wall of the narrow-bore capillary was
coated with a thin layer of a liquid adsorbent. This technol-
ogy not only enhanced separation capability but permitted
separations to be made with extremely small samples. These
advances in analytical technology were usually accompa-
nied by a break and an increased slope in the plot of num-
ber of identified tobacco smoke components vs. time (see
Figure 0.1). The next break in the plot and increased slope
occurred in the mid-1970s when more and more investiga-
tors enhanced the effectiveness of glass capillary gas chro-
matography by coupling the gas chromatograph to a mass
spectrometer. This permitted separation of the components
of the particular tobacco smoke fraction under study and
© 2009 by Taylor & Francis Group, LLC
78836_C000.indd 43
determination of the molecular weight and/or fracture pat-
tern of each component as it exited the chromatograph and
was analyzed in the mass spectrometer. Interpretation of the
data thus obtained, usually in concert with findings from UV,
IR, and/or NMR spectra, permitted very rapid and unequivo-
cal identification of the components from the smoke fraction
(1426, 1427). An outstanding example of the use of gas chro-
matography-mass spectrometry in the definition of tobacco
smoke composition is the study by Snook et al. (3756–3759)
on the PAHs in cigarette MSS. Over 500 individual PAHs
and their homologs were detected, and many were identified
unequivocally. The early- to mid-1970s also saw the emer-
gence of high performance liquid chromatography (HPLC)
(830a, 1361), a highly efficient and effective variation of liq-
uid column chromatography.
The traditional method used to examine CSC (or a
tobacco extract) usually involved its initial partition between
an aqueous alcohol solution and a water-immiscible organic
solvent such as hexane, cyclohexane, or diethyl ether. The
organic solvent-soluble material was then separated into sev-
eral neutral, acidic, and basic fractions. These, in turn, were
then subjected to the various analytical techniques available
at the time. Considerable success was attained in isolation
and identification of the organic solvent-soluble smoke com-
ponents. For many years, however, there was no satisfac-
tory technique available to separate, isolate, and identify
the many components in the aqueous alcohol fraction from
the aqueous alcohol-water immiscible organic solvent parti-
tion. Many of the aqueous alcohol-soluble components are
highly polar, highly oxygenated compounds, and no chro-
matographic system was available to effect clean separa-
tions. In addition, many of these components, because of
their structures, were highly labile at the temperatures used
in gas chromatographic separation. By use of the technology
known as silylation, these sometime heat-sensitive, highly
polar components were converted to chromatographable sta-
ble silyl derivatives which can be readily separated by glass
capillary gas chromatography and identified by mass and
other spectral techniques.
By use of the latest analytical technology available at the
time, the mainstream CSC from a typical cigarette was re-
examined with particular emphasis on the composition of the
aqueous alcohol-soluble material. The separation and iden-
tification of over 750 previously unidentified tobacco smoke
components were described by Schumacher et al. (3553),
Newell et al. (2769), and Heckman and Best (1587). A strik-
ing example of the effectiveness of the improved analytical
technology on tobacco smoke component identification is the
following. In 1977, Schmeltz and Hoffmann (3491) cataloged
about 420 nitrogen-containing components identified in MSS.
They indicated that the number of identified nitrogen-con-
taining tobacco smoke components had increased by about
200 since a previous review of nitrogen-containing tobacco
smoke components by Neurath (2724). In a presentation and
publication, Heckman and Best (1587) described the separa-
tion and identification of nearly 270 new nitrogen-containing
smoke components, an increase of more than 60% over the
11/24/08 3:16:44 PM
 number described by Schmeltz and Hoffmann (3491) in their
review article.
The following is another example of the impact the
improved analytical technologies had on the ability to fur-
ther define the composition of tobacco smoke: In the late
1950s to early 1960s, the composition of an aliphatic ester
fraction isolated from flue-cured tobacco by Rowland and
Latimer (3358) and from cigarette MSS by Rodgman et al.
(3294) was partially defined in both cases by Rodgman et
al. (3294). By saponification of the aliphatic ester fraction,
followed by separation of the alcohol and acid moieties,
Rodgman et al. showed that the tobacco- and tobacco smoke-
derived aliphatic ester fractions were qualitatively the same
and theoretically comprised at least 272 esters formed from
at least seventeen aliphatic acids [myristic (C14) to octaco-
sanoic (C28), oleic, linoleic, and linolenic] and sixteen nor-
mal long-chained, primary aliphatic alcohols [1-dodecanol
(C12) to 1-heptacosanol (C27)]. In 1984, with improved chro-
matographic capability and a mass spectrometric system
capable of detecting much higher molecular weights than
those used by Rodgman et al. in 1961, Arrendale et al. (103)
reexamined the aliphatic ester fraction from tobacco. The
saponification and subsequent separation of acids and alco-
hols were no longer required. Arrendale et al. were able
to identify unequivocally many of the individual esters by
glass capillary gas chromatography and mass spectroscopic
examination of the aliphatic ester fraction isolated from the
tobacco. The alcohol moiety of the esters identified ranged
from 1-tetradecanol (C14) to 1-dotriacontanol (C32); the acid
moiety ranged from lauric acid (C12) to n-dotriacontanoic
acid (C32) plus numerous iso- (from C13 to C28) and anteiso-
(C13 to C18 plus C20) isomers of several saturated aliphatic
acids. Since each ester reported by Rodgman et al. was
found in tobacco and smoke (3294), logic dictates that each
new tobacco ester found by Arrendale et al. is also present
in smoke (103). Thus, the findings by Arrendale et al. sub-
stantially increased both the number of known components
in tobacco and tobacco smoke.
Most of the studies reported in the literature from the
mid-1950s to the late 1970s to early 1980s on tobacco smoke
composition dealt with the composition of the MSS from the
cigarette. Gradually during the late 1970s, more and more
studies were reported describing the composition of cigarette
SSS [see Klus and Kuhn (2142)]. Presently, the major empha-
sis on tobacco smoke composition involves the composition
of ETS, health problems reportedly associated with passive
smoking, that is, exposure to ETS, and the levels of specific
components reported to be associated with these health prob-
lems [Ecobichon and Wu (1108a), Environmental Protection
Agency (1148, 1148a, 1148b), Guerin et al. (1445)]. SSS and
ETS are discussed in later sections. Because of the rela-
tive efforts expended on cigarette MSS, cigarette SSS, and
ETS, the numbers of identified components in each of these
smokes were reported as approximately 4800, 500, and 100,
respectively (3255). Given sufficient time and effort, any
component identified in MSS could eventually be identified
in SSS and ETS.
© 2009 by Taylor & Francis Group, LLC
78836_C000.indd 44
The approximate (and general) composition of cigarette
MSS is well defined. An 85-mm cellulose acetate filter-
tipped commercial cigarette (65-mm tobacco rod, 20-mm
filter tip) whose filler, a typical American blend of tobaccos,
weighed approximately 1000 mg was machine smoked with
the Federal Trade Commission (FTC)-prescribed smok-
ing parameters (35-ml puff volume, 2-sec puff duration, 1
puff/min; 25°C; 60% relative humidity; FTC-specified butt
length) (1177b). This cigarette gave approximately 500 mg
of total MSS. To separate the tobacco smoke aerosol into
its two major phases, the particulate phase and the vapor
phase, the smoke was passed through a Cambridge filter
pad which retains more than 99.9% of the particulate phase,
defined as total wet particulate matter (WTPM). The vapor
phase is that portion of the smoke aerosol which passes
through the Cambridge filter pad, and the major portion of
its weight is due to the components of air drawn through
the cigarette during the smoking process (nitrogen, oxy-
gen, argon, etc.).
The distribution and approximate composition of the
total MSS emerging from this cigarette are summarized in
Figure 0.4. The data in Figure 0.4 represent a consolidation
of composition data from several sources, including data
from RJRT R&D [Laurene (2299a)] plus data from Keith and
Tesh (2068), Norman (2799a), and Browne et al. (445). To
simplify the calculations throughout Figure 0.4, one value
was deliberately adjusted slightly for convenience: the total
MSS collected actually weighed slightly in excess of 497
mg, but the value 500 mg was used to calculate the percent-
ages shown throughout Figure 0.4. In addition, no attempt
was made with these data to define the degree of partition
of some components between the particulate and the vapor
phases. Because of their vapor pressure properties, signifi-
cant quantities of some smoke components are found in both
the particulate and vapor phases of cigarette MSS. These
include hydrogen cyanide, several of the simple phenols (phe-
nol, o-cresol, m-cresol, p-cresol), and several of the volatile
N-nitrosamines.
It is obvious from the data in Figure 0.4 that the particu-
late matter, whether described as WTPM, TPM, or FTC
“tar,” comprises less than 5% (100 × 22.5/500 = 4.5%) of the
total MSS emerging from the cigarette. This is true of nearly
all commercial U. S. cigarettes no matter what the FTC “tar”
yield. The composition of the MSS vapor phase has been
almost completely defined. It is estimated that components
representing less than 1 mg of the particulate phase (5.1%
of the FTC “tar,” less than 0.2% of the total MSS) remain
unidentified. If the number of unidentified components is
as high (as many as 100000) as some investigators estimate
(1422, 4103), then the level of each unidentified component
must average in the low nanogram range.
The extremely wide variations in the yields of components
delivered in the MSS during the smoking of a cigarette have
presented unique challenges to those involved not only in the
identification of smoke components but also in their quantita-
tion. Table 0.7 is a minor modification of the initial version
presented in 1996 by Green and Rodgman (1373). In it, the
11/24/08 3:16:44 PM
 TOTAL MAINSTREAM SMOKE 
93-

WET TOTAL PARTICULATE VAPOR PHASE 
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MATTER (WTPM) 
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FIGURE 0.4 Approximate composition of cigarette mainstream smoke.
logarithmic presentation is a more concise depiction of this
wide variation in the levels of selected smoke components. For
most of the components shown in Table 0.7, there obviously is a
range of values, and the extent of the range for each component
is dependent on the cigarette type under study (filtered, nonfil-
tered) and the weight of tobacco consumed during the smok-
ing of the cigarette for the analysis. In general, the locations
of the various components on the logarithmic plot have been
adjusted for a cigarette yielding about 18 to 20 mg/cigarette of
FTC “tar.” If the design of the cigarette has been modified to
reduce FTC “tar” yield, diminution of the yields of the other
components will occur but not necessarily to the same extent
as the decrease in FTC “tar” yield. Cigarette design parameters
(tobacco rod length and dimensions, filter type and dimensions,
filter-tip additives, tobacco blend and weight, processed tobac-
cos [reconstituted tobacco sheet, expanded tobacco], paper and
paper additives, and air dilution [paper porosity and filter per-
foration]) have profound effects on cigarette MSS yield and
© 2009 by Taylor & Francis Group, LLC
78836_C000.indd 45
composition. Also shown in Table 0.7 are those components
listed by Hoffmann and colleagues (1727, 1740, 1741, 1743,
1744) as “tumorigenic components of tobacco and tobacco
smoke” and cited as such by the U.S. Surgeon General (4012),
the U.S. Environmental Protection Agency (EPA) (1148a),
and the U.S. Occupational Safety and Health Administration
(OSHA) (2825). The validity and meaning of their classifica-
tion of specific tobacco smoke components as tumorigenic
were discussed by Rodgman (3265).
Yields for the vapor-phase components range from a high
of 50 to 60 mg/cigarette for carbon dioxide to lows in the
nanogram range for vinyl chloride and the volatile nitro-
samines such as N-nitrosoethylmethylamine. The major por-
tion of the nitrogen (>300 mg/cigarette) and oxygen (>65 mg/
cigarette) in MSS is derived from the air drawn through the
cigarette during the smoking process.
The number of components identified in various tobacco
types also increased substantially during the 1950s, 1960s,
11/24/08 3:16:45 PM
 TABLE 0.7
Cigarette Mainstream Smoke Components - Logarithmic Listing of Per Cigarette Yields
Vapor Phase Yield/cig Particulate Phase
-400 mg
Nitrogen -
-
- 200
-
-
-100 mg
-80
Oxygen, carbon -
dioxide -
-40
-
-
Water, carbon -20 ª
monoxide - « FTC “tar”
- ¬
-10 mg
-8
-
-
-4 Water
-
-
-2
- Humectants (glycerol,
- propylene glycol)
Acetaldehydea -1000 Og = 1 mg Nicotine
-800
Isoprenee - Total alkanes The 5 acids: palmitic,
- stearic, oleic, linoleic,
Limonene -400 linolenic
- Saturated aliphatic esters
Nitric oxide -
-200 Catechol
-
HCN -
-100 Mg Solanesol Total alkylpyridines Phenol
-80 Phytosterols
Acrolein -
1,3-Butadienee -
-40 Solanesyl esters
-
Formaldehydea ¹ -
2-Furaldehyde º -20 o-Cresol
Crotonaldehydea ­ -
Benzenea » - Phytyl esters
-10 Mg
Acrylonitrilea -8 Indole
- A-Tocopherol Indole, 3-methyl-
- Solanesyl acetate
-4 Anabasine
-
-
-2 NABa,b; indole,
- 3-ethyl-;
- NNNa,b; quinolinea

© 2009 by Taylor & Francis Group, LLC

78836_C000.indd 46 11/24/08 3:16:46 PM

 TABLE 0.7 (CONTINUED)
Cigarette Mainstream Smoke Components - Logarithmic Listing of Per Cigarette Yields
Vapor Phase Yield/cig Particulate Phase
-
- 1 Mg = 1000 ng
- 1000 ng
Propane, 2-nitro-a - 800 Nornicotine
-
-
- 400 Indole, dimethyl-
- A- and B-Duvanediols NNKa,b
- AACe
NDMAa,b - 200 A-Levantenolide
- Indole, trimethyl-,
- Carbazole Anthracene
NPYRa,b - 100 ng Pyrene; chrysenea
- 80
- Fluoranthene
- Leada, cadmiuma Benz[a]anthracenea
- 40 B-Levantenolide
- MeAACe; PhIPe
NDEAa,b - Carbazole, 2,9-
dimethyl-
Hydrazinea - 20 Arsenica 1-Naphthylamine Carbazole, 3,9-
dimethyl-
Ethyl carbamatea - Chromiuma 2-Naphthylaminea Benz[e]acephenanthrylene,c
- Indeno[1,2,3-cd]pyrene-
NEMAa,b - 10 ng Pyrenea; benzo[a]pyrenea ;
Vinyl chloridea - 8 Benzo[j]fluoranthene a
- Carbazole, 1,9-
dimethyl-
-
- 4
- Carbazole, 9-ethyl-;
- Carbazole, 4,9-
dimethyl-
- 2 Biphenyl, 4-amino-a Dibenz[a,h]anthracenea;
- Dibenzo[rst]pentaphenea,d
-
- 1000 pg = 1 ng Dibenz[a,j]acridinea
- 800 Glu-P-1e & P-2e
- Trp-P-2e
- MeIQ
- 400 Dibenzo[c,g]carbazolea Chrysene, 5- methyl-a
-
- IQe
- 200 Trp-P-1e
-
-
- 100 pg
- 80 Dibenz[a,h]acridinea
-
a This tobacco smoke component was included in a list published by Hoffmann and Hecht (1727) in which the component was one of 43 components defined
as a “tumorigenic agent in tobacco and tobacco smoke.”
b NDEA = N-nitrosodiethylamine

NDMA = N-nitrosodimethylamine
NEMA = N-nitrosoethylmethylamine
NPYR = N-nitrosopyrrolidine
NAB = N’-nitrosoanabasine
NNK = 4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone
NNN = N’-nitrosonornicotine

(Continued)

© 2009 by Taylor & Francis Group, LLC

78836_C000.indd 47 11/24/08 3:16:46 PM

 TABLE 0.7 (CONTINUED)
Cigarette Mainstream Smoke Components - Logarithmic Listing of Per Cigarette Yields
c Benz[e]acephenanthrylene is the currently accepted name for benzo[b]fluoranthene.
d Benzo[rst]pentaphene is the currently accepted name for dibenzo[a,i]pyrene.
e In a modified list of “tumorigenic agent in tobacco and tobacco smoke,” Hoffmann and Hoffmann (1740) increased the number of components from 43 to
60 and included several of the “cooked food” mutagens as well a several other MSS components (1,3-butadiene, isoprene, etc.).
Trp-P-1 = 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole
Trp-P-2 = 3-amino-1-methyl-5H-pyrido[4,3-b]indole
Glu-P-1 = 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole
Glu-P-2 = 2-aminodipyrido[1,2-a:3’,2’-d]imidazole
AAC = 2-amino-9H-pyrido[2,3-b]indole
MeAAC = 2-amino-3-methyl-9H-pyrido[2,3-b]indole
IQ = 2-amino-3-methylimidazo[4,5-b]quinoline
PhIP = 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
and 1970s both within and outside the tobacco industry. The
purpose of such studies was essentially twofold: to define
the tobacco components that (1) provided taste and aroma
to the smoke to render it acceptable to the consumer and
(2) were precursors of the smoke components asserted to
be responsible for the health problems induced by tobacco
smoke. Participating investigators over the years included
USDA personnel initially under the leadership of Stedman
in Philadelphia and subsequently by Chortyk after the move
of the USDA tobacco research group from Philadelphia,
Pennsylvania to Athens, Georgia.
The precursor research will be discussed in much greater
detail in subsequent chapters dealing with those precursors
in tobacco of MSS components considered adverse to the
smoker, for example, the precursors in tobacco of the PAHs,
the phenols, aldehydes and ketones, the N-nitrosamines, and
the N-heterocyclic amines. It is interesting to note that even
the precursor studies led to differences of opinion among the
scientists with views on the health problems associated with
components in cigarette MSS. In 1942, Roffo (3327) proposed
that the precursors of PAHs in the destructive distillate of
tobacco were the tobacco phytosterols. In 1957, Fieser com-
mented that the major precursor in tobacco of PAHs in MSS
was probably cellulose (1181). Coauthors of several presenta-
tions and publications, Wynder, Wright, and Lam differed in
their views on the major precursors in tobacco of PAHs in
tobacco smoke. Because of his research findings from 1955
to 1959, Lam was a proponent of the concept that the long-
chained aliphatic hydrocarbons were the major precursors in
tobacco of the PAHs, including B[a]P, in MSS (2255–2258).
Wynder was a proponent of the concept that the major pre-
cursors in tobacco of PAHs in MSS were the long-chained
aliphatic hydrocarbons and the phytosterols (4354).* Wright,
a colleague of Wynder from the early to the late 1950s, held a
different view from that of Wynder and that of Lam. Wright
* Even though this article was co-authored by Wynder and Wright, the view
held by Wright on the major precursors in tobacco of PAHs in smoke was
omitted from the manuscript by Wynder.
© 2009 by Taylor & Francis Group, LLC
78836_C000.indd 48
considered the major precursors of PAHs in MSS to be the
phytosterols and long-chained terpenoids such as solanesol
(4282). Eventually, precursor studies by Rodgman and Cook
(3269) in 1958 indicated that the view held by Wright was the
correct one. Their 1958 findings were subsequently confirmed
in the late 1970s at the USDA by Severson et al. (3616).
There were significant contributions by Rowland et al.
in the early 1950s from their studies on the composition of
flue-cured tobacco, studies that resulted in the isolation and
identification by classical chemical means of the 45-carbon
terpenoid alcohol solanesol (3359), its acetate and several
other of its esters (3294, 3296, 3358), neophytadiene (3345),
A-tocopherol and solanachromene (3347), the four isomeric
4-(2-butenylidene)-3,5,5-trimethyl-2-cyclohexen-1-ones (the
megastigmatrienones) (3355), and several cyclotetradecane-
diols (3220, 3221, 3351, 3360) plus their oxabicyclo derivatives
(3361). Over a decade later, with more advanced analytical
technology, Lloyd et al. (2389) identified several hundred pre-
viously unidentified flue-cured tobacco components. From
their early composition studies, similar to those of Rowland
on flue-cured tobacco, Schumacher and Vestal isolated and
identified numerous previously unidentified Oriental tobacco
components (3561), including sclareolide (3533) and the first
glucose tetraester (3535). Schumacher also defined numerous
components in Maryland tobacco (3550). Roberts and Rohde,
in their study of the composition of burley tobacco, identi-
fied numerous previously unidentified tobacco burley com-
ponents, including several cyclotetradecanediols (3219).
As analytical methodology advanced after the 1950s, the
number of identified tobacco and tobacco smoke components
escalated dramatically. In addition to its study of tobacco
smoke by Arnap (91–94) and Enzell et al. (1153, 1154), the
R&D staff at the Swedish Tobacco Company published nearly
one hundred articles on the composition of tobacco, primar-
ily Oriental tobacco. The many Swedish Tobacco Company
investigators included Aasen, Almqvist, Behr, Enzell,
Hlubucek, Kimland, Nishida, and Wahlberg, all of whom
coauthored many articles on tobacco composition (1–13, 52,
11/24/08 3:16:46 PM
 53, 84, 91–94, 227, 229–236, 1149–1157a, 1205a, 1660–1662,
2092–2095, 3315, 4083–4102). Excellent detailed summaries
of the identification of hundreds of tobacco components and
their generation from various terpenoid structures such as the
noncyclic and cyclic carotenoids and the cyclotetradecane
derivatives were presented and published in the late 1970s
and early 1980s by Enzell (1149, 1150), Enzell and Wahlberg
(1156), and Wahlberg and Enzell (4089, 4090).
In the 1960s and 1970s, the Demoles and their colleagues
at Firmenich SA in Switzerland also studied the composition
of flue-cured, burley, and Oriental tobaccos and characterized
many previously unreported compounds in each, for example,
the studies by Demole and colleagues on burley tobacco com-
position (936–944), on flue-cured tobacco composition (945,
946, 948), and on Oriental tobacco composition (947).
As noted previously, it was estimated by Wakeham (4103)
and Grob (1422) from their examination of gas chromato-
grams that the number of components in tobacco smoke far
exceeded the number of identified components. A similar
situation exists with the composition of tobaccos. As early
as the mid-1970s, DeJong and Lam (922d) commented that
the estimated number of enzymes in green leaves, including
tobacco, ranged from 1000 to 10000. Our Master Catalog
from which the various lists of component classes are derived
© 2009 by Taylor & Francis Group, LLC
78836_C000.indd 49
comprises nearly 8400 components. The chapter on enzymes
will list many of the tobacco enzymes but obviously will
not include all of the great number of enzymes reported in
tobacco.
The MSS yields for components of the particulate
phase range from that of FTC “tar” itself, shown as a
yield of about 20 mg/cigarette in Table 0.7 (1373), to that
of dibenz[a,h]acridine at an MSS yield of 0.1 ng/cigarette
(100 pg/cigarette).* The magnitude of the range of yields
for cigarette MSS components is demonstrated by the fol-
lowing: The ratio of the per cigarette yield of nitrogen (the
most plentiful MSS component shown in Table 0.7) to that
of dibenz[a,h]acridine (the lowest yield shown) is >3 × 10 9,
that is, >300 mg vs. 0.1 ng). The need for analytical meth-
odology to determine smoke components from the high
milligram to the low picogram yield was one of the driv-
ing forces behind many of the developments and improve-
ments in analytical technology for the study of complex
mixtures.
* Several new entries concerning N-heterocyclic amine data that were not
available in 1996 for inclusion by Green and Rodgman (1373) are included
in Table 0.7.
11/24/08 3:16:46 PM
 The Alphabetical Index to Components
Identified in Tobacco, Tobacco Smoke,
and Tobacco Substitute Smoke
The index was created for two purposes. The first was to
capture in one site all the basic information on the identified
tobacco and tobacco smoke components discussed in the chap-
ters of the book. The components are listed alphabetically in
the index. Second, the index may permit the reader to easily
retrieve or search for information on a specific tobacco and/or
smoke component or class of components so that further study
will be facilitated. To achieve these goals, the index was con-
structed to include the following: (1) The CAS No. for many
of the components, (2) an indication of the component identi-
fication in tobacco, tobacco smoke, or both, (3) the structure
of many of the components, (4) the table number and chapter
in which the component is not only referenced but its proper-
ties are described, particularly if they are considered adverse,
(5) for multifunctional components, several chapters and table
numbers are cited. Additionally, the publishers have provided
the index on CD. Hopefully, the searchable format of the CD
will aid the reader in retrieving any desired information.
The index comprises almost 8700 components completely
or partially identified in tobacco, tobacco smoke, and tobacco
substitute smoke. It not only includes over 8400 identified
components but also several hundred compounds not identi-
fied in tobacco or tobacco smoke but reported by Doull et al.
(1053) as tobacco ingredients used in the United States and
by Baker et al. (172a, 174b) as tobacco ingredients used out-
side the United States, as well as in a summary by Rodgman
(3266) and in our Chapter 24. Because the transfer from a
tobacco product to smoke of very few of the added ingredi-
ents has been examined, they primarily are listed as tobacco
components. Exceptions include several humectants used in
tobacco products for many years. However, it should be noted
that the detailed pyrolysis study by Baker and Bishop (172a)
indicated that many such added ingredients would transfer in
part to MSS during the tobacco smoking process.
In some instances, the reader may wonder about the pecu-
liar nature of the component listing. For example, a tobacco
smoke component initially reported as 2-butene was later
shown to be present in the smoke as cis- and trans-2-butene.
Thus, three items are listed in the index for 2-butene, namely,
© 2009 by Taylor & Francis Group, LLC
78836_C000.indd 51
2-butene (CAS No. 107-10-7), 2-butene, (Z)- (CAS No. 590-
18-1), and 2-butene, (E)- (CAS No. 624-64-6). References to
the identification of each are provided in Chapter 1, Section
I.B. 2-Butenedioic acid is similarly listed: 2-butenedioic acid
(CAS No. 6915-18-0), 2-butenedioic acid, (Z)- (maleic acid)
(CAS No. 110-16-7), 2-butenedioic acid, (E)- (fumaric acid)
(CAS No. 110-17-8).
The reader will also find in the index certain broad clas-
sifications of components, like oxidases and free radicals.
These and similar examples in the index are not there to con-
fuse the reader, as many of the individual components in the
broad classifications have specific CAS numbers. Generally,
the references associated with these classes of components
(found within the chapters noted in the index) will provide
the reader with information of a common nature. In nearly
all cases, individual components such as ascorbate oxidase,
choline oxidase, cytochrome oxidase, and glycolate oxi-
dase follow after the broadly classified component, oxidase.
Likewise, specific free radicals such as methyl-acyl radical,
ethyl-acyl radical, and propyl-acyl radical {2 isomers} may
be found in the index. For some components in the index,
several partially identified isomers exist, their number noted,
and included in the total number of components identified in
tobacco and/or smoke.
Although the number of enzymes, genes, and nucleotides
listed in the index is fewer than 500, their known number,
as noted in Chapter 22, exceeds many thousands. The pal-
try number of enzymes, genes, and nucleotides listed in
Chapter 22, Table XXII-2, was never intended to represent
the total biological agents operating in the plant. Those
selected for inclusion were from texts, research manuscripts,
and patents where active research was conducted in the past
in attempts to better understand the physiology and biochem-
istry of tobacco. As future genetic research develops, it is
envisioned that the identity and function of hundreds of thou-
sands of additional chemicals will be published.
The authors hope that the format of the index and accom-
panying CD will help the reader to reach a better understand-
ing of the components of tobacco and tobacco smoke.
11/24/08 3:16:46 PM
 1 The Hydrocarbons
I.A THE ALKANES
In his catalog of tobacco smoke components reported in early
1954, Kosak (2170) listed hentriacontane as the only alkane
identified in tobacco smoke. Subsequently, numerous inves-
tigations resulted in the identification of a great number of
alkanes in tobacco and tobacco smoke.
Over 120 alkanes, ranging from the C1 hydrocarbon
methane to the C36 hydrocarbon hexatriacontane, have been
identified in tobacco and tobacco smoke. Many of the higher
molecular weight alkanes have been reported to be present in
three isomeric forms, that is, the normal, the iso (2-methyl-),
and the anteiso (3-methyl-) isomer:
n-alkane H3C-(CH2)n-CH3
iso-alkane H3C-CH(CH3)-(CH2)n-1-CH3
anteiso-alkane H3C-CH2-CH(CH3)-(CH2)n-2-CH3
In 1958, Barbezat-Debreuil (181), using column chromato-
graphy and x-ray analysis to examine the alkanes in tobacco
and tobacco smoke, reported her identification of branched iso-
mers in the alkane fraction from both sources. The next year,
Carruthers and Johnstone (613) reported the results of their
study on the long-chained alkanes in tobacco and the smoke
from cigarettes containing it. Their analyses involved gas-
liquid chromatography and mass spectroscopy. They also noted
that the minor differences between the mass spectroscopic
data for tobacco and smoke were not significant because, at
that time, the precision of such an analysis was not high. Their
findings are summarized in Tables I.A-1 and I.A-2.
Cuzin et al. (883) in their study of Gauloise cigarette
mainstream smoke (MSS) reported that 1.2% of the total
particulate matter (TPM) consisted of n-C25, n-C26, n-C28,
n-C29, n-C30, n-C31, and n-C32 alkanes and 75% of this weight
involved the C30, C31, and C32 compounds. They reported that
their evidence indicated no n-alkane higher than the n-C32
alkane was present. However, in 1960 Kosak and Swinehart
(2176) reported the presence in cigarette MSS of the n-al-
kanes from C22 to C36 and branched alkanes from C21 to C32.
Table I.A-3 summarizes their findings. Possibly due to the
status of analytical methodology at the time, Dymicky and
Stedman (1081) had earlier suggested the possible presence
of n-tetracontane (C40H82) in tobacco but their finding has
never been confirmed. In 1967, Ivanov and Ognyanov (1893b)
reported the isolation of a crystalline alkane mixture, m.p.
62–64°C, which they proposed might contain a series of
alkanes from C25 to C40.
Carugno (619) reported the C31 alkanes to be the most
abundant in tobacco but also noted that the C27, C29, C30, C32,
and C33 homologs were present in appreciable amounts. Only
a small portion of the alkanes in the alkane fraction from the
© 2009 by Taylor & Francis Group, LLC
78836_C001.indd 1
MSS from four tobacco types and a commercial tobacco blend
was found with carbon chain lengths equal to or less than C24;
only trace amounts of alkanes at or below n-hexadecane were
found by Spears et al. (3768). They also reported that nearly
48% of an alkene-free alkane fraction (0.75 mg/cig) from MSS
consisted of n-hentriacontane (0.182 mg/cig), n-dotriacontane
(0.108 mg/cig), and n-tritriacontane (0.069 mg/cig).
In their article on the pyrolysis of tobacco constituents,
Badger et al. (142) reproduced a gas chromatogram provided
by Reid on the alkanes in a tobacco sample. The peaks for the
alkanes from C23 to C33 are readily discernible in the chro-
matogram. Badger et al. estimated that the tobacco alkane
fraction amounted to 0.32% of the tobacco weight. Based on
their pyrolysis studies, Badger et al. also proposed an elaborate
mechanism for the formation of the polycyclic aromatic hydro-
carbons (PAHs). It involved the degradation of the alkanes to
smaller fragments, followed by recombination of the frag-
ments into substituted cyclic entities and their aromatization.
As listed in Table I.A-4, adapted from Mold et al. (2595),
about 25% to 50% of the total alkanes in tobacco comprise
nearly equal amounts of the iso and anteiso isomers of
the alkanes. In the series of normal- and iso-alkanes, the
homologs with odd-numbered carbons predominate, with the
C31 and C33 homologs being present in the largest amounts.
In the anteiso-alkanes, the alkanes with even-numbered car-
bons predominate, with the C32 homolog being present in the
largest amount. The data provided by Mold et al. (2595) were
reproduced by Tso in his 1990 book (3973).
As Stedman (3797) noted in his 1968 review of the com-
position of tobacco and smoke, it was thought at one time that
anteiso-alkanes comprised only those homologs with even-
numbered carbons, but eventually homologs with odd-num-
bered carbons were reported by Carugno and Rossi (625) and
Chortyk et al. (727). Carugno and Rossi (625) reported the
presence of both normal and branched C21 to C34 alkanes in
cigarette smoke condensate (CSC).
In a later comparison of the composition of the alkane
fraction in a reference tobacco (University of Kentucky 1R1)
and its cigarette MSS, Chortyk et al. (727) reported that “the
ratio among the constituents in leaf paraffins is almost identi-
cal [with] the ratio among the smoke paraffins.” It is possible,
however, that changes in agronomic practices over the years
since the 1970s may have resulted in tobaccos whose con-
tents of alkanes and distribution among the alkane homologs
are substantially different from those of the tobaccos studied
in the 1960s and 1970s. This, of course, would also affect the
content and distribution among the alkane homologs in the
tobacco smoke.
Table I.A-5 summarizes the tobacco smoke alkane iso-
mers described by Stedman (3797) and those known to be
11/13/08 6:40:25 PM
 2 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.A-1
Relative Percentage Composition of Tobacco Alkanes in Tobacco and
Cigarette Smoke, Based on Mass Spectroscopic Analysis (613)
Tobacco Cigarette Smoke
No. of Carbons n- iso- Total n- iso- Total
25 0.9 0 0.9 0 0 0
26 0.6 0 0.6 0.5 0 0.5
27 3.0 0.9 3.9 5.2 0.8 6.0
28 0.1 0 0.1 0.5 0 0.5
29 6.6 15.9 22.5 5.2 15.3 20.5
30 0.9 2.5 3.4 1.0 1.5 2.5
31 24.1 24.4 48.5 25.7 20.2 45.9
32 3.9 2.4 6.3 4.3 1.9 6.2
33 10.8 3.3 14.1 14.3 3.5 17.8
Total 50.9 49.3 100.3 56.7 43.2 99.9

present in 1992. The number of identified alkanes in these

TABLE I.A-2 three isomeric forms was almost doubled during the period
Relative Percentage Composition of n-Alkanes 1968 to 1992.
Many of the isomeric C8 through C36 alkanes have been
in Tobacco and Cigarette Smoke, Based on
identified in the organic solvent-soluble extracts from one or
Gas-Liquid Chromatographic Analysis (613) more of the major tobacco types (flue-cured, burley, Oriental,
No. of Carbons Tobacco Cigarette Smoke Maryland). Their presence in tobacco smoke is the result of
n-24 … 0.1 their volatilization during the puff and smolder phases of
n-25 0.5 0.6 the smoking process and subsequent direct transfer from the
n-26 0.3 0.4 tobacco to its MSS and sidestream smoke (SSS). The bulk of
n-27 7.5 6.3 these higher alkanes are found in the particulate phase of the
n-28 0.6 1.1 smoke aerosol with traces of the lower ones (C8-C12) in the
n-29 8.8 7.4
vapor phase.
n-30 3.9 3.8
n-31 47.0 48.4 The lower molecular weight alkanes (C1 through C7) are
n-32 12.5 13.0 found predominately in the vapor phase of the MSS and SSS
n-33 18.9 22.8 aerosols, and are readily separated and identified by a variety
n-34 … 1.1 of analytical techniques.
In general, the n-alkanes from C1 to C4 are gases, those
from C5 to C16 are liquids, and those above C17 are solids.
TABLE I.A-3 The melting points and boiling points of some of the solid
Alkane Content of Cigarette Mainstream Smoke alkanes in tobacco and smoke are summarized in Table
(2176) I.A-6.
As a result of the successful induction in the mid-1950s
No. of Carbons Normal Branched of carcinomas on the skin of mice painted repeatedly with
21 … 0.16 concentrated solutions of CSC (4306a), the search for the
22 0.11 0.21 causative agent in the condensate began. The demonstration
23 0.49 0.21 in the early 1930s of the tumorigenicity of dibenz[a,h]anthra-
24 0.92 0.21
cene (DB[a,h]A) (2078) and benzo[a]pyrene (B[a]P) (796a,
25 2.50 0.16
26 1.40 1.63 797) to mouse skin triggered an enormous research effort
27 6.60 0.87 between 1932 and 1953, excluding the World War II years,
28 1.80 13.90 which involved the synthesis of hundreds of PAHs and their
29 6.30 2.31 testing for tumorigenicity. Because many of them were found
30 3.30 15.33 to be tumorigenic to mouse skin, particularly those tetracy-
31 22.90 0.90 clic and higher, the PAHs were proposed in the mid-1950s by
32 4.80 1.13
many investigators as possible causative agents for the lung
33 9.70 …
34 1.20 … cancer type (squamous cell carcinoma) observed in cigarette
35 0.97 … smokers. This proposal led to the demonstration of the pres-
36 0.05 … ence of numerous PAHs in CSC, determination of their lev-
% of Total 63.0 37.0 els, and studies to elucidate their precursors in the tobacco.

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 2 11/13/08 6:40:27 PM

 The Hydrocarbons 3

TABLE I.A-4
Relative Percentage Composition of Tobacco Alkanes Based on Gas-Liquid Chromatographic Data [Figures
rounded from those provided by Mold et al. (2595)]
Commercial Tobacco Blend Flue-Cured Tobacco Burley Tobacco Oriental Tobacco
No. of Carbons n- iso- ante- n- iso- ante- n- iso- ante- n- iso- ante-
25 1.7 — — 2.0 — — 1.15 — — 1.4 — —
26 0.8 — — 1.0 — — 0.5 — — 0.7 — —
27 7.7 — — 5.7 — — 4.8 — — 8.6 — —
28 0.9 — 0.1 1.4 — 0.4 1.1 — 0.4 1.8 — 0.2
29 6.7 1.2 — 5.9 3.1 — 5.4 2.5 — 7.9 1.8 —
30 3.2 — 5.6 3.1 — 6.7 2.9 — 6.8 5.5 — 5.3
31 26.3 10.9 — 24.5 14.3 — 27.5 12.6 — 23.2 6.7 —
32 4.9 — 13.0 4.2 — 11.3 5.6 — 11.7 7.4 — 8.9
33 10.8 5.6 — 7.2 6.4 — 8.1 6.5 — 12.8 4.9 —
34 — — 1.2 — — 2.9 — — 2.6 — — 2.3

TABLE I.A-5
Alkane Isomers Identified in Cigarette Mainstream Tobacco Smoke, 1968 vs. 1992
1968a 1992
Carbon Number Carbon Number
normal iso anteiso normal iso anteiso
C1-C9 C4-C6 C6 C1-C36 C4-C6 C6-C8
C12-C36 C27-C33 … … C8-C9 C11-C12
… … … … C11-C13 C16-C18
… … … … C16-C18 C21-C36
… … … … C21-C36 …
a From Stedman (3797).

Despite the fact that in 1942 the phytosterols in tobacco
had been proposed by Roffo (3327) as the precursors in
tobacco of PAHs in a “destructive distillate” of tobacco,
the tobacco phytosterols were essentially ignored in the
early 1950s. Because of the research results described
by Lam (2255–2258) on the pyrogenesis of PAHs from
alkanes, the high molecular weight alkanes in tobacco
were proposed as the precursors of the PAHs in tobacco
smoke. Roffo’s suggestion on phytosterols was discounted
by Wynder and Hoffmann (4320, 4322) because his
research did not involve tobacco smoke but involved the
composition and specific tumorigenicity of “destructive
distillates” from control and organic solvent-extracted
tobacco.

TABLE I.A-6
Melting Point and Boiling Point Data for n-Alkanes
n-Alkane Formula m.p. °C b.p. °C n-Alkane Formula m.p. °C b.p. °C
Undecane C11H24 25.6 196 Heneicosane C21H44 40.4 357
Dodecane C12H26 9.6 216 Docosane C22H46 44.4 369
Tridecane C13H26 6 230 Tricosane C23H48 47.4 380
Tetradecane C14H30 5.5 251 Tetracosane C24H50 51.1 391
Pentadecane C15H32 10 268 Pentacosane C25H52 53.3 402
Hexadecane C16H34 18.1 280 Triacontane C30H62 66.0 450
Heptadecane C17H36 22.0 303 Pentatriacontane C35H72 74.6
Octadecane C18H38 28.0 308 Hexatriacontane C36H74 75
Nonadecane C19H40 32.0 330 Tetracontane C40H82 81.0
Eicosane C20H42 36.4 343 Pentacontane C50H102 92

© 2009 by Taylor & Francis Group, LLC

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 4 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.A-7
Chronology of Studies on Alkanes in Tobacco and Tobacco Smoke
Selected Studies Of
Alkanes as Polycyclic Aromatic
Year Alkanesa in Tobacco Alkanes in Tobacco Smoke Hydrocarbon Precursors

1901 Thorpe and Holmes (3914)

1930 Kurilo (2239, 2240)
1934 Chibnall et al. (701)
1934, 1937 Wenusch (4184, 4192, 4194)
1935 Schürch and Winterstein (3562) Schürch and Winterstein (3562)
1936 Brückner (450)
1941 Palfray et al. (2890)
1942 Hukusima and Oike (1848)
1954 Kosak (2170)
1955, 1956 Lam (2255–2257) Lam (2255–2257)
1956 Dickey and Touey (966)
1956
1956 Onishi and Yamasaki (2863) Kosak (2172)
1956, 1957 Wright and Wynder (4354) Kosak et al. (2177)
Wright and Wynder (4284)
Wynder and Wright (4354)
1956, 1957 Rodgman (3240, 3242)
1957 Rowland (3345)
1957 Izawa et al. (1905)
1958 Clemo (767) Clemo (765)
1958 Cuzin et al. (876) Cuzin et al. (876)
1958 Rayburn and Wartman (3091) Trillat and Cuzin (3964) Rayburn and Wartman (3091)
1958 Rayburn et al. (3092) Van Duuren and Kosak (4030) Rayburn et al. (3092)
1958 Rodgman and Cook (3269) Rodgman and Cook (3269)
1958, 1959 Wynder et al. (4355, 4356)
1959 Dymicky and Stedman (1081) Carruthers and Johnstone (613)
1959 Gladding and Wright (1308) Cuzin (877)
1959, 1960 Stedman and Rusaniwskyj, (3807, 3808)
1960 Schepartz (3431) Schepartz (3431)
Kosak and Swinehart (2176)
1961 Izawa (1900)
1962 Carugno (619) Carugno (619)
1962, 1963 Spears et al. (3768)
1964, 1967 Wynder and Hoffmann (4319, 4332) Wynder and Hoffmann (4319, Wynder and Hoffmann (4319,
4332) 4332)
1965, 1966 Ivanov and Ognyanov (1893, 1893a) Osman et al. (2875). Badger et al. (142)
1966, 1967 Carugno and Rossi (625) Carugno and Rossi (625)
1967 Mokhnachev et al. (2583) Mokhnachev et al. (2583)
1968 Hoffmann and Wynder (1798) Hoffmann and Wynder (1798) Hoffmann and Wynder (1798)
1968 Schlotzhauer and Schmeltz (3465)
1970 Jenkins et al. (1935)
1974, 1975 Chortyk et al. (727) Chortyk et al. (727)
1978 Severson et al. (3608)
1979 Severson et al. (3616)
1989 Bass et al. (208)
2003 Coleman and Gordon (776)
a Most of the studies dealt with alkanes C10 and greater.

Although Zeise (4406) and Kissling (2100, 2102) reported evidence provided by Thorpe and Holmes (3914) left little
the isolation of alkane-like components from tobacco and doubt as to the presence of the alkanes in tobacco leaf. The
tobacco smoke, Kosak (2170) in his catalog of smoke com- Thorpe-Holmes report was followed by numerous descriptions
ponents classified their data as inconclusive. However, the of the isolation of alkanes from tobacco and tobacco smoke

© 2009 by Taylor & Francis Group, LLC

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 The Hydrocarbons 5

Table I.A-8
Polycyclic Aromatic Hydrocarbons from Tobacco Aliphatic Hydrocarbons Pyrolyzed in Air at Various
Temperatures
Quantity (μg) of PAH Formed on Pyrolysis (in air) of Aliphatic
Tobacco Hydrocarbons (1.0 g)
At 800°C At 700°C At 600°C
Polycyclic Aromatic Hydrocarbon PAH, µg/g PAH/ B[a]P a PAH, µg/g PAH/ B[a]P a PAH, µg/g
Naphthalene 14260 41.94 [2/5]b 4760 158.7 0
Acenaphthene 0 0 [3/5]c 0 0 0
Acenaphthylene 3520 10.35 [3/5]c 480 16.00 0
Phenanthrene 3840 11.29 [3/5]c 580 19.33 0
Anthracene 580 1.71 [3/5]c 110 3.67 0
Pyrene 960 2.82 [4/5]d 320 10.67 0
Fluoranthene 1700 5.00 [4/5]d 24 0.80 0
Chrysene 400 1.18 [4/5]d 86 2.87 0
Perylene 34 0.10 [5/5]e 4 0.13 0
Benzo[a]pyrene 340 1.00 30 1.00 0
Benzo[e]pyrene 400 1.18 [5/5]e 80 2.67 0
Dibenzo[def,mno]chrysene 42 0.12 [6/5]f <1 <0.03 0
TOTALS 26076 86.87 6474 21.47 0
a B[a]P = benzo[a]pyrene
b [2/5] = bicyclic/pentacyclic B[a]P
c [3/5] = tricyclic/pentacyclic B[a]P

d [4/5] = tetracyclic/pentacyclic B[a]P

e [5/5] = pentacyclic/pentacyc lic B[a]P

f [6/6] = hexacyclic/pentacyclic B[a]P

(see Table I.A-7 for a cross section of some of the published
reports, particularly those issued prior to the 1980s). Also
included in Table I.A-7 are references to some of the studies
in which the alkanes were investigated as PAH precursors by
pyrolysis or by “spiking” of the tobacco filler in a cigarette.
In 1934, Chibnall et al. (701) were among the first investi-
gators to report that the alkane fraction, comprising a mixture
of several individual alkanes, melted sharply over a narrow
temperature range (63.3–63.8°C), a melting point behavior
for a mixture that was contrary to the organic chemistry
teachings of the day.
From the results of studies on the pyrolysis of the “tobacco
paraffins,” which comprise the n-, iso-, and anteiso-alkanes,
it was suggested by Lam (2255–2258), Wynder et al. (4356),
Wynder and Hoffmann (4319, 4332), and Hoffmann and
Wynder (1798) that these components were the major precur-
sors in tobacco of the PAHs in tobacco smoke. However, in
1958, Rayburn and his colleagues (3091, 3092) challenged the
proposal that the tobacco alkanes were the major precursors of
the smoke PAHs, but their experimental data were not overly
conclusive in support of their challenge. Nevertheless, it should
be realized that in one sense Rayburn et al. were partly correct:
as PAH precursors, the tobacco alkanes do contribute to the
PAHs in tobacco smoke but their contribution is much less sig-
nificant than other precursors (the phytosterols and terpenoids
such as solanesol) in tobacco [cf. Wright (4282), Rodgman and
Cook, (3269, 3286), Severson et al. (3616)].
Table I.A-8, adapted from Lam (2257), demonstrates
the relationship between PAH generation and pyrolysis
temperature for aliphatic tobacco hydrocarbons (the alkanes)
pyrolyzed in air at several temperatures. Calculation of the
yield ratios [PAH µg/g:B[a]P µg/g] of the other PAHs vs. B[a]P
reveals significant information: in this simple case of pyroly-
sis, there is little consistency between the change in ratios of
PAH/B[a]P as the temperature is increased from 700°C to
800°C. For example, in the case of the tetracyclic hydrocar-
bons, the PAH/B[a]P ratio decreases for pyrene and chrysene
but increases for fluoranthene. For the pentacyclic hydro-
carbons, the ratio decreases for both perylene and benzo[e]
pyrene. For the hexacyclic hydrocarbon dibenzo[def,mno]
chrysene, the ratio increases. These same trends exist whether
the PAH/B[a]P ratios are calculated in terms of molar yields
or, as in Table I.A-8, in terms of the absolute quantities
(micrograms of PAH generated per gram of aliphatic tobacco
hydrocarbons pyrolyzed). The significance of these data and
calculations is their demonstration in 1956 that in even the
simplest pyrolysis situation,* B[a]P is not a valid “indicator”
or “marker” for the PAHs with four or more rings and/or their
* For several decades, Wynder, Hoffmann, and some other investigators
asserted that the fate of a given tobacco component during inert atmo-
sphere pyrolysis was equivalent to its fate in the oxygen-deficient (but not
oxygen-free) atmosphere in the tobacco rod during the cigarette smoking
process [see Wynder and Hoffmann (4320, 4332), Hoffmann and Wynder
(1798)]. At the same time, many other investigators maintained that the
two processes were not equivalent. Hoffmann and colleagues demon-
strated in 1979 with radiolabeled nicotine that the two processes were not
equivalent, and they suggested that this nonequivalence observed for the
fate of nicotine was applicable to the fate of other tobacco components
(3512).

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 5 11/13/08 6:40:29 PM

 6 The Chemical Components of Tobacco and Tobacco Smoke
supposed relationship to tumorigenic activity as suggested
by Wynder and Hoffmann (4317, 4320, 4332). In addition to
these data by Lam, other contrary data that demonstrated
the invalidity of the concept of B[a]P as an “indicator” or
“marker” for PAHs with four or more rings and the tumori-
genicity of the substrate (CSC, pyrolysate, etc.) containing
them were generated not only in studies by Wynder et al.
(4355, 4356), but also in studies by Campbell and Lindsey
(583), Rodgman (3240), Rodgman and Cook (3269, 3286),
Gori (1329, 1330, 1332, 1333), the National Cancer Institute
(2683), and Severson et al. (3616).
When used as a solvent for B[a]P in mouse skin-painting
tests, the C10, C12, or C16 n-alkanes—although noncarcinogenic
per se in this bioassay—were reported by Horton et al. (1835)
to accelerate the tumor-producing capability of B[a]P and 1,2-
dihydro-3-methylbenz[j]aceanthrylene (3-methylcholanthrene).
Horton et al. reported that n-octane, the C8 alkane, did not
exhibit this property. The acceleration finding of the C10, C12,
or C16 n-alkanes was incorporated by Carruthers and Johnstone
(613) into an explanation of why the percent of tumor-bearing
animals (% TBAs) was much greater in mice painted with CSC
than could be predicted by the levels of tumorigenic polycyclic
hydrocarbons in the CSC. They extrapolated the finding of this
property of the C10, C12, and C16 n-alkanes to the longer chained
homologs in cigarette smoke.
In contrast, however, to the findings of Horton et al. (1835),
Wynder and Hoffmann (4314, 4319, 4332) reported that the
specific tumorigenicity of B[a]P in mouse skin-painting
experiments was significantly “inhibited” when it was admin-
istered with the individual alkanes n-hentriacontane (C31H64)
or n-pentatriacontane (C35H72) and the ratio of the alkane:
B[a]P was either 200:1 or 100:1. These ratios are much less
than those encountered in CSC. Wynder and Hoffmann also
reported that increasing the level of the alkane fraction in
the applied CSC from 3% to 4% (a 33% increase) resulted
in a decrease (from 40% to 24%) in the % TBAs after 19
TABLE I.A-9
Ratios for Individual Polycyclic Aromatic Hydrocarbons in Gasoline Engine Exhaust
“Tar” (EET) and Cigarette Smoke Condensate (CSC)
Polycyclic Aromatic Ratio
Hydrocarbon PAHEET:PAHCSC
Benz[a]anthracene 600:1
Benz[a]anthracene, alkyl- >10:1
Benz[e]acephenanthryleneb 640:1
Benzo[ghi]fluoranthene 1500:1
Benzo[j]fluoranthene 85-110:1
Benzo[k]fluoranthene 200-360:1
11H-Benzo[b]fluorene 100:1
Benzo[ghi]perylene 255-340:1
Chrysene 87-115:1
Chrysene, alkyl- a 33-45:1
Dibenz[a,h]anthracene 17-25:1
a Similar to 5-methylchrysene
b Formerly known as benzo[b]fluoranthene
c Formerly known as anthanthrene
© 2009 by Taylor & Francis Group, LLC
78836_C001.indd 6
months and a decrease (from 24% to 18%) of % TBAs with
malignant tumors. Surprisingly, Wynder and Hoffmann did
not consider these decreases significant! These alkane-B[a]
P data, originally presented at an American Association for
Cancer Research meeting (4314), did not appear in any jour-
nal but were included in the Wynder-Hoffmann review (4319)
and book (4332) on tobacco smoke carcinogenesis.
Although they did not catalog their bioassay findings from
the alkane-B[a]P experiments in their extensive tabulation
of the induction of carcinoma in skin-painting studies with
tobacco products [see pp. 330–331 in (4319) and pp. 370–371
in (4332)], Wynder and Hoffmann offered the following
explanation for the result observed:
The effect of alkanes may not be inhibitory to tumorigenic-
ity but rather a consequence of having influenced resorp-
tion. The tumor response data of these experiments clearly
express a delay of tumor appearance, a result that we believe
to be due to the retarding effect of the n-alkanes.
Earlier, Wynder and Wright (4354) had reported that the
slight tumorigenicity observed with an alkane fraction of
tobacco smoke condensate in a mouse skin-painting bioas-
say was due not to the alkanes per se but to trace amounts of
PAHs in the alkane fraction.
In later experiments with gasoline engine exhaust “tar”
vs. CSC, the observed tumorigenicities observed by Wynder
and Hoffmann (4315) did not parallel the levels of the PAHs
considered to be the major contributors to the observed skin
tumors. To explain the difference (and the less than antici-
pated tumorigenicity of the exhaust “tar”), the authors attrib-
uted the depressed tumorigenicity of the exhaust “tar” not
only to alkanes but also to nontumorigenic PAHs present in
engine exhaust “tar” at levels far in excess of those of the tum-
origenic PAHs such as B[a]P and DB[a,h]A (see Table I.A-9).
Although the ratios are not as great for CSC as for exhaust
“tar,” it should be noted that the levels of nontumorigenic
Polycyclic Aromatic Ratio
Hydrocarbon PAHEET:PAHCSC
Dibenzo[def,mno]chrysenec >440:1
Benzo[a]pyrene 45:1
Benzo[a]pyrene, alkyl- >10:1
Benzo[e]pyrene 4200:1
Fluoranthene 275-390:1
Fluoranthene, alkyl- 230-275:1
Indeno[1,2,3-cd]pyrene >80:1
Indeno[1,2,3-cd]fluoranthene >30:1
Pyrene 500-700:1
Pyrene, alkyl- 3-4:1
Triphenylene 4400:1
11/13/08 6:40:30 PM
 The Hydrocarbons
(and antitumorigenic) PAHs in CSC far exceed those of the
tumorigenic PAHs. Wynder and Hoffmann (4315) summa-
rized their findings as follows:
It was anticipated that the … exhaust gas “tar” and nicotine
would be many times more active than tobacco smoke con-
densate. However, … it is only approximately twice as active.
This relatively small increase in biological activity of exhaust
gas “tar” raises the question of possible anticarcinogenic fac-
tors that may be more prevalent in engine exhaust “tar” … one
may theorize that some of the noncarcinogenic polynuclear
hydrocarbons that are present in engine exhaust gas “tar” in
far greater concentrations than in tobacco smoke condensate
may interfere with the resorption of the “tar.” Some of the oily
materials in gasoline engine exhaust “tar” and the paraffins in
tobacco smoke condensate may also act as anticarcinogens.
In their comparison of the composition of the alkane frac-
tion in a reference tobacco (University of Kentucky 1R1) and
its cigarette MSS, Chortyk et al. (727) reported that “the ratio
among the constituents in leaf paraffins is almost identical
[with] the ratio among the smoke paraffins.” They interpreted
this finding as suggesting the paraffins undergo little pyrolytic
degradation during the smoking process. Although octatria-
contane has not been identified in either tobacco or tobacco
smoke, Bass et al. (208) employed [18-14C]octatriacontane to
study its transfer to cigarette smoke. Their findings with this
alkane agreed with those of Chortyk et al. (727) on the series
of alkanes in tobacco and their transfer to smoke and with
those of Jenkins et al. (1935) on the transfer of [16,17-14C]
dotriacontane from tobacco to smoke.
Table I.A-10 lists the alkanes identified in mainstream
tobacco smoke. The citations do not necessarily include
every reference to the identification or discussion of a par-
ticular alkane.
I.B THE ALKENES AND ALKYNES
In his summary of the identified components of tobacco
smoke, Kosak (2170) listed only one unequivocally identi-
fied alkene or alkyne. It was ethyne (acetylene). Johnstone
and Plimmer (1971) listed the following alkenes and alkynes
identified in tobacco smoke: cis- and trans-butene, 1,3-buta-
diene, methyl-1,3-butadiene (isoprene), ethene, ethyne, meth-
ylethyne, propene, methylpropene, squalene and isosqualene,
and several phytadienes. Less than a decade later, Stedman
(3797) described and/or discussed nearly 235 acyclic alk-
enes and alkynes identified in tobacco smoke. This number
includes the cis and trans isomers in the homologous mono-
alkene series discussed below.
In Table I.B-1 are listed the nearly 330 acyclic alkenes and
alkynes in tobacco smoke whose identifications have been
reported to date.
The lower molecular weight acyclic unsaturated hydrocar-
bons (alkenes, alkadienes, alkynes, etc.) occur primarily, if not
totally, in the vapor phase of mainstream smoke (MSS). Even
though some of the vapor-phase components of cigarette MSS
have been shown to be significant in vitro ciliastats, the low
© 2009 by Taylor & Francis Group, LLC
78836_C001.indd 7
7
molecular weight hydrocarbons (alkanes, alkenes, alkynes)
were not considered by Caroff et al. (604, 605) to be involved
because of their low concentrations in the smoke. The smoke
components (aldehydes, ketones, hydrogen cyanide, formic and
acetic acids, phenol) reported to be significant in vitro ciliastats
are relatively highly water-soluble, whereas the low molecu-
lar weight hydrocarbons, generally considered non-ciliastatic
in in vitro systems, show extremely low solubility in water.
Rodgman et al. (3306) and Dalhamn et al. (892, 893) described
the differences in oral absorption of the tobacco smoke com-
ponents isoprene (20%) vs. acetaldehyde (60%) or acetone
(56%). It has also been noted by Wynder and Hoffmann (4332)
that these compounds do not appear to play a significant role
in tobacco smoke carcinogenesis: “Their [the alkenes] level in
the smoke is rather low (0.01%) and they would, therefore, not
be active even if they were tumor promoters.”
In the National Cancer Institute study on the “less haz-
ardous” cigarette, which involved chemical and biological
(mouse skin-painting bioassay) studies on four series* (1329,
1330, 1332, 1333) of experimental cigarettes and appropri-
ate controls, an interesting correlation was reported with the
first series of cigarettes (1329): although no correlations were
observed between the benzo[a]pyrene (B[a]P) content or the
benz[a]anthracene (B[a]A) content of the cigarette smoke
condensate (CSC) and the percent of tumor-bearing ani-
mals (% TBA), a correlation— classified as significant—was
observed between the isoprene content of the MSS and the %
TBA. This observed isoprene-% TBA correlation was heat-
edly discussed and debated for the following year. In the sec-
ond, third, and fourth series of cigarette, the isoprene-% TBA
correlation was not observed, that is, it had disappeared! It
should be noted that the manipulations involved in the col-
lection and preparation of the CSCs for the bioassay virtually
preclude the presence of isoprene in the material applied to
the host animals.
In its review of smoke composition and the relationship
between smoke components and health, the International
Agency for Research on Cancer (IARC; 1870) devoted very lit-
tle space to the volatile acyclic hydrocarbons and just two para-
graphs to the nonvolatile members of this compound group.
Among the alkenes listed as tobacco smoke components
are several series of isomeric isoprenoid compounds, includ-
ing the phytadienes (3247), the solanesenes (3297), and the
squalenes (2175, 3297, 4033), plus several homologous series
of monoalkenes (1144).
A series of phytadiene isomers with a pair of conjugated
double bonds in different internal and terminal positions
were identified in the MSS from cigarettes containing the
American blend (3247). Similar series of phytadienes were
identified in the MSSs from cigarettes containing individual
tobaccos (flue-cured, burley, Oriental). The evidence indi-
cated the presence of at least the following four basic combi-
nations of the conjugated linkages within an isoprenoid unit
* The four series of cigarettes involved a total of 98 test cigarettes and about
30 reference (Kentucky Reference 1R1) and standard cigarettes, divided
almost equally among the four series.
11/13/08 6:40:31 PM
 8 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.A-10
Alkanes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.




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© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 8 11/13/08 6:40:34 PM

 The Hydrocarbons 9

TABLE I.A-10 (CONTINUED)

Alkanes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 9 11/13/08 6:40:36 PM

 10 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.A-10 (CONTINUED)

Alkanes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke.

1561-00-8

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 10 11/13/08 6:40:38 PM

 The Hydrocarbons 11

TABLE I.A-10 (CONTINUED)

Alkanes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(%)





&&


&
$
'(

&##*!,
%.
&&
)$&"


&&
)+)*!*+*

)$&"








  


'*%

 




 




 



 

 








 



'*%
!$* /#
 







'*%
!$* /#




  


'*%
$* /#



 

 




 


 


'*%

* /#



 
 




 
 




'*%

$* /#



 
 




 

 




'**(!&%*%






 








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.&)%
$* /#




 









  


 

  


.&)%

$* /#






 



 
  



 



.%


 




 

 

 







 

 



 











 















 


 

 

  


.%
$* /#


 
 
 



 





.%

$* /#

 



  
 







.%
 **($* /#
  
 












0' /*%1

 


.%
$!.*+(
-!*
'%*%

 







.%


 

 





 






 







 
 













 




 

 




 








 



 





 






 
 

 

 


.%
!$* /#






 



  




.%
!$* /#






 
 

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 11 11/13/08 6:40:41 PM

 12 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.A-10 (CONTINUED)

Alkanes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

!"!+!(!,





))


)
'!
*!+

)&&!-$/!
( !0
))
,')%!


))
,.,-$-.-!

,')%!








 



!0(!
 $'!-#1&









 





!0(!

'!-#1&




 
 




 
  





!0(!
 -!-+'!-#1&

 






  





 

!0-+$)(-(!


 
 













 


 

 





 

 


!-#(!






 
 


 






 






 
 
 

  





 






 
 







 

 
 
 
 


 
 
 
 


 











 




 


 




 
 






 

 















 


 



 






 










 
 
 
 




 
 








)(),(!





 
 


 
 







  













 







 
 
 




 









 
 





   



 















 









 








 











 


 
 




 


)(),(!
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)((!
'!-#1&


© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 12 11/13/08 6:40:43 PM

 The Hydrocarbons 13

TABLE I.A-10 (CONTINUED)

Alkanes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

 ! * ' +





((


(
&
) *

(%% ,#.
' /
((
+&($


((
+-+,#,-,

+&($










(',*#(','






 




 


,(+'





 




 








  










 









 
 
 



 








 
 
   









 














 


 








 











 


 
 




 


,(+' 
& ,"0%



 









 






   



 



 






 
   













 

 


 





 


,(+' 

& ,"0%




 











 
  





 












, '


 


 


 


 




  

 



 
 





   






 






 


 
 
 

 

, ' 
& ,"0%


 



 




, ' 

& ,"0%

 



 
 


 

,'






 



 



  




,' 
#& ,"0%
 



  






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& ,"0%

 

 






 


,' 
& ,"0%







,,*#(','










 






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& ,"0%


 



 


 



  


 



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& ,"0%

 
 



 
  

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 13 11/13/08 6:40:45 PM

 14 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.A-10 (CONTINUED)

Alkanes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

 )&*





''


'
%
()

'$$+"-
&.
''
*%'#


''
*,*+"+,+

*%'#








 


&+&


 


 


 









 




 

















 





 









 



 

 


&+&
%+!/$

 
 
 



  


  


&+&

%+!/$

 
 
 



 
 


 


&+&
 ++)%+!/$

  


 



























































0()"*+&1


 


&+&
 +)"%+!/$

0&')()"*+&1
  
 



 


&+&


 
 









 



 








 








 

 


 



 







 





 


  


&+&


"+!/$

 
 



 




&+&
"%+!/$



 
 






 








&+&
%+!/$



 








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%+!/$













  


 
 
 



 
 


 

 



 


 

 


&+&

%+!/$

 


 
 






  

 


 
 



 

 



 



 





&++)"'&+&


 




 
 
 






 



 















 







 







 



&++)"'&+&
%+!/$






 



  



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%+!/$




 



 
 






)'(&


 













 

 



 
 









 

 
 








 



 
 

 









 



 




 

 












 

 




 

 









 
 



 
 





© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 14 11/13/08 6:40:48 PM

 The Hydrocarbons 15

TABLE I.A-10 (CONTINUED)

Alkanes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

 )&*





''


'
%
()

'$$+"-
&.
''
*%'#


''
*,*+"+,+

*%'#








 


)'(&
%+!/$





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+)'&+&

 




 



 



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+)'*&
%+!/$




 


 


+)'*&
%+!/$





 




  




+)'*&

%+!/$





 



 
  





+)&


 


 
 








 


  

 
  


 












 







 







 



 


  

+)&
%+!/$

 



 




+)&

%+!/$

 



 
 


 

+)&
 +)"%+!/$




 


+)+)"'&+&




 




 

 






 


 
 
 




 









 


 










 







 





  


+)+)"'&+&
%+!/$

 
 
 








 






 



 





+)+)"'&+&

%+!/$

 
 
 



 





 
 




 


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%+!/$



 







 








  



 



 







 
 
 
 







 







 


 




(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 15 11/13/08 6:40:50 PM

 16 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.A-10 (CONTINUED)

Alkanes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

 )&*





''


'
%
()

'$$+"-
&.
''
*%'#


''
*,*+"+,+

*%'#










)"'&+&

%+!/$




 
 










 
  







 





 


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)"'*&
%+!/$

 
 








  






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%+!/$





 



 
 









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)"&
%+!/$

 



 




)"&

%+!/$

 



 
 






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%+!/$

 
 







 





  












 





 

  


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© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 16 11/13/08 6:40:53 PM

 The Hydrocarbons 17

TABLE I.B-1
Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke
Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 17 11/13/08 6:40:54 PM

 18 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.B-1 (CONTINUED)

Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 18 11/13/08 6:40:55 PM

 The Hydrocarbons 19

TABLE I.B-1 (CONTINUED)

Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 19 11/13/08 6:40:57 PM

 20 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.B-1 (CONTINUED)

Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 20 11/13/08 6:41:05 PM

 The Hydrocarbons 21

TABLE I.B-1 (CONTINUED)

Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 21 11/13/08 6:41:09 PM

 22 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.B-1 (CONTINUED)

Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 22 11/13/08 6:41:12 PM

 The Hydrocarbons 23

TABLE I.B-1 (CONTINUED)

Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 23 11/13/08 6:41:14 PM

 24 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.B-1 (CONTINUED)

Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 24 11/13/08 6:41:17 PM

 The Hydrocarbons 25

TABLE I.B-1 (CONTINUED)

Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 25 11/13/08 6:41:19 PM

 26 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.B-1 (CONTINUED)

Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 26 11/13/08 6:41:21 PM

 The Hydrocarbons 27

TABLE I.B-1 (CONTINUED)

Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 27 11/13/08 6:41:24 PM

 28 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.B-1 (CONTINUED)

Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 28 11/13/08 6:41:27 PM

 The Hydrocarbons 29

TABLE I.B-1 (CONTINUED)

Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 29 11/13/08 6:41:29 PM

 30 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.B-1 (CONTINUED)

Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 30 11/13/08 6:41:32 PM

 The Hydrocarbons 31

TABLE I.B-1 (CONTINUED)

Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 31 11/13/08 6:41:34 PM

 32 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.B-1 (CONTINUED)

Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 32 11/13/08 6:41:37 PM

 The Hydrocarbons 33

TABLE I.B-1 (CONTINUED)

Alkenes and Alkynes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 33 11/13/08 6:41:39 PM

 34 The Chemical Components of Tobacco and Tobacco Smoke

or between contiguous units: Phytadienes I to IV with the potential to generate anthraqui-

nonecarboxylic acids in the reaction sequence described are
CH3 CH2
shown in Figure I.B-1. Phytadienes I, II (n = 3), and IV can
{  exist as cis and trans isomers. The remaining phytadienes in
-CH=C-CH=CH- =CH-C-CH2-CH2- Figure I.B-1 can exist as cis cis, cis trans, trans cis, and trans
CH2 CH3 trans isomers. In Figure I.B-2 are shown the phytadienes (V,
VI) that do not appear to form Diels-Alder adducts.
 {
As noted previously, even if they did form the Diels-Alder
-CH2-C-CH=CH- =CH-C=CH-CH2- adducts, they would not yield alkylanthraquinones because
of the absence of hydrogen atoms at the 1- and/or 4-posi-
The mixture of smoke phytadienes was separated into
tions. Figure I.B-1 also summarizes the various anthraqui-
groups of phytadienes by alumina column chromatography.
nonecarboxylic acids which could arise from the phytadienes
Because Rowland (3345) had used the Diels-Alder reaction
of neophytadiene with 1,4-naphthoquinone to great advantage depicted.
in its characterization, this same reaction sequence was used In their study of the smoke from British cigarettes, Johnstone
in the phytadiene study. Treatment of each phytadiene frac- and Quan (1973) reported that at least 99% of the acyclic phyta-
tion with 1,4-naphthoquinone gave Diels-Alder adducts which dienes comprised neophytadiene. They made no comment on the
were converted to anthraquinonecarboxylic acids by sequen- presence of phytadiene isomers in the remaining 1%. Since no
tial oxidations, first to alkylanthraquinones and then to car- quantitative data were provided by Rodgman (3247) in his study
boxylic acids. The number and positions of the carboxyl groups of the phytadiene isomers in tobacco smoke, comparisons of the
permitted assignment of the conjugated double bonds in the two investigations are not possible. The Johnstone-Quan study
phytadiene. The phytadiene series contained 3-methylene-7,11, involved the study of tobacco smoke from flue-cured tobacco
15-trimethyl-1-hexadecene (neophytadiene), 3,7,11,15-tetram- cigarettes, whereas the Rodgman study involved smoke from
ethyl-1,3-hexadecadiene, 2,6,10,14-tetramethyl-1,3-hexadeca- cigarettes containing a cased American blend (flue-cured, burley,
diene, a 1,2,4-trialkyl-1,3-butadiene, and possibly as many as Oriental, and Maryland tobaccos).
nine other conjugated phytadienes (excluding cis and trans iso- Because of the similarities among the infrared absorp-
mers). No evidence was obtained to indicate that six of the pos- tion spectra of the gross phytadiene fraction in cigarette
sible isomeric conjugated phytadienes were present in MSS. MSS (3247), the mixture of phytadiene isomers described by
They may have either been unreactive in the Diels-Alder reac- Rowland (3345), and the mixture of phytadienes generated by
tion with 1,4-naphthoquinone or, if reactive, gave an adduct heating neophytadiene (180ºC, 2.5 h), Rodgman suggested
that was not oxidizable to an alkylanthraquinone. that the isomeric conjugated phytadienes in tobacco smoke
The several groups of possible conjugated phytadienes are resulted from thermal isomerization of neophytadiene during
more completely defined in structures I through VI: the smoking process. However, as Lam et al. (2260) suggested,
CH3 CH2 CH3
e  e
H[CH2-CH-CH2-CH2]n-CH2-C-CH=CH-[CH2-CH-CH2-CH2]3-n-H
I
CH3 CH3 CH3
e e e
H[CH2-CH-CH2-CH2]n-CH=C-CH=CH-[CH2-CH-CH2-CH2]3-n-H
II
CH3 CH3 CH3 CH3
e e e e
H[CH2-CH-CH2-CH2]m-CH2-CH-CH2-CH=CH-C=CH-CH2-[CH2-CH-CH2-CH2]2-m-H
III
CH3 CH3 CH2 CH3
e e e e
H[CH2-CH-CH2-CH2]m-CH2-CH-CH2-CH=CH-C-CH-CH2-[CH2-CH-CH2-CH2]2-m-H
IV
CH3 CH3 CH3 CH3
e e e e
H[CH2-CH-CH2-CH2]m-CH2-CH-CH=CH-CH=C-CH2-CH2-[CH2-CH-CH2-CH2]2-m-H
V
CH3 CH3 CH3 CH3
e e e e
H[CH2-CH-CH2-CH2]m-CH2-C=CH-CH=CH-CH-CH2-CH2-[CH2-CH-CH2-CH2]2-m-H
VI

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 34 11/13/08 6:41:40 PM

 The Hydrocarbons 35

I, n = 3a III, m = 2d

I, n = 2b III, m = 1d

I, n = 1b III, m = 0d

I, n = 0b IV, m = 2b
II, n = 0b

II, n = 3c IV, m = 1b

II, n = 2d IV, m = 0b

II, n = 1d
LEGEND
aYields anthraquinone-2-carboxylic acid.
bYields anthraquinone-1,3-dicarboxylic acid.
cYields anthraquinone-1,2-dicarboxylic acid.
dYields anthraquinone-1,2,4-tricarboxylic acid.

FIGURE I.B-1 Phytadienes with potential to yield Diels-Alder adducts and subsequently alkylanthraquinones and anthraquinonecarboxylic
acids.

it is highly possible that the various phytadienes may be gener-
ated during the smoking process from phytol or phytyl esters
in the tobacco. VanDeMeent et al. (4015) reported that chloro-
phyll-bound phytol yielded several phytadienes when various
geological materials containing chlorophylls were pyrolyzed
at 610ºC. Lam et al. (2260) reported the presence of at least
five different phytadienes in a pyrolysate from phytol heated at
550°C. Neither VanDeMeent et al. nor Lam et al. described the
structures of the phytadienes they had identified.
Another series of isoprenoid hydrocarbons isolated from
cigarette MSS by Rodgman et al. (3297) comprised the solane-
sol-related solanesenes. Dehydration of solanesol or pyrolysis
of solanesyl acetate yields a mixture of solanesenes similar to
that isolated from cigarette MSS. VII and VIII are the major
components of the solanesene mixture in tobacco smoke.
CH2 CH3
 e
R-CH2-C-CH=CH2 R-CH=C-CH=CH2
VII VIII
CH3
e enriched fraction did not significantly alter its sebaceous
where R = H-[CH2-C=CH-CH2]8-
Sodium-alcohol reduction of the mixture gave dihydroso-
lanesene whose infrared spectrum vs. that of the solanesenes
was consistent with the migration of the terminal double bond
to an internal position. The Diels-Alder reaction sequence used
by Rowland (3345) in the characterization of neophytadiene
from tobacco and the various phytadienes in cigarette MSS by
Rodgman (3247) was applied to the solanesene mixture. It pro-
vided confirmatory evidence for the presence of the solanesene
VII: reaction of the isolated solanesene mixture with 1,4-naph-
thoquinone, followed by air oxidation of the adduct, apparently
yielded a single 2-alkylanthraquinone rather than the anticipi-
tated mixture of 2-alkyl- and 1,2-dialkylanthraquinones. Only
anthraquinone-2-carboxylic acid was isolated and identified as
a product of the alkylanthraquinone-to-anthraquinonecarbox-
ylic acid oxidation. The failure to demonstrate the presence
of anthraquinone-1,2-dicarboxylic acid was attributed to the
inertness of solanesene VIII in the Diels-Alder reaction.
Wynder and Hoffmann (4319) reported that the phyta-
dienes did not produce hyperplasia or destroy sebaceous
glands when applied to mouse skin. They also reported
(4316) that removal of terpenoid hydrocarbons such as the
phytadienes from a polycyclic aromatic hydrocarbon (PAH)-
gland suppression. From this result they concluded that “the

V, m = 2 VI, m = 2

V, m = 1 VI, m = 1

V, m = 0 VI, m = 0

FIGURE I.B-2 Phytadienes with little or no potential to form Diels-Alder adducts.

© 2009 by Taylor & Francis Group, LLC

78836_C001.indd 35 11/13/08 6:41:42 PM

 36
terpenes may not contribute significantly to the tumorigenic
activity of tobacco smoke.”
Entwhistle and Johnstone (1144) described six homologous
series of monoalkenes isolated from tobacco smoke, includ-
ing all of the possible cis and trans isomers. They reported
the total delivery of these series in cigarette MSS to be about
3 μg/cigarette. These series did not appear to be present
in tobacco leaf. Their precursors in tobacco have not been
defined. However, Carruthers and Johnstone (614) earlier had
reported that long-chained alkenes in tobacco smoke did not
result from the dehydration of the corresponding alcohol dur-
ing the smoking process.
Monoalkene Series n=
H2C=CH-(CH2)n-CH3 7 through 25
H2C=C(CH3)-(CH2)n-CH3 9 through 28
CH3-CH=CH-(CH2)n-CH3 a 9 through 28
CH3-C(CH3)=CH-(CH2)n-CH3 8 through 27
CH3-CH=CH-(CH2)n-CH=(CH3)2 a 7 through 26
CH3-CH=CH-(CH2)n-CH(CH3)-CH2-CH3 a 6 through 25
a cis and trans isomers
Rodgman et al. (3294) described the composition of an
aliphatic ester fraction isolated from MSS generated by cig-
arettes fabricated from an American tobacco blend, burley
tobacco, or Oriental tobacco. Aliphatic ester fractions almost
identical with those from the smokes were also isolated from
flue-cured tobacco, burley, and Oriental tobaccos. With
the analytical technology available in the early 1960s, the
aliphatic ester fraction was shown to consist of a series of
esters whose alcohol moiety varied from 1-dodecanol (C12) to
1-heptacosanol (C27), inclusive. The acid moiety ranged from
tetradecanoic acid (C14) to octacosanoic acid (C28), inclusive,
plus the C18 unsaturated acids, oleic and linolenic.
More than two decades later, Arrendale et al. (103)
extended the identification of the components of the aliphatic
ester fraction from tobacco. The alcohol moiety ranged from
1-hexadecanol (C16) to 1-tetratriacontanol (C34). Esters with
1-hentriacontanol and 1-tritriacontanol as the alcohol moi-
eties were not detected. The acid moiety ranged from dode-
canoic acid (C12) to dotriacontanoic acid (C32). An ester with
hentriacontanoic acid as the acid moiety was not detected. For
a given number of carbons, the acid moiety not only included
the normal acid but also in several cases included the iso and/
or anteiso acid, for example, esters were identified with n-,
iso-, and anteiso-pentadecanoic acid as the acid moieties.
Even though Arrendale et al. (103) limited their study to
an ester fraction isolated from tobacco, it seems logical to
assume, based on the findings of Rodgman et al. (3294) on
the equivalence of the aliphatic ester fractions isolated from
various smokes and tobaccos, that each ester identified by
Arrendale et al. would appear in tobacco smoke.
Controlled thermal degradation of higher molecular weight
aliphatic esters generates an alkene and an acid (950c, 3294).
© 2009 by Taylor & Francis Group, LLC
78836_C001.indd 36
The Chemical Components of Tobacco and Tobacco Smoke
Thermal degradation during the smoking process of the ali-
phatic esters identified in tobacco could conceivably yield
some of the alkenes in the series described by Entwhistle and
Johnstone (1144).
R-CH2-CH2-OOC-R1 l R-CH=CH2 + R1-COOH
2,6-Dimethyl-2,4,6-octatriene (alloöcimene) was reported
by Wynder and Hoffmann (4316) as a significant tobacco
smoke component (0.5% of CSC) with cocarcinogenic activ-
ity. However, Mold et al. (2597) presented contradictory data
which indicated that if 2,6-dimethyl-2,4,6-octatriene were
present in smoke, its level was less than 0.006%.
I.C THE ALICYCLIC HYDROCARBONS
The cyclic aliphatic hydrocarbons in tobacco and tobacco
smoke include compounds whose ring sizes range from cyclo-
propane through cyclooctane, cyclononane, cycloundecane,
and cyclotetradecane. Theoretically, cyclooctatetraene could
be included in the listing of monocyclic aromatic hydrocar-
bons. Numerous hydrocarbons with cyclopentane and cyclo-
hexane rings were reported as tobacco and tobacco smoke
components in the late 1950s through the mid-1960s (see
Table I.C-1). Tobacco smoke hydrocarbons with a cyclobu-
tane ring were reported by Stedman in 1963 (3795). Three
dimethylcyclopropanes were reported in 1970 by Bartle and
Novotny (200). 1,3,5-Cycloheptatriene and cyclooctatetraene
were reported by Enzell et al. (1154) and Mauldin (2506),
respectively. A hydrocarbon with the cycloheptatriene ring
had been reported previously as a tobacco smoke component
in 1947 by Ikeda (1857): the bicyclic aromatic hydrocarbon
azulene, an isomer of naphthalene.
Several fused-ring alicyclic hydrocarbons obviously
derived from tobacco sterols were reported in 1989 in tobacco
smoke by Benner et al. (273).
In addition to a low level of cholesterol {1a}, tobacco
usually contains substantial levels of several phytosterols
[campesterol {Ib}, B-sitosterol {Ic}, stigmasterol {Id}, ergos-
terol {1e}] structurally similar to cholesterol. These phytos-
terols differ slightly from cholesterol in the structure of the
long side chain (Figure I.C-1). They are present in tobacco
in both the free and bound form (as glycosides, esters, etc.),
and they are transferred as such to mainstream smoke (MSS).
The sterols constitute about 0.2% of the tobacco weight. As
shown in Figure I.C-1, pyrolysis of cholesterol {Ia} yields
chrysene {III}, Diels hydrocarbon {IV}—a methylcyclopen-
taphenanthrene—and numerous other polycyclic aromatic
hydrocarbons (PAHs). Both PAHs noted have also been
identified in pyrolysates of the major tobacco phytosterols
[Wynder et al. (4356), Van Duuren, (4022)]. While none of
the sterols {Ia-Ie} has been shown to generate the potent tum-
origen 1,2-dihydro-3-methylbenz[j]aceanthrylene (3-methyl-
cholanthrene) on pyrolysis, Falk et al. (1171) reported that
cholesterol and cholesterol esters do generate the mouse-
skin tumorigens 4-cholesten-3-one {Va} and 3,5-cholesta-
diene {VIa}. Veldstra (4042a) reported that the pyrolysis
of cholesteryl oleate also yielded 3,5-cholestadiene {VIa}.
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 The Hydrocarbons 37

TABLE I.C-1
Alicyclic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke
Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

(Continued )

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 38 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.C-1 (CONTINUED)

Alicyclic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Hydrocarbons 39

TABLE I.C-1 (CONTINUED)

Alicyclic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 40 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.C-1 (CONTINUED)

Alicyclic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Hydrocarbons 41

TABLE I.C-1 (CONTINUED)

Alicyclic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 42 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.C-1 (CONTINUED)

Alicyclic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Hydrocarbons 43

TABLE I.C-1 (CONTINUED)

Alicyclic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 44 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.C-1 (CONTINUED)

Alicyclic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Hydrocarbons
TABLE I.C-1 (CONTINUED)
Alicyclic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke
Cholesteryl oleate was probably a component of the mixture
of steryl esters described in flue-cured tobacco by Rowland
and Latimer (3358) and in tobacco smoke by Rodgman
et al. (3296). The steryl esters included sterols esterified with
a series of saturated (palmitic, stearic, etc) and unsaturated
(oleic, linoleic, etc.) acids.
In the late 1950s to early 1960s, Rodgman proposed that
the tobacco phytosterols—campesterol, B-sitosterol, stigmas-
terol, and ergosterol—might generate compounds analogous
to those generated from cholesterol, that is, 4-campesten-3
-one {Vb}, 3,5-campestadiene {VIb}, B-4-sitosten-3-one
{Vc}, 3,5-sitostadiene {VIc}, 4-stigmasten-3-one {Vd}, 3,5-
© 2009 by Taylor & Francis Group, LLC
78836_C001.indd 45
45
stigmastadiene {VId}, ergosten-3-one {Ve}, 3,5-ergostatriene
{VIe}on thermal degradation of these tobacco phytosterols or
their esters during the smoking process. These campesterol-,
B-sitosterol-, stigmasterol- and ergosterol-related compounds
might also be mouse-skin tumorigens as are their choles-
terol counterparts. For nearly a decade, Rodgman and Cook
(3286) were unsuccessful in their periodic efforts to isolate
any of these steryl ketones or dienes from cigarette smoke
condensate (CSC) and identify them. However, Benner
et al. (273) did subsequently identify two of these 3,5-dienes,
3,5-campestadiene {VIb} and 3,5-stigmastadiene {VId}, in
tobacco smoke, see also Eatough et al. (1099, 1100).
11/13/08 6:42:08 PM
 46 The Chemical Components of Tobacco and Tobacco Smoke

LEGEND
Sterol, R=
CH3 R Ia cholesterol -(CH2)3-CH(CH3)2
CH3
CH3 Ib campesterol -(CH2)2-CH(CH3)-CH(CH3)2
Ic β-sitosterol -(CH2)2-CH(C2H5)-CH(CH3)2
CH3 Id stigmasterol -CH=CH-CH(C2H5)-CH(CH3)2
Ie ergosterola -CH=CH-CH(CH3)-CH(CH3)2
H3C II 1,2-dihydro-3-methylbenz[j]aceanthrylene
IV O
(3-methylcholanthrene)
CH3 R V R
CH3
CH3 CH3 III chrysene IV Diels hydrocarbon
CH3
Va 4-cholesten-3-one VIa 3,5-cholestadiene
CH3 CH3 Vb 4-campesten-3-one VIb 3,5-campestadiene
Vc β-4-sitosten-3-one VIc β-3,5-sitostadiene
Vd stigmasten-3-one VId 3,5-stigmastadiene
Ve ergostadien-3-one VIe 3,5,7-ergostatriene
HO
II a
I VI Ergosterol has a double bond at the 7-position

III

FIGURE 1.C-1 Possible sterol degradation products.

Johnstone and Quan (1973) reported that flue-cured
tobacco smoke contains several hydrocarbons related to
neophytadiene: An aliphatic acyclic hydrocarbon nor-
phytene (2,6,10,14-tetramethyl-1-pentadecene) and the four
alicyclic hydrocarbons {VII-X, Figure I.C-2} that are dimers
of neophytadiene. These dimers are identical with the
major products generated when neophytadiene is heated at
190 to 200°C. The dialkylethenylcyclohexenes {IX and X}
were a small proportion of the mixture. The more plenti-
ful pair {VII and VIII} each absorbed two equivalents of
hydrogen to form saturated hydrocarbons and were readily
dehydrogenated to p- and m-alkylbenzene derivatives read-
ily separable by column chromatography on alumina. Nitric
acid oxidation of these benzenoid hydrocarbons generated
p-benzenedicarboxylic (terephthalic) and m-benzenedi-
carboxylic (isophthalic) acids, respectively. Johnstone and
Quan (1973) considered and rejected the possibility that the
dimer mixture may have been artifactually produced dur-
ing the laboratory generation, collection and fractionation
of the CSC. They noted that “At no time was the conden-
sate subjected to temperatures above 80°C, and that only
for short periods, so it is likely that the dimers were formed
during the smoking process.”
The isolation and identification in the late 1950s and early
1960s of several polyhydronaphthalene derivatives in tobacco
and smoke, for example, A- and B-levantenolide* (799, 801,
* α- and β-Levantenolide are listed by Chemical Abstracts as decahydro-
3,3’a,6’,6’,9’a-pentamethyl- and 3’a,4’,5’,5’a,6’,7’,8’,9’,9’a,9’b-decahydro-
3,3’a,6’,6’,9’a-pentamethylspiro[furan-2(3H),2’(1’H)-naphtho[2,1-b]
furan]-5(4H)-one, respectively.
1299), A2-levantanolide† (1290, 1300), 12A-hydroxy-13-
epimanoyl oxide‡ (800, 1298, 3281), sclareolide§ (3272,
3533), and sclaral¶ (3534), subsequently led to the identifica-
tion of many more such derivatives [see Enzell and Wahlberg
reviews (1156, 1157, 4089, 4090)] among which were several
polyhydronaphthalenes, such as decahydronaphthalene (222–
224), 4,7-dimethyl-1,2,3,5,6,8a-hexahydro-1-(1-methylethyl)-
naphthalene, (1156, 1256, 4090), and its isomer 4,7-dimethyl-1,
2,4a,5,6,8a-hexahydro-1-(1-methylethyl)-naphthalene
(A-muurolene) (404), and two isomers of 1,8a-dimethyl-
7-(1-methylethenyl)-1,2,3,5,6,7,8,8a-octahydronaphthalene
(valencene and eremophilene) (404).
A similar situation occurred with the cyclotetradecanes.
Subsequent to the isolation and identification of several
hydroxy derivatives and epoxy derivatives of unsaturated
cyclotetradecane from tobacco (3195, 3220, 3221, 3361) and
smoke (3361), several trimethyl-(1-methylethyl)-substituted
cyclotetradecatrienes and tetraenes were identified in tobacco
(1149, 1149a, 3853) and/or smoke (2726).
Table I.C-1 lists the cyclic aliphatic hydrocarbons identi-
fied in tobacco and tobacco smoke.
† α2-Levantanolide is listed by Chemical Abstracts as dodecahydro-3,
3’a,6’,6’,9’a-pentamethylspiro[furan-2(5H),2’(1’H)-naphtho[2,1-b]furan]-
5-one.
‡ 12α-Hydroxy-13-epimanoyl oxide is listed by Chemical Abstracts as
3-ethenyldodecahydro-3,4a,7,7,10a-pentamethyl1H-Naphtho[2,1-b]
pyran-2-ol.
§ Sclareolide is listed by Chemical Abstracts as decahydro-3a,6,6,9a-
tetramethylnaphtho[2,1-b]furan-2(1H)-one.
¶ Sclaral is listed by Chemical Abstracts as dodecahydro-3a,6,6,9a-
tetramethylnaphtho[2,1-b]furan-2-ol.

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 The Hydrocarbons
R R
R
R
VII VIII
R = -CH2 -{(CH2)2 -CH(CH3)-CH2}3 -H
FIGURE I.C-2 Phytadiene dimers.
I.D THE MONOCYCLIC AROMATIC
HYDROCARBONS
In this section, monocyclic aromatic hydrocarbons are defined
as those compounds with one or more nonfused aromatic
rings, for example, benzene, biphenyl, terphenyl, and stilbene.
Some authors might classify the aromatic hydrocarbons with
two or more nonfused rings as polycyclic aromatic hydro-
carbons (PAHs). Table I.D-1 lists the monocyclic aromatic
hydrocarbons identified in tobacco and/or tobacco smoke.
None of these compounds was included in Kosak’s 1954
catalog of tobacco smoke components (2170). Johnstone and
Plimmer (1971) listed only five such compounds [benzene,
ethenylbenzene (styrene), methylbenzene (toluene), 1,2,4-
trimethylbenzene (pseudocumene), 1,3,5-trimethylbenzene
(mesitylene)]. By 1964, Elmenhorst and Reckzeh (1139) listed
eleven such hydrocarbons (see Table I.D-1). In 1968, Stedman
(3797) listed twenty monocyclic aromatic hydrocarbons. The
list presented in 1980 by Ishiguro and Sugawara (1884) indi-
cated this number had doubled. To date, over eighty monocy-
cylic aromatic hydrocarbons have been identified in tobacco
and/or its smoke.
In its 1986 review of tobacco smoke components and their
relationship to health, the IARC (1870) discussed only three
monocyclic aromatic hydrocarbons, namely, benzene, meth-
ylbenzene (toluene), and ethenylbenzene (styrene):
Tobacco smoke contains traces of other volatile com-
pounds found to be carcinogenic in humans or in experi-
mental animals.
Benzene, a human carcinogen [IARC (1868)], has been
reported in the MS of cigarettes (12–48 μg/cigarette) and in
the SS of a 100-mm U.S. filter cigarette (453 μg/cigarette)
[Wynder and Hoffmann (4332); Elmenhorst and Schultz
(1140); Jermini et al. (1947)]. It can be assumed that benzene
is formed during the burning of tobacco either from precur-
sors with an aromatic or cyclohexane ring or by pyrosyn-
thesis from primary radicals such as C6H5. … The most
abundant volatile hydrocarbon in tobacco smoke is toluene
(methylbenzene), which has been reported to occur at levels
of up to 164 μg/cigarette in MS and 904 μg in the SS of a
100-mm U.S. nonfilter cigarette (1140, 1947, 4332).
With regard to the carcinogenic activity (actually its leukemo-
genic activity) of benzene, it was noted: “Sufficient evidence
© 2009 by Taylor & Francis Group, LLC
78836_C001.indd 47
47
R R
R R
IX X
in animals with new data from US National Toxicology
Program (sufficient evidence in humans).” The carcinoge-
nicity of ethenylbenzene was described as follows: “Limited
evidence [in] animals (inadequate evidence in humans).”
In 1989, Hoffmann and Hecht (1727) included benzene in
their list of forty-three tumorigens in tobacco and tobacco
smoke. They discussed the role of exposure to benzene in
tobacco smoke as follows:
Significant amounts of benzene are found in cigarette MS
(up to 50 μg/cigarette). Sufficient evidence exists that this
aromatic hydrocarbon causes leukemia in humans [IARC
(1868)]. On the basis of analytical data for exhaled breath, it
has been calculated that a smoker inhales about 2 mg of ben-
zene per day while a nonsmoker inhales only 0.2 mg per day
[Wallace et al. (4111)]. Former epidemiological studies have
not demonstrated a strong association of smoking and leu-
kemia [IARC (1868)]. However, a recent prospective study
among 248,000 U.S. veterans indicates that cigarette smok-
ers have a significant increase in mortality from leukemia
[Kinlen and Rogot (2096)].
Examination of the compendia of compounds tested for
carcinogenicity [Hartwell (1543, 1544), Shubik and Hartwell
(3664, 3665), Thompson et al. (3908)] reveals that not only
has benzene been tested for its carcinogenicity per se to skin
(mouse, rat, guinea pig, rabbit, monkey) but also it has been
used as the solvent for application of hundreds of compounds
(PAHs, their alkyl and other derivatives, plus their nitrogen,
oxygen, and sulfur analogs; quinones; aromatic aza-arenes;
aromatic amines; sterols and sterol-related compounds) to
the skin of a variety of laboratory animals. In many of these
latter experiments, groups of “solvent control” animals were
painted with benzene at the same time as other test groups
were painted with benzene solutions of the compound(s)
under investigation. Despite the hundreds of animals skin-
painted with benzene, only in very few cases were carci-
nomas or other tumors observed at the painting site in the
“solvent control” benzene-treated animals or in the animals
treated in the benzene carcinogenicity studies.
Examination of the references listed for benzene provides
an indication of the amount of research and discussion perti-
nent to the presence of benzene in tobacco smoke.
Rodgman and Green (3300) in their discussion of toxicants
in tobacco and tobacco smoke noted that subsequent lists and
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 48 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.D-1
Monocyclic Aromatic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke
Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

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 The Hydrocarbons 49

TABLE I.D-1 (CONTINUED)

Monocyclic Aromatic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 50 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.D-1 (CONTINUED)

Monocyclic Aromatic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Hydrocarbons 51

TABLE I.D-1 (CONTINUED)

Monocyclic Aromatic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 52 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.D-1 (CONTINUED)

Monocyclic Aromatic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Hydrocarbons 53

TABLE I.D-1 (CONTINUED)

Monocyclic Aromatic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 54 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.D-1 (CONTINUED)

Monocyclic Aromatic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Hydrocarbons
discussions generated after that of IARC (1870) included not
only benzene but also ethenylbenzene (styrene) [see Table 2
in (3265) and Table 1 in (3300)] and methylbenzene (toluene)
[see Table 1 in (3300)].
I.E THE POLYCYCLIC AROMATIC
HYDROCARBONS
Classified as toxicants in many of the substances to which
humans are exposed are the polycyclic aromatic hydrocarbons
(PAHs). Such exposures include air pollutants from a vari-
ety of sources, foodstuffs and beverages, and tobacco smoke.
Since the early 1950s, the composition of the latter has been
more completely defined than that of any other consumer
product. Over 5200 components have been identified in
tobacco smoke and among these are over 500 PAHs either
completely or partially identified.
Because of the tumorigenicity of many PAHs, much
research has been conducted in attempts to define the relation-
ship between the PAH structures and their specific tumori-
genicities in laboratory animals. None of the theories to date
completely answers all the questions. In 2006 Rodgman and
Perfetti (3306a) cataloged the PAHs completely or partially
identified in cigarette smoke, as a prelude to an attempt to
develop a more reasonable PAH structure-tumorigenicity rela-
tionship. Additionally, they tabulated the PAHs considered in
several previous studies on structure-tumorigenicity relation-
ships, studies that dealt primarily with all-benzenoid PAHs.
The majority of the information included in Section I.E comes
from the 2006 article from Rodgman and Perfetti (3306a).
Tobacco and tobacco products in the forms of leaf, shred-
ded or grounded tobacco, and various forms of cigars and
cigarettes have been available to individuals for ages. For
centuries people have enjoyed tobacco but have been admon-
ished of its potential health concerns. Health concerns for
cigarette smokers have increased steadily since the early
1950s due to the rapid development and advancement in sepa-
ration sciences, toxicology and medicine. In his 1954 publica-
tion, Kosak (2170) was the first person to catalog compounds
reported in tobacco smoke. His list contained fewer than 100
compounds and a significant number were incorrectly char-
acterized. Today over 5200 compounds have been identified
as components in tobacco smoke [see Figure 1, p. 140 in
(1373)]. Over the past fifty years, the tobacco industry has
made significant progress in both the identification of tobacco
and smoke components and the development of technologies
to reduce cigarette smoke yields. Significant efforts continue
in government, academia, and especially the tobacco indus-
try to understand the health effects of smoking and to develop
cigarette products with reduced health risks for smokers. One
class of tobacco smoke components that has been studied
extensively and intensively is the polycyclic aromatic hydro-
carbons (PAH) due to their potential health concerns.
Periodically, tobacco researchers have reported the prog-
ress on the identification of tobacco and smoke components.
Review articles by Johnstone and Plimmer (1971) and Izawa
(1900) detailed the tobacco and smoke research conducted
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55
over 100 years. Izawa listed 440 identified smoke components
by 1961. Quin (3059) published a review of components found
in tobacco and smoke. Herrmann (1625) reviewed phenolic
compounds in tobacco smoke. In 1963, Philip Morris (2939)
published a monograph on tobacco and smoke composition,
a copy of which was provided to the Advisory Committee on
smoking and health to the U.S. Surgeon General (3999). In
1964, Elmenhorst and Reckzeh (1139) tabulated the aromatic
hydrocarbons identified in tobacco smoke. Kuhn (2226) pub-
lished an article on alkaloids in tobacco and smoke. In their
1967 book, Wynder and Hoffmann (4332) discussed tobacco
and smoke chemistry and the results of animal studies with
tobacco smoke. Elmenhorst and Schultz (1140) listed 250
low-boiling components and vapor-phase components identi-
fied in tobacco smoke. In his 1968 review, Stedman (3797)
listed nearly 1200 identified tobacco and smoke components.
The next year, Neurath (2724) reported on the presence of
180 nitrogen-containing compounds in smoke. With the
meaningful advancements in analytical methodology, the
number of tobacco and smoke components increased dramat-
ically (1371). At R. J. Reynolds Tobacco Company (RJRT),
Schumacher et al. (3553), Heckman and Best (1587), and
Newell et al. (2769) identified over 1500 compounds in the
water-soluble and ether-soluble fractions of tobacco smoke.
In 1977, Schmeltz and Hoffmann (3491) cataloged nearly 500
N-containing compounds identified in tobacco smoke but
their catalog did not include the more than 230 N-containing
compounds newly identified in tobacco smoke by Heckman
and Best (1587). Between 1974 and 1978, Snook et al. (3732,
3756–3759) published the results of their massive study of the
PAHs identified in tobacco smoke, a study that was followed by
an equally definitive one published in 1981 on the aza-arenes
in tobacco smoke (3750). In 1980, Ishiguro and Sugawara
(1884) listed 1889 identified tobacco smoke components in
their monograph. However, a tally of the reported tobacco
smoke components at that time exceeded 2500. No additional
catalogs of the total number of identified components of ciga-
rette mainstream smoke (MSS) have been published since the
1980 Ishiguro and Sugawara (1884) publication. Smith et al.
(3712) recently reported the chemical structures of the 253
identified phenols reported in cigarette MSS.
Numerous catalogs of PAHs identified in MSS have been
compiled from 1955 through 2005. Table I.E-1 is a chronol-
ogy of catalogs of PAHs in MSS. It contains the year of each
catalog, author (and reference), and the number of PAHs listed.
The catalogs prior to 2006 contain much overlap in terms of
the PAHs identified. In 2006 Rodgman and Perfetti (3306a)
published a report that attempted to eliminate the overlap and
clearly present the 539 PAHs identified in MSS. The intent of
this section is to present a referenced catalog of the completely
or partially characterized* PAHs in tobacco, tobacco MSS,
and MSS of tobacco substitutes. The catalog to follow (Table
I.E-6) contains the CAS registration number, chemical name,
structure, and alphabetical listing of references on PAHs.
* The term “partially characterized” or “partially identified” indicates that
the position of one or more alkyl substituents was not determined.
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 56 The Chemical Components of Tobacco and Tobacco Smoke

of extensive data generated on the specific tumorigenicity

TABLE I.E-1 of about 25% of the hundreds of PAHs synthesized between
Chronology of Catalogs of PAHs in MSS 1929 and the early 1950s (1543, 1544), PAHs were considered
the most likely tumorigenic agents in cigarette MSS even
No. of PAHs
though their presence was not certain. Eventually, numerous
Year Author Listed Ref.
PAHs were identified in cigarette MSS. Because of its MSS
1954 Kosak 4 a 2170
level and its high specific tumorigenicity in several bioassays,
1955 Latimer 10 2270
1957 Latimer and Rodgman 33 2292a
one PAH was subjected to intense scrutiny: Benzo[a]pyrene
1958 Rodgman 36 3245 (B[a]P). As a carcinogen, B[a]P elicited carcinomas at the
1959 Johnstone and Plimmer 57 1971 painting site in the mouse-skin bioassay. As a sarcogen, B[a]
1960 Rodgman and Menz 68 3301 P elicited sarcomas in rodent bioassays involving subcutane-
1962 Rodgman et al. 77 3303 ous injection.
1963 Philip Morris 61 2939 One class of tobacco smoke components studied exten-
1963 Rodgman et al. 77 3304
sively is the polycyclic aromatic hydrocarbons. As reported
1964 Elmenhorst and Reckzeh 70 1139
1965 Rodgman et al. 85 3302
by Rodgman (3262), between 1950 and 1970, an extensive
1967 Rodgman and Woosley 85 3308 amount of research was conducted on tobacco- and cigarette
1968 Stedman 79 3797 smoke-related topics. The information generated led to the
1975 Roberts et al. 206 3224 development of several significant cigarette design technolo-
1976 Snook et al. 252b 3758 gies that resulted in the modification of the delivery and com-
1977 Snook et al. 157b 3756 position of cigarette MSS.
1978 Snook et al. 438b 3757
The following is a brief chronology of the events occur-
1980 Ishiguro and Sugawara 191 1884
1997 Williams et al. 427c 4249
ring in the tobacco smoke-PAH situation. In 1939, the PAHs
2005 Rodgman and Perfetti 539d 3306a anthracene, phenanthrene, and B[a]P were reported as com-
a
ponents of a tobacco-related material by Roffo (3323–3325)
Three of the PAHs listed were identified in a destructive distillate of
and his son (3316, 3318). In discussions of tobacco smoke, the
tobacco, not in tobacco smoke.
Roffo findings are generally disregarded because the three
b In the three articles on the PAH study by Snook et al. (3756–3758),
PAHs they reported were not detected in tobacco smoke but
some identified PAHs were listed in more than one article.
in a destructive distillate of tobacco. However, Roffo did
c In several instances, more than one isomer was reported for some report another finding that led to much research both within
monoalkyl-, dialkyl-, trialkyl-, and tetraalkyl-PAHs but the positions of
and outside the tobacco industry. Roffo reported that com-
the alkyl groups were not determined. In the case of such multiple alkyl
parison of the destructive distillate of tobacco with that of
isomers, only one was listed in this report.
d
an ethanol-extracted tobacco indicated (3327) that the PAH
This list includes the number of isomers of monoalkyl-, dialkyl-, trial-
content and specific tumorigenicity of the extracted tobacco
kyl-, and tetraalkyl-PAHs reported where the positions of the alkyl
groups were not determined.
destructive distillate were reduced from those of the destruc-
tive distillate from the control tobacco. Roffo speculated that
the precursors of the tumorigenic PAH components of his
distillates were ethanol-soluble phytosterols. Eventually his
The significant increase in the number of studies on prediction, as far as it went, was found to be true for ciga-
tobacco smoke composition was triggered by the following rette MSS (3269, 3616). Because he was unaware of the pres-
events: (a) The results in the early 1950s from several retro- ence in tobacco of long-chained terpenoids such as solanesol,
spective epidemiology studies (1026a, 1027, 3529, 4306b) in identified in flue-cured tobacco in 1957 by Rowland et al.
which it was reported that an association existed between cig- (3359), Roffo obviously could not include them in his 1942
arette smoking and the incidence of lung cancer in smokers, precursor prediction. It should be noted that the findings by
(b) a 1953 report of the production of skin carcinoma in sus- Roffo on destructive distillates of tobacco were subsequently
ceptible laboratory animals skin painted repeatedly with a equivalent to the effects observed in smoked tobacco, that
concentrated solution of cigarette MSS condensate suppos- is, organic solvent-extraction of a tobacco or tobacco blend
edly produced under conditions simulating the human smok- which was then incorporated into cigarettes gave MSS with
ing of a cigarette (4306a), (c) the realization in 1954 that very reduced PAH levels and specific tumorigenicity to mouse
little (2170) was known about the composition of tobacco skin compared to the MSS from control tobacco. However,
smoke to which consumers had been exposed for nearly 400 usually the reduction in specific tumorigenicity was less than
years, and (d) the incorporation of chromatography into the the reduction in PAHs, particularly B[a]P.
overall methodology of the fractionation of complex mix- The generation in the early 1950s of carcinomas in lab-
tures such as tobacco smoke. oratory animals (mice) skin-painted with a solution of the
Naturally, these findings raised several questions. The mainstream “tar” from commercial cigarettes (4306a) led to
first dealt with the identity of the cigarette MSS component(s) numerous studies to identify the possible causative agent(s) in
responsible for the smoking-lung cancer association in smokers the “tar.” Since much more tumorigenicity data and knowl-
and the skin tumor induction in laboratory animals. Because edge were available on PAHs than on any other class of

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 The Hydrocarbons
compounds, most of the effort was concentrated on identify-
ing PAHs in cigarette smoke condensate (CSC) as the possi-
ble cause of the tumorigenicity. Because of its demonstrated
potency as an initiator of carcinomas on skin painting and
the wealth of information on it, B[a]P became the target of
much research on CSC. In 1951, Hartwell (1544) listed nearly
350 studies on the tumorigenicity of B[a]P administered in
various ways to various species. The other previously stud-
ied PAHs were dibenz[a,h]anthracene (DB[a,h]A) and 1,2-
dihydro-3-methylbenz[ j]aceanthrylene (3-methylcholan-
threne) with 240 and 303 reported biological studies, respec-
tively. Benz[a]anthracene (B[a]A) and 7,12-dimethylbenz[a]
anthracene (DMB[a]A) were listed with twenty and thirty-
two studies, respectively. In the twenty studies reported by
Hartwell (1544), a malignant tumor was noted in only one
instance with B[a]A.
Although B[a]P was reported as a CSC component in
the mid-1950s by several American (55–57, 592–594) and
British investigators (820) on the basis of spectral evidence,
Fieser, as late as 1957 (1181), considered the published evi-
dence to be inadequate as proof of the presence of B[a]P in
CSC. Obviously, in 1957 Fieser was unaware of the report by
Rodgman in 1956 (3240) on the isolation of crystalline B[a]
P from MSS or the reports by Falk and Kotin in 1955 and
1956 (1172) on the determination of the per cigarette yields of
B[a]P (plus B[a]A and dibenzo[def,p]chrysene) in MSS and
sidestream smoke (SSS). Shortly thereafter, in 1959, Wynder
and Hoffmann reported the isolation of B[a]P in crystalline
form from CSC (4307), thus ending the controversy about its
presence in cigarette smoke.
In 1954, knowledge of cigarette MSS composition was
extremely limited. As mentioned earlier, Kosak (2170) listed
fewer than 100 components reported in tobacco smoke
and many of those listed were incorrect. Some of the early
research on cigarette MSS composition, particularly the
PAHs, was conducted at RJRT.* Complete details of the
experimental procedures and findings are available on the
Internet at www.rjrtdocs.com.
The initial RJRT PAH investigation involved eleven PAHs in
the MSS from nonfiltered cigarettes (3240, 3244) [(see Table 1
in (3262)]. Naphthalene, anthracene, pyrene, fluoranthene, and
B[a]P, isolated in crystalline form, were characterized by UV
absorption spectral data as well as by classical chemical means
(mixture melting point, IR spectra, derivatization, and deriva-
tive properties). The other six PAHs were identified on the
basis of agreement of their UV absorption spectra with those
of authentic samples or with published UV data.
* Numerous formal in-house reports and memoranda authored by RJRT
R&D personnel are cited herein. Many have been published totally or in
part in peer-reviewed journals and/or presented totally or in part at sci-
entific conferences (Tobacco Chemists’ Research Conferences, American
Chemical Society Symposia on Tobacco and Smoke, CORESTA
Conferences, etc.). Whether published, presented, or neither, copies of all
RJRT reports cited are stored in various repositories such as the one in
Minnesota. Their contents are available on the Internet address indicated.
Experimental procedures used, data collected, and interpretations sum-
marized here are described in detail in the reports cited.
© 2009 by Taylor & Francis Group, LLC
78836_C001.indd 57
57
The second RJRT investigation involved the MSS from
filter-tipped cigarettes (3249, 3273) [see Table 2 in (3262)].
In that study forty-four PAHs, including the eleven PAHs
found in the initial study were identified (3240, 3244). Of the
forty-four PAHs, fourteen were isolated in crystalline form
and characterized by both UV spectral and classical chemi-
cal means [see Table 1 in (3262)]. B[a]P, B[a]A, DB[a,h]A,
and several other PAHs were also isolated in crystalline form
from the CSC (3240, 3244, 3273). The other thirty were iden-
tified from the agreement of their UV absorption spectra with
those of authentic samples or with published spectra. B[a]P,
B[a]A, and DB[a,h]A had been reported to be tumorigenic to
mouse skin although the bioassay data for B[a]A were con-
tradictory (983, 1543, 1544).
Although much of the early research at RJRT R&D on the
identification of PAHs in MSS and the effect of various tobacco
blends and/or treatments on their MSS yields was summarized
in several recent publications (3262, 3307), other members of
the U.S. tobacco industry were also much involved in similar
research in the 1960s and 1970s. The following paragraphs
provide a few examples of their early efforts.
At Philip Morris in 1963, Robb et al. (3191) described
the identification of fourteen PAHs (naphthalene, fluorene,
anthracene, 9-methylanthracene, phenanthrene, fluoranthene,
pyrene, 1-methylpyrene, B[a]P, B[e]P, DB[a,h]A, benz[e]ace-
phenanthrylene, perylene, benzo[ghi]perylene), biphenyl, and
the aza-arene, carbazole, in cigarette MSS. Almost all the
details in this 1963 Philip Morris in-house report were sub-
sequently presented at the 1964 CORESTA meeting and pub-
lished in 1965 (3191). Also at Philip Morris, Carpenter (606a)
in 1964 described the per cigarette B[a]P yields from several
commercial cigarettes; Oakley (2817a) in 1965 reported the
per cigarette B[a]P yields from cigarettes fabricated from
different tobacco types (flue-cured, burley, Oriental); Segura
(3579a) in 1966 reported the contribution of cigarette paper
to the per cigarette B[a]P yield; Johnson (1962b) in 1965
described the effect of a tobacco additive, aluminum chlo-
ride, on the MSS B[a]P yield; and Oakley (2817b) in 1966
determined the difference in per cigarette B[a]P yield in MSS
and SSS.
At British American Tobacco Company (BAT) in 1966,
Chakraborty and Thornton (646a) studied the effect of vari-
ous additives on MSS PAHs. The changes in the per cigarette
yields of a variety of PAHs were determined. They included
anthracene, B[a]A, benzo[ghi]fluoranthene, benzo[k]fluo-
ranthene, B[a]P, B[e]P, chrysene, fluoranthene, fluorene,
methylfluorene, phenanthrene, several alkylphenanthrenes,
dimethylphenanthrene, pyrene, and several benzofluorenes.†
Although studies on PAHs in MSS were conducted at
RJRT and Liggett and Myers Tobacco Company (L&M) in
the 1960s, publications only dealt with analytical techniques.
For example, in 1963 Mold et al. (2596a) at L&M described
† At the Internet address, http://legacy.library.ucsf.edu/cgi, by inserting the
topic “aromatic polycyclic hydrocarbons,” one may access over twenty
BAT and Brown and Williamson (B&W) memoranda by Chakraborty,
Thornton, and others on PAHs in tobacco smoke.
11/13/08 6:42:29 PM
 58
the use of a compound, tetramethyluric acid, that complexes
with polycyclic compounds. It was a procedure reminiscent of
the finding of the water-soluble purine-PAH complex defined
by Weil-Malherbe (4161a), a finding subsequently developed
into an alternative analytical method for the determination of
PAHs and aza-arenes in tobacco smoke and other media by
Rothwell and Whiteheart (3337–3340). Although the study
was not described as relating to tobacco smoke, Cundiff and
Markunas (869) at RJRT in 1963 reported a titrimetric analysis
of the nitro groups in numerous PAH:2,4,7-trinitrofluorenone
complexes as a means to define the molecular weight of the
PAH. All but one of the PAH:2,4,7-trinitrofluorenone com-
plexes could be obtained from the PAH fraction of cigarette
MSS. Of course, there were also methods developed for the
in-house determination of specific PAHs, particularly B[a]
P by Bell (239a) at Lorillard, Oakley and Stahr (2820a) at
Philip Morris, and Walker (4110) and Stamey et al. (3787,
3789) at RJRT.
These and many other in-house reports on PAHs demon-
strate that the early PAH research was not limited to aca-
demic or governmental laboratories or to laboratories at
private institutions such as the Sloan-Kettering Institute,
American Health Foundation, or Roswell Park Memorial
Institute. Many of the tobacco industry reports on PAHs
listed above may now be accessed at the Internet addresses
cited in the references.
Additional PAHs, both tumorigenic and nontumorigenic,
were subsequently identified in CSC but the level of B[a]
P in CSC could account for very little (1056, 3310, 3311,
4354) or less than 2% of the observed skin-painting effect
(4312, 4354), the contribution of all the known tumorigenic
PAHs in CSC could account for not much more than 3% of
the observed effect. These findings led to the proposal by
Wynder and Wright (4354) that CSC contained a PAH that
either possessed the same specific tumorigenicity as B[a]P
but was present at about fifty times the B[a]P level or present
in MSS was an unknown PAH that was “supercarcino-
genic” compared to B[a]P, that is, its specific tumorigenicity
to mouse skin was forty to fifty times that of B[a]P. After
an eighteen-month search, Wright, a colleague of Wynder
from the early to the late 1950s, concluded that neither type
of PAH was present in CSC. Subsequently, the absence of a
“supercarcinogen” in CSC was confirmed by the identifica-
tion of hundreds of PAHs in the PAH fraction of CSC by
Snook et al. (3756–3759). Detailed examination of their lists
does not reveal the presence of a PAH structurally different
from any of those previously classified with regard to their
specific tumorigenicity on mouse-skin painting.
No other CSC fraction possessed specific tumorigenicity
to mouse-skin comparable to the PAH fraction. In the mid-
1950s, the tumorigenicity of the N-nitrosamines in CSC was
not an issue, for several reasons: (1) the tumorigenicity of
an N-nitrosamine was first defined in 1956 (2441a), (2) the
presence of N-nitrosamines in MSS was not suggested until
the early 1960s (422, 423, 1057), and (3) of the more than
300 N-nitrosamines tested for tumorigenicity, only one type
not found in tobacco smoke—the N-nitrosoalkylureas—was
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The Chemical Components of Tobacco and Tobacco Smoke
found to be tumorigenic to mouse skin [e.g., see Appendixes
A–D in (2991)].
Consideration of all the tumorigenic PAHs and their levels
in CSC could account for no more than 3% of the observed
biological activity in mouse skin-painting studies. In 1961,
Wynder and Hoffmann (4312) stated:
The polynuclear aromatic hydrocarbons are mainly formed
during the combustion of tobacco. The tobacco of our stan-
dard cigarettes contains only very minute quantities of
benzo(a)pyrene [sic] (0.02 ppm). A bioassay indicates that
these polycyclic hydrocarbons of the condensate by them-
selves, however, can account for not more than 3 per cent of
the total biological activity.
In 1967, they reiterated their 1961 comment (4340):
Without belaboring the point as to whether BaP as such con-
tributes to the carcinogenicity of tobacco smoke condensate,
we can certainly agree that the concentration of BaP may be
regarded as an “indicator” of carcinogenic PAH in tobacco
smoke condensate … While BaP and other carcinogenic
PAH can by themselves account for only a small portion of
the total tumorigenic activity of cigarette smoke condensate,
probably less than 2%, they are, nevertheless, of obligatory
importance as tumor initiators.
Hoffmann and Wynder (1800) reported that the major
carcinogenicity of CSC resided in the CSC fraction contain-
ing the bulk of the PAHs. However, the levels in CSC of the
nonalkylated carcinogenic PAHs could explain no more than
1% to 3% of the observed activity. They also reported that the
artificial doubling and tripling of the levels of the seventeen
known tumorigenic PAHs in CSC significantly increased the
tumorigenicity of the CSC. However, their biological findings
were contradicted by those of Roe (3310, 3311) and Lazar
et al. (2320) who reported that increasing the level of B[a]
P in CSC by a factor of ten or thirty, respectively, produced
no increase in the specific carcinogenicity of the CSC. Roe
(3310, 3311) also noted that the CSC level of B[a]P, despite its
known tumorigenic potency, accounted for very little of the
observed specific tumorigenicity of CSC to mouse skin. The
opposite of these observations were the findings that potently
tumorigenic PAHs such as DB[a,h]A on subcutaneous injec-
tion [Dobrovolskaia-Zavadskaia (1021)] and B[a]P on mouse
skin painting [Poel et al. (2970a)] exhibited a threshold value.
Wynder et al. (4303) reported that mice skin painted with the
equivalent of the B[a]P content of the CSC from over 500 cur-
rent cigarettes developed no carcinomas. Rabbits were found
to be even more resistant to higher dose levels of B[a]P.
Paralleling the research on the presence or absence of
PAHs in cigarette MSS, their precursors in tobacco, their
mechanism of formation, their contribution to laboratory
animal tumorigenesis, and their possible involvement in the
smoking-health issue was extensive research on ways to gen-
erate a “less hazardous” cigarette by removal of PAHs from
or reduction of their per cigarette yields in MSS. To success-
fully resolve these questions, much pioneering research and
development were initiated in late 1954 (3262). When the
question of the presence of PAHs in MSS was resolved, with
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 The Hydrocarbons
many PAHs identified, and their per cigarette MSS yields
determined, much effort was expended to develop tech-
nologies to reduce their MSS yield, particularly the yields
of those PAHs reported to be tumorigenic to CSC-painted
mouse skin. In the early 1960s, a “less hazardous” cigarette
was defined on the basis of three criteria [see p. iii in (1329);
p. 372 in (4319); pp. 503, 531 in (4332)]: (1) the per cigarette
yield of a specific toxicant has been lowered, (2) the ratio of
the specific toxicant to MSS “tar” has been lowered, and (3)
the specific tumorigenicity of the MSS “tar” as measured in
the mouse skin-painting bioassay has been lowered. With the
advent of meaningful tests for mutagenicity and genotoxicity,
criterion (3) has been modified to include them.
The tobacco industry and nonindustry scientists investigated
many additional approaches in the attempt to design a “less
hazardous” cigarette [see Table 5 in (3262), Table 14 in (3300)].
Two examples of technologies that appeared to be promising
but presented other toxicant problems were the organic solvent-
extraction of tobacco and the use of oxidative additives.
The extraction concept was patterned after the findings
of Roffo (3327) with one addition, the hexane extract of the
tobacco was partitioned between hexane and aqueous etha-
nol to separate the flavorful compounds from those consid-
ered to be the PAH precursors, that is, the phytosterols, the
aliphatic hydrocarbons, the long-chained terpenoids (116,
121, 3189). When the extracted tobacco was smoked in ciga-
rette form, its CSC showed much lower PAH levels than the
control tobacco CSC (3241, 3246, 4356) and reduced tum-
origenicity (4356). The flavorful components, when returned
to the extracted tobacco and smoked in cigarette form, con-
tributed little to the total PAHs or B[a]P in the MSS [see
Figure 1, Table 3, and accompanying text in (3262)]. The
solvent extraction removed from the tobacco not only many
of the PAH precursors but also much of several potent anti-
carcinogens to such tumorigens as B[a]P and DB[a,h]A, for
example, long-chained aliphatic hydrocarbons, d-limonene,
A-tocopherol, A- and B-1,5,9-trimethyl-12-(1-methylethyl)-
4,8,13-cyclodecatriene-1,3-diol [see Table 11 in (3300)].
Thus, because of their removal from the tobacco, the anti-
carcinogens obviously could not be transferred to MSS dur-
ing smoking. Before some of the problems were discovered,
the investigation of the benefits supposedly derived from the
organic solvent-extraction of tobacco led to several patents
on the technology (121, 2713, 2717, 3189). The earliest major
non-tobacco industry proponents of the contribution of the
extraction technology to a “less hazardous” cigarette eventu-
ally dismissed it with the comment that the technology was
“impractical both technically and economically” (4311) and
“of academic interest only” (4306d). Most of the findings on
tobacco components that were, and tobacco components that
were not, significant precursors of MSS PAHs in this early
study were confirmed some years later by Severson et al.
(3616). The problems arising from the organic solvent extrac-
tion included the increased levels of nitrate and the biopo-
lymers cellulose, starch, and pectin in the solvent-extracted
tobacco. These consequences increased the yields of nitric
oxide, N-nitrosamines, and phenols (3277) in the MSS.
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59
Although nitrate addition reduced the per cigarette yields
of FTC “tar,” MSS PAHs, phenols, and CSC tumorigenic-
ity to mouse skin (1797), it was subsequently shown, as pre-
dicted (1798), to significantly increase the yields of MSS
N-nitrosamines and nitrogen oxides (480). Thus, the recom-
mendation to add nitrate to tobacco to reduce MSS PAHs
was eventually replaced by the recommendation to use low-
nitrate tobacco in the cigarette blend and/or remove nitrate
from the tobacco (480). This reversal of recommendations
was paralleled by another concerning the level of long-
chained hydrocarbons such as n-hentriacontane in tobacco:
Originally, it was proposed to reduce MSS PAHs by selection
of tobaccos with low levels of such components or remove
the PAH precursors by organic solvent extraction. This was
replaced by a proposal to select tobaccos with high levels of
such components (480).
By the early 1960s, several cigarette design technologies
developed by the tobacco industry and used in commercial
products were categorized as significant in their contribu-
tion to the “less hazardous” cigarette (4310). Ultimately, the
initial four design technologies (tobacco blend, effective and
efficient filtration, reconstituted tobacco sheet (RTS), and air
dilution via cigarette paper porosity) were increased to eight
(tobacco blend, filter tip, filter tip additives, RTS, paper addi-
tives, expanded tobacco, air dilution [paper porosity], and air
dilution [filter tip perforation]). Their significance was rec-
ognized in “less hazardous” cigarette design by the National
Cancer Institute (NCI) (2683)* and the U.S. Surgeon General
[see Table 6 in (3262), Table 15 in (3300), 3999, 4005, 4009,
4010]. It should be noted that the first two technologies con-
sidered significant were used before 1954. Tobacco or tobacco
blend selection had been used since 1913, even before the first
tumors were induced in a laboratory animal by skin paint-
ing with a solution of coal tar (4361). RTS was introduced
into cigarette blends in 1953 when little was known about
the chemical composition or biological properties of tobacco
smoke (2170) or the effect of RTS inclusion in the blend on
them. When knowledge of tumor induction with CSC and
the presence of PAHs including B[a]P became available, it
was shown that use of these two technologies resulted in a
cigarette whose MSS was in compliance with that in the defi-
nition of a “less hazardous” cigarette (3300).
Of course, the initial thrust of this across-the-board reduc-
tion was aimed at reducing the MSS “tar” delivery because
of extrapolation by Wynder et al. (4351) of their 1957 mouse-
skin bioassay findings:
Although it is difficult to estimate a comparable exposure
level for man, the human data in line with the animal data
indicate that a reduction in total tar exposure will be followed
* All eight cigarette design technologies eventually classified as significant
by NCI, several U.S. Surgeon Generals, and other investigators on the
basis of the 10-year NCI Smoking and Health Program on the “less haz-
ardous” cigarette had been incorporated into one or more U.S. commer-
cial cigarette products prior to the first meeting of the Tobacco Working
Group formed in 1968 for the NCI program. In other words, from 1968 to
1978, no new design technology was generated in the NCI Smoking and
Health Program on the “less hazardous” cigarette.
11/13/08 6:42:31 PM
 60
by a decrease in tumor formation. For this reason, measures
directed toward this reduction are of utmost importance …
The minimum dose of tar capable of producing papillomas
in mice is about one third, of producing cancer one half, that
of the optimum dose …The practical implications of these
data and their relationship to the human cancer problem have
been emphasized.
In his 1957 testimony during the filter-tipped cigarette
hearings, Wynder reiterated this opinion that reducing “tar”
exposure dose by 40% to 50% would substantially reduce
lung cancer induction in smokers (4296).
Examination of the sales-weighted average “tar” deliv-
ery for U.S. commercial cigarettes reveals that the 40% to
50% reduction in MSS “tar” delivery considered vital by
Wynder in 1957 was achieved in the late 1960s, that is, a
reduction from 38 to 39 mg/cigarette to 19 to 20 mg/ciga-
rette. Further examination reveals that by the early 1980s,
the sales-weighted average “tar” was reduced to about 12
mg/cigarette, that is, an additional 40% reduction had been
achieved [see Figure 3 in (3262)]. Corresponding reductions
in the per cigarette yields of total PAHs in general, B[a]P
in particular (4158), and nicotine were also observed. These
reductions were also accompanied by a reduction in the spe-
cific tumorigenicity (mouse-skin painting) of the MSS CSC
(4005).
By year-end 1963, ninety-one of the ninety-seven PAHs
identified in MSS were reported in the published literature.
Six PAHs, identified in MSS by Rodgman and Cook (3273),
had not been reported publicly at that time. However, by 1970,
identification in MSS of all but one (cholanthrene) of the nine-
ty-seven had been reported. Despite the availability of such
information, only eighteen MSS PAHs were discussed by the
Advisory Committee in its 1964 Report to the U.S. Surgeon
General, thirteen as mainstream CSC components and five
as carbon black components (3999). The detailed discus-
sion of so few MSS PAHs and citation of so few publications
were done despite the fact the committee had been provided
with a detailed Philip Morris monograph on tobacco and
smoke composition, a monograph that listed sixty-one PAHs
identified in tobacco smoke plus many pertinent published
references to them (2939, 3262). The Advisory Committee
did note, however, that twenty-seven other nontumorigenic
PAHs—none specifically named—had been identified in
tobacco smoke. The twenty-seven unnamed PAHs had to
include several of those PAHs, for example, naphthalene,
Bay region
L region
FIGURE I.E-1 The L region, K region, and bay region of benz[a]anthracene.
© 2009 by Taylor & Francis Group, LLC
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The Chemical Components of Tobacco and Tobacco Smoke
anthracene, phenanthrene, fluoranthene, pyrene, which had
been reported to significantly inhibit the action of potently
tumorigenic PAHs such as B[a]P and DB[a,h]A in laboratory
animal studies. Of the ninety-seven PAHs known to him,
Rodgman (3262) discussed the forty-four PAHs identified at
RJRT plus thirty-four other PAHs reported in the literature in
numerous reports between 1954 and 1964 and in a summary
1964 report on ten-year research on cigarette MSS (3251).
Interestingly, Chapter 6, in the Advisory Committee’s report
on cigarette smoke chemistry and the tumorigenic PAHs,
was primarily authored by Fieser, one of the two eminent
American PAH authorities at that time.
For over half a century, numerous theories have been
advanced in attempts to explain the relationship between the
tumorigenicity of polycyclic aromatic hydrocarbons (PAHs)
in treated laboratory animals and a variety of their structural
properties, including such properties as their K-, L-, and bay-
regions, electron distribution, bond orders, bond strengths, res-
onance, octanol-water partitioning, and the like (Figure I.E-1).
Such studies were triggered by the discovery that certain
PAHs when administered to laboratory animals via skin
painting or subcutaneous injection induced carcinomas or
sarcomas, respectively. DB[a,h]A, synthesized independently
by Clar (760) and Fieser and Dietz (1184) in 1929, was shown
to be a potent tumorigen to laboratory animals by Kennaway
and Hieger (2078). Shortly thereafter, Cook et al. (797) iso-
lated several PAHs from coal tar, characterized one of them
as the previously unknown benzo[a]pyrene (B[a]P), and
demonstrated that it too was a potent tumorigen to laboratory
animals (194). Over the next two decades, the first demonstra-
tions of the carcinogenicity of two pure compounds, DB[a,h]
A and B[a]P, led to the synthesis and subsequent testing for
tumorigenicity in laboratory animals of literally hundreds of
PAHs and their alkyl derivatives plus other derivatives.
During this time, the variation in biological responses
observed with laboratory animals to individual PAHs even-
tually led to numerous unacceptable extrapolations of the
results to PAH-exposed humans. To put the laboratory animal-
to-human extrapolation in perspective, Shear and Leiter
(3627) in 1941 issued a list of pertinent factors to be consid-
ered in such an extrapolation. Despite a diminution in PAH
synthesis and tumorigenicity research during World War II,
the wealth of experimental data available in the late 1940s
to early 1950s on the high-to-slight tumorigenic potency
of some PAHs and the nontumorigenicity of other PAHs
K region
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 The Hydrocarbons
induced investigators to seek reasons for the observed dif-
ferences in tumorigenicity and to attempt to develop explana-
tions for them. Among those involved in the generation of
the major early theories on the relationship between PAH
structural properties and PAH tumorigenicity or lack of it
were Coulson (829), Pullman and Pullman (3003), Daudel
and Daudel (906a), Fieser et al. (1180a), Fieser (1180b), and
Lacassagne et al. (2247a). Much meaningful input to these
theories was provided by other investigators such as Pauling
(2910a) in the United States, Boyland, Weigert, and Mottram
(423a) in the United Kingdom, and Buu-Hoï in France [see
more than thirty Buu-Hoï references listed in (2247a)]. More
recent studies include those by Herndon et al. (1623a, 2435a),
Rubin (3365), Trosko (3966a), L. Zhang et al. (4410c), and Y.
Zhang, a graduate student under Herndon (4410d).
Because it was issued at the beginning of the extensive
research on the composition of tobacco smoke with particu-
lar emphasis on the nature and levels of the PAHs in it, it is
interesting to examine the lengthy 1955 review by Pullman
and Pullman (3003) on the relationship between electronic
structure and the tumorigenicity of a number of benzenoid
hydrocarbons. Their publication was a detailed update of
the 1953 review by Coulson (829) and included much data
generated in the interim. The Pullmans used calculations
based on three theoretical indexes of the K and L regions
of the aromatic hydrocarbons. The indexes included carbon
localization energy (CLE), bond localization energy (BLE),
and para localization energy (PLE) [see Table 1 in (3003)].
The Pullmans (3003), by use of their CLE, BLE, and PLE
calculations pertinent to the K and L regions in the PAHs,
also attempted to relate the structures of various PAHs and
their alkylated derivatives not only to their tumorigenic-
ity but also to their rate of reaction in certain well-known
reactions, for example, the Diels-Alder reaction with maleic
anhydride, reaction with osmium tetroxide, reaction with
lead tetraacetate, and photooxidation. Table I.E-2 lists the
hydrocarbons discussed by the Pullmans in 1955 with an
indication of those, thirty-four in all, that were identified in
tobacco smoke before and after 1955.
The Pullmans did introduce into their discussion various
PAH metabolites, their diols and phenols, but not the epox-
ides which were unknown at that time. Even though it had
been known since 1951 (3814), no explanation was offered
for the inhibition of the activity of a potently tumorigenic
PAH by co-administration of a weakly tumorigenic or non-
tumorigenic PAH. Lastly, of course, neither the Pullmans
nor Coulson discussed the fact that a bioassay finding with
a highly susceptible strain or species of laboratory animal
administered an individual PAH in an excessive dose has
little relationship to the situation where a human is exposed
by a different administration route to a mixture of PAHs with
various degrees of tumorigenicity plus other known antitum-
origenic compounds.
By year-end 1955, very few of the PAHs considered by the
Pullmans had been reported as tobacco smoke components.
More had been identified in other sources such as air pollu-
tion. In the following discussion, the comments in the early
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78836_C001.indd 61
61
1950s about the inadequacy of the evidence indicating the
presence of B[a]P in tobacco smoke (1181) are disregarded.
Table I.E-3 lists the PAHs reported in tobacco smoke at that
time. Of the fourteen PAHs reported, only eight were included
by the Pullmans in their assessment: naphthalene, anthra-
cene, phenanthrene, B[a]A, B[a]P, B[e]P, dibenzo[def,mno]
chrysene, and pyrene. Of course, only one of the eight, B[a]P,
was considered at that time a significant and potent tumorigen
to mouse skin. At that time, the tumorigenicity of B[a]A was
questioned, and still was questioned in the mid-1980s (983).
As noted previously, Pullman and Pullman not only
updated the electronic structure-tumorigenicity information
generated after the Coulson 1953 review but also attempted
to extend the theory to alkyl-PAHs. Examination of their
review reveals that they discussed, in addition to 1,2-dihydro-
3-methylbenz[j]aceanthrylene, a total of twelve alkyl-PAHs
(see Table I.E-3). It is obvious from their discussion that the
prediction of tumorigenicity for most of these twelve PAHs
was not calculated but derived from published biological data.
However, examination of the biological data in Hartwell (1543,
1544) and Shubik and Hartwell (3664, 3665) indicates that at
least sixty-four totally benzenoid alkyl-PAHs had been tested
for tumorigenicity by 1955. Several 1,2-dihydromethylbenz[j]
aceanthrylenes had been tested for tumorigenicity by 1955,
but they were not included in our count of sixty-four. This
raises the question: Why was the prediction not calculated
for more of the sixty-four alkyl-PAHs, the tumorigenicity
of which was known at that time (1543, 1544, 3664, 3665)?
Pullman and Pullman noted: “It must be acknowledged that
the extension of the theory to substituted derivatives of poly-
cyclic hydrocarbons is at present far from having achieved a
completely consistent and satisfactory form.”
Many of the more recent theories on the relationship
between PAH structural properties and tumorigenicity suffer
somewhat from this and other deficiencies [see Herndon et al.
(1623a, 2435a), Rubin (3365), Trosko (3966a), L. Zhang et al.
(4410c), and Y. Zhang (4410d)]. Much studied in recent years
has been the application of the quantitative structure-activity
relationship (QSAR) method to PAHs.
Although many theories have involved the relationships
between observed laboratory-derived biological data on indi-
vidually administered PAHs and their structural elements, do
they speak to the exposure situation experienced by humans?
Whether the exposure is by inhalation of air pollutants or
tobacco smoke, by ingestion of foodstuffs or beverages, by
dermal contact, or by a combination of the exposures, very
few of any human exposures involve exposure to a single PAH
similar to the exposure of laboratory animals treated with a
single PAH by skin painting or subcutaneous injection. One
such example of human exposure to a single PAH was the
past use of naphthalene as the major ingredient in mothballs.
Numerous PAHs have been either completely of partially
characterized in many air pollutants, foodstuffs, beverages,
and contact tars and dusts. Of all the products to which
humans are exposed, none has been characterized to the
extent of tobacco smoke. Over 5200 components have been
identified in it, nearly twice as many as in the next consumer
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 62 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.E-2
Benzenoid Hydrocarbons Discussed by Pullman and Pullman (3003)
No. in Pullman and Pullman Considered Tumorigenica
Aromatic Hydrocarbon Discussed CAS No. (3003) in 1955

Monocyclic
Benzeneb 71-43-2 I no

Bicyclic
Naphthalene 91-20-3 II no

Tricyclic
Anthracene 120-12-7 III no
Phenanthrene 85-01-8 IV no

Tetracyclic
Naphthacene 92-24-0 VII no
Benz[a]anthracene 56-55-3 VI ?
Benz[a]anthracene, 2,10-dimethyl- — XLIII ?
Benz[a]anthracene, 7,12-dimethyl- 57-97-6 XLII yes
Benz[a]anthracene, 7-methyl- 2541-69-7 XLIV yes
Benzo[c]phenanthrene 195-19-7 V yes
Benzo[c]phenanthrene, 1,2-dimethyl- — XLVIII no
Chrysene 218-01-9 VIII ?
Chrysene, 2,3-dimethyl- c — XLIX no
Triphenylene 217-59-4 X no
Pyrene 129-00-0 IX no

Pentacyclic
Benzo[b]chrysene 214-17-5 XXIII no
Benzo[c]chrysene 194-69-4 XIII yes
Benzo[g]chrysene 196-78-1 XIV yes
Pentacene 135-48-8 XVIII no
Benzo[a]naphthacene 226-88-0 XVII no
Dibenz[a,h]anthracene 53-70-3 XII yes
Dibenz[a,j]anthracene 224-41-9 XV yes
Pentaphene 222-93-5 XIX no
Perylene 198-55-0 XXV no
Picene 213-46-7 XXI no
Benzo[b]triphenylene 215-58-7 XX no
Benzo[a]pyrene 50-32-8 XI yes
Benzo[a]pyrene, 2-methyl- d — XLVII yes
Benzo[a]pyrene, 3-methyl- — XLVII yes
Benzo[a]pyrene, 5-methyl- — XLVII yes
Benzo[a]pyrene, 6-methyl- 2381-39-7 XLVII yes
Benzo[a]pyrene, 7-methyl- 63041-77-0 XLVII yes
Benzo[a]pyrene, 8-methyl- 63041-76-9 XLVII no
Benzo[a]pyrene, 9-methyl- — XLVII no
Benzo[e]pyrene 192-97-2 XVI no
Dibenzo[b,g]phenanthrene 195-06-2 XXIV no
Dibenzo[c,g]phenanthrene 188-52-3 XXII no
Benz[j]aceanthrylene, 1,2-dihydro-3-methyl- e 56-49-5 XLV yes

Hexacyclic
Anthra[1,2-a]anthracene 195-00-6 XXXV no
Benzo[c]pentaphene 222-54-8 XXXVII no
Benzo[rst]pentaphene 189-55-9 LIV (yes) f
Benzo[pqr]picene 189-96-8 LVII no
Dibenzo[b,def]chrysene 189-64-0 XXVII yes
Dibenzo[b,k]chrysene 217-54-9 XXXVI no
Dibenzo[c,mno]chrysene 196-28-1 LVI no
Dibenzo[def,mno]chrysene 191-26-4 XXXI no
Dibenzo[def,p]chrysene 191-30-0 XXVI yes

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 The Hydrocarbons 63

TABLE I.E-2 (CONTINUED)

Benzenoid Hydrocarbons Discussed by Pullman and Pullman (3003)
No. in Pullman and Pullman Considered Tumorigenic a
Aromatic Hydrocarbon Discussed CAS No. (3003) in 1955
Dibenzo[a,j]naphthacene 227-04-3 XXXIII no
Dibenzo[a,l]naphthacene 226-86-8 XXXIV no
Dibenzo[fg,op]naphthacene 192-51-8 XXIX no
Naphtho[1,2,3,4-def]chrysene 192-65-4 XXVIII ?
Naphtho[2,1,8-qra]naphthacene 196-42-9 XXX no
Naphtho[1,2-b]triphenylene 215-26-9 XXXII no

Heptacyclic
Benzo[a]naphtho[8,1,2-lmn]naphthacene 190-01-2 LV no
Dibenzo[fg,qr]pentacene 197-74-0 XL no

Octacyclic
Dinaphtho[1,2-b:1,2-k]chrysene 214-13-1 XXXIX no
Naphthaceno[2,1,12,11-opqra]naphthacene 188-42-1 LVIII ?g
Phenanthro[1,10,9,8-opqra]perylene 190-39-6 XLI no

Nonacyclic
Dinaphtho[1,2-b:1,2-n] perylene — XXXVIII no

Decacyclic
Pentacenopentacene — LIX ?g
a Tumorigenic in mouse skin-painting study.
b Benzene was reported as a component of the vapor phase of tobacco smoke in 1955 by Resnik and Holmes (3106) and Laurene (2293).
c A dimethylchrysene was subsequently reported in tobacco smoke, but the positions of the methyl groups were not defined.

d At least two methyl B[a]Ps were subsequently reported in tobacco smoke, but the position of the methyl group in each case was not defined.

e This PAH is not totally benzenoid; its structure includes a cyclopentanoid ring..

f In 1955, the tumorigenicity of benzo[rst]pentaphene had not been determined; later it was reported to be tumorigenic.

g Although no calculation was made on this PAH, Pullman and Pullman (3003) predicted it would be tumorigenic.

TABLE I.E-3
Polycyclic Hydrocarbons Reported in Tobacco Smoke by Year-End 1955
References Issued in the Year
Hydrocarbon 1947 1953 1954 1955
Acenaphthylenea 818 819, 821 820, 2365
Azulenea, b 1857 2365
Anthracene 818 785, 819 820, 2352, 2365, 3578
Anthracene, 2-methyl- 820
Benz[a]anthracene 2352, 2425, 2426
Benzo[ghi]perylene 819 820, 2365, 2425, 2426
Benzo[a]pyrene 785, 819, 821, 2335 55–57, 593, 1172, 2011, 2365, 3578, 4353
Benzo[e]pyrene 2352
Dibenzo[def,mno]chrysene 819 820, 2365
Fluoranthene a 819 820, 2365
Naphthalene 3578
Naphthalene, 2-methyl- 820
Phenanthrene 819 820, 2365
Pyrene 818 785, 819 820, 2352, 2365, 2425, 2426

a Molecule has a cyclopentanoid ring, thus it was not considered by Pullman and Pullman (3003).
b Molecule does not possess a benzenoid structure.

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 64
product, coffee, subjected to detailed compositional analysis.
Of the identified tobacco smoke components, about 11% were
either completely or partially identified as PAHs. It should
also be noted that in the detailed examination of tobacco
smoke, the over 5200 identified components account for over
98% of the weight of cigarette MSS. It has been estimated,
based on detailed gas chromatograms, that the number of
actual components in cigarette MSS may be twelve to twenty
times the number of identified ones (4103).
Of the more than 500 PAHs either completely or partially
identified in cigarette MSS, relatively few PAHs, originally
thirteen in all, were repeatedly defined as significant tumori-
gens (1727, 1808, 1871). Eventually, the International Agency
for Research on Cancer (IARC) redefined the tumorigenicity
of chrysene. Thus, it was deleted from all subsequent lists
(1740, 1741, 1743, 1744, 2825) except one (1217). MSS is
not the only source of most of the twelve PAHs still consid-
ered as significant tumorigens in cigarette MSS. Except for
5-methylchrysene, most have also been identified as signifi-
cant PAH components of gasoline and diesel engine exhaust
gases (1406a, 4315) and many common foodstuffs and bever-
ages (1345, 2438).
When one is dealing with a complex mixture, which in
turn contains an assortment of PAHs ranging from bicyclic
to decacyclic, one cannot extrapolate the biological effect
observed by administration of an individual PAH to the bio-
logical effect of that PAH in such a complex mixture. It has
long been known from laboratory studies that certain nontu-
morigenic or slightly tumorigenic PAHs when administered
by skin painting or subcutaneous injection in an equimolar
dose level with a highly tumorigenic PAH partially or totally
inhibit its tumorigenicity. Few studies have been done to
determine the effect of a non- or low-tumorigenic PAH on
the tumorigenicity of a highly tumorigenic PAH when its
level greatly exceeds that of the potent tumorigen. Also, there
are differences in the classification of the potency of the tum-
origenicity of some PAHs. For example, B[a]A is classified
by some as a potent or significant tumorigen (1871) but by
others as only slightly tumorigenic (983).
The list of either totally or partially identified PAHs in
CSC gradually increased but in the mid-1970s the mas-
sive definitive PAH study by United States Department of
Agriculture (USDA) personnel in Athens, Georgia, increased
the number of known PAHs in CSC to well over 500 (3732,
3756–3759). Although not isolated individually, their identifi-
cations, whether total or partial, have generally been accepted
across the board.
Numerous authors, including Hoffmann and Hecht (1727),
listed the PAH dibenzo[a,l]pyrene as a significant tumorigen
in tobacco smoke. However, Hecht eventually stated (1557)
that “the presence in cigarette smoke of dibenzo[a,l]pyrene,
a highly carcinogenic PAH, had not been confirmed.” One
should weigh the comment by Hecht against the current
status of defined MSS composition. Since the appreciable
decline in detailed tobacco smoke composition studies after
the late 1970s, no individual investigator or no research
group has reported the confirmation of the identities of
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78836_C001.indd 64
The Chemical Components of Tobacco and Tobacco Smoke
many of the PAHs (3756-3759), aza-arenes (3750, cf. 3414),
nitrogen-containing components (1587), or ether- (2769) and
water-soluble components (3553) reported in cigarette MSS
in the 1970s. While many components have been confirmed
by other investigators at the same institution as the authors,
examination of the post-1980 literature indicates that the
identities of nearly half the new components described in
the above-mentioned studies have not been confirmed by
investigators at other institutions. Because of such a situa-
tion, would Hecht also discount their presence in cigarette
MSS in the same way as he discounted the presence of
dibenzo[a,l]pyrene?
Although most of the past theories have attempted to
define the relationship between structural properties of the
PAHs and their specific tumorigenicity as measured individ-
ually in skin-painting studies, little has been done to explain
the behavior of a PAH when it is present in a complex mix-
ture that includes a host of PAHs some of which are known
antitumorigens as well as numerous known non-PAH antitu-
morigens (1174).
It has been known for over sixty years that co-adminis-
tration of a potently tumorigenic PAH with an equimolar
quantity of a nontumorigenic PAH often results in substantial
reduction in percent tumor bearing animals (%TBA).
In 1953, Coulson noted [see p. 51 in (829)]:
The action of inhibitors may be thought of as a competition
between the carcinogenic and noncarcinogenic compounds
for available sites on the enzyme. If sufficient noncarcino-
genic molecules are able to occupy suitable sites, then the
irreversible mutation cannot occur. We can see that inhibi-
tors, in order to compete with the carcinogenic compounds,
should themselves possess a K-region.
Some of the PAHs that substantially reduce or totally
inhibit the tumorigenicity of several of the most potent tum-
origens known are listed in Table I.E-4. Obviously, neither
naphthalene nor anthracene has a K-region, a requirement
proposed by Coulson for the inhibitory property.
Although many of the inhibition studies were conducted
with the tumorigenic and inhibiting PAHs administered
in equimolar quantities, it should be remembered that this
is not the case in the PAH mixture in CSC. Table I.E-5 is
derived from CSC PAH data presented by Hoffmann and
Wynder (1788, 1798) and Rodgman (3273). The per cigarette
yield data in Table I.E-5 were the averages of the data gen-
erated from two different commercial American cigarettes.
One was unfiltered and yielded 36.8 mg/cigarette of total
particulate matter (TPM) (1788); the other was a filtered
cigarette that yielded 37.5 mg/cigarette of TPM (3273). The
disparity between the relative yields in each category was
less than 5%.
In the early structure-biological activity studies, PAHs with
a pentacyclic ring were not included in the discussion of most
theories but pentacyclic compounds in which the pentacycle
contained nitrogen were, that is, benzacridines (829, 2247a).
In the discussion of his theory, Coulson (829) did mention
several cyclopentanoid compounds: six benzacridines and
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 The Hydrocarbons 65

TABLE I.E-4
Inhibition of Tumorigenicity of Potently Tumorigenic PAHs by Non-Tumorigenic
or Weakly Tumorigenic PAHs
PAH a CAS No. Effective Against References
Naphthalene 91-20-3 B[a]P, DB[a,h]A 844
Anthracene 120-12-7 B[a]P, DB[a,h]A 844
Phenanthrene 85-01-8 DMB[a]A 976, 3685
Fluoranthene 206-44-0 B[a]P, DMB[a]A 976, 3685, 3686
Pyrene 129-00-0 DB[a,h]A, DMB[a]A 976, 3685, 3686
Benz[a]anthracene 56-55-3 B[a]P, DB[a,h]A 426, 4332
Benzo[e]pyrene 192-97-2 B[a]P, DB[a,h]A, DMB[a]A 976, 3685, 3686
Benzo[b]triphenylene 215-58-7 MC b, DB[a,h]A, DMB[a]A 976, 3683, 3686

a Each PAH listed is a component of cigarette MSS.

b MC = 3-methylcholanthrene = 1,2-dihydro-3-methylbenz[j]aceanthrylene.

two PAHs, 2,3-dihydro-1H-benzo[a]cyclopent[h]anthracene
and 10,11-dihydro-9H-benzo[a]cyclopent[i]anthracene.
In her 1996 thesis, Zhang (4410d) noted the numerous
sources of PAHs to which humans are exposed, for example,
air pollutants, foodstuffs and beverages, effluents from fac-
tories, vehicles, and heat and power sources. Zhang particu-
larly stressed tobacco smoke, its complexity, and some of the
PAHs contained therein:
Tobacco smoke is a complex mixture which is estimated to
contain at least 150 compounds in the gas phase and more
than 2000 compounds have been identified in the particulate
phase. Table 1a lists some PAHs that exist in the particulate
phase of cigarette smoke.
In her Table 1, Zhang (4410d) listed nineteen MSS PAHs
reported in 1978 by Hoffmann et al. (1781).
Unfortunately, the inconsistent use of PAH nomenclature
sometimes makes it difficult to follow the phases of the study
by Zhang [see Table 7 and Appendix A in (4410d)].
Another study, initiated by Martin et al. (2479), involved
an attempt to develop a meaningful relationship between PAH
structure, chemical properties, and biological properties,
specifically the effect of PAHs on specific tumorigenicity in
skin painting. Reported for naphthalene- and pyrene-related
PAHs were the following molecular parameters: the mea-
sured and calculated log of the octanol-water partition coeffi-
cient (MlogP, ClogP), molecular volume (MgVol), calculated

TABLE I.E-5
Levels of PAH Classes in Cigarette Mainstream Smoke
Mainstream Smoke Yielda
Assumed Approximate Nanomolar Ratio,
PAH Category mol. wt. Yield ng/cig Approximate Nanomoles e PAH:B[a]P
Bicyclic 128b 4140 (77.1)d 32.3 293
Tricyclic 178c 720 (13.4) 4.0 36
Tetracyclic 228 420 (7.9) 1.8 16
Pentacyclic 278 72 (1.3) 0.26 2.4
B[a]P 252 27 (0.49)f 0.11 1.0
Non-B[a]P pentacyclic 278 45 (0.81)f 0.16 1.5
Hexacyclic 328 14 (0.3) 0.04 0.36
TOTALS 5366 (100.0)

a Data reported by Hoffmann and Wynder (1788, 1798) from a nonfiltered cigarette, total particulate matter = 36.8 mg/cig, were averaged
with data reported by Rodgman and Cook (3273) for a filtered commercial cigarette, total particulate matter = 37.5 mg/cig.
b The molecular weight of naphthalene = 128, that of indene = 116. It is realized that the average molecular weight of the bicyclic PAH
mixture will differ slightly from those of the parent PAH because of the presence of numerous homologs (methylnaphthalenes, dimeth-
ylnaphthalenes, etc.).
c The presence of tricyclic PAH homologs results in molecular weight slightly different from 178.
d Values in parentheses represent the fraction % of the PAH category in the total PAH fraction.
e Nanomoles calculated with the approximate molecular weights in Column 2.
f The sum of the fraction % of B[a]P and the fraction % of non-B[a]P pentacyclic PAHs equals 1.3%.

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 66
molar refractivity (CMR), and the number of valence elec-
trons (NVE). The second phase of the study involved similar
data for anthracenes, phenanthrenes, and indenes (3300a).
All PAHs in the first two phases of this study (2479, 3300a)
are reported components of cigarette MSS. The ultimate goal
is to use these data to facilitate a QSAR on MSS PAHs. If
such a meaningful relationship can be derived for the more
than 500 MSS PAHs, then it probably can be applied to any
PAH from any source.
As a prelude to this attempt to develop a possibly rea-
sonable explanation for the PAH structure-tumorigenicity
relationship, the PAHs completely or partially identified in
cigarette smoke have been cataloged. For each PAH, the
nomenclature used in Tables I.E-1, I.E-4, and I.E-5 is the
most recent proposed by the International Union of Pure and
Applied Chemistry (IUPAC).
The tobacco smoke PAH references cited in Table I.E-6
are not necessarily all that are available, particularly for those
PAHs such as B[a]P and DB[a,h]A that have been the subject
of much research and discussion for over half a century. In
most cases, included is a reference to the publication or presen-
tation by the investigator(s) who first reported a particular PAH
in MSS. References of articles and/or presentations on specific
PAHs that contained evidence later criticized are included plus
references to the misinterpretations or errors. The criticism
by Fieser (1181) in 1957 of the shortcomings of the evidence
(55–57, 592-594, 820) supposedly indicating the presence
of B[a]P in cigarette smoke has already been mentioned.
Two other notable situations involved 1,2-dihydrobenz[j]
aceanthrylene (cholanthrene) and dibenzo[def,p]chrysene
(formerly named dibenzo[a,l]pyrene, initially 1,2,3,4-diben-
zopyrene). These two PAH identifications, based solely on
UV spectral data, were found to be incorrect. In their study,
Rodgman and Cook (3273) incorrectly defined a PAH as 1,2-
dihydrobenz[j]aceanthrylene (cholanthrene). In the massive
study by USDA personnel on the identification of MSS PAHs,
1,2-dihydrobenz[j]aceanthrylene was not among the several
benzocyclopentanthracenes reported (3756, 3759). The other
incorrectly characterized PAH was dibenzo[def,p]chrysene.
For its identification, not only Rodgman and Cook (3273) but
also Bonnet and Neukomm (397), Lyons and Johnson (2430),
Lyons (2427), Wynder and Wright (4354), and Pyriki (3033)
relied on published UV spectral data purportedly those of syn-
thetic dibenzo[def,p]chrysene (dibenzo[a,l]pyrene). However,
in 1966, Lavit-Lamy and Buu-Hoï (2314) determined that the
published UV spectral data were not those of dibenzo[a,l]
pyrene but of the isomeric dibenz[a,e]aceanthrylene
(dibenzo[a,e]fluoranthene), generated during the supposed
synthesis of dibenzo[a,l]pyrene. The authentic dibenzo[def,p]
chrysene (dibenzo[a,l]pyrene) was identified in MSS in 1977
(3756), but its MSS level has never been reported.
Some authorities insist that the B[a]P and 4-(methylnitros-
amino)-1-(3-pyridinyl)-1-butanone (NNK) in cigarette smoke
are the major causes of lung cancer in cigarette smokers
[Hecht (1557), Hecht and Hoffmann (1571a), Hoffmann and
Hecht (1727), the World Health Organization (4279a)] despite
the following:
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78836_C001.indd 66
The Chemical Components of Tobacco and Tobacco Smoke
1. Neither B[a]P nor any other PAH in CSC either
individually or in combination with the other PAHs
in CSC can explain more than a few percent of the
biological response observed in skin painting with
CSC [Druckrey (1056), Roe (3310, 3311), Wright
and Wynder (4283), Wynder (4296), Wynder and
Hoffmann (4307, 4312, 4343, 4343a, 4354)].
2. Neither B[a]P nor any other PAH in CSC either
individually or in combination with the other
PAHs and assorted promoters (phenols) in CSC
can explain more than a few percent of the biologi-
cal response observed in skin painting with CSC
(4332).
3. In general, the N-nitrosamines in CSC are not tum-
origenic to mouse skin but are organ-specific tum-
origens [Preussmann and Stewart (2991),*] a point
stressed in numerous reviews issued between the
mid-1960s and the late 1990s on N-nitrosamines
[Rodgman (3256)] and recognized by Hoffmann
and Hecht [see p. 75 in (1727)].
4. NNK has never been shown to induce lung cancer
in a laboratory animal by inhalation (1727).
While the minor contribution of B[a]P to the tumorige-
nicity of CSC to mouse skin has been recognized since the
mid-1950s (4353, 4354), its presence in CSC has elicited con-
tinued interest since that time. Examination of the references
to various smoke components reveals an interesting fact
about B[a]P: When all the cigarette smoke components are
tabulated with regard to similar selection of references across
the board, very few tobacco smoke components exceed B[a]
P in the number of pertinent references available. Obviously,
the smoke component discussed most in publications and
presentations between the mid-1950s and 2005 was nicotine.
Next was acetaldehyde, followed by B[a]P.
Another interesting fact about B[a]P is that, despite its
minimal contribution to mouse-skin tumorigenicity from
CSC, almost every year since the mid-1950s there has been
at least one publication on a new and/or improved method to
quantitate the yield of B[a]P in MSS [see Table 6 in (3306b)].
In 2004, CORESTA published its recommended method for
the determination of B[a]P in tobacco smoke (825a). Much
emphasis has been placed on the determination of B[a]P in
the MSS from fewer and fewer cigarettes. Before the advent
of all the newly introduced and subsequently improved spec-
tral and chromatographic systems, estimations of individual
PAHs required the CSC from many cigarettes. For example,
in their studies on the effect of various treatments of tobacco
on the PAHs in MSS, Rodgman and Cook (3241, 3246, 3269,
3274, 3275) chemically analyzed the MSS from 3600 ciga-
rettes for each control and treated sample. For the MSS PAH
* Subsequent to the publication of the Preussmann and Stewart review
(2991), Deutsch-Wenzel et al. (956a) reported that in a skin-painting study
with N’-nitrosonornicotine (NNN), tumors were initiated at the site of
application. The specific tumorigenic potency of NNN was estimated to
be only 0.8% of that of B[a]P. However, no dose response relationship was
observed with NNN over a treatment range of 12.5 to 200 μg.
11/13/08 6:42:37 PM
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TABLE I.E-6
Polycyclic Aromatic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke
Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

(Continued )

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 68 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.E-6 (CONTINUED)

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 The Hydrocarbons 69

TABLE I.E-6 (CONTINUED)

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TABLE I.E-6 (CONTINUED)

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 The Hydrocarbons 71

TABLE I.E-6 (CONTINUED)

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 72 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.E-6 (CONTINUED)

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 The Hydrocarbons 73

TABLE I.E-6 (CONTINUED)

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 74 The Chemical Components of Tobacco and Tobacco Smoke

TABLE I.E-6 (CONTINUED)

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 The Hydrocarbons 75

TABLE I.E-6 (CONTINUED)

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TABLE I.E-6 (CONTINUED)

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 The Hydrocarbons 77

TABLE I.E-6 (CONTINUED)

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TABLE I.E-6 (CONTINUED)

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 The Hydrocarbons 79

TABLE I.E-6 (CONTINUED)

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TABLE I.E-6 (CONTINUED)

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 The Hydrocarbons 81

TABLE I.E-6 (CONTINUED)

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TABLE I.E-6 (CONTINUED)

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 The Hydrocarbons 83

TABLE I.E-6 (CONTINUED)

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TABLE I.E-6 (CONTINUED)

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TABLE I.E-6 (CONTINUED)

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TABLE I.E-6 (CONTINUED)

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TABLE I.E-6 (CONTINUED)

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TABLE I.E-6 (CONTINUED)

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TABLE I.E-6 (CONTINUED)

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TABLE I.E-6 (CONTINUED)

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TABLE I.E-6 (CONTINUED)

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TABLE I.E-6 (CONTINUED)

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TABLE I.E-6 (CONTINUED)

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TABLE I.E-6 (CONTINUED)

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TABLE I.E-6 (CONTINUED)

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TABLE I.E-6 (CONTINUED)

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TABLE I.E-6 (CONTINUED)

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TABLE I.E-6 (CONTINUED)

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TABLE I.E-6 (CONTINUED)

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TABLE I.E-6 (CONTINUED)

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TABLE I.E-6 (CONTINUED)

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 102
TABLE I.E-6 (CONTINUED)
Polycyclic Aromatic Hydrocarbons in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke
analyses in the fifty treated and control samples described in
(3246), more than 183000 cigarettes were smoked, the con-
densate collected, and processed. Nowadays, only a few ciga-
rettes are needed for similar analyses. To permit comparison
of the chemical data with the biological findings of Wynder
et al. (4306a), the smoking procedure used by them was ini-
tially duplicated in the Rodgman-Cook studies in the 1950s,
that is, the cigarettes on a manifold were machine smoked
(35-ml puff volume, 2-sec puff duration, 3 puffs/min) with
a collection system that duplicated the one described by
Wynder et al. (4306a). This smoking regime differed from
the usual 35-ml puff volume, 2-sec puff duration, 1 puff/min
described by Bradford et al. (423b) in 1936 and used by most
investigators in smoke studies after that date.
Table I.E-7 summarizes the PAHs identified in CSC that
were included in earlier descriptions of proposed structure-
tumorigenicity theories.
Examination of Table I.E-7 indicates that most of the
PAHs considered in the various theoretical systems designed
to establish a relationship between molecular structure and
tumorigenicity are totally benzenoid. Only a few PAHs
with a combined benzenoid-cyclopentanoid structure were
included in the early studies. Lacassagne et al. (2247a) in
their discourse on structure-tumorigenicity relationship
mentioned a few benzenoid PAHs but their major empha-
sis was on the structure-tumorigenicity relationship of
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The Chemical Components of Tobacco and Tobacco Smoke
numerous angular benzacridines. While the number of aza-
arenes, including the benzacridines, in CSC is less than the
number of PAHs, nearly 200 have been identified, many
by the USDA group at Athens, Georgia (3750). With the
knowledge that CSC contains nontumorigenic PAHs that
have been shown to substantially reduce the tumorigenicity
of several potently tumorigenic PAHs, consideration of the
study of Lacassagne et al. raises several interesting ques-
tions with regard to tobacco smoke composition. (1) Do any
of the benzacridines or other aza-arenes in CSC partially or
totally inhibit the tumorigenicity of the tumorigenic ben-
zacridines or other aza-arenes? (2) Do any of the benzacri-
dines inhibit the tumorigenicity of tumorigenic PAHs? (3)
Do any of the PAHs reduce the tumorigenicity of the tum-
origenic aza-arenes?
The mixture known as CSC is so complex that it is not
possible to ascribe its biological activity to any individual
component because of the known behavior of that component
when administered individually.
I.F SUMMARY
Detailed examination of the lists presented in the five sec-
tions on hydrocarbons indicates that over 1200 hydrocarbons
have been identified to date in tobacco and tobacco smoke.
The data are summarized in Table I.E-8.
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The Hydrocarbons
TABLE I.E-7
Tobacco Smoke PAHs Discussed in Various Publications on the Relationship Between PAH Structure and Tumorigenicity
Pullman-
Fieser et al. Herndon Lacassagne Martin et al. Pullman Trosko-Upham Zhang et al. Y. Zhang
PAH Discussed Coulson (829) (1180a) (1623a, 2435a) et al. (2247a) (2479) (3003) Rubin (3365) (3966a) (4410c) (4410d)

Acenaphthylene — — X — — — — — — X
Acenaphthylene, — — — — — — — — — X
1,2-dihydro-
Anthracene X X X — — X — X X X
Anthracene, dimethyl- a — — — — — — — X [1] — X [5]
Anthracene, 9,10- — — — — — — — — X X
dimethyl-
Anthracene, 1-methyl- — — — — — — — X — —
Anthracene, 2-methyl- — — — — — — — X — —
Anthracene, 9-methyl- — — — — — — — — — X
Anthracene, trimethyl- — — — — — — — — — X [1]
Azulene — — X — — X — — — —
Benz[a]aceanthrylene — — X — — — — — — X
Benz[j]aceanthrylene, — — — — — — — — X X
1,2-dihydro-
Benz[j]aceanthrylene, — — — X — X X X X
1,2-dihydro-3-methyl-
Benz[e]acephenanthrylene — — X — — — — — X X
Benz[e]acephenanthrylene, — — — — — — — — — X [6]
methyl-
Benz[a]anthracene X X — X — X — — — X
Benz[a]anthracene, X [8] c — — — — — — — X [6] X [23]
dimethyl- a
Benz[a]anthracene, X — — X — X X X X X
7,12-dimethyl-
Benz[a]anthracene, ethyl- — — — — — — — — X [1] —
Benz[a]anthracene, X — — — — — — — — X
1-methyl-
Benz[a]anthracene, X — — — — — — — — X
2-methyl-
Benz[a]anthracene, X — — — — — — — — X
3-methyl-
Benz[a]anthracene, X — — — — — — — — X
4-methyl-
Benz[a]anthracene, X — — — — — — — X X
5-methyl-
Benz[a]anthracene, X — — — — — — — X —
6-methyl-

103
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104
TABLE I.E-7 (CONTINUED)
Tobacco Smoke PAHs Discussed in Various Publications on the Relationship Between PAH Structure and Tumorigenicity
Pullman-
Fieser et al. Herndon Lacassagne Martin et al. Pullman Trosko-Upham Zhang et al. Y. Zhang
PAH Discussed Coulson (829) (1180a) (1623a, 2435a) et al. (2247a) (2479) (3003) Rubin (3365) (3966a) (4410c) (4410d)

Benz[a]anthracene, X — — — — — — — X X
8-methyl-
Benz[a]anthracene, X — — X — — — — X X
9-methyl-
Benz[a]anthracene, X — — — — — — — X X
10-methyl-
Benz[a]anthracene, X — — — — — — — X X
12-methyl-
Benz[a]anthracene, — — — — — — — — X [1] —
propyl-
Benz[a]anthracene, X [1] — — — — — — — X [2] —
tetramethyl-
Benz[a]anthracene, X [3] — — — — — — — X [3] X [13]
trimethyl-
Benzo[b]chrysene — — X — — X — — — X
1H-Benzo[a]cyclopent[h] X — — — — — — — — —
anthracene, 2,3-dihydro-

The Chemical Components of Tobacco and Tobacco Smoke

9H-Benzo[a]cyclopent[i] X — — — — — — — — X
anthracene, 10,11-
dihydro-
Benzo[ghi]fluoranthene — — — — — — — — — X
Benzo[ghi]fluoranthene, — — — — — — — — — X
2-methyl-
Benzo[ghi]fluoranthene, — — — — — — — — — X
3-methyl-
Benzo[j]fluoranthene — — — — — — — — X X
Benzo[k]fluoranthene — — X — — — — — — X
Benzo[k]fluoranthene, — — — — — — — — — X [3]
methyl-
7H-Benzo[c]fluorene — — — — — — — — — X
Benzo[a]naphthacene — — X — — X — — — X
Benzo[rst]pentaphene — — X — — — X — X X
Benzoperylene — — — — — — — — — —
Benzo[ghi]perylene — — X — — — — — X X
Benzo[c]phenanthrene X — X — — X — — X X
Benzo[c]phenanthrene, X [4] — — — — — — — X [6] X [6]
methyl-
Benzopyrene d — — — — — — — — X —
Benzo[a]pyrene — — X — X X X X X X
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The Hydrocarbons
Benzo[a]pyrene, — — — — X — — — — —
7,8-dihydro-
Benzo[a]pyrene, — — — — X — — — — X [9]
dimethyl- a
Benzo[a]pyrene, methyl- b — — — — X — — — — X [1]
3H-Benzo[cd]pyrene, — — — — X — — — — —
4,5-dihydro-
Benzo[e]pyrene — — X — X X X X X X
Benzo[e]pyrene, dimethyl- — — — — X — — — — —
Benzo[e]pyrene, methyl- — — — — X — — — — X [12]
Benzo[e]pyrene, trimethyl- — — — — X — — — — —
Benzo[b]triphenylene — — X — — X X — X X
1,1’-Binaphthalene — — — — X — — — — —
1,1’-Binaphthalene, — — — — X — — — — —
methyl-
Chrysene X — X X — X — X X X
Chrysene, dimethyl- a — — — — — X [1] — — X [1] X [10]
Chrysene, 1-methyl- — — — — — — — — — X
Chrysene, 2-methyl- — — — — — — — — X X
Chrysene, 3-methyl- — — — — — — — — X X
Chrysene, 4-methyl- — — — — — — — — X X
Chrysene, 5-methyl- — — — — — — — — X X
Chrysene, 6-methyl- — — — — — — — — X X
Coronene — — X — — — — — X X
4H-Cyclopenta[def] — — — — — — — — — X
chrysene
Cyclopenta[cd]pyrene — — — — X — — — — —
Dibenz[a,e]aceanthrylene — — X — — — — — — X
Dibenz[a,h]anthracene X X X X — X X — X X
Dibenz[a,j]anthracene X — X — — X — — X X
Dibenzo[b,def]chrysene — — X — — X — — X X
Dibenzo[def,mno]chrysene — — X — — X — — — X
Dibenzo[def,p]chrysene
— — X — — X — — X X
13H-Dibenzo[a,i]fluorene — — — — — — — — — X
Dibenzo[a,j]naphthacene — — — — — X — — — —
Dibenzo[de,qr] — — X — — — — — — —
naphthacene
Dibenzo[fg,op] — — X — X X — — — X
naphthacene
Dibenzopyrene — — — — X — — — — —
Fluoranthene — — X — — — — — — X
Fluoranthene, 2-methyl- — — — — — — — — — X
Fluoranthene, 3-methyl- — — — — — — — — — X

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106
TABLE I.E-7 (CONTINUED)
Tobacco Smoke PAHs Discussed in Various Publications on the Relationship Between PAH Structure and Tumorigenicity
Pullman-
Fieser et al. Herndon Lacassagne Martin et al. Pullman Trosko-Upham Zhang et al. Y. Zhang
PAH Discussed Coulson (829) (1180a) (1623a, 2435a) et al. (2247a) (2479) (3003) Rubin (3365) (3966a) (4410c) (4410d)

Fluoranthene, 7-methyl- — — — — — — — — — X
Fluoranthene, 8-methyl- — — — — — — — — — X
9H-Fluorene — — — — — — — — — X
Indeno[1,2,3-cd]pyrene — — — — X — — — X X
Indeno[1,2,3-cd]pyrene, — — — — X — — — — —
dimethyl-
Indeno[1,2,3-cd]pyrene, — — — — X — — — — —
methyl-
Naphthacene X — — — — X — — — X
Naphthalene X X X X X X — — — X
Naphthalene, dihydro- — — — — X — — — — —
Naphthalene, — — — — X — — — — —
dihydromethyl-
Naphthalene, 1,2-dihydro- — — — — X — — — — —
3-methyl-
Naphthalene, 1,2-dihydro- — — — — X — — — — —
1,1,6-trimethyl-

The Chemical Components of Tobacco and Tobacco Smoke

Naphthalene, 1,2-dihydro- — — — — X — — — — —
1,5,8-trimethyl-
Naphthalene, dimethyl- — — — — X — — — — —
Naphthalene, — — — — X — — — — —
1,2-dimethyl-
Naphthalene, — — — — X — — — — —
1,3-dimethyl-
Naphthalene, — — — — X — — — — —
1,4-dimethyl-
Naphthalene, — — — — X — — — — —
1,5-dimethyl-
Naphthalene, — — — — X — — — — —
1,6-dimethyl-
Naphthalene, — — — — X — — — — —
1,7-dimethyl-
Naphthalene, — — — — X — — — — —
1,8-dimethyl-
Naphthalene, — — — — X — — — — —
2,3-dimethyl-
Naphthalene, — — — — X — — — — —
2,6-dimethyl-
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The Hydrocarbons
Naphthalene, — — — — X — — — — —
2,7-dimethyl-
Naphthalene, dimethyl- — — — — X — — — — —
2-ethenyl-
Naphthalene, — — — — X — — — — —
dimethylethyl-
Naphthalene, dimethyl- — — — — X — — — — —
2-phenyl-
Naphthalene, dimethyl- — — — — X — — — — —
1,2,3,4-tetrahydro-
Naphthalene, 1-ethenyl- — — — — X — — — — —
Naphthalene, 2-ethenyl- — — — — X — — — — —
Naphthalene, — — — — X — — — — —
2-ethenylmethyl-
Naphthalene, 1-ethyl- — — — — X — — — — —
Naphthalene, 2-ethyl- — — — — X — — — — —
Naphthalene, ethylmethyl- — — — — X — — — — —
Naphthalene, 1-ethyl- — — — — X — — — — —
3-methyl-
Naphthalene, 1-ethyl- — — — — X — — — — —
7-methyl-
Naphthalene, 1-ethyl- — — — — X — — — — —
8-methyl-
Naphthalene, 2-ethyl- — — — — X — — — — —
3-methyl-
Naphthalene, 2-ethyl- — — — — X — — — — —
6-methyl-
Naphthalene, 2-ethyl- — — — — X — — — — —
7-methyl-
Naphthalene, hexamethyl- — — — — X — — — — —
Naphthalene, methyl- — — — — X — — — — —
Naphthalene, 1-methyl- — — — — X — — — — —
Naphthalene, 2-methyl- — — — — X — — — — —
Naphthalene, — — — — X — — — — —
(1-methylethyl)-
Naphthalene, — — — — X — — — — —
methylphenyl-
Naphthalene, methyl- — — — — X — — — — —
2-phenyl-
Naphthalene, 1-(1- — — — — X — — — — —
methylpropyl)-
Naphthalene, methyl- — — — — X — — — — —
1,2,3,4-tetrahydro-
Naphthalene, 2-methyl- — — — — X — — — — —
1,2,3,4-tetrahydro-

(Continued)

107
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78836_C001.indd 108

108
TABLE I.E-7 (CONTINUED)
Tobacco Smoke PAHs Discussed in Various Publications on the Relationship Between PAH Structure and Tumorigenicity
Pullman-
Fieser et al. Herndon Lacassagne Martin et al. Pullman Trosko-Upham Zhang et al. Y. Zhang
PAH Discussed Coulson (829) (1180a) (1623a, 2435a) et al. (2247a) (2479) (3003) Rubin (3365) (3966a) (4410c) (4410d)

Naphthalene, pentamethyl- — — — — X — — — — —
Naphthalene, 1-phenyl- — — — — X — — — — —
Naphthalene, 2-phenyl- — — — — X — — — — —
Naphthalene, 1-propyl- — — — — X — — — — —
Naphthalene, 2-propyl- — — — — X — — — — —
Naphthalene, 1,2,3,4- — — — — X — — — — —
tetrahydro-1,1,6-
trimethyl-
Naphthalene, tetramethyl- — — — — X — — — — —
Naphthalene, trimethyl- — — — — X — — — — —
Naphthalene, — — — — X — — — — —
1,2,4-trimethyl-
Naphthalene, — — — — X — — — — —
1,2,6-trimethyl-
Naphthalene, — — — — X — — — — —
1,3,6-trimethyl-
Naphthalene, — — — — X — — — — —

The Chemical Components of Tobacco and Tobacco Smoke

1,4,5-trimethyl-
Naphthalene, — — — — X — — — — —
1,6,7-trimethyl-
Naphthalene, — — — — X — — — — —
2,3,6-trimethyl-
Naphtho[1,2,3,4-def] — — X — — X — — X X
chrysene
Naphtho[2,1,8-qra] — — X — — X — — — X
naphthacene
Naphtho[1,2-b] — — X — — X — — — X
triphenylene
Ovalene — — X — — — — — X —
Pentacene — — X — — X — — X X
Pentaphene X — — — — X — — — X
Perylene — — X — — X — — — X
Phenanthrene X X X X — X — X X X
Phenanthrene, dimethyl- — — — — — — — — X [1] —
Phenanthrene, methyl- — — — — — — — X — —
Phenanthrene, tetramethyl- — — — — — — — — X [1] —
Picene — — — — — X — — — —
Pyrene X — X — X X — X — X
Pyrene, dihydro- — — — — X — — — — —
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78836_C001.indd 109

The Hydrocarbons
Pyrene, dimethyl- — — — — X — — — — —
Pyrene, 3,4-dimethylene- — — — — X — — — — —
Pyrene, hexamethyl- — — — — X — — — — —
Pyrene, 1-hexyl- — — — — X — — — — —
Pyrene, methyl- — — — — X — — — — —
Pyrene, 1-methyl- — — — — X — — — — X
Pyrene, 2-methyl- — — — — X — — — — X
Pyrene, 4-methyl- — — — — X — — — — X
Pyrene, pentamethyl- — — — — X — — — — —
Pyrene, tetramethyl- — — — — X — — — — —
Pyrene, trimethyl- — — — — X — — — — —
5H-Tribenzo[a,f,l]trindene, — — — — — — — — X —
10,15-dihydro-
Triphenylene X — X — — X — X X X
Triphenylene, methyl- — — — — — — — — — X [1]

a The positions of the two methyl groups were not specified.

b The position of the methyl group was not specified.
c Number in square brackets indicates the number of isomers included in the study.

d The nature of the benzopyrene was not specified.

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 110 The Chemical Components of Tobacco and Tobacco Smoke

TAble I.e-8
Distribution of Identified hydrocarbons between Tobacco and Tobacco smoke
number of Identified hydrocarbons in Tobacco and Tobacco smoke
hydrocarbon Table Total smoke Tobacco smoke and Tobacco
Alkanes Table I.A-10 132 111 96 75
Alkenes and alkynes Table I.B-1 363 347 42 25
Alicyclics Table I.C-1 142 95 61 16
Monocyclic aromatic Table I.D-1 98 89 39 30
Polycyclic aromatic Table I.E-6 586a 575a 86 74
Totals 1321 1217 324 220
a This number includes the various isomers of alkyl-PAHs reported in which the position of the alkyl group or groups has
not been precisely defined.

It is obvious from the tabulation that the PAHs represent
nearly 44% of the hydrocarbons identified to date and a sub-
stantial number of them are smoke components. The one cat-
egory in the PAHs that is found to an appreciable extent in
a particular type of tobacco, Latakia tobacco, is the bicyclic
aromatic hydrocarbon naphthalene and its homologs (1135,
2784). The few remaining PAHs present in both tobacco and
its smoke include several tricyclic, tetracyclic, and pentacy-
clic PAHs, for example, anthracene, phenanthrene, pyrene,
and B[a]P. As a result of the study by Bentley and Burgan
(285) in the early days of the concern about B[a]P in tobacco
smoke and its origin, the presence of B[a]P and the other
PAHs in tobacco is usually attributed to its contamination by
pollutants during transportation, curing, etc.

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 2 Alcohols and Phytosterols
II.A Alcohols
Periodically, tobacco researchers have reported the prog-
ress on the identification of tobacco and smoke components.
Review articles by Johnstone and Plimmer (1971) and Izawa
(1900) detailed much of the tobacco and smoke research con-
ducted over the preceding century. Izawa listed 440 identified
smoke components by 1961. The next year, Quin (3059) pub-
lished a review of components found in tobacco and smoke.
Herrmann (1625) reviewed phenolic compounds in tobacco
smoke. In 1963, Philip Morris (2939) published a monograph
on tobacco and smoke composition, a copy of which was
provided the Advisory Committee on smoking and health to
the U.S. Surgeon General (3999). In 1964, Elmenhorst and
Reckzeh (1139) tabulated the aromatic hydrocarbons identi-
fied in tobacco smoke. Kuhn (2228, 2229) published articles
on alkaloids in tobacco and their pyrolysis products in smoke.
In their 1967 book, Wynder and Hoffmann (4332) discussed
tobacco and smoke chemistry and the results of animal stud-
ies with tobacco smoke. Elmenhorst and Schultz (1140) listed
250 low-boiling components and vapor-phase components
identified in tobacco smoke. In his 1968 review, Stedman
(3797) listed nearly 1200 identified tobacco and smoke com-
ponents. The next year, Neurath (2724) reported on the pres-
ence of 180 N-containing compounds in smoke.
With the meaningful advancements in analytical method-
ology, the number of identified tobacco and smoke compo-
nents increased dramatically (1373). In an in-house catalog
assembled at R. J. Reynolds Tobacco Company (RJRT) in
1975, Roberts et al. (3224) listed 2783 identified components
of tobacco and tobacco smoke. During the mid-1970s at
RJRT, Schumacher et al. (3553), Heckman and Best (1587),
and Newell et al. (2769) identified over 1540 compounds
in the water-soluble and ether-soluble fractions of tobacco
smoke. Of these, over 820 compounds were newly reported
as tobacco smoke components. In 1977, Schmeltz and
Hoffmann (3491) cataloged nearly 500 N-containing com-
pounds identified in tobacco smoke but their catalog did not
include the more than 230 N-containing compounds newly
identified in tobacco smoke by Heckman and Best (1587).
Between 1974 and 1978, Snook et al. (3756–3758) published
the results of their massive study of the PAHs and a num-
ber of benzofurans identified in tobacco smoke, a study that
was followed by an equally definitive one on the identifica-
tion of aza-arenes and monocyclic N-containing compounds
in tobacco smoke (3750). In 1980, Ishiguro and Sugawara
(1884) listed 1889 identified tobacco smoke components
in their monograph. However, a tally of the tobacco smoke
components reported at that time exceeded 2500. No addi-
tional catalogs of the total number of identified components
© 2009 by Taylor & Francis Group, LLC
78836_C002.indd 111
of cigarette mainstream smoke (MSS) have been published
since the 1980 Ishiguro and Sugawara (1884) publication.
Smith et al. (3712) recently reported the chemical structures
of the 253 identified phenols reported in cigarette MSS.
In the past, different authors had different views on the
classification of alcohols in tobacco and tobacco smoke. In
our catalog, we employ a system different from those used
by our forerunners. In 1954, Kosak (2170), in his smoke com-
ponent compilation, listed seven “alcohols”: four alcohols
(methanol, glycerol, diethylene glycol, and ethylene glycol)
and three phenols (phenol, “phenols,” and catechol). He did
not list either levoglucosan or a “phytosterol” as an alcohol
but listed both as miscellaneous smoke components. In 1959,
Johnstone and Plimmer (1971) listed thirteen alcohols plus
five phytosterols identified in tobacco and/or smoke.
In his 1968 review, Stedman (3797) divided the alcohols
into three categories, namely, alcohols, sterols, and oxygen-
ated isoprenoid constituents. The latter category contained
constituents other than those with an alcoholic hydroxyl
group, for example, farnesyl acetone (a ketone), solanach-
romene (a phenol), the tocopherols (phenols), and the levan-
tanolides and levantenolide (ether-lactone combinations). In
the category usually considered alcohols, Stedman listed a
total of twenty-five alcohols (fifteen aliphatic, two aromatic,
five polyols, and three cyclic).
In our catalog, we have considered three types of compo-
nents with hydroxyl groups: (1) components with a carboxyl
group and its hydroxyl group (discussed in Chapter IV), (2)
components with an hydroxyl group attached to a monocyclic
or polycyclic benzenoid nucleus, that is, a phenol (discussed
in Chapter IX), and (3) an hydroxyl group attached to a satu-
rated or unsaturated aliphatic, alicyclic, or nonbenzenoid
nucleus, which may or may not include another functional
entity. An example of category (3) is the first item in Table
II.A-1, hydroxyacetaldehyde (glycolaldehyde), which is both
an alcohol and aldehyde. The saturated aliphatic alcohols
range from methanol to 1-triacontanol with alkyl homologs
included in some cases, for example, 1-butanol and 2-methyl-
1-propanol. The unsaturated aliphatic alcohols include 2-pro-
pen-1-ol (allyl alcohol) and such terpenoid structures as the
C10 alcohol 3,7-dimethyl-1,6-octadien-3-ol (linalool), the
C20 alcohol 3,7,11,15-tetramethyl-2-hexadecen-1-ol (phytol),
and the C45 alcohol 3,7,11,15,19,23,27,31,35-nonamethyl-2,
6,10,14,18,22,26,30,34-hexatriacontanonaen-1-ol (solanesol).
Examples of the alicyclic alcohols range from cyclopentanol
to various carotenediols and triols to numerous cyclotetradec-
adienols, diols, and triols. Other alicyclic alcohols include a
great variety of carbohydrates such as glucose and fructose
plus the cases where such carbohydrates are linked to another
component such as a phytosterol to form a glycoside.
111
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 112 The Chemical Components of Tobacco and Tobacco Smoke

Table II.A-1
Tobacco and Tobacco Smoke Components Identified by Classical Chemical Methods
Year Investigator (Reference) Component(s) Identified Smoke Tobacco

1953 Sasaki (3413) 2,3-Butanedione + —

1956 Rowland et al. (3359) Solanesol — +
1956 Rowland (3345) Neophytadiene — +
1956 Rowland (3347) α-Tocopherol, solanachromene — +
1957 Kosak et al. (2178) Stigmasterol + —
1958 Kosak and Swinehart (2175) Squalene + —
1958 Philippe and Hackney (2941) Nitrous oxide, methyl nitrite — +
1958 Wender et al. (4164) Scopoletin + —
1959 Dieterman et al. (969) Esculetin — +
1959 Dymicky and Stedman (1082) Campesterol — +
1959 Gladding et al. (1307) Neophytadiene + +
1959 Rodgman and Cook (3271) α-Tocopherol + —
1959 Kobashi and Sakaguchi (2145) Glucose, fructose, arabinose, xylose + —
1960 Carruthers and Johnstone (614) Docosanol, solanesol — +
1960 Schumacher (3535) β-D-Glucopyranose, 6-acetate 2,3,4-tris((+)-3-methylpentanoate) — +
1960 Yang et al. (4376) Caffeic acid + —
1962 Roberts and Rowland (3221) α- and β-4,8,13-Duvatriene1,3-diol — +
1962 Cook and Rodgman (801) α- and β-Levantenolide + —
1962 Rodgman and Cook (3280) Eugenol, isoeugenol + —
1962 Yang and Wender (4378) Protocatechuic acid, 5-hydroxymethylfurfural + —
1964 Philippe and Honeycutt (2943) Methyl isocyanate + —
1965 Zane et al. (4402) 4-O-Caffeoylquinic acid — +

With our method of defining an alcohol in tobacco and/
or smoke, the alcohols number over 1400. We realize that
some readers may disagree with our classification of several
hydroxypyridines as alcohols but the ones listed appear not
only in this chapter, but also appear in Chapter XVII.B, in
which monocyclic N-containing six-membered ring com-
pounds are described and cataloged.
Present analytical technology to identify a component in a
complex mixture such as tobacco smoke or a tobacco extract
involves the generation of a variety of spectra from which the
compound may be characterized. The spectra may include
separation of the component from the mixture by glass capil-
lary gas chromatography, its retention time, plus those gen-
erated by ultraviolet, infrared, nuclear magnetic resonance,
and mass spectroscopy studies. Nowadays, seldom is the
component in the complex isolated in a tangible amount. In
the early days, the study of the composition of tobacco was
accomplished by so-called classical chemical procedures.
The following example illustrates how an isolated terpenoid
alcohol was subsequently characterized: Ozonization of
the compound followed by degradation of the ozonide and
derivatization of the degradation products with 2,4-dinitro-
phenylhydrazine yielded the 2,4-dinitrophenylhydrazones of
the compounds shown in Figure II.A-1: Glycolic aldehyde
(hydroxyacetaldehyde) {II}, levulinaldehyde (4-oxopentanal)
{III}, and acetone (2-propanone) {IV}. These findings led to
the assignment in 1956 of the structure {I}in Figure 11.A-1
by Rowland et al. (3359) to the terpenoid alcohol they named
solanesol.
In the mid-1950s, the determination of the molecular
weight of compounds with a molecular weight above 300 to
400 was difficult and often inaccurate. As a result, Rowland
et al. were unable to precisely define the molecular weight
of solanesol and therefore its structure. Originally, they had
intended to report that solanesol was either a C45 compound
(I, n = 8 in Figure II.A-1) or a C50 compound (I, n = 9 in Figure
II.A-1) but were forced to choose one or the other. Because
the majority of known isoprenoids at that time were terpe-
noids, that is, multiples of C10, and relatively few were sesqui-
terpenoids, that is, multiples of C15, Rowland et al. elected to
report solanesol as a pentaterpenoid, that is, a C50 compound.
In 1957, Mold and Booth (2590) reported the identification of
solanesol in cigarette mainstream smoke (MSS).
Subsequently, with more advanced analytical technol-
ogy, Erickson et al. (2A01)) and Shunk et al. (2A03) reported
in back-to-back publications in 1959 that a more precise
CH3 CH3
HOCH2-CH=C-CH2-CH2-CH=C-CH3
n
I
HOCH2-CH=O H3C-CO-CH2-CH2-CH=O H3C-CO-CH3
II III IV
Figure II.A-1  The degradation products from ozonized solanesol.

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 Alcohols and Phytosterols 113

molecular weight method indicated that solanesol was a C45
compound (I, n = 8 in Figure II.A-1) with the formula C45H74O
(molecular weight, 630), 3,7,11,15,19,23,27,31,35-nonamethyl-
2,6,10,14,18,22,26,30,34-hexatriacontanonaen-1-ol.
Since its characterization in 1956, solanesol has had an
interesting history as a tobacco component. It is present:
1. In the different types of tobacco (flue-cured, burley,
Oriental, Maryland) (3295)
2. In the smoke from each when smoked in cigarette
form (2559, 3270, 3295)
3. As a variety of esters in tobacco [Rowland and
Latimer (3358)] and tobacco smoke [Rodgman and
Cook (3270), Rodgman et al. (3286)]
It generates isoprene [Gil-Av and Shabtai (1286); Grossman
et al. (1431, 1432)], several solanesenes [Rodgman et al.
(3297)], and numerous polycyclic aromatic hydrocarbons
[Rodgman and Cook (3269), Severson et al. (3616)] during
the smoking process. It was proposed by Wright (4282) as a
more significant precursor in tobacco of polycyclic aromatic
hydrocarbons (PAHs) in MSS than the aliphatic long-chained
hydrocarbons, and eventually was found to be such by
Rodgman and Cook (3269) and Severson et al. (3616). More
recently solanesol was studied as an indicator of environ-
mental tobacco smoke (ETS) in room space [Ogden (2829),
Ogden and Maiola (2833, 2834), Robinson et al. (3230), Tang
et al. (3868)].
In the early tobacco and tobacco smoke studies, the chemi-
cal nature of one or two components was defined by means of
classical chemical procedures and described in an appropriate
publication, for example, the identification of the previously
discussed terpenoid alcohol solanesol in flue-cured tobacco
(3359), the phenols eugenol and isoeugenol identified in the
mainstream smoke (MSS) from Oriental tobacco (3280), and
maltol identified in the MSS from an ingredient-free German
tobacco blend (1131). A random selection of several of these
early studies is presented in Table II.A-1.
However, as analytical methodology became more sophis-
ticated and precise, many more components—sometimes
several hundred newly identified in tobacco or smoke—were
reported in a single publication. In his pioneer research on
glass capillary gas chromatography in 1965, Grob (1416), in
his study of the MSS from cigarettes containing additive-
free tobacco, identified sixty-three components, a number
of which were polar components. Later, some of the polar
components in MSS identified by Grob are also listed in the
Doull et al. catalog of cigarette flavor ingredients (1053).
In the 1950s, the organic solvent extraction of tobacco was
studied extensively with the purpose of removing PAH pre-
cursors from the tobacco. Incorporated into one process was
an aqueous alcohol-hexane partition to separate the polar,
more flavorful tobacco components from the lipophilic PAH
precursors. At that time, almost nothing was known about
the nature of the polar tobacco components, although it was
apparent they made a considerable positive contribution to
the flavor and aroma of cigarette MSS. Despite the lack of
knowledge about the precise nature of the polar components,
it was demonstrated they were not significant PAH precur-
sors (3262). Our inability at that time to separate highly polar
compounds in a complex mixture contributed to our lack of
knowledge of the nature of the polar components in tobacco
and/or tobacco smoke. This situation continued during years
of intensive effort on cigarette MSS composition but was
finally resolved and utilized by Schumacher et al. (3553) in
the 1970s. Of the total of 1545 MSS components identified by
Schumacher et al. (3553), Newell et al. (2769), and Heckman
and Best (1587), 828 (53.6%) were new to the tobacco smoke
literature at the time of the publication and a great number of
them were highly polar compounds (see Table II.A-2).

Table II.A-2
Tobacco and Tobacco Smoke Studies in Which Components Were Identified by a Combination of Spectral
Technologies
Year Investigator (Reference) No. of Identified Components Smoke Tobacco Newa

1965 Grob (1416) 63 + — 27

1973/74 Schumacher and Vestal (3561) 118 — + 25
1974/76 b Lloyd et al. (2389) 323 — + 132
1974/77 Schumacher et al. (3553) 479 + — 387
1975 Newell et al. (2769) 643 + — 173
1976 Snook et al. (3758) 115 + — NIc
1977 Snook et al. (3756) 157 + — NI
1978 Snook et al. (3757) 536 + — NI
1978 Heckman and Best (1587) 423 + — 268
1982/82 Schumacher (3550) 97 — + 1
2004 Peng et al. (2917a) 408 — + NI
2005 Leffingwell and Alford (2339a) 334 — + 49
a Newly reported components to tobacco and/or smoke at the date of the publication.
b The first date is that of a scientific conference presentation, the second is that of a publication in a peer-reviewed scientific journal.
c NI = not indicated was the number of components not previously identified in tobacco or tobacco smoke.

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 114 The Chemical Components of Tobacco and Tobacco Smoke
With regard to tobacco components, Lloyd et al. (2389)
identified 275 previously unidentified components of addi-
tive-free flue-cured tobacco, 132 new to all additive-free
tobacco types. Many of these compounds were highly
polar and considered significant contributors to MSS
flavor and aroma. Similar detailed studies were conducted
on the composition of burley tobacco by Roberts and Rohde
(3219), Oriental tobacco by Schumacher and Vestal (3561),
and Maryland tobacco by Schumacher (3550). Years later, it
became apparent that many of the highly polar components
of tobacco and tobacco smoke were identical with similar to
many of the components used in the flavor formulations, that
is, the “top dressing,” added to a specific tobacco blend to
impart its unique smoking characteristics (1053). Randomly
selected publications on the identification of many additive-
free tobacco and/or tobacco smoke components are listed in
Table II.A-2.
The description of the isolation and/or identification of a
great number of tobacco and/or smoke components was not
always the case even after the development of sophisticated
analytical technologies that generated informative spectral
data. Between the early 1970s and the late 1980s, the research
group at the Swedish Tobacco Company in Stockholm,
Sweden, generated a great number of publications on flue-
cured and Oriental tobacco composition in many of which
only a single component or a few newly identified tobacco
components were described. Admittedly, much attention was
paid to the definition of the stereoisomerism of some of the
components described individually. Selected examples of
their extensive study of tobacco composition are presented
in Table II.A-3.
Periodically between the mid-1970s and late 1980s,
the Swedish Tobacco Company group published excellent
reviews of their tobacco component studies and other mean-
ingful related studies in the scientific literature, for example,
Enzell (1149, 1149a), Enzell and Wahlberg (1156), Enzell et al.
(1157), Wahlberg and Eklund (4086a), and Wahlberg and
Enzell (4089, 4090).
Table II.A-3
Tobacco Components Identified Post-1975
Year Investigator (Reference)
1971 Aasen et al. (9a)
1971 Enzell et al. (1155)
1974 Aasen et al. (6)
1975 Aasen et al. (1)
1977 Behr et al. (230)
1977 Behr et al. (231)
1978 Behr et al. (229)
1979 Behr et al. (234)
1982 Wahlberg et al. (4084)
1983 Wahlberg et al. (4087)
1983 Wahlberg et al. (4098)
1984 Wahlberg et al. (4083)
1986 Wahlberg et al. (4102)
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78836_C002.indd 114
In addition to his isolation of the alcohol solanesol and con-
tribution to its characterization, Rowland was involved in the
isolation and characterization of the hydroxylated flue-cured
tobacco components solanachromene and α-tocopherol,
each of which is a phenol. The solanachromene has not been
identified in tobacco smoke but α-tocopherol, a well-known
anticarcinogen, was identified as a cigarette MSS component
in 1959 (3271) and many times since in MSS and ETS, for
example, see Risner (3170).
In their 1962–1963 study of hydroxylated tobacco compo-
nents, Rowland and colleagues next isolated several 1,3- and
1,5-diols from tobacco. Structurally, these diols were shown to
be related to the alicyclic diterpenoid hydrocarbon cembrene,
previously isolated in 1951 from plant tissue by Haagen-Smit
et al. (2A02) and characterized in 1962 as 3,7,11-trimethyl-14-
(1-methylethyl)-1,3,6,10-cyclotetradecatetraene (see {V} in
Figure II.A-2) by Dauben et al. (905a). The 1,3-diol and 1,5-diol
isolates were demonstrated to possess the cyclotetradeca-
triene structures shown as {VI} and {VII}, respectively, in
Figure II.A-2 [Rowland (3351, 3352), Rowland and Roberts
(3360)]. Additional studies indicated the presence in tobacco
not only of the diols {VI} and {VII} but also the two oxabi-
cyclo compounds {VIII} and {IX} derived from the 1,5-diol
{VII}. A third oxabicyclo type {X} was eventually identified
in tobacco (9, 12, 4089–4091). The four compounds {VI} to
{IX} were reported by Rowland et al. to be present in ciga-
rette MSS (3361). Cembrene {V} was eventually identified in
1966 in tobacco by Reid (1097a) and in Japanese tobacco in
1980 by Takagi et al. (3853).
The reports of these cyclotetradecatrienediols and their
ethers by Rowland, Roberts, and their colleagues led to an
intensive study of tobacco by the Swedish Tobacco Company
research team. Their study involved the isolation, char-
acterization, and stereochemical definition of nearly 100
compounds containing the 14-carbon ring [Aasen et al.
(12), Arndt et al. (94a), Behr et al. (235, 236), Wahlberg et
al. (4083–4085, 4091, 4098–4100), Wahlberg and Eklund
(4086a, 4088), Wahlberg and Enzell (4091)].
Components Identified
5-Methoxy-6,7-dimethylbenzofuran
Norsolanesene
(9R)-9-Hydroxy-4-megastigmen-3-one,
5,6-Epoxy-3-hydroxy-7-megastigmen-9-one (2 isomers)
3,3-Dimethyl-7-hydroxy-2-octanone
2,6-Dimethyl-10-oxo-3,6-undecadien-2-ol, 3-methyl-4-oxo-2-nonen-8-ol
2,6-Dimethyl-2,7-octadiene-1,6-diol
5,8-Epoxy-6-megastigmene-3,9-diol, 3,6-epoxy-7-megastigmene-5,9-diol
8,11-Epoxy-2,6-cembradiene-4,12-diol
7,8-Epoxy-4-basmen-6-one
Hydroperoxycembratrienediols [5 in all]
Cembratrienols [6 in all]
A new sucrose ester
11/13/08 4:59:23 PM
 Alcohols and Phytosterols 115

H3C CH3
OH 6
10 10 8 7
1 H3C
14 9 12 11 9 5
3 11 13 1 OH
11 CH3 14 2
8 6 4 123 1 4
10 7 5 3 2
13 3
7 OH
5
CH3 OH
V VI VII
3,7,11-Trimethyl-14-(1- 1,5,9-Trimethyl-12-(1- 1,5,11-Trimethyl-8-(1-
methylethyl)-1,3,6,10- methylethyl)- 4,8,13- methylethyl)- 2,6,11-
cyclotetradecatetraene cyclotetradecatriene-1,3-diol cyclotetradecatriene-1,5-diol
{cembrene}

H3C CH3 H3C CH3

H3C CH3
OH CH3 CH3
10 6 OH 13 9
H2C
8 10 6 12 11 10
11 H 3C 8
9 7 5 8 14
2 CH3 11 9 7 5 O OH
1 4 O CH3 1
12 2 6 7
1 4 3 5
3 HO 2 4
3
CH3
O CH3 CH3 O
VIII IX X

1,5-Dimethyl-11-methylene-8-(1- 1,5,11-Trimethyl-8-(1- 8-Hydroxy-4,8,14-trimethyl-11-

methylethyl)-15- methylethyl)-15- (1-methylethyl)-15-
oxabicyclo[10.2.1]pentadeca-2,6- oxabicyclo[9.3.1]pentadeca-2,6- oxabicyclo[12.1.0]pentadeca-
dien-5-ol diene-5,12-diol 4,9-dien-6-one

Figure II.A-2  Tobacco and/or tobacco smoke alcohols related to cembrene.

Much research was conducted after the mid-1950s to iden- tumorigenicity of several PAHs, Barry et al. (194) reported
tify alcohol components in the particulate phase of cigarette that a third PAH, 3-methylcholanthrene, was also a highly
MSS primarily because some were found to contribute con- potent tumorigen. 3-Methylcholanthrene was subsequently
sumer acceptable flavor and aroma properties to the MSS. named 1,2-dihydro-3-methylbenz[j]aceanthrylene. Because
As noted by Rodgman (3266), many components, including of their structural similarity, 1,2-dihydro-3-methylbenz[j]
alcohols, used by the tobacco industry in its flavor formula- aceanthrylene became the object of the search in the
tions [see listing by Doull et al. (1053)] are known compo- pyrolysate from cholesterol (Figure II.B-1).
nents of additive-free tobacco and/or its smoke. Thus, such Cholesterol and several similarly structured phytoster-
additives are not strangers to the tobacco and/or its smoke ols (campesterol, β-sitosterol, and stigmasterol) are compo-
but their addition increases the consumer acceptable flavor. nents of tobacco and a portion of each is transferred intact
Table II.A-4 lists some of the tobacco and/or tobacco smoke to smoke during the smoking process. The phytosterols in
alcohol components that have been or are used in flavor tobacco have been reported by numerous investigators, for
formulations. example, Traetta-Mosca (3942b), Kobel and Neuberg (2153a),
Table II.A-5 is a catalog of the alcohols identified in Shmuk (3656a), Khanolkar et al. (2087), and Venkatarao
tobacco and/or tobacco smoke. Of the 1462 alcohols identi- et al. (4042b). All have been reported in tobacco as glyco-
fied to date, 531 have been reported in tobacco smoke, 1152 sides by Bolt and Clarke (390), Dymicky and Stedman (1079),
in tobacco, and 221 in both tobacco and tobacco smoke. Kallianos et al. (2018, 2019), and Khanolkar et al. (2087) and
long-chained saturated and unsaturated acid esters (3296).
Theoretically, all could yield 1,2-dihydrobenz[j]acean-
II.B PHYTOSTEROLS
thrylene and/or 1,2-dihydro-3-methylbenz[j]aceanthrylene
The alcohol category in tobacco and tobacco smoke includes during the smoking process.
the phytosterols, the plant-derived sterols. The sterols have To date, the identification of this PAH in tobacco smoke
been examined in considerable detail over the years, an has been reported by only one investigator, Kröller (2191).
examination that did not actually originate in the study of Dihydrobenz[j]aceanthrylene (cholanthrene) was not among
tobacco and/or its smoke. In 1928, Kennaway and Sampson the several PAHs isomeric with 1,2-dihydrobenz[j]acean-
demonstrated the tumorigenicity of the pyrolysate from thrylene reported by Snook et al. (3756–3758). In the late
the sterol cholesterol (2080). Their study preceded the first 1940s there was much interest in 1,2-dihydro-3-methylbenz[j]
reports of induction of skin cancer in laboratory animals with aceanthrylene because of its possible generation from choles-
two individual compounds, the PAHs dibenz[a,h]anthracene terol during the heating of cholesterol-containing foodstuffs.
(DB[a,h]A) in 1930 by Kennaway and Hieger (2078) and While 1,2-dihydro-3-methylbenz[j]aceanthrylene could actu-
benzo[a]pyrene (B[a]P) in 1932 by Cook et al. (796a, 797). ally be synthesized from cholesterol by a series of sophisti-
Both PAHs subsequently were classified as highly potent cated chemical reactions (1184a), attempts to generate it by
tumorigens. Based on the results of their detailed study of the pyrolysis of cholesterol were unsuccessful.

© 2009 by Taylor & Francis Group, LLC

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 116 The Chemical Components of Tobacco and Tobacco Smoke

Table II.A-4
Tobacco and/or Smoke Alcohols Used in Flavor Formulations
Identified In
CAS No. Chemical Abstracts Nomenclature As Listed by Doull et al. (1053) Smoke Tobacco

60-12-8 Benzeneethanol phenethyl alcohol + +

100-51-6 Benzenemethanol benzyl alcohol + +
105-13-5 Benzenemethanol, 4-methoxy- anisyl alcohol — +
98-85-1 Benzenemethanol, α-methyl- α-methylbenzyl alcohol — +
122-97-4 Benzenepropanol 3-phenyl-1-propanol + +
507-70-0 Bicyclo[2.2.1]heptane-2ol, endo-1,7,7,-trimethyl- borneol + +
107-88-0 1,3-Butanediol 1,3-butanediol + +
71-36-3 1-Butanol butyl alcohol + +
98-55-5 3-Cyclohexene-1-methanol, α,α,4-trimethyl- α-terpineol + +
562-74-3 3-Cyclohexen-1-ol, 4-methyl-1-(1-methylethyl)- 4-carvomenthol + +
112-30-1 1-Decanol capric alcohol — +
7212-44-4 1,6,10-Dodecatrien-3-ol, 3,7,11-trimethyl- nerolidol + +
64-17-5 Ethanol ethyl alcohol + +
57-48-7 D-Fructose sugars + +
59-23-4 D-Galactose sugars + +
50-99-7 α-D-Glucose sugars + +
57-50-1 α-D-Glucopyranoside, β-D-fructofuranosyl-  {sucrose} sugars + +
50-99-7 α-D-Glucose sugars + +
111-27-3 1-Hexanol hexyl alcohol — +
104-76-7 1-Hexanol, 2-ethyl- 2-ethyl-1-hexanol + +
544-12-7 3-Hexen-1-ol 3-hexen-1-ol — +
31103-86-3 Mannose sugars + +
78-70-6 1,6-Octadien-6-ol, 3,7-dimethyl- linalool — +
106-25-2 2,6-Octadien-1-ol, 3,7-dimethyl- nerol — +
111-87-5 1-Octanol 1-octanol — +
3391-86-4 1-Octen-3-ol 1-octen-3-ol — +
106-22-9 6-Octen-1-ol, 3,7-dimethyl- dl-citronellol + +
71-41-0 1-Pentanol amyl alcohol — +
57-55-6 1,2-Propanediol propylene glycol + +
56-81-5 1,2,3-Propanetriol glycerol + +
78-83-1 1-Propanol, 2-methyl- isobutyl alcohol + +
104-54-1 2-Propen-1-ol, 3-phenyl- cinnamyl alcohol + —
118-71-8 4H-Pyran-4-one, 3-hydroxy-2-methyl- maltol + +
50-70-4 Sorbitol a glucitol — +
a  orbitol (glucitol)) is not included in the Doull et al. list (1053) but is included in flavor formulations used by cigarette manufacturers outside of the U.S.
S
[see Table 7A in (3266)].

As shown in Figure II.B-2, pyrolysis of cholesterol {Ia}
yields chrysene {III}, Diels′ hydrocarbon {IV}—a methyl-
cyclopentaphenanthrene—and numerous other PAHs. Both
PAHs noted have also been identified in pyrolysates of the
major tobacco phytosterols [Wynder et al. (4356), Van Duuren
(4022)]. More recently in the early 1970s, Hecht et al. (1560)
discussed the generation of chrysene and alkylchrysenes by
pyrolysis of phytosterols.
Although none of the sterols {Ia–Id} has been shown to
generate the potent tumorigen 1,2-dihydro-3-methylbenz[j]
aceanthrylene (3-methylcholanthrene) on pyrolysis, Falk et al.
(1171) reported that cholesterol and cholesterol esters on
pyrolysis do generate the mouse-skin tumorigens 4-cholesten-
3-one {Va} and 3,5-cholestadiene {VIa}. Veldstra (4042a)
reported that the pyrolysis of cholesteryl oleate also yielded
3,5-cholestadiene {VIa}. Cholesteryl oleate was probably a
component of the mixture of phytosteryl esters described in
flue-cured tobacco by Rowland and Latimer (3358). Its ana-
logs stigmasteryl oleate and β-sitosteryl oleate were among
the phytosteryl esters in tobacco smoke characterized by
Rodgman et al. (3296). The other identified phytosteryl
esters included stigmasterol and β-sitosterol esterified with
saturated acids (lauric, palmitic, stearic, and myristic) and
unsaturated acids (linolenic and linoleic) (3296).
Relative to the low level of cholesterol {1a}, tobacco
usually contains substantial levels of several phytosterols

© 2009 by Taylor & Francis Group, LLC

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 Alcohols and Phytosterols 117

Table Ii.A-5
Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke
Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 117 11/13/08 4:59:35 PM

 118 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 118 11/13/08 4:59:36 PM

 Alcohols and Phytosterols 119

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 119 11/13/08 4:59:38 PM

 120 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 120 11/13/08 4:59:55 PM

 Alcohols and Phytosterols 121

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 121 11/13/08 4:59:58 PM

 122 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 122 11/13/08 5:00:03 PM

 Alcohols and Phytosterols 123

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 123 11/13/08 5:00:05 PM

 124 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 124 11/13/08 5:00:07 PM

 Alcohols and Phytosterols 125

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 125 11/13/08 5:00:10 PM

 126 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 126 11/13/08 5:00:13 PM

 Alcohols and Phytosterols 127

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 127 11/13/08 5:00:21 PM

 128 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 128 11/13/08 5:00:23 PM

 Alcohols and Phytosterols 129

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 129 11/13/08 5:00:26 PM

 130 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 130 11/13/08 5:00:28 PM

 Alcohols and Phytosterols 131

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 131 11/13/08 5:00:33 PM

 132 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 132 11/13/08 5:00:35 PM

 Alcohols and Phytosterols 133

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 133 11/13/08 5:00:48 PM

 134 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 134 11/13/08 5:00:49 PM

 Alcohols and Phytosterols 135

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 135 11/13/08 5:00:52 PM

 136 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 136 11/13/08 5:00:54 PM

 Alcohols and Phytosterols 137

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 137 11/13/08 5:00:57 PM

 138 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 138 11/13/08 5:01:00 PM

 Alcohols and Phytosterols 139

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 139 11/13/08 5:01:03 PM

 140 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 140 11/13/08 5:01:05 PM

 Alcohols and Phytosterols 141

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 141 11/13/08 5:01:08 PM

 142 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 142 11/13/08 5:01:10 PM

 Alcohols and Phytosterols 143

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 143 11/13/08 5:01:13 PM

 144 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 144 11/13/08 5:01:15 PM

 Alcohols and Phytosterols 145

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 145 11/13/08 5:01:18 PM

 146 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 146 11/13/08 5:01:20 PM

 Alcohols and Phytosterols 147

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 147 11/13/08 5:01:23 PM

 148 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 148 11/13/08 5:01:25 PM

 Alcohols and Phytosterols 149

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 149 11/13/08 5:01:28 PM

 150 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 150 11/13/08 5:01:30 PM

 Alcohols and Phytosterols 151

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 151 11/13/08 5:01:33 PM

 152 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 152 11/13/08 5:01:35 PM

 Alcohols and Phytosterols 153

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 153 11/13/08 5:01:38 PM

 154 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 154 11/13/08 5:01:40 PM

 Alcohols and Phytosterols 155

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 155 11/13/08 5:01:43 PM

 156 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 156 11/13/08 5:01:45 PM

 Alcohols and Phytosterols 157

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 157 11/13/08 5:01:48 PM

 158 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 158 11/13/08 5:01:51 PM

 Alcohols and Phytosterols 159

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 159 11/13/08 5:01:53 PM

 160 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 160 11/13/08 5:02:03 PM

 Alcohols and Phytosterols 161

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 161 11/13/08 5:02:06 PM

 162 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 162 11/13/08 5:02:14 PM

 Alcohols and Phytosterols 163

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 163 11/13/08 5:02:16 PM

 164 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 164 11/13/08 5:02:18 PM

 Alcohols and Phytosterols 165

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 165 11/13/08 5:02:21 PM

 166 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 166 11/13/08 5:02:30 PM

 Alcohols and Phytosterols 167

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 167 11/13/08 5:02:31 PM

 168 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 168 11/13/08 5:02:34 PM

 Alcohols and Phytosterols 169

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 169 11/13/08 5:02:37 PM

 170 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 170 11/13/08 5:02:41 PM

 Alcohols and Phytosterols 171

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 171 11/13/08 5:02:43 PM

 172 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 172 11/13/08 5:02:46 PM

 Alcohols and Phytosterols 173

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 173 11/13/08 5:02:49 PM

 174 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 174 11/13/08 5:02:51 PM

 Alcohols and Phytosterols 175

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 175 11/13/08 5:02:54 PM

 176 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 176 11/13/08 5:02:57 PM

 Alcohols and Phytosterols 177

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 177 11/13/08 5:02:59 PM

 178 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 178 11/13/08 5:03:02 PM

 Alcohols and Phytosterols 179

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C002.indd 179 11/13/08 5:03:12 PM

 180 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Alcohols and Phytosterols 181

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 182 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Alcohols and Phytosterols 183

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 184 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Alcohols and Phytosterols 185

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 186 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Alcohols and Phytosterols 187

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 188 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Alcohols and Phytosterols 189

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 190 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Alcohols and Phytosterols 191

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 192 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Alcohols and Phytosterols 193

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 194 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Alcohols and Phytosterols 195

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 196 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Alcohols and Phytosterols 197

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 198 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Alcohols and Phytosterols 199

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 200 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Alcohols and Phytosterols 201

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 202 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Alcohols and Phytosterols 203

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 204 The Chemical Components of Tobacco and Tobacco Smoke

Table Ii.A-5 (Continued)

Alcohols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Alcohols and Phytosterols 205

H 3C CH3 CH3
H3C
CH3
H3C
H3C

HO

Cholesterol 1,2-Dihydro-3-methylbenz[j]aceanthrylene

Figure II.B-1  Theoretical conversion of cholesterol to 1,2-dihydro-3-methylbenz[j]aceanthrylene.

CH3 R
CH3
CH3

CH3

H3C
IV O
R V R
CH3
CH3 CH3
CH3 CH3

CH3 CH3

HO
II
I VI

III
LEGEND
Sterol, R=
Ia cholesterol -(CH2)3-CH(CH3)2
Ib campesterol -(CH2)2-CH(CH3)-CH(CH3)2
Ic β-sitosterol -(CH2)2-CH(C2H5)-CH(CH3)2
Id stigmasterol -CH=CH-CH(C2H5)-CH(CH3)2
Ie ergosterola -CH=CH-CH(CH3)-CH(CH3)2

II 1,2-dihydro-3-methylbenz[j]aceanthrylene
(3-methylcholanthrene)

III chrysene IV Diels´ hydrocarbon

Va 4-cholesten-3-one VIa 3,5-cholestadiene
Vb 4-campesten-3-one VIb 3,5-campestadiene
Vc β-4-sitosten-3-one VIc β-3,5-sitostadiene
Vd stigmasten-3-one VId 3,5-stigmastadiene
Ve ergostadien-3-one VIe 3,5,7-ergostatriene
a Ergosterol has a double bond at the 7-position

Figure II.B-2  Possible sterol degradation products.

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 206 The Chemical Components of Tobacco and Tobacco Smoke
[campesterol {Ib}, β-sitosterol {Ic}, stigmasterol {Id},
and ergosterol {Ie}] structurally similar to cholesterol.
Phytosterols {Ib}, {Ic}, and {Id} differ slightly from choles-
terol in the structure of the long side chain whereas ergosterol
{Ie} not only differs slightly from cholesterol in the structure
of its long side chain but also has an extra double bond at
the 7-position (Figure II.B-2). They are present in tobacco
in both the free and bound form (as glycosides and esters),
and they are transferred as such to mainstream smoke (MSS).
The sterols constitute about 0.2% of the tobacco weight.
In the late 1950s to early 1960s, Rodgman proposed
that the tobacco phytosterols—campesterol, β-sitosterol,
stigmasterol, and ergosterol—might generate compounds
analogous to the tumorigenic 4-cholesten-3-one {Va} and
3,5-cholestadiene {VIa} generated from cholesterol, that is,
4-campesten-3-one {Vb}, 3,5-campestadiene {VIb}, β-4-
sitosten-3-one {Vc}, 3,5-sitostadiene {VIc}, 4-stigmasten-3
-one {Vd}, 3,5-stigmastadiene {VId}, ergosten-3-one {Ve},
and 3,5,7-ergostatriene {VIe}, on thermal degradation of
these tobacco phytosterols or their esters during the smok-
ing process. These campesterol-, β-sitosterol-, stigmasterol-,
and ergosterol-related compounds might also be mouse-skin
tumorigens as are their cholesterol counterparts. For nearly a
decade, Rodgman and Cook (3286) were unsuccessful in their
periodic efforts to isolate any of these phytosteryl ketones or
dienes from CSC and identify them. However, Benner et al.
(273) did subsequently identify two of these 3,5-dienes,
3,5-campestadiene {VIb} and 3,5-stigmastadiene {VId}, in
tobacco smoke, see also Eatough et al. (1099, 1100).
In 1939, the PAHs anthracene, phenanthrene, and B[a]P
were reported as components of a tobacco-related material
by Roffo (3323, 3325, 3326) and his son (3316–3318). In dis-
cussions of tobacco smoke, the Roffo findings are generally
disregarded because the three PAHs they reported were not
detected in tobacco smoke but were identified in a destruc-
tive distillate of tobacco. However, Roffo did report another
finding that led to much research both within and outside the
tobacco industry. Roffo (3327) reported that comparison of
the destructive distillate of tobacco with the destructive dis-
tillate of an ethanol-extracted tobacco indicated that the PAH
content, particularly B[a]P, and the specific tumorigenicity
of the extracted tobacco destructive distillate were reduced
from those of the destructive distillate from the control
tobacco. Roffo speculated that the precursors of the tumori-
genic PAH components of his distillates were ethanol-soluble
phytosterols. Eventually his prediction, as far as it went, was
found to be true for cigarette MSS (327, 398). In July 1954,
Rodgman—a newly hired scientist at RJRT R&D—described
the findings of the Roffos (3316–3318, 3323, 3325, 3327) to
two colleagues who were previously unaware of them. He
particularly emphasized the organic-solvent extraction of
tobacco to remove PAH precursors. The discussion resulted
within a week of one of the colleagues proposing an extrac-
tion method for removal of the phytosterols from tobacco
(114). A few months later, Rodgman initiated a lengthy study
of the effect of organic-solvent extraction on the PAH content
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78836_C002.indd 206
of its MSS (3240–3242, 3246, 3251). All of the extractions of
different tobacco types and blends with different organic sol-
vents and the fabrication of the cigarettes from the extracted
and control tobaccos were conducted by Ashburn (116, 117).
Two major mechanisms were proposed for the pyrogen-
esis of PAHs in tobacco smoke. (1) PAHs are formed by deg-
radation of organic tobacco components to simpler molecules
and/or free radicals during the pyrolysis processes occurring
in the burning cigarette, followed by recombination of these
simpler fragments to yield PAHs (the degradation-combi-
nation mechanism) [see Badger et al. (142–144) and earlier
papers]. (2) PAHs are formed unimolecularly by cyclization,
dehydration, aromatization, ring expansion, etc., of high
molecular weight tobacco components such as the phytoster-
ols, the tetradecacyclic duvanes, long-chained saturated and
unsaturated hydrocarbons, alcohols, and esters, etc. (the aro-
matization reaction) [Rodgman and Cook (3269, 3286)].
Obviously, the mechanism of formation of PAHs is not
an either-or situation. Experimental data indicate that both
mechanisms are operative in PAH formation in the burning
cigarette. Evidence for unimolecular aromatization was pro-
vided by pyrolysis data and by MSS PAH data from ciga-
rettes “spiked” with phytosterols (3269, 3286). The relatively
large increase in the levels of chrysene and methylcyclopen-
taphenanthrene (Diels’ hydrocarbon) vs. those for B[a]P and
other tetra- and pentacyclic PAHs are more readily explained
by the unimolecular aromatization of the tetracyclic sterol
than by the degradation-recombination mechanism. The for-
mation of several PAHs (chrysene, picene, several cyclopen-
taphenanthrenes, etc.) from various sterols had been reported
by Diels, Ruzicka, and their colleagues in the 1920s and 1930s
[see historical summary by Fieser and Fieser (1949)]. Early
research on PAHs in roasted and/or grilled meats evolved
from the theory that cholesterol when heated would gener-
ate the highly potent tumorigen 1,2-dihydro-3-methylbenz[j]
aceanthrylene (3-methylcholanthrene). As noted previously,
sterols in tobacco include cholesterol plus much higher levels
of several phytosterols whose structures differ only slightly
from that of cholesterol. In 1959, Wynder et al. in an adden-
dum to their publication (4356) reported that the pyrolysis
of tobacco phytosterols at 720°C and 850°C gave B[a]P and
other PAHs plus low levels of alkyl derivatives of phenan-
threne, pyrene, and chrysene.
Much of the early research on the isolation and identifi-
cation of phytosterol and their derivatives from tobacco and
tobacco smoke is summarized and referenced in the 1959
review by Johnstone and Plimmer (1971) and the 1968 review
by Stedman (3797).
Table II.B-1 chronicles many of the reported studies on
phytosterols and their derivatives in tobacco and tobacco
smoke plus the studies on the pyrolysis of phytosterols. Table
II.B-2 lists the 111 phytosterols and phytosteryl derivatives
identified in tobacco and tobacco smoke. Of these 111 com-
ponents, 44 have been reported as tobacco smoke compo-
nents, 102 as tobacco components, and 35 in both tobacco
and tobacco smoke.
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78836_C002.indd 207

Alcohols and Phytosterols

Table II.B-1
Studies on Identification of Phytosterols and Phytosteryl Derivatives in Tobacco and Tobacco Smoke
Identification in Tobacco of Identification In Tobacco Smoke of Pyrolysis Studies on Sterols
or their Inclusion in a
Year Phytosterols Derivatives of Phytosterols Phytosterols Derivatives of Phytosterols Smoked Cigarette
1913 Traetta-Mosca (3942b)
1928 Kennaway and Sampson (2080)
1935 Kobel and Neuberg (2153a) Schürch and Winterstein (3562)
1937 Shmuk (3656a)
1939 Veldstra (4042a)
1942 Roffo (3327)
1943 Venkatarao et al. (4042b)
1949 Falk et al. (1171)
1955 Khanolkar et al. (2087) (G)a Khanolkar et al. (2087)
1957 Kosak et al. (2178), Rodgman
and Chappell (3268)
1958 Rowland (3346), Dymicky and Stedman (1079), (G) Dymicky and Stedman (1079) Carruthers and Johnstone (612) Wynder et al. (4355),
Grossman and Stedman (1433) Rodgman and Cook (3269)
1959 Dymicky and Stedman (1080, 1082) (G) Dymicky and Stedman (1080, 1081) (E) Rodgman et al. (3296) Wynder et al. (4356)
1960 Stedman and Rusaniwskyj (3808)
1961 Giles (1291), Reid (3097) Sakaguchi and Kobashi (3391) (G) Kallianos et al. (2018)
1963 (G) Kallianos et al. (2019) (G) Kallianos et al. (2019)
1965 Ehrhardt et al. (1117)
1968 Cheng et al. (690)
1971 Grunwald et al. (1434)
1972 Davis (907a)
1974/5 Schmeltz et al. (3484) Schmeltz et al. (3484)
1976 Tancogne and Chouteau (3867), Lotti et al. (2400)
1977 Davis (909), Menser et al. (2531), Tojib et al. (3920),
Tancogne (3866)
1978 Severson et al. (3612)
1979 Severson et al. (3616)
1984 Chopra and Al-Kubaisi (705)
1998 Forehand and Moldoveanu (1214)
2000 Britt et al. (435)
2001 Britt et al. (433)
a (G) = glucosides, (E) = esters

207
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© 2009 by Taylor & Francis Group, LLC

 208 The Chemical Components of Tobacco and Tobacco Smoke

Table II.B-2
Phytosterols, Their Derivatives, and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Alcohols and Phytosterols 209

Table II.B-2 (continued)

Phytosterols, Their Derivatives, and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 210 The Chemical Components of Tobacco and Tobacco Smoke

Table II.B-2 (continued)

Phytosterols, Their Derivatives, and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Alcohols and Phytosterols 211

Table II.B-2 (continued)

Phytosterols, Their Derivatives, and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 212 The Chemical Components of Tobacco and Tobacco Smoke

Table II.B-2 (continued)

Phytosterols, Their Derivatives, and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

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 Alcohols and Phytosterols 213

Table II.B-2 (continued)

Phytosterols, Their Derivatives, and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 214 The Chemical Components of Tobacco and Tobacco Smoke

Table II.B-2 (continued)

Phytosterols, Their Derivatives, and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

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 3 Aldehydes and Ketones
The publication in the early 1950s of the results of several
retrospective studies on association between cigarette smok-
ing and respiratory tract cancer, particularly lung cancer, and
the study on induction of skin carcinoma in a susceptible
strain of mice painted with massive doses of cigarette tar
for the better part of their life span [Wynder et al. (4306a)]
triggered intensive interest in the composition of cigarette
mainstream smoke (MSS). Because the cigarette smoke con-
densate (CSC), or total particulate matter (TPM), the phase of
the smoke aerosol reported to be the mouse-skin tumorigen,
embodied the particulate phase of the cigarette smoke aerosol,
considerable effort was devoted to defining its composition
with emphasis on the presence in it of tumorigenic polycyclic
aromatic hydrocarbons (PAHs), particularly benzo[a]pyrene
(B[a]P). This effort was conducted by research groups both
within and outside of the tobacco industry.
However, because knowledge of the composition of
tobacco smoke was so sketchy in the mid-1950s, several
research groups initiated the detailed examination of the
tobacco smoke aerosol to define not only its physical char-
acteristics but also the composition of its vapor phase. For
most of the balance of the 1950s, the results from the compo-
sition studies of cigarette smoke vapor phase received little
attention compared to that directed at the particulate-phase
composition results.
In 1954, Kosak (2170) published a list of components
reported to be present in tobacco smoke. His list is shown
in Table III-1. The aldehydes listed included formaldehyde,
acetaldehyde, acrolein (2-propenal), butyraldehyde (butanal),
benzaldehyde, and 2-furaldehyde. In several instances, Kosak
questioned whether the analytical data reported were suffi-
cient to define unequivocally the identity of the smoke com-
ponent. The ketones listed by Kosak included 3-pentanone
(diethyl ketone), 4-heptanone (di-n-propyl ketone), 17-tritri-
acontanone (dipalmityl ketone), 2,3-butanedione (biacetyl),
and “higher” ketones.
Because the low molecular weight aldehydes such as form-
aldehyde, acetaldehyde, propionaldehyde (propanal), acrolein
(propenal), and butyraldehyde (butanal) and ketones such as
acetone, methyl ethyl ketone (2-butanone), and diethyl ketone
(3-pentanone) in cigarette MSS occur primarily in the vapor
phase, their identification and analysis in the 1950s and 1960s
were facilitated by conversion to less volatile compounds.
Many of these low molecular weight carbonyl compounds
form stable compounds with various derivatizing agents and
in many instances the derivative formation is almost quan-
titative. The use of Girard T (trimethylamine) or Girard P
(pyridine) reagent to derivatize tobacco smoke carbonyl com-
pounds was described by Seligman (3581) and Resnik and
© 2009 by Taylor & Francis Group, LLC
78836_C003.indd 215
Seligman (3108). The derivatives were separated by paper
chromatography and identified from their mass spectra.
A reagent that proved to be an excellent one to derivatize
tobacco MSS aldehydes, ketones, and keto acids was 2,4-
dinitrophenylhydrazine. Individual hydrazones were isolated
by various chromatographic means (column chromatogra-
phy, paper chromatography, and eventually HPLC) and their
levels estimated spectrophotometrically. Another ingenious
use of 2,4-dinitrophenylhydrazine was the following: The
less stable Girard T or Girard P derivatives were decomposed
and the carbonyl compounds released were converted to the
highly stable 2,4-dinitrophenylhydrazones for identification
and quantitation. Subsequently, the 2,4-dinitrophenylhydra-
zine procedure was adapted to the investigation of carbonyl
compounds in tobacco, in its headspace vapors, in sidestream
smoke (SSS), and in environmental tobacco smoke (ETS).
A third reagent used for the estimation of aliphatic aldehydes
in tobacco smoke was 3-methylbenzothiazolone hydrazone
hydrochloride [Weaving (4155), Davis and Sneade (915)].
Table III-2 summarizes some of the studies on low molec-
ular weight carbonyl components of tobacco smoke in which
various derivatizing reagents were used, the derivatives
formed were separated by a variety of techniques (column,
paper, TLC, HPLC), and identified and estimated by spectral
means (UV, IR, mass, colorimetry).
The results of many of these studies provided quantita-
tive data on the per cigarette MSS yield of several carbonyl
compounds of interest.
As the interest in the overall composition of tobacco smoke
escalated in the 1950s and 1960s, the potential of the utilization
of gas chromatography to examine and define the vapor-phase
composition was examined. For example, Seligman et al.
(3584), in their gas chromatographic study of the components
of a synthetic mixture comprising seventeen compounds
known to be present in tobacco smoke, demonstrated the feasi-
bility that the seventeen diverse compounds could be success-
fully separated by gas chromatography. Among the seventeen
standard compounds, ranging from methane to water, were
acetaldehyde, propionaldehyde, and acetone. Subsequent to
the successful separation of the compounds, the identity of
each was confirmed by mass spectroscopy.
As a requisite and adjunct to their study of selective filtra-
tion of tobacco smoke components and the effect of carbon
filters on cigarette MSS composition, Laurene et al. (2305)
developed and described a gas chromatographic analysis
of acetaldehyde, acrolein, and acetone in cigarette MSS. In
addition to the analytical methodology, Laurene et al. also
provided data on the MSS yields of acetaldehyde, acetone,
and acrolein from 65-mm nonfiltered cigarettes containing
215
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 216 The Chemical Components of Tobacco and Tobacco Smoke

Table III-1
Tobacco Smoke Components Listed by Kosak (2170)
Class Component Class Component Class Component
Hydrocarbons Hentriacontane (?) Ketones 3-Pentanone Acids Formic acid
Acetylene 4-Heptanone Acetic acid
“Unsaturated 17-Tritriacontanone (?) Butyric acid
hydrocarbons” 2,3-Butanedione Valeric acid
Azulene “Higher” ketones (?) Caproic acid
Phenanthrene (?) C7 and C8 aliphatic acids (?)
Anthracene (?) Succinic acid (?)
Benzopyrene (?) Fumaric acid (?)
“Condensed Citric acid (?)
aromatics” (?) Benzoic acid (?)
Phenolic acids (?)

Alcohols and Phenols Methanol Alkaloids Nicotine Miscellaneous Levoglucosand

Glycerol Pyridyl ethyl ketone Components “Phytosterol” (?)
Diethylene glycol Myosmine C10H14O (a furan ?)
Ethylene glycol Nicotyrine “Resins” (?)
Phenol (?) α-Socratinec “Resin acids” (?)
Catechol (?) β-Socratinec
γ-Socratinec
Obelinc
Lohitamc
Anodminc
Lathraeinc
Poikilinec
Gudhamc

Aldehydes Formaldehyde Other Pyrrole (?) Inorganic Ammonia

Acetaldehyde N-containing “Pyrroles” (?) Components Carbon monoxide
Butyraldehyde components “N-Methyl-pyrrolidines” (?) Carbon dioxide
Acrolein (?) Pyridine Hydrogen cyanide
Benzaldehyde “Picoline” (?) Hydrogen sulfide
2-Furaldehyde (?)a “Lutidine” (?) Thiocyanic acid (?)
“Collidine” (?) Oxygen
“Pyridine bases” (?) Arsenicb
Methylamine (?) “Acetates” (?)
“Chlorophyll degradation products” (?) “Chlorides” (?)
“Uric acids” (?) “Cyanides” (?)
“Nitrates” (?)
a The question mark indicates that Kosak did not consider the evidence in the literature to be definitive proof of the identity of the component.
b Probably present as As2O3.
c Subsequent study demonstrated this component was not a well-defined compound but an artifact, a mixture, or an ammonium salt [see discussion by

Johnstone and Plimmer (1971)].

d 1,6-Anhydro-β-D-glucopyranose

individual tobacco types (flue-cured or burley or Oriental
tobacco) or a blend of all three (50 mm of the tobacco rod
smoked). The effect of a charcoal filter tip on the MSS lev-
els of these carbonyl compounds was also determined. Their
data are summarized in Table III-3.
Modifications of gas chromatographic methods to deter-
mine vapor-phase carbonyl compounds in cigarette MSS
continued for more than three decades, for example, see
Miyake and Shibamoto (2564).
Figure III-1 shows the approximate composition of MSS
from a cigarette that delivers about 22.5 mg of wet total
particulate matter (WTPM) and 17.6 mg of Federal Trade
Commission (FTC) “tar.” Excluding carbon monoxide and
carbon dioxide, acetaldehyde is the vapor-phase component
usually found at the highest level in cigarette MSS.
The non-filtered cigarette MSS yield of acetaldehyde
ranged from 18 µg/cigarette [Huynh et al. (1853a)] to 2815
µg/cigarette [Miyake and Shibamoto (2564)]. The acetone
yield was slightly less than 50% of the acetaldehyde yield.
Acrolein is the next most plentiful aldehyde, followed by
formaldehyde, 2-furaldehyde, and crotonaldehyde. Per ciga-
rette formaldehyde MSS yields ranged from 3.4 µg for fil-
tered cigarettes to 283 µg in nonfiltered cigarettes [Schaller
et al. (3427), Miyake and Shibamoto (2564)].

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 Aldehydes and Ketones 217

Table III-2
Studies on Low Molecular Weight Carbonyls in Tobacco and Tobacco Smoke: Derivatizing Agents
Description Reference

Girard T or Girard P reagent

Aldehydes and ketones in cigarette MSS separated by conversion to Girard T or Girard P derivatives; derivatives Seligman (3581)
separated by paper chromatography.
Girard T or Girard P derivatives of cigarette MSS aldehydes and ketones were characterized my mass spectroscopy. Resnik and Seligman (3108)
4-Nitrophenylhydrazine (4-NPH)
To isolate and identify the low boiling aldehydes and ketones in cigarette MSS, they were derivatized with Sakuma et al. (3396)
p-nitrophenylhydrazine.
2,4-Dinitrophenylhydrazine (2,4-DNPH)
Classification of the structures of various carbonyl compounds from the UV and IR spectra of their 2,4-DNPH Jones et al. (1977a)
derivatives.
Cigarette MSS aldehydes and ketones, regenerated from Girard T or Girard P derivatives, were characterized by Seligman (3581)
conversion to their 2,4-DNPH derivatives.
2,4-DNPH derivatives of tobacco smoke carbonyls were separated by paper and column chromatography. Seligman and Edmonds (3582)
Various keto acids in tobacco seeds were identified from their 2,4-DNPH derivatives. Glock and Jensen (1312)
Levels of mono- and dicarbonyl components of cigarette MSS were estimated by spectrophotometry Harrow et al. (1540)
of their 2,4-DNPH derivatives.
The levels of low molecular weight aldehydes and ketones in cigarette MSS were estimated from their 2,4-DNPH McRae and Mold (2525)
derivatives. Mold and McRae (2591)
After removal of other oxidizable material, the glycerol content of tobacco could be estimated by oxidation of the Martin et al. (2581)
glycerol and conversion of its oxidation product to its 2,4-DNPH derivative.
Examination of 2,4-DNPH derivatives from tobacco and smoke revealed presence of several keto acids. Glock (1310)
Carbonyl components of cigar MSS were characterized by IR, UV, x-ray diffraction, and paper chromatography Schepartz and Ogg (3438)
of their 2,4-DNPH derivatives.
Examination of the 2,4-DNPH derivatives of tobacco smoke carbonyls revealed the presence of several dicarbonyl Halter et al. (1491)
compounds.
Identification of dicarbonyl components of tobacco smoke via their 2,4-DNPH derivatives. Martin (2469)
To aid in identification of aldehydes and ketones in tobacco smoke and in cellulose smoke, over 90 2,4-DNPH Fredrickson et al. (1238)
derivatives were prepared to serve as melting point and spectral standards.
Carbonyl components in cigar MSS identified after 2,4-DNPH derivative formation, followed by exchange reaction Schepartz and McDowell (3436)
of 2,4-DNPH derivatives with α-ketoglutaric acid.
α-Ketoglutaric acid exchange procedure applied to identification of low molecular weight carbonyl components of Stephens et al. (3817)
tobacco.
2,4-DNPH derivatives of low molecular weight carbonyl components of tobacco smoke were separated by TLC. Lindsey et al. (2369)
2,4-DNPH derivatives previously prepared (1238) were used to characterize carbonyl components in cigarette smoke. Frederickson et al. (1239)
Instead of α-ketoglutaric acid, oxalic acid and p-dimethylaminobenzaldehyde were used in exchange release of low Jones and Monroe (1978a)
molecular weight smoke carbonyl components from their 2,4-DNPH derivatives.
2,4-DNPH derivatives of cigarette smoke carbonyls separated by gas chromatography. Donzel (1049)
Formaldehyde level of cigarette MSS estimated by HPLC of its 2,4-DNPH derivative. Hodge and Mansfield (1670)
Mansfield et al. (2456)
The levels of C1 through C4 aldehydes and ketones in cigarette MSS were estimated by HPLC of their 2,4-DNPH Canon and Frank (591)
derivatives.
2,4-DNPH derivatives of acrolein (propenal) and acetone from tobacco smoke were separated by HPLC. Manning et al. (2452)
The level of 5-hydroxymethyl-2-furaldehyde in tobacco and tobacco smoke were estimated via its 2,4-DNPH Perini and Bell (2930)
derivative.
Volatile, low molecular weight carbonyl components of the headspace from tobacco and from MSS were quantitated Brunnemann et al. (500)
through their 2,4-DNPH derivatives.
Development of method to determine formaldehyde in cigarette sidestream smoke; method applicable to other low Bell et al. (243)
molecular weight carbonyl components of sidestream smoke.
Low molecular weight carbonyl compounds in ETS were collected as their 2,4-DNPH derivatives. DeLuca (929)
3-Methylbenzothiazolone hydrazone hydrochloride
Aliphatic aldehydes in MSS were estimated by derivative formation, followed by colorimetry. Weaving (4155)
Aliphatic aldehydes in MSS were estimated by derivative formation, followed by colorimetry. Analysis refined to Davis and Sneade (915)
permit estimation of acrolein (propenal).
Aldehyde and Ketone Derivatization
Review of compounds used to derivatize aldehydes and ketones in tobacco smoke. Green and Rodgman (1373)

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 218 The Chemical Components of Tobacco and Tobacco Smoke

Table III-3
Analysis of Cigarette Mainstream Smoke by Gas Chromatography
Puffs/cig, Acetaldehyde Acetone Acrolein
Cigarette Sample a avge µg/cig µg/cig µg/cig

Flue-cured, non-filtered 9.3 856 372 83

Burley, non-filtered 7.3 847 533 57
Oriental, non-filtered 11.0 726 385 54
Tobacco blend, non-filtered 8.0 832 440 75
Tobacco blend, carbon filtered 8.0 208 42 11
a 50-mm of 65-mm tobacco rod smoked during analysis

Because of the extreme differences between the levels of var- amines (Trp-P-1 and Trp-P-2), a logarithmic plot of the levels
ious components in cigarette smoke, levels that vary from milli- of specific MSS components was found to be a convenient way
grams per cigarette for nitrogen, carbon dioxide, and carbon to compare their deliveries. In Figure III-2, a truncated form of
monoxide to picograms per cigarette for several N-heterocyclic the original logarithmic plot presented by Green and Rodgman

TOTAL MAINSTREAM SMOKE 500 mga

WET TOTAL PARTICULATE VAPOR PHASE 477.5 mg [95.5%]

MATTER (WTPM) 22.5 mg [4.5%]b

Water 3.5 mg [0.70%]b {15.6%}c Waterd 20.0 mg [4.0%]b

Nicotine 1.4 mg [0.28%]b { 6.2%}c Nitrogen 295.0 mg [59.0%]b
“Tar” 17.6 mg [3.52%]b {78.2%}c Oxygen 65.0 mg [13.0%]b
Carbon dioxide 62.5 mg [12.5%]b
Carbon monoxide 20.0 mg [4.0%]b
Argon + helium +
Neon + hydrogen 7.5 mg [1.5%]b
“other components” 7.5 mg [1.5%]b

Alcoholse 3.5 mg [20.0%]f Hydrocarbons 3.8 mg [50.6%]g

Acids 2.9 mg [16.5%]f Aldehydes +
Aldehydes and ketones 2.5 mg [14.2%]f ketones 2.0 mg [26.7%]g
Miscellaneous 2.3 mg [13.2%]f Nitriles 0.60 mg [8.0%]g
Alkanes 1.1 mg [ 6.2%]f Miscellaneous 0.60 mg [8.0%]g
Terpenoid hydrocarbons 1.1 mg [ 6.2%]f Heterocyclics 0.15 mg [2.0%]g
Smoke pigment 0.9 mg [ 5.1%]f Alcohols 0.15 mg [2.0%]g
Alkaloid derivatives 0.8 mg [ 4.5%]f Acids 0.12 mg [1.6%]g
Esters 0.8 mg [ 4.5%]f Esters 0.08 mg [1.1%]g
Phenols 0.8 mg [ 4.5%]f
Unidentifiedh 0.9 mg [ 5.1%]f
Total weight = 17.6 mg Total weight = 7.50 mg

Note: The properties of the cigarette studied were as follows: 85-mm filtered cigarette; 68-mm, tobacco rod;
17-mm triacetin-plasticized cellulose acetate filter tip; cased commercial American blend
a It is now estimated that over 5000 components have been identified in MSS from tobacco cigarettes. Some components such
as water, the simple phenols, hydrogen cyanide, and the volatile N-nitrosamines are found in both the vapor and particulate
phases of cigarette MSS. Hence the total of the number in the two phases appears to exceed the number in the whole.
b Value in brackets represents percent of Total Mainstream Smoke weight, 500 mg.
c Value in parentheses represents percent of WTPM, 22.5 mg.
d Much of this water is contributed by the air drawn through the cigarette during puffing (35-ml puff, 1-sec duration, 1 puff/min,
total puffs = 10) in a laboratory whose atmosphere is controlled to the specifications proposed by the FTC; namely,
temperature = 25°C, relative humidity (RH) = 60%.
e This class of compounds includes added humectants (glycerol, propylene glycol) transferred from the tobacco rod to the MSS.
The transferred humectants constitute about 10 to 12% of the FTC “tar”.
f Value in brackets represents percent of FTC “tar” weight, 17.6 mg.
g Value in brackets represents percent of “Other Components” weight, 7.5 mg.
h There have been various estimates of the number of unidentified components present in extremely small amounts in the FTC
“tar”. Several investigators have estimated the number of unidentified components to range from five to twenty times the
number of identified components, i.e., from about 20000 to 100000.

Figure III-1  Approximate composition of cigarette mainstream smoke.

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 Aldehydes and Ketones 219

Mainstream smoke
Vapor phase yield/cig Particulate phase

400 mg
Nitrogen

200

100 mg
80
Oxygen, carbon
dioxide
40

Water, carbon 20
monoxide FTC “tar”
10 mg
8

4 Water

2
Humectants (gly-
cerol, propylene
Acetaldehyde 1000 µg = 1 mg glycol) Nicotine
800
Isoprene Total alkanes The acids: palmitic,
Acetone stearic, oleic, lin-
Limonene 400 oleic, linolenic
Saturated alipha-
Nitric oxide tic esters
200 Catechol

HCN
100 µg Solanesol Total alkyl Phenol
80 Phytosterols pyridines
Acrolein
1, 3-Butadiene
40 Solanesyl esters

Formaldehyde
2-Furaldehyde 20 o-Cresol
Crotonaldehyde
Benzene Phytyl esters
10 µg
8
Acrylonitrile Indole
α-Tocopherol Indole, 3-methyl-
Solanesyl acetate
4 Anabasine

Figure III-2  Cigarette mainstream smoke components: logarithmic plot.

(1373), shows the cigarette MSS yields of several of the most
plentiful vapor-phase aldehydes and acetone.
Table III-4, modified and updated from similar tables pre-
sented by Chortyk and Schlotzhauer (722) and by Baker (171a),
summarizes the major precursor relationships proposed and/
or demonstrated to date between tobacco leaf components
and tobacco smoke components. These proposals are based
in part on the results of a great variety of pyrolysis studies.
In some cases, the validation of the proposals is based on the
results obtained by addition of leaf components to tobacco
and assessing the effect on the levels of specific MSS com-
ponents when the “spiked” tobacco is actually smoked in a
cigarette and its MSS composition is compared to that of the
MSS from the control tobacco cigarette.
In their quantitation (via their 4-nitrophenylhydrazone
derivatives) of several aldehydes and ketones in the MSS
from cigarettes made from flue-cured laminae and from flue-
cured midribs, Sakuma et al. (3396) reported no significant
differences between the MSS yields of the compounds listed
in Table III-5. However, many were much reduced when the
cigarette was tipped with a charcoal filter.
From their study of the pyrogenesis of acrolein (prope-
nal) from glycerol, Doihara et al. (1023) and others deduced
that a tobacco smoking product that contains glycerol as a

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 220 The Chemical Components of Tobacco and Tobacco Smoke

Table III-4
Precursors in Tobacco of Aldehydes and Ketones in Tobacco
Aldehydes and Ketones Precursors References

Formaldehyde, acetaldehyde, 2-propenal (acrolein), sugars Gager et al. (1264, 1265)

acetone, α,β-dicarbonyls, furaldehydes Higman et al. (1647)
Houminer and Patai (1835)
Johnson et al. (1960)
polysaccharides (cellulose, starch, and/or pectin) Fredrickson (1228)
Fredrickson et al. (1238)
Newell and Best (2764)
Zamorani et al. (4398c)
lignin Martin et al. (2468a)
Scheijen and Boon (3428)
pectins Newell and Best (2764)
Scheijen et al. (3429)
C1-C5 aldehydes pectin Squire and Waymack (3779a)
C3-C4 ketones
2-Furancarboxaldehyde
Acetaldehyde cellulose Kato et al. (2046)
Propanal Sakuma et al. (3401, 3402, 3404, 3045)
Propanal, 2-methyl- (isobutyraldehyde) Wakeham and Silberman (4104)
2-Propenal Yamazaki and Saito (4369)
2-Butenal (crotonaldehyde)
2-Furancarboxaldehyde
2-Furancarboxaldehyde, 5-methyl-
2-Butanone
3-Buten-2-one
triglycerides Kitamura (2111a)

Formaldehyde glycerol Doihara et al. (1023, 1024)

Acetaldehyde
Acetone
2-Propenal
2-Propenal glycerol Harbin and Laurene (1497)
Kröller (2192, 2196)
Kobashi et al. (2144)
Wynder and Hoffmann (4337)
2-Propenal polysaccharides Burton (535)
lignin Fagerson (1170a)
Kaburaki et al. (2003)
Kato (2042)
Kato et al, (2043, 2046)
Aromatic aldehydes: lignin Kato et al. (2043)
Benzaldehyde, 3,4-dihydroxy- (protocatechualdehyde), Martin et al. (2468a)
Benzaldehyde, 4-hydroxy- Yang and Wender (4378)
Benzaldehyde, 4-hydroxy-3-methoxy- (vanillin),
Benzaldehyde, 3,5-dimethoxy-4-hydroxy- (syringaldehyde)
Direct transfer from tobacco; however, lignin is the Wender and Yang (4163)
most likely precursor of many aromatic aldehydes Yang and Wender (4378, 4379)
as well as many aromatic acids in tobacco.

humectant has an enhanced potential for the formation and
release of acrolein (propenal) during smoking [see Wynder
and Hoffmann (4337)].
In their study of the levels of acrolein, acetaldehyde, ace-
tone, hydrogen cyanide, nitrogen oxides, nicotine, and total sol-
ids in pipe tobacco MSS, Harbin and Laurene (1497) reported
that the acrolein delivery increased as the glycerol level was
increased by addition but the acrolein delivery eventually lev-
eled off when the glycerol addition exceeded 6%.
From an examination of the structure of lignin [see Ball
(176a)], it is obvious why its pyrolysis products include
a variety of phenolic aldehydes and acids, many of which

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 Aldehydes and Ketones 221

However, it was soon recognized that neither the B[a]

Table III-5 P content nor its tumorigenicity could explain the biologi-
Aldehydes and Ketones in Mainstream Smoke from cal response observed in the mouse skin-painting bioassay.
All Lamina and All-Midrib Cigarettes Similarly, neither the total content of the PAHs tumorigenic to
mouse skin nor their summed tumorigenicities could explain
In Mainstream Smoke From
the observed biological response. In fact, it was pointed out
Flue-Cured Tobacco, µg/cig
many times over the next several decades that the levels of
Carbonyl Compound Lamina Midrib
B[a]P and other tumorigenic PAHs in tobacco smoke conden-
Formaldehyde 5 10 sate accounted for less than 3% of the observed tumorigenic-
Acetaldehyde 685 779 ity [Wynder and Wright (4353, 4354), Wynder and Hoffmann
Propanal 97 81 (4307, 4308, 4312, 4316, 4317, 4319, 4332, 4342), Druckrey
Propanal, 2-methyl- 103 57
(1056), Roe (3310, 3311), USPHS (3999, 4005, 4009, 4010),
Propenal (acrolein) 184 156
Butanal 36 21
Lazar et al. (2320), Stedman (3767), Selikoff et al. (3584a),
2-Propanone (acetone) 217 220 Coultson (830)].
2-Butanone 159 186 As early as the mid-1950s, Wynder and Wright (4353) noted
that the concentration of B[a]P in CSC was insufficient to
account for its observed carcinogenicity to mouse epidermis:
“The concentration in which benzo[a]pyrene seems to be in
have been identified in cigarette MSS. Lignin is composed cigarette tar is insufficient to account for the observed carci-
of coniferyl alcohol {I}, p-coumaryl alcohol {II}, and sinapyl nogenic activity to mouse epidermis.”
alcohol {III} in a variety of ratios that are dependent on the At the 1957 Blatnik Committee hearings, Wynder reported
plant species (Figure III-3). Wright’s opinion [Wright (4282a)] on the subject as well as
his own [Wynder (4296)]. Wynder noted that much attention
had been directed at the PAH B[a]P. So much in fact that, as
The Assertion of Aldehydes
Wynder stated, B[a]P had become an issue in itself because it
and Ketones as Ciliastatic was one of the known tumorigenic substances and everyone
Tobacco Smoke Components tried to blame everything on it alone. During his testimony,
The reports by Wynder et al. (4306a, 4306c) in the early he also noted that his Sloan Kettering group had repeatedly
1950s that cigarette smoke tar or CSC was tumorigenic to stated that the amount of B[a]P in tobacco tar was insuffi-
mouse skin prompted an intense search for the responsible cient to explain the animal results published by his group.
component(s). Initially, the PAHs were selected for inves- He added that cigarette tar contained numerous other B[a]
tigation because of the wealth of chemical and biological P-related compounds much more active than B[a]P and they
data generated on a great number of them following the most likely accounted for the majority of the activity, and it
synthesis of DB[a,h]A in 1929 (760, 1184), the isolation and was more or less academic whether it was B[a]P or a dibenzo-
identification of B[a]P from coal tar in 1932 (796a, 797), pyrene or a dibenzanthracene or a substituted B[a]P because
and the demonstration of the potent tumorigenicity of both they were all formed in the same manner during the tobacco
of them to mouse skin by the Kennaway group (194, 796a, smoking process. That same year, Wynder and Wright (4354)
797, 2078). Almost immediately after the report by Wynder wrote that, to that date, no carcinogens had been identified
et al. (4306a) of the mouse skin-painting results with in large enough quantities in tobacco tar or its fractions to
tobacco tar, the PAHs were proposed by some investigators account for the observed activity in skin-painting studies:
to be the major tumor initiators in CSC. Because of its level
We have demonstrated experimentally … that 0.0001 per
in CSC and its potency in mouse-skin tumorigenesis, B[a]P
cent or even 0.0005 per cent benzopyrene in acetone will not
was defined as the most significant of the PAHs in tobacco produce any tumors in the present experimental mouse or
smoke.

CH2=CH-CH2OH CH2=CH-CH2OH CH2=CH-CH20H

OCH3 H3CO OCH3

OH OH OH
I II III

Figure III-3  Phenolic alcohol components of lignin.

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 222 The Chemical Components of Tobacco and Tobacco Smoke
rabbit groups. Thus, there is conclusive proof that the animal
results cannot be solely due to the benzopyrene content of
tobacco [sic].
The benzpyrene content of the total tar as well as the
active fractions is far too low to account alone for the posi-
tive results [in laboratory animal]. So far, no carcinogens
have been identified in large enough quantity in tobacco tar
or its fractions to account for the observed activity.
These Wynder-Wright 1957 results led to an intensive but
unsuccessful eighteen-month search for a “supercarcino-
genic” PAH. The absence of such a PAH was subsequently
confirmed by the USDA group at Athens, Georgia, by their
identification of over 500 PAHs in the PAH fraction from
cigarette MSS, an identification procedure that completely
accounted for the fraction in the cigarette smoke studied
(3732, 3736, 3756–3759).
In 1959, unable to explain the bioassay (mouse skin-paint-
ing) results with CSC on the basis of either its B[a]P content
(less than 2% explainable) or its total PAH content (less than
3% explainable), Wynder and Hoffmann (4307) at the 1959
American Association for Cancer Research (AACR) meeting
added the concept of promotion by low molecular weight phe-
nols to the concept of tumor initiation by PAHs in an attempt
(unsuccessful) to explain the bioassay results. They reiterated
their view the following year at the 1960 AACR conference
(4309): “The phenol fraction could be established as an impor-
tant promoting portion of the tobacco smoke condensate.”
A similar comment that the amount of tumorigenic PAHs
found in CSC could not by themselves account for the total
biological activity observed was included in a more detailed
publication (4307) of their AACR presentation. They also
stated (4308) that the higher PAHs played an important role
in the carcinogenicity of CSC but when the various known
concentrations of the carcinogenic PAHs as estimated in CSC
were summed, it was obvious that they could not account for
the established carcinogenicity of the CSC nor of its isolated
PAH fraction.
Several carcinogenic higher aromatic polycyclic hydrocarbons
[are] present in tobacco smoke condensate. They include
benzo[a]pyrene …, benzo[e]pyrene …, chrysene …, benz[a]
anthracene …, dibenz[a,h]anthracene …, and dibenzo[a,i]
pyrene … From the amount in which these materials have
been found in tobacco smoke condensate it was evident that
these, by themselves, could not account for the total biologi-
cal activity observed.
In 1960, Van Duuren et al. (4027) reported the identification
of several aza-arenes (dibenz[a,h]acridine, dibenz[a,j]acridine,
dibenzo[c,g]carbazole) not only structurally similar to some of
the known tumorigenic PAHs in CSC but also reported under
certain conditions to be tumorigenic to mouse skin. Adding
this class of tumorigenic cigarette smoke components to the
assessment of the tumorigenicity of CSC failed to account for
more than a few percent of the observed response.
However, it should be noted that Candeli et al. (587) could
not confirm the findings of Van Duuren et al. on the presence
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78836_C003.indd 222
of these three aza-arenes in cigarette MSS. During the next
three decades, other research groups in Germany, Japan, and
the United States were also unable to confirm the presence
in cigarette MSS of dibenz[a,h]acridine, dibenz[a,j]acridine,
and dibenzo[c,g]carbazole [3260, 3414, Table 12-7 in (172)].
Wynder and Hoffmann (4311) wrote that the PAHs in CSC
accounted for not more than 3% of the total biological activ-
ity observed in mouse-skin bioassays:
The polynuclear aromatic hydrocarbons are mainly formed
during the combustion of tobacco. The tobacco of our stan-
dard cigarettes contains only very minute quantities of
benzo(a)pyrene (0.02 ppm). A bioassay indicates that these
polycyclic hydrocarbons of the condensate by themselves,
however, can account for not more than 3 per cent of the
total biological activity.
Wynder and Hoffmann (4312) also wrote that the estab-
lished carcinogenicity of CSC to mouse epidermis could to
a great extent be accounted for on the basis of initiating car-
cinogens, largely PAHs, and promoting substances, a major
group of which was the phenols. This statement was not true
in 1961, nor is it true now.
In their lengthy 1964 review of tobacco carcinogenesis,
Wynder and Hoffmann (4319) stated that no one could deny
that tobacco products were tumorigenic even though no sin-
gle component in tobacco smoke could by itself or jointly
with other components account for the observed tumorigenic
activity of such tobacco products to the skin of laboratory
animals: “It is furthermore true that none of the agents is
carcinogenic in the concentrations in which they are present
in tobacco products.”
Wynder and Hoffmann (4332) expressed similar views
on the tumorigenicity of tobacco smoke components in their
1967 book, but they continued to maintain that the PAHs in
cigarette smoke were important as tumor initiators:
While BaP and other carcinogenic PAH can by themselves
account for only a small portion of the total tumorigenic
activity of cigarette smoke condensate, probably less than
2%, they are, nevertheless, of obligatory importance as
tumor initiators.
The next year, Wynder and Hoffmann (4342) wrote:
Carcinogenic polynuclear hydrocarbons in the concentra-
tions present in tobacco “tar” clearly do not, by themselves,
account for the observed carcinogenicity.
On several occasions, the U.S. Surgeon General in his
periodic reports on smoking and health discussed the rela-
tionship between the levels of PAHs in cigarette smoke, their
tumorigenic potency to mouse skin, and the observed biolog-
ical response with CSC in mouse skin-painting bioassays.
The results of a number of such assays [mouse skin-painting]
present a puzzling anomaly: the total tar from cigarettes has
about 40 times the carcinogenic potency of the benzo(a)
pyrene present in the tar. The other carcinogens known
11/24/08 12:21:18 PM
 Aldehydes and Ketones 223

to be present in tobacco smoke are, with the exception of In the late 1930s, Mendenhall and Shreeve (2530a)
dibenzo(a,i)pyrene, much less potent than benzo(a)pyrene and Proetz (2991a) described their studies on ciliastasis.
and they are present in smaller amounts. Apparently, there- Mendenhall and Shreeve (2530a) reported that nicotine in
fore, the whole is greater than the sum of the known parts. cigarette MSS did not appear to be a contributor to ciliastasis
(3999)
in extirpated bovine tracheal tissue exposed to cigarette MSS,
but the difference they observed between the smokes from
Unable to explain the observed tumorigenicity to mouse
nonmentholated vs. mentholated cigarettes indicated that
skin of cigarette smoke condensate in terms of its content
menthol had a ciliastatic effect. However, in 1952, Rakieten
of known tumorigenic PAHs and/or tumorigenic aza-arenes,
et al. (3072b) reported no difference between the MSSs from
Wynder and Hoffmann (4307, 4309–4313) added the concept
nonmentholated vs. mentholated cigarettes in the ciliastasis
of promotion to their arsenal with particular emphasis on
induced in ciliated tissue from humans, rabbits, or rats. Their
this property of the nontumorigenic PAH and low molecu-
findings conflicted with those reported by Mendenhall and
lar weight phenolic components in the CSC. Inclusion of the
Shreeve. Rakieten et al. (3072b) also reported that nicotine
concepts of initiation, promotion, and cocarcinogenesis by
contributed only slightly to the observed ciliastatic effect of
cigarette smoke components could only account for a small
cigarette MSS.
percentage of the number of tumor-bearing animals in the
Representative studies on ciliastasis produced by cigarette
mouse skin-painting studies. This inability to explain the
MSS include those of Dalhamn (891a), Falk et al. (1175),
results observed in laboratory animals was a major credit-
Kotin and Falk (2179), and Ballenger (178). In all these stud-
ability problem in the attempt to relate the laboratory animal
ies, cigarette MSS was reported to be ciliastatic in in vitro
data with CSC to human smoking experience.
systems. Falk et al. reported that nicotine was involved in the
In an attempt to offset their failure to explain the mouse
ciliastasis induced by cigarette smoke. However, Guillerm et
skin-painting bioassay results with CSC on the basis of its
al. (1451a) reported that neither nicotine nor hydrogen cya-
content of tumorigenic PAHs and aza-arenes, promoting and/
nide was a contributor to the ciliastasis produced by cigarette
or cocarcinogenic phenols, and promoting and/or cocarcino-
MSS when tested individually at the concentrations deter-
genic nontumorigenic PAHs, Wynder and Hoffmann (4314,
mined in cigarette MSS. They reported that all the aldehydes
4315) added the concept of ciliastasis in an attempt (unsuc-
and ketones tested at their concentrations in cigarette MSS
cessful) to explain cigarette smoke tumorigenicity in smok-
were ciliastatic and acetaldehyde and acrolein appeared to
ers’ lungs. It was proposed that impairment of ciliary action
act synergistically in the ciliastatic action.
would result in prolonged exposure of the ciliated tissue to
In 1962, Wynder and Hoffmann (4314) combined the
the inhaled particle and the tumorigens contained therein.
ciliastasis concept with the three tumorigenesis factors
Obviously, ciliastasis is not relevant to the initiation of tumors
mentioned above: It was proposed that impairment of cili-
in the mouse skin-painting bioassay with CSC.
ary action would result in prolonged exposure of the ciliated
Cilia are small, hair-like entities covering the surface of
tissue to the inhaled particle and the tumorigens contained
certain portions of the upper respiratory tract* and these beat
therein. For the CSC, they reported low molecular weight
rhythmically and synchronously to move a thin layer of mucus
phenols to be in vitro ciliastats and that cellulose acetate
upward toward the mouth where it is swallowed or expecto-
filters plasticized with triacetin substantially reduced the cili-
rated. Inhaled particles may be entrained in this mucus and
astatic effect of phenols. The same year, Davis and George
thus removed from the respiratory tract by its cilia-induced
(911a) reported the effectiveness of triacetin-plasticized cel-
movement. Impairment of ciliary activity results in a failure
lulose acetate in reducing the phenols level in cigarette MSS
to clear particles from the respiratory tract. This impairment
with the corresponding reduction of the observed ciliastasis.
of ciliary activity, known as ciliastasis, may be produced by a
Because of the assertion that low molecular weight phe-
variety of inhaled materials. A detailed definition of cilia and
nols were promoters for tumorigenic PAHs and thus played
description of their action appear in Rivera (3184a). Many of
a role in CSC tumorigenesis and possibly in cancer causa-
the early laboratory investigations on ciliastasis produced by
tion in smokers, research was underway to find methods to
cigarette MSS and/or its components were studies involving
reduce their levels in cigarette MSS, for example, the studies
ciliated tissue from clams, mussels, or extirpated lung tissue
at Lorillard on selective phenols filtration by Spears (2399,
from rabbits, etc.
3765), at R.J. Reynolds Tobacco Co. (RJRT) by Laurene
Usually, Hilding (1652a) is credited with initiating the
(2295) and Laurene et al. (2306), by Hoffmann and Wynder
interest in respiratory tract ciliastasis produced by cigarette
(1791), Mokhnachev et al. (2579), and Morie (2628, 2629,
MSS. In 1956 and 1957, he reported the results of his studies
2636) and on phenol precursors by Rodgman et al. (3251,
of the effect of cigarette smoke on ciliated tissue in the lungs
3277, 3305, 3306), and by Wynder and Hoffmann (4317) on
of cows. However, numerous reports on studies of the cili-
the precursors in tobacco of the low molecular weight phe-
astatic action of cigarette MSS had appeared in the literature
nols in tobacco smoke. Obviously, the results of these studies
during the preceding two decades.
were equally applicable to reducing levels of phenols because
of their alleged ciliastatic action in the respiratory tract.
* Other anatomical sites in the mammalian body possess ciliated tissue, but Wynder and Hoffmann (4317) and Wynder et al. (4350)
these have no relevance to the discussion of tobacco smoke inhalation. reported the results of their study of the ciliastatic components

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 224 The Chemical Components of Tobacco and Tobacco Smoke

in cigarette smoke condensate: Nicotine was not a factor in and his colleagues (893a, 894b) on the ciliastatic activity of
the ciliastasis of CSC; the phenolic fraction and the acidic filtered and nonfiltered cigarette MSS and by Wynder (4301).
fraction were significant ciliastats. In 1965, Wynder et al. (4304) wrote:
The same year, Kensler and Battista (2083, 2084) reported
their findings on the ciliastatic activity of vapor-phase com- The principal volatile ciliatoxic components appear to be
ponents of cigarette MSS and its reduction by activated water-soluble … Important considerations are the tempera-
carbon filters. Falk et al. (1173a, 1175) also described the ture of the respiratory tract … and the nature of the overlying
mucous coat, the layer that all ciliastatic components pen-
effect of many of the same smoke components on mucus
etrate to act upon cilia …
flow. Hydrogen cyanide, acrolein, formaldehyde, acetalde-
hyde, nitrogen oxides, ammonia, and phenol were considered
In their study, Rodgman et al. (3306) showed that pas-
important vapor-phase ciliastats.*
sage of cigarette MSS over moistened filter paper strips sub-
The Kensler-Battista research on the effectiveness of
stantially reduced the levels of the vapor-phase ciliastats but
carbon in reducing vapor-phase ciliastats in cigarette MSS
did not produce much effect on the “tar” delivery. Rodgman
was reported within a few months of the publication of the
and Cook (3289) examined a variety of carbon-containing
Reader’s Digest article on the effectiveness of carbon-con-
filter tips and found that the delivery of several vapor-phase
taining filters in reducing ciliastats in cigarette MSS and the
ciliastats (the aldehydes and ketones) could be reduced
appearance in the marketplace of Liggett and Myers (L&M)
substantially by some of them. In some instances, the cili-
Lark cigarette. Its filter included a chamber filled with a
astatic components adsorbed on the carbon were eluted from
specially treated carbon based on a patent issued to Keith
the carbon as the fire cone approached the filter tip and the
of L&M R&D. The Kensler-Battista study was performed at
filter tip temperature was increased. As a result, the levels of
A.D. Little and was contracted by L&M (2083, 2084).
these components were inordinately increased in the last few
Because of these reports on vapor-phase components of
puffs from the cigarette. RJRT was not the only U.S. tobacco
cigarette MSS, emphasis at RJRT R&D was shifted from
company interested in the removal of water-soluble ciliastats
attempts to reduce the levels of the phenols reported to be
from cigarette MSS. †
promoters or cocarcinogens to attempts to reduce the levels
Industrial Bio-Test Laboratories (3A12), under contract
of vapor-phase components reported to be ciliastatic. These
to RJRT, conducted a series of studies on in vitro ciliastasis
vapor-phase components included the simpler, volatile phe-
of cigarette MSS from 1964 through 1967. Major findings
nols which equilibrate between MSS vapor phase and par-
included: (1) The theory of reduction of the levels of cili-
ticulate phase. From 1963 to 1972, a great variety of filter-tip
astats in the smoke stream by moist surfaces was confirmed.
additives were examined with respect to their ability to
(2) The ciliastatic activity of the MSS particulate phase was
remove specific MSS components reported to be ciliastatic
essentially unchanged by passage over moist surfaces. (3)
in in vitro experiments.
The ciliastatic activity of cigarette MSS was substantially
After the Kensler-Battista publications, numerous publica-
reduced by passage of the MSS through a carbon-containing
tions appeared on the reduction of the delivery of ciliastatic
filter tip.
components by filter tips (893a), on the ciliastatic action of
In 1966, Dalhamn (891a) and Dalhamn and Rylander
nicotine (178), and on the ciliastatic activity of phenol (295).
(893c) reported on the effect of filtration on the delivery of
In a preliminary study, Rodgman et al. (3306) examined the
ciliastatic compounds in MSS. They reported that in vitro
removal of water-soluble vapor-phase ciliastatic components
ciliastats were present in both the vapor and particulate
from cigarette MSS by saliva and mucous secretions in the
phases of MSS.
upper respiratory tract. They reported that the levels of repre-
In their 1964 lengthy review and 1967 book, Wynder and
sentative ciliastats such as the aldehydes and ketones were sub-
Hoffmann (4319, 4332) commented on ciliastasis induced by
stantially reduced in the oral cavity, resulting in a diminution
cigarette MSS:
of the levels reaching the ciliated tissue in the lower respira-
tory tract. Rodgman et al. also emphasized that such oral cav- All studies reported to date have shown that cigarette smoke
ity absorption of water-soluble ciliastats did not substantially affects the metachronic activity of cilia, a motion that is nec-
affect the levels of ciliastatic components in the particulate essary to propel the viscid mucoid mass. During inhalation,
phase. External impetus for this investigation was provided in the absence of effectively beating cilia, mucus flow slows
by comments in the Advisory Committee’s 1964 Report to down and perhaps stops. At that time, components in ciga-
the U.S. Surgeon General (3999) on the possible oral cavity rette smoke may act upon the underlying cells, as can the
removal of water-soluble ciliastats, by comments by Dalhamn entrapped particles.

* Because of its vapor pressure properties, phenol is present in both the
particulate phase and the vapor phase of cigarette MSS aerosol. Thus, it
is amenable to removal from the vapor phase by selective filtration and
to reduction of its level in the particulate phase by all the technologies
whereby MSS particulate phase or “tar” delivery is reduced, for example,
filtration efficiency, air dilution (increased paper porosity, filter-tip venti-
lation), and inclusion of expanded tobacco in the blend.
† In 1965, American Tobacco marketed the Waterford cigarette whose
filter contained encapsulated water. Prior to smoking the cigarette, the
smoker would gently squeeze the filter tip, rupture the capsules to release
the encapsulated water which would spread throughout the interstices
between the filter-tip fibers. Water-soluble MSS vapor-phase components
would be “scrubbed” from the smoke stream. The Waterford had a very
short life in the marketplace.

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 Aldehydes and Ketones 225
In their mid-1960s publications, Wynder and Hoffmann
commented several times on the fact that most of the known
ciliastatic components of MSS demonstrated to be ciliastatic
in various in vitro systems were water soluble and this prop-
erty would markedly influence their fate and behavior during
and after inhalation. Wynder and Hoffmann (4330) noted:
As far as human smoking habits are concerned, it remains
also to be estimated to which extent volatile smoke compo-
nents reach the bronchial tree. Preliminary studies indicate
that a significant proportion of the gaseous components is
being retained within the oral cavity.
Later, Wynder and Hoffmann [see p. 542 in (4332)] wrote:
Water-soluble volatile components, which are primarily
responsible for the results of the acute in vitro short-term
cilia toxicity tests, are, to a large extent, removed when ciga-
rette smoke contacts the saliva in the mouth and the abun-
dant secretions of the trachea and main bronchi.
They added [see p. 646 in (4332)]:
In man’s manner of smoking, however, volatile components are
retained to a significant degree in the oral cavity and may, there-
fore, be far less important than when tested experimentally.
These words, perhaps prophetic, were shown to be true
by Dalhamn et al. (892), who reported in 1968 that as much
as 60% of the water-soluble (and ciliastatic) components of
cigarette MSS were absorbed in the oral cavity of the human
smoker, whereas the absorption of water-insoluble (and non-
ciliastatic) components such as isoprene was low (about 20%).
They also reported that about 16% of the MSS particulate
matter was retained in the mouth. Mouth absorption of acet-
aldehyde and acetone averaged about 57%. Earlier, Rodgman
et al. (3306) had conducted a study similar to but much less
elaborate than that of Dalhamn et al. (892). Rodgman et al.
studied the mouth absorption of components of the MSS
from five different brands: The total absorption of all vapor-
phase aldehydes and ketones averaged 53%; the absorption of
isoprene averaged less than 10%.
The more than a dozen cigarette brands tipped with
carbon-containing filter tips were already losing market
share by the time Dalhamn et al. reported the results of their
study of the mouth absorption of water-soluble vapor-phase
components (892). Their scientific communication, plus the
consumer unacceptable “carbon-filter” off-taste, produced
not only a further reduction of sales but also diminished
interest, both within and outside of the tobacco industry, in
vapor-phase ciliastats as participants in respiratory problems
attributed to cigarette MSS.
From 1968 through 1972, study continued not only at RJRT
R&D but also throughout the tobacco industry on ways to
reduce the levels of vapor-phase components, many of which
were reported to be ciliastatic in in vitro systems. The major
effort was aimed at reducing the level of hydrogen cyanide
(a potent in vitro ciliastat) because of its level in cigarette
© 2009 by Taylor & Francis Group, LLC
78836_C003.indd 225
MSS (about 200 to 400 µg from a cigarette delivering 15 to
25 mg of FTC “tar”), its toxicity (other than ciliastasis) when
examined alone, and the fact that consumers would be more
familiar with the toxic properties of hydrogen cyanide (also
known as hydrocyanic acid or “cyanide”) than with the toxic
properties of MSS components such as acrolein or phenol.
Most of the effort during this period dealt with filter-tip addi-
tives other than carbon.
Thus, in the late 1960s it was known that in vitro cili-
astatic components in the vapor phase of MSS were not
reaching the ciliated areas of the respiratory tract in the
concentrations first considered to be a problem and the
levels of the ciliastatic components in the MSS particulate
phase could be controlled by the filtration methods used to
control “tar” delivery. Another technology to control the
per cigarette deliveries of both vapor-phase and/or partic-
ulate-phase MSS components (whether they be ciliastatic
or not) was air dilution via filter-tip ventilation. At RJRT
R&D, basic research on this cigarette design technology,
subsequently classified as significant in the generation of a
“safer” or “less hazardous” cigarette, was pursued into the
mid-1970s (3116a, 3119a, 3120).
Dalhamn (891c) stated with regard to a “less hazard-
ous” cigarette:
If … one were to venture a reply to the question of what a less
hazardous cigarette would be like, I cannot for the moment
find a better one than that given by Rylander and myself
[to the 1968 Consumer Subcommittee of the U.S. Senate
Committee on Commerce]:
Our belief, based upon the scientific knowledge available
at present, is that the only way to guarantee a reduction in
the harmful effects of inhaled smoke is to decrease the over-
all exposure. This can be done by reducing the number of
cigarettes smoked or by using filter cigarettes, provided the
reduction brought about by the filter will equal in all respects
and for all potentially hazardous compounds the reduction in
dose obtained if the number of cigarettes is reduced. Due to
the limited amount of data and the difficulty of extrapolating
from laboratory findings to man, we believe that a reduction
of only selected components of cigarette smoke cannot be
accompanied by a statement guaranteeing a reduction in the
harmful effects of inhaled smoke.
The topic dealing with ciliastasis and MSS ciliastats
(from testing in in vitro systems) is of particular interest with
respect to the ETS situation because of the data showing:
1. The major ciliastatic components in tobacco
smoke are water soluble. These include formalde-
hyde, acetaldehyde, crotonaldehyde, ethyl carbam-
ate, and hydrazine:* all are water-soluble tobacco
smoke components that appear as tumorigens
* Other water-soluble tobacco smoke components categorized as ciliastats
on the basis of in vitro test results include ammonia, hydrogen cyanide,
acrolein, acetone, nitrogen dioxide, and low molecular weight phenols.
The phenols are distributed between the particulate and vapor phases of
tobacco smoke.
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 226 The Chemical Components of Tobacco and Tobacco Smoke

Table III-6
In vitro Ciliary Activity, Cigarette Smoke Fractions, and Dose Level
Smoke Fraction From Which Immediate & Complete Complete Ciliastasis No Apparent
Aqueous Extract was Obtained % Of Smokea Ciliastasis at Dcb in 10-40 min at D10 Ciliastasis at Do Dc/Do

Phenolic fraction   9.3 (16.0)d 0.03 0.015 0.002 15

Acidic fraction c   2.2 (11.0) 0.04 0.02 0.007 6
Neutral fraction 47.2 (0.9) — 0.27 0.034 8e
“Insoluble” fraction 14.0 (20.0) 1.1 0.55 0.055 20
Basic fraction   8.7 (65.0) 1.95 0.98 0.08 24
a The unit for Dc, D10, and Do is g/100 ml.
b The values for each fraction as a percentage of total smoke condensate were previously described by Wynder and Hoffmann (4311, 4312)
c Phenol-free.

d Number in parentheses is percentage of smoke fraction that is soluble in water.

e Value for D10/Do.

on the various published lists of tumorigens in 6 to 24, that is, a 24-fold dilution of every mainstream ciga-
tobacco smoke (1727, 1740, 1741, 1743, 1744). rette smoke condensate fraction tested in this study resulted
2. Dose reduction (effectively, dilution) of MSS or in or would result in a non-ciliastatic situation.
some of its “ciliastatic” components or ciliastatic The data in Table III-6 originally presented at the annual
fractions eventually results in a dose or concentra- AACR meeting by Wynder and Hoffmann (4314) were subse-
tion level at which no ciliastasis is produced in the quently published, but in less detail, by Wynder et al. (4350).
in vitro systems used.
3. A large proportion of the inhaled MSS components Ciliastasis Studies With Individual
categorized as ciliastats (and in some instances as
Cigarette Mainstream Smoke
tumorigens) does not reach the ciliated areas of the
respiratory tract because of their removal from the Components
smoke stream during passage over the moist tis- Examination of the in vitro ciliastasis produced by a variety
sues of the mouth and trachea [see Rodgman et al. of MSS components reveals that for all components stud-
(3306), Dalhamn et al. (892)]). ied there is a level below which no ciliastasis is observed.
4. Ciliastatic compounds inhaled nasally are removed Guillerm et al. (1451a) reported the results of their study of
from the inhaled gas stream by “resorption.” the effect of various MSS components in the in vitro system,
This raises the question as to how much formaldehyde or ciliated rat trachea. Concentrations less than those shown in
acetaldehyde or crotonaldehyde in ETS, an already extremely Table III-7 produced no ciliastasis in ciliated rat trachea. All
dilute system, will reach the lung whether inhaled orally or of the compounds listed in Table III-7 are primarily vapor-
nasally! Are the levels of these tobacco smoke components phase components of MSS.
in ETS sufficient for these compounds to be included on the Wynder et al. (4350) in their study of the phenolic com-
Hoffmann and Hecht list (1727), the Occupational Safety and ponents of cigarette smoke also reported that reduction of
Health Administration (OSHA) list (2825), the Hoffmann
and Hoffmann lists (1740, 1741, 1743), or the Hoffmann
et al. list (1744)?
Table III-7
Lowest Concentrations in Ringer Solution Leading
Ciliastasis Studies with Cigarette
to Ciliastasis in Ciliated Rat Trachea
Smoke Condensate Fractions
Compound Concentration, µg/L
Wynder and Hoffmann (4314) and Wynder et al. (4350) in
their study with mussels of the ciliastatic activity of aqueous Propenal 90
Formaldehydea 200
extracts of various fractions of cigarette smoke condensate
Acetaldehydea 3000
demonstrated that reduction of the applied dose of each of Propanal 3500
the fractions tested eventually changed the ciliastasis from Propanal, 2-methyl- 4500
“immediate and complete” to “none.” Their findings are 2-Furaldehyde 7500
summarized in Table III-6. 2-Butanone 80000
Calculation of the ratio Dc/Do, where Dc is the dose pro- 2-Propanone 100000
ducing “immediate and complete” ciliastasis and Do is the a On various lists of tobacco smoke tumorigens (1727, 1740, 2825).
dose producing “zero” ciliastasis, gives values ranging from

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 Aldehydes and Ketones 227
the concentrations of solutions of the simple phenols (phenol,
o-cresol, m-cresol, p-cresol, o-ethylphenol, and 2,4-dimeth-
ylphenol) from 1.0% to 0.05% (a 20:1 dilution) reduced the
ciliary activity of each solution in an in vitro system (ciliated
mussel tissue) to zero:
At the highest concentration (1.0%), the phenol derivatives
demonstrated greater ciliastatic effects than did phenol itself.
At the lowest concentrations tested (0.05%), none of the phe-
nols induced ciliastasis.
Nose Inhalation of Environmental
Tobacco Smoke vs. Mouth
Inhalation of Mainstream Smoke
On several occasions, Rodgman (3255, 3255a, 3257) dis-
cussed the effect of water solubility of tobacco smoke com-
ponents reported to be ciliastatic in in vitro systems on the
ultimate exposure of the smoker’s lungs to MSS or the non-
smoker’s lungs to ETS.
Early in the study of the effect of MSS components on
ciliary activity in in vitro systems, it was realized that all
of the MSS components (formaldehyde, acetaldehyde,
acrolein, hydrogen cyanide, formic acid, acetic acid, etc.)
that produced ciliastasis in the in vitro systems were water
soluble. This observation led to proposals by Dalhamn and
Sjoholm (894b), Dalhamn and Rylander (893a), Rodgman
et al. (3306), Wynder (4301), USPHS (3999), Wynder et al.
(4304, 4305), and Wynder and Hoffmann (4332, 4342) that
this water solubility would result in removal of substantial
amounts of the in vitro ciliastatic components from the MSS
by their solution in the aqueous fluids coating the surfaces
of the oral cavity and trachea during the time that the MSS
was held in and/or traversed these portions of the respiratory
tract. The levels of ciliastats reaching the ciliated areas in the
smoker’s lower respiratory tract would produce insignificant
ciliastasis, if any at all. This “scrubbing” of ciliastatic com-
ponents from the inspired MSS stream was demonstrated in
smokers by Rodgman et al. (3306) and Dalhamn et al. (892,
893). Nasally inhaled components are removed in the nasal
cavity by “resorption,” a process similar to the “scrubbing”
of water-soluble components from gas streams such as MSS
vapor phase.
Dalhamn, in his 1961 study of ciliastatic activity, demon-
strated that sulfur dioxide was a powerful ciliastat in vitro at
or below 100 ppm but did not produce ciliastasis in vivo at
or below 100 ppm because much of the sulfur dioxide was
removed in the nasal cavity (891a). Sulfur dioxide was sub-
sequently identified as a minor tobacco smoke vapor-phase
component (3882). Dalhamn (891a) found that in rabbits
exposed to 300, 200, and 100 ppm of sulfur dioxide, the per-
centage showing cessation of ciliary activity within 45 min
was 90, 60, and 0, respectively. Removal of inhaled com-
ponents in the nasal cavity, termed “resorption,” is similar
to the “scrubbing” of water-soluble components from gas
streams, such as the MSS vapor phase. This nasal resorp-
tion is an important process not only from a ciliastasis-MSS
component point of view but also from an ETS point of view
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78836_C003.indd 227
since ETS, in contrast to MSS which is primarily inhaled via
the mouth, is inhaled primarily through the nose. ETS vapor-
phase components that would be removed through resorption
in the nasal cavity include formaldehyde, acetaldehyde, cro-
tonaldehyde, hydrazine, and possibly ethyl carbamate, five
MSS components listed by Hoffmann and Hecht (1727) as
“tumorigens” in MSS. Thus, very little, if any, of these water-
soluble components, already highly diluted in ETS, would
reach the lungs and the ciliated tissue to be involved in lung
cancer causation attributed to ETS by some authors. As noted
by Aviado (126a), data from inhalation studies in animals
indicate it is unlikely that either formaldehyde or hydrazine
contribute to pulmonary carcinogenesis.
In 1965, Dalhamn and Rylander (893b) commented on the
possible differences in the effects produced by mouth inhala-
tion vs. nose inhalation of tobacco smoke:
The most important point is probably that the smoke is
administered through the mouth. If smoke is administered
through the nose quite different absorption conditions are
present, and it is likely that the smoke which enters the lungs
differs considerably from that inhaled through the mouth.
This could also be one of the factors which explains why in
animal experiments no tumor-producing effects have been
found by tobacco smoke in inhalation studies where the
smoke was administered through the nose.
In 1968, Dalhamn et al. published the results of their
studies with humans on the mouth absorption (892) and lung
retention (893) of various components of cigarette smoke.
As noted earlier, the findings that a substantial percentage of
the levels of MSS water-soluble components demonstrated to
be ciliastatic in vitro is absorbed in the oral cavity lessened
the interest in ciliastasis produced by MSS components. The
data generated by Dalhamn et al. also served a second useful
purpose in that they demonstrated: (1) the remarkable dif-
ference, albeit with respect to only a few MSS smoke com-
ponents, between the compositions of inhaled and exhaled
MSS, and (2) all of the few components measured in the
inhaled MSS were found in the exhaled MSS, that is, none
was 100% retained in the lungs, etc., nor 100% absorbed in
the oral cavity.
These data are summarized in Tables III-8 and III-9. It is
obvious that mouth absorptions of such water-soluble cilia-
stats as acetaldehyde (60%) and acetone (56%) are substantial
(Table III-8), whereas the mouth absorptions of the relatively
water-insoluble components isoprene (20%), toluene (28%),
and CO (3%) are much less.
The data in Table III-9 are derived from those of Dalhamn
et al. (892, 893). The change in the composition of the MSS
delivered by the cigarette to the composition of the MSS
exhaled by the smoker is readily seen from the ratios, for
example, acetaldehyde is inhaled by the smoker at a ratio of
31.3 µg/mg total particulate matter but is exhaled at a ratio of
8.3 µg/mg total particulate matter; acetone is inhaled at a ratio
of 19.0 µg/mg total particulate matter but exhaled at a ratio of
66.7 µg/mg total particulate matter. Similarly, the MSS com-
position is altered by holding the smoke in the mouth without
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 228 The Chemical Components of Tobacco and Tobacco Smoke

Table III-8
Lung Retention and Mouth Absorption of Several Cigarette Mainstream Smoke Components
Per Cigarette Mainstream Smoke
Inhalation into Lungs Held in Mouth for 2 sec
Smoke Component Delivery Retention % Exhaled Absorbed in Moutha % Exhaled

Acetaldehyde, µg 940 930 99 10 560 60 380

Acetone, µg 570 490 86 80 320 56 250
Acetonitrile, µg 320 282 91 28 230 74 80
Isoprene, µg 560 554 99 6 110 20 450
Toluene, µg 250 232 93 18 70 28 180
CO, mg 30.0b 16.2 54 13.8 0.9 3 29.1
TPM, mg 30.0 28.8 96 1.2 4.8 16 25.2
a No inhalation
b Per cigarette CO yield assumed to be the same as per cigarette TPM yield.

inhalation. Since these exhaled smokes, whether originally
inhaled, held in the mouth with no or minimal inhalation,
or some blend of both (inhalation and mouth retention ulti-
mately contribute to ETS), it is obvious that the contribution
is not equivalent quantitatively to the MSS originally gener-
ated by the cigarette.
The data presented by Dalhamn et al. (892, 893) on lung
retention of MSS components were similar to data reported
earlier by Laskowski (2267) and to data on lung retention and
mouth absorption of ciliastats by Rodgman et al. (3306). The
various sets of data are summarized in Table III-10. Each set
of data indicates that exhaled MSS is substantially different
quantitatively from the inhaled MSS.
If cigarette MSS is mouth inhaled and held for any length
of time (a few seconds) in the mouth prior to being drawn
into the lungs, some of the MSS water-soluble vapor-phase
components are “scrubbed” from the smoke stream and
reach the ciliated areas at much reduced concentrations. This
is also true to a lesser degree for water-soluble components
of the particulate phase (see Tables III-8, III-9, and III-10).
The exposure of the lungs to “resorbed” entities alleged to
be tumorigenic will be much less than some authors claim.
Similarly, in nose inhalation of ETS, some of its water-soluble
components (formaldehyde, acetaldehyde, crotonaldehyde,
ethyl carbamate, hydrazine)—alleged to be tumorigenic at
the levels in MSS—will be “resorbed” in the nasal cavity and
reach ciliated areas at concentrations reduced not only by the
“resorption” mechanism but also by the dilution inherent in
ETS generation from exhaled MSS and sidestream smoke
produced during inter- and intrapuff smoldering. The expo-
sure of the lungs to these “tumorigens”’ will obviously be
substantially less than some writers claim.
Thus, these mechanisms—“scrubbing” and “resorption”—
effective in substantially diminishing the amounts of MSS
water-soluble in vitro ciliastats that reach the lung during active
smoking will be operative during ETS inhalation, whether oral
or nasal, and diminish the amounts of the same and similar
ETS components that reach the lung. This diminution in
amounts will be particularly pertinent in the case of the smoke
components formaldehyde, acetaldehyde, crotonaldehyde,

Table III-9
Difference Between Composition of Inhaled and Exhaled Mainstream Smoke and
Between Mouth-Held and Exhaled Mainstream Smoke
Per Cigarette Ratios, µg/g TPM or µg/g TPM
Inhalation into Lungs and Held in Mouth for 2 seca and
Smoke Component Delivery Ratio Exhaled, Exhaled MSS Ratio Exhaled, Exhaled MSS Ratio

Acetaldehyde, µg 31.3 8.3 15.1

Acetone, µg 19.0 66.7 9.9
Acetonitrile, µg 10.3 23.3 3.2
Isoprene, µg 18.7 5.0 17.9
Toluene, µg 8.3 15.0 3.2
CO, mg 1.0b 11.5 1.15
TPM, mg 1.0 1.0 1.0
a No inhalation
b Per cigarette CO yield assumed to be the same as per cigarette TPM yield

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 Aldehydes and Ketones 229

Table III-10
Lung Retention and Mouth Absorption Data
% Retention or Absorption
Laskowski (2267) Rodgman et al. (3306) Dalhamn et al. (892, 893)
Smoke Component LRa MAa LR MA LR MA

Aldehydes & ketonesb 99 — 80–90 40–67 — —

Acetaldehyde —c — — — 99 60
Acetone — — — — 86 56
Acetonitrile — — — — 91 74
Isoprene — — 80–92 5-10 99 20
Toluene — — — — 93 28
TPM — — 80–90 10–15 96 16
Nicotine 67 — — — — —
Pyridine 98 — — — — —
Ammonia 98 56 — — — —
Phenols 57 — — — — —
Carboxylic acids 44 — — — — —
CO — — — — 54 3
a LR = percentage retained in lungs; MA = percentage absorbed in mouth
b About 70 to 75% of the volatile aldehydes and ketones in MSS is acetaldehyde plus acetone. For cigarettes in the 1950s and
1960s, the acetaldehyde:acetone ratio approximated 2:1.
c — = not determined.

ethyl carbamate, and hydrazine on the Hoffmann and
Hoffmann “List of 60” (1740).
The following paragraphs include comments about two
of the much researched smoke components formaldehyde
and acetaldehyde.
Formaldehyde yields in cigarette range from 3.4 µg for fil-
tered cigarettes to 283 µg in unfiltered cigarettes (2564, 3427).
This compound is usually found in the vapor phase. The sug-
gested formation mechanism for formaldehyde is destructive
distillation and pyrolysis of celluloses, starch, pectins, lignin,
and sugars [Burton (535), Chortyk and Schlotzhauer (722),
Gager et al. (1264, 1265), Green (1351), Johnson et al. (1960),
Stedman (3797)].
In both indoor and outdoor air in the United States, form-
aldehyde is usually present at the generally nonirritating level
of approximately 0.06 ppm (1145a). In May 1992, OSHA
ruled the exposure limit to formaldehyde be reduced from
3 ppm to 0.75 ppm (2683a). Although most significant expo-
sure to formaldehyde is generally industrial, it also naturally
occurs in food, for example, fruits and vegetables (2111b).
Levels of formaldehyde in fruits and vegetables range from
3.3 µg/g in spinach to 17.3 µg/g in apples (3986a).
Formaldehyde is tumorigenic and mutagenic only at doses
many-fold higher than that seen in cigarette MSS. Whether
formaldehyde is mutagenic at noncytotoxic doses remains
controversial due to the small number of studies and the vari-
ability of results (1873a). Formaldehyde reportedly has been
found to induce aneuploidy (2363a, 2868a). In addition, results
from some studies have suggested that humans routinely
exposed to formaldehyde display increases in chromosomal
aberrations and sister chromatid exchanges in peripheral lym-
phocytes. However, rodents treated with formaldehyde in vivo
gave negative results for chromosomal aberrations and assays
for lethal mutations. Additional rodent studies on DNA dam-
age showed unconvincing results as well (1873a).
The overall tumorigenicity of formaldehyde was tested
in two strains of rats and one strain of mice. Significant
increases in squamous cell carcinomas of the nasal cavity
were observed in both rat strains after inhaling highly cyto-
toxic doses of formaldehyde. However, no carcinomas were
observed in any of the mice inhaling the same dose (2086a).
In other studies to evaluate formaldehyde tumorigenicity,
mice and hamsters were exposed via inhalation, rats via sub-
cutaneous injection, and rabbits via exposure in oral tanks. At
the time, the results from these studies were considered inad-
equate to evaluate the tumorigenic risk to humans. Although
formaldehyde was tumorigenic in rats when administered at
very high dose levels (2610a, 3789b), the evidence of its tum-
origenicity in humans was considered by the International
Agency for Research on Cancer (IARC) to be inadequate,
until 2005 (3A03). Recently, IARC reevaluated the evidence
on formaldehyde and reclassified it as a Group 1 human car-
cinogen (3A16).
As noted previously, the reported MSS yield of acetalde-
hyde ranged from 18 µg/cigarette (1853a) to 2815 µg/ciga-
rette (2564) for nonfiltered cigarettes. However, a substantial
difference exists between the analytically derived yields of
acetaldehyde and other water-soluble vapor-phase compo-
nents reported to be ciliastatic and the smoker’s exposure to
them. Dalhamn et al. (892) described how a substantial per-
centage of water-soluble components such as acetaldehyde
are removed from the vapor phase of the smoke stream by
solution in the aqueous fluids coating the oral cavity, thus
never reaching the upper or lower respiratory tract. The

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 230 The Chemical Components of Tobacco and Tobacco Smoke

proposed mechanisms of formation for acetaldehyde are
destructive distillation and pyrolysis and its major precur-
sors are reported to be the celluloses, pectins, starch, lignin,
and sugars [Burton (535), Chortyk and Schlotzhauer (722),
Gager et al. (1264, 1265), Green (1351), Johnson et al. (1960),
Stedman (3797)].
Additional complexities exist regarding the predictability
of biological activity. For example, a significant amount of
vapor-phase water-soluble components such as formaldehyde
and acetaldehyde are “scrubbed” from the smoke stream into
solution by the fluids coating the oral cavity and upper respi-
ratory tract; thus they reach the lung at a diminished level
(892, 893). Similarly, only a modest percentage of a water-
insoluble component such as isoprene is retained by the
smoker because a significant portion of it is exhaled. In light
of these phenomena and the fragmentary nature of the data
on actual exposure and retention, the possible physiological
effect of formaldehyde, acetaldehyde, and isoprene at the
cited cigarette MSS delivery ranges cannot be extrapolated.
Very few studies have been performed in which a smoking
machine or system was modified to approximate the effect
of oral cavity fluids on the retention of specific MSS compo-
nents. It has been known since the early 1950s and confirmed
in the 1960s that different classes of smoke components are
retained to different degrees by the smoker (892, 2267, 3255,
3257, 3306). Thus, the composition of the cigarette MSS
retained by the smoker is significantly different from that
exhaled by the smoker. Also, both the biologically retained
and exhaled smokes are obviously different compositionally
from the cigarette MSS retained and analyzed by the smok-
ing machine-collection system.
While much emphasis was placed on the aldehyde and
ketone components in the vapor phase of cigarette MSS
because of their in vitro ciliastatic activity, much research was
also conducted after the mid-1950s to identify aldehyde and
ketone components in the particulate phase of cigarette MSS
primarily because many were found to contribute consumer
acceptable flavor and aroma properties to the MSS. As noted
by Rodgman (3266), many of the aldehydes and ketones used
by the tobacco industry in its flavor formulations [see listing
by Doull et al. (1053)] are known components of untreated
tobacco and/or its smoke. Thus, such additives are not strang-
ers to the tobacco and/or its smoke but their addition increases
the consumer acceptable flavorants. Table III-11 lists some
of the tobacco and/or tobacco smoke components that have
been or are used in flavor formulations.

Table III-11
Tobacco and/or Tobacco Smoke Aldehydes and Ketones Used in Flavor Formulations
CAS No. Chemical Abstracts Nomenclature As Listed by Doull et al. (1053) Smoke Tobacco

Aldehydes

100-52-7 Benzaldehyde benzaldehyde + +

10031-82-0 Benzaldehyde, 4-ethoxy- p-ethoxybenzaldehyde — —
90-02-8 Benzaldehyde, 2-hydroxy- salicylaldehyde + +
121-33-5 Benzaldehyde, 4-hydroxy-3-methoxy- vanillin + +
120-14-9 Benzaldehyde, 3,4-dimethoxy- veratraldehyde — +
529-20-4 Benzaldehyde, 2-methyl- o-tolualdehyde + +
620-23-5 Benzaldehyde, 3-methyl- m-tolualdehyde + +
104-87-0 Benzaldehyde, 4-methyl- p-tolualdehyde + +
122-03-2 Benzaldehyde, 4-(1-methylethyl)- cuminaldehyde + +
122-78-1 Benzeneacetaldehyde phenylacetaldehyde + +
4411-89-6 Benzeneacetaldehyde, α-ethylidene- 2-phenyl-2-butenal + +
120-57-0 1,3-Benzodioxole-5-carboxaldehyde piperonal + +
96-17-3 Butanal, 2-methyl- 2-methylbutyraldehyde + —
590-86-3 Butanal, 3-methyl- 3-methylbutyraldehyde + +
25152-84-5 2,4-Decadienal trans, trans-2,4-decadienal + +
112-31-2 Decanal {capraldehyde} decanal — +
66-25-1 Hexanal {caproic aldehyde} hexanal + +
6728-26-3 2-Hexenal, (E) 2-hexenal + +
110-62-3 Pentanal valeraldehyde + +
78-84-2 Propanal, 2-methyl- isobutyraldehyde + +
104-55-2 2-Propenal, 3-phenyl- cinnamaldehyde + +
13679-70-4 2-Thiophenecarboxaldehyde, 5-methyl- 5-methyl-2-thiophenecarboxaldehyde + +
7774-82-5 2-Tridecenal 2-tridecenal — +
Ketones
107-88-0 1,3-Butanediol 1,3-butanediol + +
431-03-8 2,3-Butanedione {diacetyl} 2,3-butanedione + +

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 Aldehydes and Ketones 231

Table III-11 (Continued)

Tobacco and/or Tobacco Smoke Aldehydes and Ketones Used in Flavor Formulations
CAS No. Chemical Abstracts Nomenclature As Listed by Doull et al. (1053) Smoke Tobacco
78-93-3 2-Butanone 2-butanone + +
513-86-0 2-Butanone, 3-hydroxy- acetoin + +
5471-51-2 2-Butanone, 4-(4-hydroxyphenyl)- 4-(p-hydroxyphenyl)-2-butanone + —
23696-85-7 2-Buten-1-one, 1-(2,6,6-trimethyl-1,3-cyclohexadien-1-yl)- 4-(2,6,6-trimethylcyclohexa-1,3-dienyl)-but-2- + +
{β-damascenone} en-4-one
35044-68-9 2-Buten-1-one, 1-(2,6,6-trimethyl- 4-(2,6,6-trimethylcyclohex-2-enyl)-but-2-en-4- + +
23726-92-3 cyclohex-1-enyl)- {β-damascone} one
623-15-4 3-Buten-2-one, 4-(2-furanyl)- 4-(2-furyl)-3-buten-2-one + +
122-57-6 3-Buten-2-one, 4-phenyl- 4-phenyl-3-buten-2-one + +
127-41-3 3-Buten-2-one, 4-(2,6,6-trimethyl-2-cyclohexen-1-yl)- α-ionone + +
14901-07-6 3-Buten-2-one, 4-(2,6,6-trimethyl-1-cyclohexen-1-yl)- β-ionone + +
89-80-5 Cyclohexanone, 5-methyl-2-(1-methylethyl)- l-menthone + +
1125-21-9 2-Cyclohexene-1,4-dione, 2,6,6-trimethyl- 2,6,6-trimethylcyclohex-2-ene-1,4-dione + +
13215-88-8 2-Cyclohexen-1-one, 4-(2--(2-butenylidene)-3,5,5- 4-(2-butylidene-3,5,5-trimethyl)-2-cyclohexen- + +
trimethyl- 1-one
99-49-0 2-Cyclohexen-I-one, 2-methyl-5-(1-methylethyl)- l-carvone + +
89-81-6 2-Cyclohexen-1-one, 3-methyl-6-(1- d-piperitone — +
6091-50-5 methylethyl)-
13494-06-9 1,2-Cyclopentanedione, 3,4-dimethyl- 3,4-dimethyl-1,2-cyclopentanedione + —
13494-07-0 1,2-Cyclopentanedione, 3,5-dimethyl- 3,5-dimethyl-1,2-cyclopentanedione + —
80-71-7 2-Cyclopenten-1-one, 2-hydroxy-3-methyl- methylcyclopentenolone + +
100-06-1 Ethanone, 1-(4-methoxyphenyl)- acetanisole + +
98-86-2 Ethanone, 1-phenyl- acetophenone + +
32974-92-8 Ethanone, 1-(5-ethylpyrazintl)- 2-acetyl-3-ethylpyrazine + —
1193-79-9 Ethanone, 1-(2-furanyl 5-methyl)- 2-acetyl-5-methylfuran + +
122-00-9 Ethanone, 1-(4-methylphenyl)- 4-methylacetophenone + +
1333-52-4 Ethanone, 1-(naphthalenyl)- methyl naphthyl ketone + —
22047-25-2 Ethanone, 1-pyrazinyl- acetylpyrazine — +
1122-62-9 Ethanone, 1-(2-pyridinyl)- 2-acetylpyridine + +
350-03-8 Ethanone, 1-(3-pyridinyl)- 3-acetylpyridine + +
1072-83-9 Ethanone, 1-(1H-pyrrol-2-yl)- methyl 2-pyrrolyl ketone + +
24295-03-2 Ethanone, 1-(2-thiazolyl)- 2-acetylthiazole + —
110-43-0 2-Heptanone 2-heptanone + +
5166-53-0 3-Hexen-2-one, 5-methyl- 5-methyl-3-hexen-2-one + +
119-61-9 Methanone, diphenyl- benzophenone + —
1937-54-8 6,8-Nonadien-2-one, 8-methyl-5-(1-methylethyl)- solanone + +
821-55-6 2-Nonanone 2-nonanone + +
600-14-6 2,3-Pentanedione 2,3-pentanedione + —
123-76-2 Pentanoic acid, 4-oxo- levulinic acid + +
107-87-9 2-Pentanone 2-pentanone + +
141-79-7 3-Penten-2-one, 4-methyl- {mesityl oxide} 4-methyl-3-penten-2-one + +
127-17-3 Propanoic acid, 2-oxo- pyruvic acid + +
4940-11-8 4H-Pyran-4-one, 3-hydroxy-2-ethyl- ethylmaltol + —
118-71-8 4H-Pyran-4-one, 3-hydroxy-2-methyl- maltol + +
593-08-8 2-Tridecanone 2-tridecanone — +
3796-70-1 5,9-Undecadien-2-one, 6,10-dimethyl- {geranylacetone} 6,10-dimethyl-5,9-undecadien-2-one — +
112-12-9 2-Undecanone 2-undecanone + +

Tables III-12 and III-13 list the aldehydes and ketones, number 1090, of which 656 have been identified in smoke,
respectively, reported as tobacco and/or tobacco smoke com- 647 in tobacco, and 213 in both. Table III-14 depicts the chro-
ponents. The aldehydes number 263, with 143 identified in nology of many of the studies on aldehydes and ketones in
tobacco smoke, 199 in tobacco, and 79 in both. The ketones tobacco and tobacco smoke.

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 232 The Chemical Components of Tobacco and Tobacco Smoke

Table III-12
Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke
Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

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 Aldehydes and Ketones 233

Table III-12 (Continued)

Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )
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 234 The Chemical Components of Tobacco and Tobacco Smoke

Table III-12 (Continued)

Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C003.indd 234 11/24/08 12:21:27 PM

 Aldehydes and Ketones 235

Table III-12 (Continued)

Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 236 The Chemical Components of Tobacco and Tobacco Smoke

Table III-12 (Continued)

Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C003.indd 236 11/24/08 12:21:29 PM

 Aldehydes and Ketones 237

Table III-12 (Continued)

Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C003.indd 237 11/24/08 12:21:30 PM

 238 The Chemical Components of Tobacco and Tobacco Smoke

Table III-12 (Continued)

Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C003.indd 238 11/24/08 12:21:31 PM

 Aldehydes and Ketones 239

Table III-12 (Continued)

Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 240 The Chemical Components of Tobacco and Tobacco Smoke

Table III-12 (Continued)

Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C003.indd 240 11/24/08 12:21:33 PM

 Aldehydes and Ketones 241

Table III-12 (Continued)

Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 242 The Chemical Components of Tobacco and Tobacco Smoke

Table III-12 (Continued)

Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C003.indd 242 11/24/08 12:21:36 PM

 Aldehydes and Ketones 243

Table III-12 (Continued)

Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 244 The Chemical Components of Tobacco and Tobacco Smoke

Table III-12 (Continued)

Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C003.indd 244 11/24/08 12:21:38 PM

 Aldehydes and Ketones 245

Table III-12 (Continued)

Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C003.indd 245 11/24/08 12:21:39 PM

 246 The Chemical Components of Tobacco and Tobacco Smoke

Table III-12 (Continued)

Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C003.indd 246 11/24/08 12:21:40 PM

 Aldehydes and Ketones 247

Table III-12 (Continued)

Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C003.indd 247 11/24/08 12:21:41 PM

 248 The Chemical Components of Tobacco and Tobacco Smoke

Table III-12 (Continued)

Aldehydes in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C003.indd 248 11/24/08 12:21:42 PM

 Aldehydes and Ketones 249

Table III-13
Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke
Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

(Continued )

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 250 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Aldehydes and Ketones 251

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 252 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C003.indd 252 11/24/08 12:21:48 PM

 Aldehydes and Ketones 253

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C003.indd 253 11/24/08 12:21:49 PM

 254 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C003.indd 254 11/24/08 12:21:50 PM

 Aldehydes and Ketones 255

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C003.indd 255 11/24/08 12:21:51 PM

 256 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C003.indd 256 11/24/08 12:21:54 PM

 Aldehydes and Ketones 257

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C003.indd 257 11/24/08 12:21:54 PM

 258 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C003.indd 258 11/24/08 12:21:55 PM

 Aldehydes and Ketones 259

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 260 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C003.indd 260 11/24/08 12:21:57 PM

 Aldehydes and Ketones 261

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 262 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C003.indd 262 11/24/08 12:21:59 PM

 Aldehydes and Ketones 263

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C003.indd 263 11/24/08 12:22:00 PM

 264 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C003.indd 264 11/24/08 12:22:02 PM

 Aldehydes and Ketones 265

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C003.indd 265 11/24/08 12:22:03 PM

 266 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C003.indd 266 11/24/08 12:22:04 PM

 Aldehydes and Ketones 267

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C003.indd 267 11/24/08 12:22:05 PM

 268 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C003.indd 268 11/24/08 12:22:06 PM

 Aldehydes and Ketones 269

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 270 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C003.indd 270 11/24/08 12:22:08 PM

 Aldehydes and Ketones 271

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 272 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C003.indd 272 11/24/08 12:22:10 PM

 Aldehydes and Ketones 273

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C003.indd 273 11/24/08 12:22:11 PM

 274 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C003.indd 274 11/24/08 12:22:12 PM

 Aldehydes and Ketones 275

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 276 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Aldehydes and Ketones 277

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 278 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Aldehydes and Ketones 279

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 280 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Aldehydes and Ketones 281

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 282 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Aldehydes and Ketones 283

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 284 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Aldehydes and Ketones 285

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 286 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Aldehydes and Ketones 287

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 288 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Aldehydes and Ketones 289

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 290 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Aldehydes and Ketones 291

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 292 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Aldehydes and Ketones 293

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 294 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Aldehydes and Ketones 295

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 296 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Aldehydes and Ketones 297

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 298 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Aldehydes and Ketones 299

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 300 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Aldehydes and Ketones 301

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 302 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Aldehydes and Ketones 303

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 304 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Aldehydes and Ketones 305

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 306 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Aldehydes and Ketones 307

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 308 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Aldehydes and Ketones 309

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 310 The Chemical Components of Tobacco and Tobacco Smoke

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Aldehydes and Ketones 311

Table III-13 (Continued)

Ketones in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

Table III-14
Chronology of Studies on Aldehydes and Ketones in Tobacco Smoke
NOTE: While many of the following items deal with the identification and quantitation of formaldehyde in cigarette MSS, SSS, and ETS,
the evidence for the presence of formaldehyde (H2C=O) per se is scant. Data indicate that formaldehyde is present as its hydrate, i.e., as
dihydroxymethane [H2C(OH)2], which in most instances behaves chemically and biologically the same as formaldehyde.
Year Event

1843 Acrolein (propenal) was first identified as a component in the destructive distillate from fat by Redtenbacher (3093b).
1859 Formaldehyde (methanal) was discovered by Butlerov (3A02).
1867 Formaldehyde was rediscovered by A.W. Von Hofmann (3A24).
1904 Thoms (3912) reported the presence of formaldehyde in cigarette smoke.
1909 From his toxicologic study of cigarette smoke, Lehmann (2343) reported the presence of formaldehyde in cigarette smoke.
1926 Neuberg and Kobel in their study of the aldehydes reported the presence of several aldehydes, including formaldehyde (2702a).
1927 Neuberg and Ottenstein (2706) report the presence of formaldehyde in tobacco smoke.
1931 Neuberg and Burkard (2701) reported the presence of formaldehyde, acetaldehyde, butyraldehyde (butanal),
3-hydroxybutyraldehyde (3-hydroxybutanal, aldol), benzaldehyde, 3-pentanone, and 4-heptanone in cigarette smoke.
1932 McNally (2524) reported the presence of formaldehyde and acrolein (propenal) in tobacco smoke.
1933 Pfyl (2937) confirmed the finding of Neuberg and Burkard (2701) on the presence of acetaldehyde in tobacco smoke.
1936 In his study of the irritant factors in cigarette smoke, Bogen (1936) classified formaldehyde, acetaldehyde, and acrolein
(propenal) as “irritant factors” in cigarette smoke and rated formaldehyde as a major contributor to cigarette smoke irritation.
1937 Prentiss (2988a) reported that acrolein (propenal) was a powerful lachrymator; even at 3 ppm (7mg/m3) acrolein was
reported to be highly irritating to the conjunctiva and to the respiratory tract.
1939 Proetz (2991a) attributed ciliastasis on upper respiratory tract mucosa of rabbits exposed to cigarette smoke to the aldehydes
in the smoke.
1939 Ribeiro (3126) reported the presence of acrolein (propenal) in tobacco smoke.
1939 Wenusch (4202) reported 2-furaldehyde and acetone in cigarette smoke.
1939 Roffo (3324) reported 2-furaldehyde in cigarette smoke.
1939 Schmalfuss (3475) reported biacetyl (2,3-butanedione) in tobacco smoke.
1940 Smirnov et al. (3A19) listed 3-pentanone as a tobacco smoke component.
1954 In his catalog of the components of tobacco smoke reported to mid-1954, Kosak (2170) provided references to reports in
tobacco smoke of the following aldehydes: Formaldehyde [Neuberg and Ottenstein (2706), Neuberg and Burkard (2702),
McNally (2524)], acetaldehyde [Neuberg and Burkard (2702), Pfyl (2937)], butyraldehyde (butanal) [Neuberg and Burkard
(2702)], acrolein (propenal) [McNally (2524)], benzaldehyde [Neuberg and Burkard (2702)], 2-furaldehyde [Wenusch
(1939), Roffo (3324)].
(Continued )

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 312 The Chemical Components of Tobacco and Tobacco Smoke

Table III-14 (continued)

Chronology of Studies on Aldehydes and Ketones in Tobacco Smoke
Year Event

Kosak also cataloged reports on the following ketones in tobacco smoke: 3-Pentanone (diethyl ketone) [Neuberg and
Burkard (2702)], 4-heptanone (dipropyl ketone) [Neuberg and Burkard (2702)], 17-tritriacontanone (dipalmityl ketone)
[Schürch and Winterstein (3562)], and 2,3-butanedione (biacetyl) [Schmalfuss (3475)].
1955 In his study of the vapor phase of cigarette MSS, Laurene (2293) identified acrolein (propenal).
1956 Buyske et al. (564) reported butyraldehyde (butanal) and crotonaldehyde (2-butenal) in cigarette MSS.
1959 In their review of the components of tobacco and tobacco smoke, Johnstone and Plimmer (1971) listed 18 aldehydes and
ketones in tobacco smoke.
1959 In anticipation of their possible utility in the identification of aldehydes and ketones that might be present in the MSS from
an all-tobacco and/or an all-cellulose cigarette, Fredrickson et al. (1238) prepared over 90 2,4-dinitrophenylhydrazone
derivatives for use as standards and cataloged their infrared spectra. The spectral data were used several years later by
Fredrickson et al. to identify numerous aldehydes and ketones in tobacco smoke (1239).
1961 Guillerm et al. (1451a) reported the ciliastatic activity of acetaldehyde and acrolein (propenal) in liquid and in vapor form in
an in vitro system. They also reported the synergistic ciliastatic activity of these two aldehydes in cigarette MSS exposure
studies.
1963 Horton et al. (3A11) reported that exposure of mice via inhalation to formaldehyde induced hyperplasia and metaplasia in
the lung and typical hyperplastic changes in the trachea but the tracheal tissue changes did not progress to invasive
carcinoma.
1963 Kensler and Battista (2083, 2084) reported significant ciliatoxicity for formaldehyde and acrolein and their levels in
cigarette MSS were reduced by passage of the smoke through a charcoal-containing filter.
1963 In a study with human ciliated tonsillar epithelium, George (3A09) reported not only was phenol a strong ciliastat but also that
acrolein (propenal) was an even stronger ciliastat.
1963 Murphy et al. (3A17) reported that exposure of guinea pigs to low concentrations of acrolein (propenal) resulted in an
increase in total respiratory flow resistance plus decreased respiratory rates and increased tidal volume.
1964 Even though the Advisory Committee to the U.S. Surgeon General (3999) reported that formaldehyde and acrolein
(propenal) were two of the components of cigarette MSS considered to be inhibitors of ciliastatic transport activity, the
Committee concluded: No one of these [ciliastatic components] occurs at levels high enough to produce the effect noted for
smoke.
1964 Laurene et al. (2305) described an analytical method for the quantitative determination of acetaldehyde, acrolein (propenal),
and acetone in cigarette MSS. Subsequently, an improvement in the analytical procedure for these three carbonyl
components was reported by Laurene and Harbin (2302).
1964 From their study of the pyrogenesis of acrolein (propenal) from glycerol, Doihara et al. (1023) and others deduced that a
tobacco smoking product that contains glycerol as a humectant has an enhanced potential for the formation and release of
acrolein (propenal) during smoking [see Wynder and Hoffmann (4337)].
1965 In testing the ciliatoxicity of cigarette MSS aldehydes to clam gill cilia, Wynder et al. (4330) reported that formaldehyde,
acrolein (propenal), and crotonaldehyde (2-butenal) showed the highest toxicity. They also reported that acrolein was about
twice as ciliatoxic as phenol in the clam gill cilia test [see also Wynder and Hoffmann (p. 253 in (4332)]. In addition to their
aldehyde ciliatoxicity results, Wynder et al. (4330) also noted the serious error introduced into the results obtained in their
study of the ciliatoxicity of low molecular weight acids in tobacco smoke.
1965 To quantitate the level of formaldehyde in cigarette MSS, Newsome et al. (2782) reported on a colorimetric method
involving chromatropic acid.
1965/1966 Walker and Kiefer (4109) examined the effect of cigarette MSS vapor phase on clam gill cilia. Removal of the acrolein region
from the chromatographed vapor phase resulted in a significant reduction in the ciliastatic activity. Contrary toxicity results
were reported for the same MSS in which the levels of acrolein (propenal) and acetaldehyde were reduced by 66% and 82%,
respectively, by a “hydrazide” filter. The ciliastatic activity of the vapor phase of the “hydrazide” filtered MSS was, within
experimental error, the same as that of the unfiltered smoke. Wynder and Hoffmann (4337) offer a possible explanation for
these contradictory results: Acrolein administered alone is quite toxic but in the cigarette smoke vapor phase its effect is
“masked” or “neutralized” by other smoke components (identity not specified).
1966 In their study of the levels of acrolein, acetaldehyde, acetone, hydrogen cyanide, nitrogen oxides, nicotine, and total solids in
pipe tobacco MSS, Harbin and Laurene (1497) reported that the acrolein delivery increased as the glycerol level was
increased by addition but the acrolein delivery leveled off when the glycerol addition exceeded 6%.
1967 Wynder and Hoffmann (4337) discussed the conversion of the glycerol, used as a humectant in tobacco smoking products,
to acrolein (propenal) during the smoking process.

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 Aldehydes and Ketones 313

Table III-14 (continued)

Chronology of Studies on Aldehydes and Ketones in Tobacco Smoke
Year Event

1968 In their study of the ciliastatic components of cigarette smoke MSS vapor phase, Dalhamn et al. (892, 893) reported that the
absorption of the vapor-phase ciliastats by the fluids coating the oral cavity resulted in significant reductions of acetaldehyde
(60%) and acetone (56%), i.e., significant levels of these in vitro ciliastats failed to reach the ciliated lung tissue and thus
were unable to exert the ciliatoxicity asserted by some investigators.
1968 In his review of the components of tobacco and tobacco smoke, Stedman (3797) listed references to some 46 aldehydes and
ketones in tobacco smoke.
1970 Martin and Thacker (2478) described the quantitation of several aldehydes (piperonal, ethylvanillin, vanillin) used as
flavorants in cigarette tobacco.
1971 Despite the reported findings of Dalhamn et al. (892, 893), the Royal College of Physicians (3363) noted that acrolein
(propenal) was one of the most important ciliastatic components of tobacco smoke, possibly contributing to the causes of
pulmonary disease by interfering with the self-cleansing mechanism of the lung and thereby allowing more prolonged
contact between the lining of the bronchial tubes and the carcinogenic agents in the smoke.
1971/1973 From their study of 85-mm nonfiltered cigarettes made from each of four varieties of flue-cured tobacco, Rathkamp et al. (3087,
3088) reported that the MSS acetaldehyde deliveries ranged from 800 to 1,280 µg/cig; the acrolein (propenal) deliveries ranged
from 51 to 102 µg/cig.
1972 The U.S. Surgeon General (4003) classified formaldehyde as a suspected contributor to the health hazard of smoking snf
acrolein (propenal) as a probable health hazard in cigarette smoke.
1972 Testa and Joigny (3885) reported that the per cigarette delivery of acrolein (propenal) from a cigarette made from black
tobacco was 65.7 µg.
1975 Tsuchiya et al. (3986a) reported that the levels of formaldehyde in fruits and vegetables ranged from 3.4 µg/g in spinach to
17.3 µg/g in apples.
1976 Kitchen et al. (2111b) noted that the most significant exposure to formaldehyde is generally industrial but formaldehyde
occurs naturally in many foodstuffs, e.g., fruits and vegetables.
1976 Osha standards for exposure to air contaminants require an employee’s exposure to acrolein (propenal) not exceed an 8-hr
time-weighted average of 0.25 mg/m3 (0.1 ppm) in the workplace air, in any 8-hr shift, during a 40-hr work week.
1976 Extensive experimental smoking in an unventilated room provided index levels for acrolein (propenal) that accumulated
during the cigarette smoking. The industrially permitted threshold limit value (TLV) for acrolein (0.1 ppm; 0.25 mg/m3) was
only exceeded under experimental conditions where as large number of cigarettes were burned in a closed room [Weber et
al. (3A25)] .
1977 In his discussion of the vapor phase of cigarette MSS, Norman (2799a) listed per cigarette deliveries of 1200 µg and 70 µg for
acetaldehyde and acrolein (propenal), respectively.
1977 Mansfield et al. (2456) described an analytical method to quantitate formaldehyde in cigarette MSS.
1977 In their study of the effect of inhaled acrolein (propenal) on the tumorigenicity of benzo[a]pyrene or N-nitrosodiethylamine,
Feron and Kruysse (3A08) conducted inhalation and intratracheal experiments with two groups of 18 male and 18 female
6-wk old Syrian hamsters. One group was exposed to 9.2 mg/m3 (4 ppm) of acrolein in air (7 hr/day, 5 d/wk, 52 wk). The
other group was similarly exposed to acrolein via inhalation but received an intratracheal installation of 0.9% saline. All
animals alive at 81 wk were sacrificed. Only one female had a tracheal papilloma. Tumors at other sites were not increased vs
untreated controls.
1977 In its assessment of tobacco smoke components reported to be ciliastatic, the Royal College of Physicians (3364) reported
that acrolein (propenal) appeared to be the most important.
1979 According to the Chemical Industrial Institute of Toxicology (CIIT) (3A04), data supporting the tumorigenicity of
formaldehyde were first reported on 8 October, 1979 [see Battelle Institute (3A01)].
1979 U.S. Surgeon General (4005) reported acrolein (propenal) to be one of the major toxic agents in the vapor phase of unaged
cigarette MSS.
1980 Swenberg et al. (3A21) reported the induction of squamous cell carcinomas in the nasal cavities of rats exposed to cigarette
MSS plus 15 ppm of formaldehyde in chambers, 30 hr/wk for 18 months. The authors noted that reported per cigarette
deliveries for formaldehyde ranged from 20 to 90 µg; for acrolein (propenal), deliveries ranged from 10 to 40 µg. Swenberg
et al. listed acrolein as a ciliatoxic agent in cigarette MSS.
1981 In its report, the Battelle Institute (3A01) described the induction of tumors in rats and mice exposed via inhalation to
formaldehyde.
(Continued )

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 314 The Chemical Components of Tobacco and Tobacco Smoke

Table III-14 (continued)

Chronology of Studies on Aldehydes and Ketones in Tobacco Smoke
Year Event

1981 According to Niosh, workers who smoke cigarettes are exposed to additional levels of formaldehyde since cigarette MSS
contains as much as 40 ppm of formaldehyde by volume. It was deduced that an individual who smokes a pack a day (20
cigarettes) would inhaled 0.38 mg of formaldehyde whereas occupational exposure at 3 ppm could result in a daily intake of
29.0 mg (3A04).
1982 Dalbey (3A06) reported that 88 male Syrian hamsters exposed to 70 ppm of formaldehyde vapor (5 hr/d, 5 d/wk) for their
lifetime showed no detectable respiratory tract tumors. No respiratory tract tumors were observed in a similar inhalation
experiment involving male hamsters exposed to 30 ppm of formaldehyde (5 hr/d, 1d/wk) for their lifetime.
1982 In its assessment of the literature on formaldehyde, the IARC (3A13) reported that it considered the evidence sufficient that
formaldehyde was carcinogenic to rats. However, the IARC also stated that the epidemiological data [to that time] did not
provide adequate evidence to assess the carcinogenicity of formaldehyde in man.
1982 The U.S. Surgeon General (4010) reported that formaldehyde and acrolein (propenal) were “tumorigenic” and each was “a
major toxic agent” in the vapor phase of cigarette MSS.
1982 In a discussion of low-delivered doses of alleged carcinogenic compounds, Starr (3789b) note: Even though formaldehyde
has been demonstrated to be mutagenic/genotoxic in test systems of one kind or another, we do not know that is in the
human case. Formaldehyde is a major chemical building block in our society. Its outright ban would cause dramatic changes
in society [also see Starr in Clary et al. (3A05)].
1982 At the Chemical Industrial Institute of Toxicology (CIIT) meeting, Fayerweather stated:
When the epidemiological studies are viewed as a whole, the data suggest that formaldehyde has not been responsible for
producing cancer in man [see Fayerweather in Clary et al. (3A05)].
1983 Jenkins et al. (1932) at the Oak Ridge National Laboratory (ORNL) analyzed the MSS from 32 commercial brands of
cigarettes marketed in the U.S. for their deliveries of specific smoke components. Included was acrolein (propenal) whose
deliveries ranged from 33 to 141 µg/cig.
1983 Kerns et al. (2086b) reported significant increases in squamous-cell carcinomas of the nasal cavity were observed in both
strains of rats after inhaling highly cytotoxic doses of formaldehyde. However, no carcinomas were observed in mice after
inhaling the same dose. In other studies to evaluate the carcinogenicity of formaldehyde, mice and hamsters were exposed
via inhalation, rats via subcutaneous injection and rabbits via exposure in oral tanks. The results from these studies have
been considered inadequate to evaluate the carcinogenic risk to humans (3A06, 3A13).
1984 From its study of formaldehyde, the United States Department of Health and Human Services (USDHHS) (3A23) reported:
The data are sparse and conflicting and do not yet provide persuasive evidence of a causal relation between exposure to
formaldehyde and cancer in man. It concluded: Although some epidemiological studies noted that there may be an
association between formaldehyde exposure and some forms of cancer, the data from these studies are not sufficient, at this
time, for quantitative risk modeling.
1984 The Environmental Protection Agency (EPA) (3A07) noted:
There may be a reasonable basis to conclude that certain exposures to formaldehyde present a significant risk of widespread
harm to human beings.
This statement contradicts a previous one by the EPA in 1982 that no significant risks to human were expected from
formaldehyde!
1984 From their assessment of components of indoor air found to be tumorigenic in laboratory animals, Sterling and Arundel
(3A20) suggested that formaldehyde was potentially carcinogenic to humans.
1984 Theiss et al. (3A22) reported a statistically significant increase in the number of lung adenomas in mice after inhaling air
containing 15 ppm of formaldehyde for 18 weeks.
1984 Acetaldehyde deliveries ranged from 18 to 2815 µg/cig for nonfiltered cigarettes [Huynh et al. (1853a), Miyake and Shibamoto
(2564)].
1985 A proposal to lower the exposure limit of formaldehyde from 5 to 1 ppm was under consideration by OSHA (3A18).
1985 Although formaldehyde was reported by Starr and Gibson (3789b) to be carcinogenic in rats when administered at very high
dose levels, IARC found the weight of evidence of its carcinogenicity in humans to be inadequate.
1986 The IARC (1870) listed the delivery range for acrolein (propenal) in cigarette MSS vapor phase as 10 to 110 µg/cig and
classified it as a ciliatoxic component.
1985/1986 Formaldehyde was reported in two studies to induce aneuploidy [Liang and Brinkley (2363a), Oshimura and Barrett
(2868a)].

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 Aldehydes and Ketones 315

Table III-14 (continued)

Chronology of Studies on Aldehydes and Ketones in Tobacco Smoke
Year Event

1986 Brunnemann et al. (500) determined several volatile aldehydes and ketones in tobacco headspace and tobacco smoke by
derivatization with 2,4-dinitrophenylhydrazine. Tobacco smoke carbonyl components identified included: Formaldehyde,
acetaldehyde (1000 µg/cig), propionaldehyde (propanal), acrolein (propenal), isobutyraldehyde (2-methylpropanal),
crotonaldehyde (2-butenal), methacrolein (2-methylpropenal), benzaldehyde (1 µg/cig), and acetone.
1987 Bell et al. (243) used the formation of the 2,4-dinitrophenylhydrazone derivative of formaldehyde in SSS as the means to
quantitate the level of formaldehyde in SSS.
1987 In its review of formaldehyde, the IARC noted that formaldehyde is carcinogenic and mutagenic only at doses far in excess of
that seen in cigarette MSS. Whether formaldehyde is mutagenic at non-cytotoxic dose levels remains controversial because of
the small number of studies and the variability of the results (3A14). The IARC (3A15) also noted that results from some
studies suggest that humans routinely exposed to formaldehyde display increased chromosomal aberrations and sister
chromatid exchanges in peripheral lymphocytes. Nevertheless, rodents treated with formaldehyde in vivo gave negative results
for chromosomal aberrations and assays for lethal mutations; other rodent studies on DNA damage gave equivocal results.
1988 Deluca (929) described a 2,4-dinitrophenylhydrazine procedure for the collection of carbonyl compounds in ETS.
1989 Formaldehyde deliveries in MSS vapor phase range from 3.4 µg for filtered cigarettes to 283 µg in unfiltered cigarettes
[Schaller et al. (3427), Miyake and Shibamoto (2564)].
1990 Hoffmann and Hecht (1727) included formaldehyde, acetaldehyde, and crotonaldehyde (2-butenal) in their list of 43
tumorigenic components of tobacco and tobacco smoke. Their text accompanying the list plus the authors’ disregard of how
the tumorigenicity of many of the 43 components was determined experimentally raises serious questions as to why many
of the components were listed.
1990 The EPA (1148) cited the Hoffmann-Hecht list of 43 tumorigenic components in tobacco and tobacco MSS in their effort to
indict ETS as a significant health hazard.
1992 In their treatise on ETS, Guerin et al. [(3A10), see p. 197 in (1446)] at ORNL discussed in detail the levels of formaldehyde
in indoor and outdoor air. They noted:
It might be expected that environmental tobacco smoke would be an important contributor to indoor air concentrations of
formaldehyde because formaldehyde is known to be a constituent of cigarette smoke. Popular commercial cigarettes deliver
approximately 20-90 micrograms of formaldehyde in their mainstream smoke and 1-2 milligrams of formaldehyde in their
SSS. While this contribution may at first appear highly significant, it has generally been found to be very minor when
compared with other sources.
1992 OSHA ruled that the exposure limit for formaldehyde should be reduced from 3 ppm to 0.75 ppm.
1994 OSHA (2825) in its list of 43 tumorigenic components of tobacco smoke included only formaldehyde and acetaldehyde but
not crotonaldehyde (2-butenal).
1994 NCI (2683a) reported on the OSHA 1992 ruling that the exposure limit for formaldehyde should be reduced from 3 ppm to
0.75 ppm.
1994 Although formaldehyde was reported by Monticello and Morgan (2610a) to be carcinogenic in rats when administered at
very high dose levels, IARC found the weight of evidence of its carcinogenicity in humans to be inadequate.
1995 Formaldehyde deliveries in MSS vapor phase range from 3.4 µg for filtered cigarettes to 283 µg in unfiltered cigarettes
[Schaller et al. (3427), Miyake and Shibamoto (2564)]. Acetaldehyde deliveries ranged from 18 to 2815 µg/cig for non-
filtered cigarettes [Huynh et al. (1853a), Miyake and Shibamoto (2564)].
1996 Green and Rodgman (1373) reviewed presentations during the first half century (1947-1996) of the TCRC on the subject of
the identification and quantitation of aldehydes and ketones in cigarette MSS and SSS as well as in ETS.
1997/1998 Hoffmann and Hoffmann (1740, 1741) in their lists of 60 tumorigenic components of tobacco and tobacco smoke included
only two aldehydes - formaldehyde and acetaldehyde. Crotonaldehyde (2-butenal) include in the 1990 Hoffmann-Hecht list
(1727) was omitted from the Hoffmann-Hoffmann (1740), an omission that paralleled the 1994 OSHA list (2825).
1998 According to information from the Environmental Health Center (EHC) (1145a), formaldehyde is usually present at the
non-irritating level of about 0.06 ppm.
1999 Smith et al. discussed the IARC classification of the tobacco smoke vapor-phase components formaldehyde and
acetaldehyde as IARC Group 2A [Smith et al. (3713)] and Group 2B [Smith et al. (3714)] carcinogens, respectively.
2003 In a discussion of the various lists of tumorigenic components in tobacco and tobacco smoke issued between 1986 and
2003, Rodgman and Green (3300) and Rodgman (3265) noted that formaldehyde, acetaldehyde, crotonaldehyde
(2-butenal), and acrolein (propenal) were included in the majority of them (1217, 1740, 1741, 1743, 1744, 1808, 1870,
2825)
2006 IARC revaluated formaldehyde and classifies it as a Group 1 carcinogen (3A03, 3A16).

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 4 Carboxylic Acids
IV.A  The Carboxylic Acids
Numerous organic acids have been identified in tobacco.
These volatile, nonvolatile, and amino acids have been dis-
cussed in-depth by Tso [see Chapter 24 in (3973)]. The major
nonvolatile acids are 2-hydroxy-1,2,3-propanetricarboxylic
(citric), hydroxybutanedioic (malic), and ethanedioic (oxalic).
The minor nonvolatile acids are hydroxyacetic (glycolic),
butanedioic (succinic), propanedioic acid (malonic), butene-
dioic (E) (fumaric acid), and 2-oxopropanoic (pyruvic). The
major volatile acids in tobacco are acetic and formic acid;
minor volatile acids are propanoic, 2-furancarboxylic acid
(2-furoic), benzoic, α-methylbutyric, β-methylvaleric, and
numerous others. Over forty amino acids and related com-
pounds have been identified in tobacco [Leffingwell (2337)].
The number of identified carboxylic acids in tobacco and
tobacco smoke has escalated greatly since the publication in
1954 by Kosak (2170) of his list of identified components in
tobacco smoke. The Kosak list included the following car-
boxylic acids in tobacco smoke: formic acid, acetic acid,
butanoic acid, pentanoic acid (valeric acid), hexanoic acid
(caproic acid), 7- and 8-carbon carboxylic acids, butanedioic
acid (succinic acid), butenedioic acid (E) (fumaric acid),
benzoic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid (cit-
ric acid), and phenolic acids. Kosak questioned the identifica-
tion data of many of the acids listed. Johnstone and Plimmer
(1971), in their 1959 catalog of tobacco and tobacco smoke
components, listed fifty-two specific acids plus a range of sat-
urated aliphatic acids. However, Johnstone and Plimmer listed
tobacco and smoke amino acids in a different section of their
report and included nicotinic acid and nicotinamide as amino
acids [see Table 11 in (1971)]. Also, listed in a third section
were such carboxylic acids as 3-[[3-(3,4-dihydroxyphenyl)-1-
oxo-2-propenyl]oxy]-1,4,5-trihydroxycyclohexanecarboxylic
acid (chlorogenic acid), 1,3,4,5-tetrahydroxycyclohexanecar-
boxylic acid (quinic acid), and 3,4,5-trihydroxy-1-cyclohex-
ene-1-carboxylic acid (shikimic acid) [see Table 9 in (1971)].
Similar separation problems are encountered on examination
of the various assignments of carboxylic acids in the 1968
review by Stedman [see Tables IX, X, and XIV in (3797)]. In
our report, any compound with a carboxyl group is cataloged
in this chapter.
Table IV.A-1 summarizes the numbers of carboxylic acids
and amino acids identified to date in tobacco and tobacco
smoke. Their listing and references are presented in subse-
quent tables.
Despite the number of acids identified in tobacco and
tobacco smoke, very few of the tobacco smoke acids have been
indicted as toxicants. In 1964, Boyland et al. (4A01) described
the induction of a bladder carcinoma in one of sixteen mice
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(6.5%) implanted with a cholesterol pellet containing 3-(3,4-
dihydroxyphenyl)-2-propenoic acid (caffeic acid). However,
the carcinogenicity could not be attributed to the acid when
it was observed that five of the seventy-seven mice (6.5%)
implanted with the cholesterol pellet alone developed blad-
der carcinomas. Although caffeic acid was not included in
any of the pre-2001 listings by the International Agency for
Research on Cancer (IARC) (1871), Hoffmann and Wynder
(1808), Hoffmann and Hecht (1727), Hoffmann et al. (1773),
Hoffmann and Hoffmann (1740, 1741, 1742), it was listed in
the two 2001 publications by Hoffmann and Hoffmann (1743)
and Hoffmann et al. (1744), primarily because of its phenolic
nature. In the latter two articles, formic, acetic, and propanoic
acids are listed as major mainstream smoke (MSS) vapor-
phase components [Table 5-1 in (1743), Table 2 in (1744)] and
hexadecanoic acid (palmitic acid), octadecanoic acid (stearic
acid), 9-octadecenoic acid (oleic acid), 9,12-octadecadienoic
acid (linoleic acid), 9,12,15-octadecatrienoic acid (linolenic
acid), and 2-hydroxypropanoic acid (lactic acid) are listed as
major MSS particulate-phase components [Table 5-2 in (1743),
Table 3 in (1744)].* By inclusion of per cigarette yields from
the mid-1950s to the date of the publication, these long-chained
saturated and unsaturated acids and lactic acid are listed as
major particulate-phase components. No comment is made as
to whether that statement about the per cigarette yields of the
six acids is valid for cigarettes manufactured post-1995.
The formic, acetic, and propanoic acids listed as major
MSS vapor-phase components were defined as ciliastats by
Wynder et al. (4304, 4350) in the mid-1960s [see summary
graph, p. 254, Table VII-31 in (4332)]. However, Wynder and
Hoffmann (4332) were among the first to comment on the fact
that all vapor-phase ciliastats are water soluble and therefore
may be removed from the smoke stream by solution in the
fluids coating the oral cavity. In their 1967 book [see p. 646
in (4332)], they stated:
In man’s manner of smoking, however, volatile components are
retained to a significant degree in the oral cavity and may, there-
fore, be far less important than when tested experimentally.
The validity of their 1967 statement had been demonstrated
by the results of studies in 1964 by Rodgman et al. (3306,
4A02) and subsequently in 1968 by Dalhamn et al. (892) on
the removal of substantial amounts of water-soluble vapor-
phase ciliastats from inhaled MSS by the oral cavity fluids.
* From a comparison of the listings in (1743) and (1744), it should be noted
that in the particulate-phase acids listed in (1744) stearic acid has been
inadvertently omitted and its per cigarette MSS yield assigned to palmitic
acid.
317
11/13/08 5:11:41 PM
 318 The Chemical Components of Tobacco and Tobacco Smoke
Table IV.A-1
Acids Identified in Tobacco and Tobacco Smoke to Date
Acid Category Total Smoke
Carboxylic acids 52 37
745 354
Amino acids 28 4 26
103 30
It is interesting to note that all but two (formic acid, octa-
decanoic acid [stearic acid]) of the MSS vapor-phase and
particulate-phase acids discussed above—whether identified
in tobacco, tobacco smoke, or both—are listed by Doull et
al. (1053) as compounds included in the flavor formulations
added to a tobacco blend by U.S. cigarette manufacturers to
enhance consumer acceptability of the product.
Table IV.A-2 lists the tobacco and/or smoke carboxylic
acids that, according to the Doull et al. listing (1053), are or
have been used recently as components in flavor formulations
for tobacco. It should also be noticed that the flavor ingredi-
ent additions in Table IV.A-2 include fifteen amino acids.
Table IV.A-3 is a catalog of the carboxylic acids identi-
fied to date in tobacco, tobacco smoke, and tobacco substitute
smoke. Of the 745 components listed, 354 have been identi-
fied in smoke, 614 in tobacco, and 223 in both. Because of
the recent interest in several amino acid degradation products
generated during the tobacco smoking process, a separate
section (IV.B) is devoted to the amino acids and a discussion
of their behavior during pyrolysis and the smoking process.
IV.B The Amino Acids and Related
Compounds
Amino acids, both as free acids and as acids bound within
protein molecules, are present in all of the tobacco types
(flue-cured, burley, Oriental, Maryland) used in the American
tobacco blend.
The diversity and levels of amino acids in various
tobaccos have been presented by Gori [see Table 2 in (1329),
Table  2 in (1330)] and Tso and Chaplin [see Table  8 in
(3975)]. Leffingwell (2337), in his report on nitrogen com-
ponents of leaf and their relationship to smoking quality,
reported in 1976 that there were forty-three amino acids iso-
lated from tobacco. Examples of amino acids occurring free
and/or bound in tobaccos include α- and β-alanine, α-and
γ-aminobutyric acid, arginine, aspartic acid, cysteic acid,
cysteine, cystine, glutamic acid, glycine, histidine, isoleu-
cine, leucine, lysine, methionine, norleucine, ornithine, phe-
nylalanine, proline, serine, threonine, tryptophan, tyrosine,
and valine (3983b).
The presence in cigarette MSS of numerous free amino
acids and amino acid-derived compounds was demonstrated
in the mid-1950s. This occurred soon after the publication of
the results of several cigarette smoke-related epidemiological
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Tobacco Tobacco and Smoke Reference
43 29 Table 8 in (1971)
614 223 Table IV.A-3
2 Table 11 in (1971)
102 29 Table IV.B-7
and biological studies led to a massive escalation in tobacco
smoke composition studies; for example, Buyske et al. (562)
reported the identification of glutamic acid and its deriva-
tive glutamine (glutamic acid 5-amide) in tobacco smoke.
Other amino acids identified in tobacco smoke include ala-
nine, aspartic acid (and asparagine), cysteine, glycine, leu-
cine, ornithine, phenylalanine, proline, serine, threonine, and
valine [Ishiguro and Sugawara (1884)].
In the early 1960s, pyrocoll (dipyrrolo[a,d]pyrazine-5,10-
dione) was identified in cigarette MSS by Mold et al. (2592),
who proposed that the amino acid proline, either free or
bound, was its precursor. During their study of the isolation
and identification of N-heterocyclic components (the indoles
and carbazoles) in cigarette MSS, Rodgman and Cook (3279)
confirmed the presence of pyrocoll. Two decades earlier, Van
Order and Linwall (4B01) had demonstrated that dry distilla-
tion of the amino acid tryptophan yielded indole and 3-meth-
ylindole (skatole), both of which were subsequently identified
as tobacco smoke components by Rodgman and Cook (3279).
Roberts [see citation in Rodgman and Cook (3279)] had also
identified indole as a component of burley tobacco.
By means of pyrolysis studies (850°C, nitrogen atmo-
sphere) with the amino acids lysine, leucine, and tryptophan,
Patterson et al. (2902) demonstrated that each of the three
amino acids yielded the N-heterocyclic compounds indole,
quinoline, isoquinoline, several nitriles, and a series of PAHs
ranging in complexity from bicyclic to tetracyclic (their find-
ings are summarized in Table IV.B-1). In their study, B[a]
P was found only in the pyrolysate from leucine. From their
own findings and from a previous report by Jarboe and Rosene
(1923a) that quinoline and isoquinoline were components of
a nicotine pyrolysate, Patterson et al. (2902) suggested that
the precursors in tobacco of the aza-arenes quinoline and
isoquinoline in tobacco smoke might be nicotine and/or the
amino acids. They also reported that tryptophan, on a per
mole pyrolyzed basis, yielded a phenol fraction whose weight
was more than five times that generated from lysine and about
thirty times that from leucine.
In another series of experiments, Patterson et al. (2903)
reported (1) the effect of the pyrolysis temperature on the
composition of the pyrolysate from the amino acid pheny-
lalanine with emphasis on the levels of PAHs generated and
(2) the effect of other compounds (tryptophan or pyrrole) on
the composition of the pyrolysate when mixtures of equimo-
lar quantities of tryptophan and phenylalanine or pyrrole and
11/13/08 5:11:42 PM
 Carboxylic Acids 319

Table IV.A-2
Tobacco and/or Tobacco Smoke Carboxylic Acids Used in Flavor Formulations
Identified In
CAS No. Chemical Abstracts Nomenclature As Listed by Doull et al. (1053) Smoke Tobacco

64-19-7 Acetic acid acetic acid + +

107-95-9 β-Alanine β-alanine + +
74-79-3 L-Arginine L-arginine — +
5794-13-8 L-Asparagine monohydrate asparagine + +
56-84-8 L-Aspartic acid l-aspartic acid + +
103-82-2 Benzeneacetic acid phenylacetic acid + +
65-85-0 Benzoic acid benzoic acid + +
147-71-7 Butanedioic acid, 2,3-dihydroxy- tartaric acid — +
6915-15-7 Butanedioic acid, hydroxyl- malic acid + +
107-92-6 Butanoic acid butyric acid + +
116-53-0 Butanoic acid, 2-methyl- 2-methylbutyric acid + +
503-74-2 Butanoic acid, 3-methyl- isovaleric acid + +
13201-46-2 2-Butenoic acid, 2-methyl- methyl-2-butenoic acid + +
52-90-4 L-Cysteine L-cysteine + +
334-48-5 Decanoic acid capric acid + +
143-07-7 Dodecanoic acid lauric acid + +
6899-05-4 L-Glutamic acid L-glutamic acid + +
6899-04-3 L-Glutamine L-glutamine + +
111-14-8 Heptanoic acid enanthic acid + +
57-10-3 Hexadecanoic acid palmitic acid + +
110-44-1 2,4-Hexadienoic acida sorbic acid a + +
142-62-1 Hexanoic acid caproic acid + +
4536-23-6 Hexanoic acid, 2-methyl- 2-methylhexanoic acid + +
1289-40-3 2-Hexenoic acid 2-hexenoic acid + —
71-00-1 L-Histidine L-histidine — +
73-32-5 DL-Isoleucine DL-isoleucine — +
56-87-1 L-Lysine L-lysine — +
112-05-0 Nonanoic acid nonanoic acid + +
506-21-8 9,12-Octadecadienoic acid linoleic acid + +
463-40-1 9,12,15-Octadecatrienoic acid linolenic acid + +
112-80-1 9-Octadecenoic acid oleic acid + +
124-07-2 Octanoic acid caprylic acid + +
109-52-4 Pentanoic acid valeric acid + +
97-61-0 Pentanoic acid, 2-methyl- 2-methylvaleric acid + +
105-43-1 Pentanoic acid, 3-methyl- 3-methylpentanoic acid + +
646-07-1 Pentanoic acid, 4-methyl- 4-methylpentanoic acid + +
123-76-2 Pentanoic acid, 4-oxo- levulinic acid + +
591-80-0 4-Pentenoic acid 4-pentenoic acid + +
63-91-2 L-Phenylalanine L-phenylalanine + +
147-85-3 L-Proline L-proline + +
77-92-9 1,2,3-Propanetricarboxylic acid, 2-hydroxy- citric acid + +
79-09-4 Propanoic acid propionic acid + +
50-21-5 Propanoic acid, 2-hydroxy- lactic acid + +
79-31-2 Propanoic acid, 2-methyl- isobutyric acid + +
127-17-3 Propanoic acid, 2-oxo- pyruvic acid + +
501-52-0 Propanoic acid, 3-phenyl- 3-phenylpropionic acid + +
499-12-7 1-Propene-1,2,3-tricarboxylic acid aconitic acid + +
621-82-9 2-Propenoic acid, 3-phenyl- cinnamic acid + +
544-63-8 Tetradecanoic acid myristic acid + +
72-19-5 L-Threonine L-threonine + +
60-18-4 L-Tyrosine L-tyrosine — +
7004-03-7 Valine valine + +
a 2 ,4-Hexadienoic acid (sorbic acid) is not included in the Doull et al. list (1053) but is included in flavor formulations used by ciga-
rette manufacturers outside of the U.S. [see Table 7A in (3266)].

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 320 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3
Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke
Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

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 Carboxylic Acids 321

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 322 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 323

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 324 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 325

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 326 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 327

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 328 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 329

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 330 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 331

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 332 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 333

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 334 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 335

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 336 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 337

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 338 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 339

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 340 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 341

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 342 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 343

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 344 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 345

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 346 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 347

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 348 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 349

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 350 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 351

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 352 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 353

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 354 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 355

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 356 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 357

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 358 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 359

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 360 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 361

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 362 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 363

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 364 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.A-3 (Continued)

Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 365
Table IV.A-3 (Continued)
Carboxylic Acids in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke
phenylalanine were pyrolyzed. The results from this study
are summarized in Table IV.B-2. The difference between the
pyrogenesis of PAHs from phenylalanine and the mixture of
equimolar quantities of phenylalanine and the amino acid
tryptophan prompted Patterson et al. (2903) to propose the
addition of amino acids to tobacco as a possible means to
control the PAH content of the CSC:
These results suggest the possibility that aromatic hydrocar-
bon content of tobacco “tar” may be affected by the amino acid
composition of the tobacco and that it might be possible to
affect deliberately the amount of aromatics and bases formed
by adding suitable additives, such as amino acids, to the
tobacco.
Of course, in 1971 when Patterson et al. offered this sug-
gestion, the presence in amino acid pyrolysates of the so-
called “cooked food” mutagens and the inordinately high
mutagenicity of several of them were unknown.
Higman et al. (1647) also reported the generation of PAHs,
phenols, pyridines, indole, quinoline, and other aromatic
bases during the pyrolysis of amino acids and proteins from
tobacco [see the review on pyrogenesis of smoke components
by Chortyk and Schlotzhauer (722)]. The pyrolysis results
reported by Higman et al. are summarized in Table IV.B-3.
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78836_C004.indd 365
Tryptophan was also found to be the precursor in
tobacco of two other N-heterocyclic compounds, namely
harman (1-methyl-9H-pyrido[3,4-b]indole) and norharman
(9H-pyrido[3,4-b]indole), in tobacco smoke. These com-
pounds were originally identified in tobacco and tobacco
smoke by Philip Morris R&D personnel in 1961 and 1962
[Poindexter and Carpenter (2972)] and in 1963 [Poindexter
et al. (2972)]. That tryptophan was indeed a precursor in
tobacco of the two harmans in smoke was demonstrated by
addition of radiolabeled tryptophan to cigarette tobacco and
identification of radiolabeled harman and norharman in the
MSS.
In the mid-1970s, pyrolysis studies with several amino
acids led to the isolation and identification of several addi-
tional polycyclic N-heterocyclic compounds which are
reported not only to be tumorigenic to mouse skin but also
to show inordinately high mutagenicity when tested in the
Ames bioassay with Salmonella typhimurium. The impe-
tus for these particular amino acid pyrolysis studies was not
the attempt to define the relationship between tobacco leaf
precursors and tobacco smoke components but the observa-
tion that the extracts of broiled, fried, or roasted foodstuffs
(meat, fish, poultry, etc.) were highly mutagenic in the Ames
bioassay (Salmonella typhimurium). These N-heterocyclic
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 366 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.B-1
Components in Pyrolysates from the Amino Acids Lysine, Leucine, and Tryptophan
(2902)
Yield, mg/mole of Amino Acid Pyrolyzed
Pyrolysate Component Lysine a Leucine Tryptophan

Nitrogen Compounds
Hydrogen cyanide +b + +
Aniline 60 5 —
Quinoline 160 8 17.7
Isoquinoline 80 6 2.4
Benzonitrile 470 40 1370
o-Tolunitrile 30 + 610
m-Tolunitrile 30 30 +
p-Tolunitrile 20 + +
Phenylacetonitrile 6 — 400
Indole 20 + 610
1-Naphthonitrile 10 30 350
2-Naphthonitrile — — 170

Cyclic Hydrocarbons
Styrene 5 20 —
Biphenyl 10 30 +
Bibenzyl 2 — +
Indene 40 70 —
Naphthalene 210 620 1100
Naphthalene, 1-methyl- 10 40 +
Naphthalene, 2-methyl- 10 50 —
Acenaphthene 20 — —
Acenaphthylene 30 19 3
Fluorene 10 80 140
Anthracene/phenanthrene 30 250 7900
Fluoranthene 10 90 210
Pyrene 10 110 270
Pyrene, methyl- 2 20 —
Benzofluorene 10 30 150
Chrysene 10 50 110
Triphenylene + + +
Benz[a]anthracene + + +
Benzopyrene — 30 —
a Pyrolyzed as lysine monohydrochloride
b + indicates the presence of compound;
— indicates the absence of the compound.

compounds, all amines, derived from the amino acids and/
or proteins in heated foodstuffs, were often described as
“cooked food” mutagens. Eventually they were defined as
N-heterocyclic amines. In a later chapter, the N-heterocyclic
amines will be discussed in greater detail.
The studies in the 1970s on the tumorigenicity and muta-
genicity of extracts of cooked foodstuffs were reminiscent
of the studies in the 1920s by Kennaway (2074–2076, 2080),
who reported the tumorigenicity of extracts of heated food-
stuffs or pyrolysates from heated organic compounds such
as cholesterol, and by Roffo (4A03–4A05), who reported the
tumorigenicity of pyrolyzed cholesterol. Subsequently it was
shown that many of the foodstuff pyrolysates and the choles-
terol pyrolysates contained a spectrum of PAHs, including
B[a]P. Identification of the highly mutagenic N-heterocyclic
compounds in amino acid pyrolysates was followed by iden-
tification of some of them not only in broiled or roasted meats
but also in mainstream CSC.
In 1977, Sugimura et al. (3829) reported the identification
of the potent mutagens 3-amino-1-methyl-5H-pyrido[4,3-b]
indole (coded Trp-P-2) and 3-amino-1,4-dimethyl-5H-
pyrido[4,3-b]indole (coded Trp-P-1) in pyrolysates from
tryptophan. The next year, Yamamota et al. (4365a) identified
two additional highly mutagenic compounds in pyrolysates

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 Carboxylic Acids 367

Table IV.B-2
Pyrolysis of Phenylalanine. A. Effect of Pyrolysis Temperature. B. Effect of Equimolar Addition of Tryptophan
or Pyrrole (2903)
Material Pyrolyzed
Phenylalanine (Phe) Pyrolyzed at Phe Phe + Tryb Phe + Pyrc
Pyrolysate Component a 450°C 650°C 850°C 950°C 850°C 850°C 850°C

Monocyclic Aromatic Hydrocarbons

Biphenyl — 1270 10300 4360 10300 2980 2240
Bibenzyl 10300 12000 2550 + 2550 — 345

Polycyclic Aromatic Hydrocarbons

Indene — 0.36 2.73 — 2.73 — 0.17
Naphthalene 0.12 1.45 3.50 1.27 3.50 3.52 5.60
Naphthalene, 1-methyl- — + — — — — 0.73
Naphthalene, 2-methyl- — — — — — 2.98 0.34
Acenaphthene — 0.48 1.94 <0.18 1.94 0.054 0.086
Acenaphthylene — 1.70 2.55 0.73 2.55 0.40 0.99
Fluorene 0.42 1.33 4.50 0.85 4.50 0.78 0.65
Phenanthrene/anthracene 4.12 9.70 20.00 7.90 20.00 1.44 2.41
Benzofluorene — 0.48 1.94 2.60 1.94 0.22 0.39
Fluoranthene — 0.48 1.27 0.60 1.27 0.16 0.04
Pyrene – 3.50 3.20 1.20 3.20 0.30 0.39
Pyrene, methyl- — — 3.20 <0.60 3.20 0.22 +
Chrysenes — 0.48 2.55 1.58 2.55 0.16 0.30

N-Containing Compounds
Benzonitrile 1.27 0.85 7.88 1.27 7.88 3.80 1.46
o-Tolunitrile — 0.36 2.85 0.06 2.85 0.68 0.26
m-Tolunitrile — 0.06 — 0.06 — 1.38 0.26
p-Tolunitrile — 0.18 0.18 — 0.18 0.38 0.26
Phenylacetonitrile – 1.40 — — — 0.22 0.13
1-Naphthonitrile — 1.40 — — — 1.14 1.00
Indole — 2.30 0.72 — 0.72 17.35 0.86
Quinoline — 1.80 12.00 0.30 12.00 25.75 1.30
Isoquinoline — 3.00 10.90 0.18 10.90 1.10 0.43
a Yield of pyrolysis component in mg/g of compound or mixture pyrolyzed.
b Pyrolysis involved equimolar quantities of phenylalanine and tryptophan (total mol. wt. = 369).
c Pyrolysis involved equimolar quantities of phenylalanine and pyrrole (total mol. wt. = 232).

from glutamic acid: 2-aminodipyrido[1,2-a:’,2’-d]imidazole (coded AαC) and 2-amino-3-methyl-9H-pyrido[2,3-b]indole

(coded Glu-P-2) and 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]
imidazole (coded Glu-P-1).
Table IV.B-4 lists several polynuclear N-heterocyclic
amines that exhibit extremely high mutagenicity levels in the
Ames bioassay, are amino acid pyrolysis products, and have
been identified in various broiled, fried, or roasted foodstuffs
as well as in CSC [Sugimura (3828c)]. On a per microgram
basis, B[a]P in the Ames bioassay with Salmonella typhimu-
rium (Strain TA 98) shows about 200 revertants/µg. Several
of the amino acid-derived compounds in Table IV.B-4 exceed
the B[a]P effect with the TA 98 strain by factors ranging from
about 10 to over 2100.
Yoshida and Matsumoto (4388) reported the identification
of two α-carbolines in CSC: 2-amino-9H-pyrido[2,3-b]indole
(coded MeAαC). These and several other such compounds
were reported in CSC by Yamashita et al. (4367, 4368). The
quantitative levels of the possibly amino acid-derived, muta-
genic N-heterocyclics in CSC are shown in Table IV.B-4. In
their studies they emphasized in particular the identification
and quantitation of 2-amino-3-methylimidazo[4,5-f]quino-
line (coded IQ) because of its inordinately high mutagenic-
ity (found to be 433000 and 490000 revertant/µg in several
determinations) in the Ames bioassay with Salmonella typh-
imurium strain TA 98.
Demonstration of the mutagenicity of the compounds listed in
Table IV.B-4 was followed by demonstration of their tumorige-
nicity in various laboratory animals. Ohgaki et al. (2849b) dem-
onstrated the tumorigenicity of 2-amino-3-methylimidazo[4,5-f]

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 368 The Chemical Components of Tobacco and Tobacco Smoke

[1,2-a:3′,2′-d]-imidazole (Glu-P-2), 2-amino-9H-pyrido[2,3-b]

Table IV.B-3 indole (AαC), and 2-amino-3-methyl-9H-pyrido[2,3-b]indole
Components in Pyrolysates from Amino Acids (MeAαC) were tumorigenic in mice, and Takayama et al.
(Proline and Glycine) and Proteins (Casein and (3862d) reported Glu-P-1 and Glu-P-2 to be tumorigenic
Collagen) (1647) in rats.
In a 1989 manuscript that was subsequently published,
Amino Acid or Protein
Hoffmann and Hecht (1727) discussed amino acid-derived
Pyrolysate Component a, b Casein Collagen Proline Glycine aromatic amines in cigarette MSS as follows:
Nitrogen Compounds Of the known carcinogenic pyrolysis products of the amino
Hydrogen cyanide + + + +
acids, so far only 2-amino-3-methylimidazo(4,5-f)quinoline
Pyridine + + + +
has been detected in trace amounts of 0.26 ng in the smoke of
a Japanese filter cigarette [Yamashita et al. (4368)].
Pyridine, 2-methyl- + + + +
Pyridine, 3-methyl- + + + +
Apparently, Hoffmann and Hecht had overlooked not only
Pyridine, 4-methyl- + + + +
Pyridine, 3-vinyl- + + — — the reports of the identification in CSC of several other
Aniline + + + — known “carcinogenic” pyrolysis products of amino acids, for
Pyrrole + + + + example, 2-amino-9H-pyrido[2,3-b]indole (AaC) and 2-ami-
Quinoline + + + — no-3-methyl-9H-pyrido[2,3-b]indole (MeAaC) (4388) or
Isoquinoline + + + — 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and
Indole + + + — 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) (4367) but
Benzonitrile + + — + also the reports on the tumorigenicity of several other
o-Tolunitrile + + + —
N-heterocyclic amines in different laboratory animals (1835a,
m-Tolunitrile + + + —
2491a, 2849, 2849a, 2849b, 3862b, 3862c, 3865c).
Cyclic Hydrocarbons Table IV.B-5 summarizes the reported MSS levels of the
Benzene + + + — N-heterocyclic amines considered to be significant tum-
Toluene + + + + origens by Hoffmann and Hoffmann (1740, 1741) plus the
Styrene + + — + assessment of the IARC (1870) on their tumorigenicity in
Xylenes + + — + laboratory animals and humans.
Indene + + — + During tobacco growth, curing, aging, and/or the smok-
Naphthalene + + — — ing process, the amino acids in tobacco may react with
Fluorene + + — —
ammonia and/or amino acids to yield Amadori compounds
Phenols which, when heated during the smoking process, will gen-
Phenol + + — — erate a variety of pyrazines [Green et al. (1376)]. Many of
o-Cresol + — — — the pyrazines found in tobacco smoke are highly flavorful
m-Cresol + + — — and contribute uniquely to the aroma and taste not only of
p-Cresol + + — — tobacco smoke but also of a variety of consumer food prod-
Phenol, ethyl- + + — — ucts [Maga and Sizer, (2439)], such as coffee, tea, cocoa,
Xylenol + + — — roasted peanuts, and roasted, broiled, or fried meats, poul-
a +
 indicates the presence of compound; — indicates the absence of the try, and fish.
compound. Table IV.B-6 lists the tobacco and/or smoke amino
b In the publication by Higman et al., actual pyrolysis yield data are listed
acids that, according to the Doull et al. listing (1053), are
for each compound. or have been used recently as components in flavor for-
mulations for tobacco. In their tabulation of possible fla-
vorants for tobacco smoking products, Leffingwell et al.
quinoline (IQ) in mice. Takayama et al. (3862c) and Tanaka (2341) listed the contributions to tobacco smoke taste and
et al. (3865c) reported its tumorigenicity in rats. 3-Amino-1, aroma of twenty-three amino acids added individually to
4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1- cigarette tobacco filler.
methyl-5H-pyrido[4,3-b]indole (Trp-P-2) were reported to be Table IV.B-7 lists the amino acids and related compounds
tumorigenic in mice by Matsukura et al. (2491a) and in rats by identified in tobacco, tobacco smoke, and tobacco substitute
Hosaka et al. (1835a) and Takayama et al. (3862d). smoke. In Table IV.B-7, a total of 103 such components are
Ohgaki et al. (2849b) reported that 2-amino-6-methy- listed, of which 30 have been identified in smoke, 102 in
ldipyrido[1,2-a:3′,2′-d]imidazole (Glu-P-1), 2-aminodipyrido tobacco, and 29 in both smoke and tobacco.

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 Carboxylic Acids 369

Table IV.B-4
Amino Acid-Derived N-Heterocyclic Amines
Compound Mutagenicitya, rev/µg Level in CSC,
Code Name TA 98 TA 100 ng/cigb

IQ Imidazo[4,5-f]quinoline, 2-amino-3- 433000 7000 0.26

methyl- 490000
Trp-P-1 5H-Pyrido[4,3-b]indole, 3-amino-1,4-dimethyl- 39000 1700 0.29–0.48
Trp-P-2 5H-Pyrido[4,3-b]indole, 3-amino-1-methyl- 104200 1800 0.82–1.1
Glu-P-1 Dipyrido[1,2-a:3’,2’-d]imidazole, 2-amino-6-methyl- 49000 3200 0.37–0.89
Glu-P-2 Dipyrido[1,2-a:3’,2’-d]imidazole, 2-amino- 1900 1200 0.25–0.88
AaC 9H-Pyrido[2,3-b]indole, 2-amino- 300 20 25–260
MeAaC 9H-Pyrido[2,3-b]indole, 2-amino-3-methyl- 200 120 2–37
a Salmonella typhimurium, strain TA 98 or TA 100, with S-9 mix.
b See Hoffmann and Hoffmann (1740, 1741).

Table IV.B-5
Summary of Lists of Tumorigenic N-Heterocyclic Amines in Tobacco Smoke
IARC (1870) Evaluation of Evidence
re Tumorigenicity In
Hoffmann and Hoffmann and Laboratory
Component Hecht (1727) OSHA (2825) Hoffmann (1740, 1741) MSS Level wt/cig Animals Humans

Glu-P-1 — — + 0.37–0.89 ng sufficient —

Glu-P-2 — — + 0.25–0.88 ng sufficient —
Trp-P-1 — — + 0.29–0.48 ng sufficient —
Trp-P-2 — — + 0.82–1.1 ng sufficient —
AaC — — + 25–260 ng sufficient —
MeAaC — — + 2–37 ng sufficient —
IQ — — + 0.26 ng sufficient probable
PhIP — — + 11–23 ng sufficient possible
IQ — — + 0.26 ng sufficient probable

Table IV.B-6
Tobacco and/or Tobacco Smoke Amino Acids Used in Flavor Formulations
Identified In
CAS No. Chemical Abstracts Nomenclature As Listed by Doull et al. (1053) Smoke Tobacco

107-95-9 β-Alanine β-alanine + +

74-79-3 L-Arginine L-arginine — +
5794-13-8 L-Asparagine monohydrate asparagine + +
56-84-8 L-Aspartic acid l-aspartic acid + +
52-90-4 L-Cysteine L-cysteine + +
6899-05-4 L-Glutamic acid L-glutamic acid + +
6899-04-3 L-Glutamine L-glutamine + +
71-00-1 L-Histidine L-histidine — +
73-32-5 DL-Isoleucine DL-isoleucine — +
56-87-1 L-Lysine L-lysine — +
63-91-2 L-Phenylalanine L-phenylalanine + +
147-85-3 L-Proline L-proline + +
72-19-5 L-Threonine L-threonine + +
60-18-4 L-Tyrosine L-tyrosine — +
7004-03-7 Valine valine + +

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 370 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.B-7
Amino Acids and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 371

Table IV.B-7 (Continued)

Amino Acids and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 372 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.B-7 (Continued)

Amino Acids and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 373

Table IV.B-7 (Continued)

Amino Acids and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 374 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.B-7 (Continued)

Amino Acids and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 375

Table IV.B-7 (Continued)

Amino Acids and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 376 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.B-7 (Continued)

Amino Acids and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 377

Table IV.B-7 (Continued)

Amino Acids and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 378 The Chemical Components of Tobacco and Tobacco Smoke

Table IV.B-7 (Continued)

Amino Acids and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carboxylic Acids 379

Table IV.B-7 (Continued)

Amino Acids and Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 5 The Esters
While no esters were reported in tobacco smoke by Kosak
(2170) in his 1954 compilation of reported tobacco smoke
components, the number of esters in tobacco and its smoke has
increased dramatically over the years and now exceeds 1000.
In 1955, Latimer (2270) collated and reported component data
from Chemical Abstracts and listed only one set of esters
reported in tobacco and its smoke, the “glycerides.” In 1959,
Johnstone and Plimmer (1971) listed sixteen identified esters
from these two sources. Between the Johnstone and Plimmer
review and that of Stedman (3797) in 1968, the number of iden-
tified esters in tobacco and/or smoke escalated to over 300.
The research leading to the major part of the increase
involved identification of the following classes of esters: (1)
esters from long-chained aliphatic alcohols and saturated
and unsaturated acids, (2) esters from solanesol and acetic
acid and numerous saturated and unsaturated acids, (3) esters
from several phytosterols and numerous saturated and unsat-
urated acids, and (4) β-amyrin and numerous saturated and
unsaturated acids.
One other significant finding that stimulated much subse-
quent research on sugar esters was the isolation, identifica-
tion, and synthesis of a specific ester in Oriental tobacco by
Schumacher (3535) in 1960 and its identification a year later
in Oriental tobacco smoke by Rodgman and Cook (3278).
The ester was 6-acetyl-2,3,4-tris-d-3-methylvaleryl-β-D-
glucopyranoside, that is, glucose esterified with the two ali-
phatic acids, acetic and 4-methylpentanoic (β-methylvaleric).
The Schumacher research leading to the identification of
this ester was described in detail by Green and Rodgman
(1373) during the Symposium of the 50th Tobacco Research
Chemists’ Conference.
In his 1968 review of tobacco and smoke components,
Stedman [see p. 165 and Table VI in (3797)] discussed at
some length the procedures used to identify 272 esters of
long-chained aliphatic alcohols in tobacco smoke. However,
Stedman not only failed to cite the source of his discussion,
an article by Rodgman et al. (3294), but also omitted from
his text and ester tabulation that an identical series of esters
was identified by Rodgman et al. in an aliphatic ester frac-
tion obtained from Rowland and Latimer, who had isolated
the fraction from flue-cured tobacco (3358) during their 1958
study of the solanesyl esters in tobacco.
The identification of the numerous esters in the aliphatic ester
fraction from tobacco and smoke led to the identification of a
series of solanesyl and phytosteryl esters of saturated and unsat-
urated aliphatic acids in tobacco and smoke (3296) and a similar
series of β-amyrin esters in tobacco by Fredrickson (1230).
As mentioned previously, the characterization of the glucose
ester in tobacco by Schumacher (3535) and the discov-
ery that it generated the flavorful acid, 4-methylpentanoic
© 2009 by Taylor & Francis Group, LLC
78836_C005.indd 381
(β-methylvaleric) during the smoking process, led many years
later to a series of studies aimed at determining the struc-
ture of the sucrose esters in tobacco. Despite the numerous
studies, seldom was the precise structure of a sucrose ester
defined. The various studies included those of Rivers (3185)
in the early 1980s and of Severson et al. (3606), Schlotzhauer
et al. (3473), Wahlberg et al. (4102), and Danehower (896) in
the mid- to late 1980s.
Several studies on tobacco and tobacco smoke composi-
tion, including studies of the long-chained aliphatic ester frac-
tion, ultimately led to an interesting extrapolation by Green
and Rodgman [see endnote 39 in (1373)] on the number of
smoke components. Because of the limitations of analytical
technology at the time of the Rodgman et al. study (3294)
on the long-chained aliphatic ester fraction from tobacco and
smoke, the higher molecular weight esters could neither be
determined nor characterized. However, it was noted that
qualitatively the tobacco ester fraction and the smoke ester
fraction were similar. Every ester identified by Rodgman
et al. in the smoke ester fraction was found in the tobacco
ester fraction. Minor quantitative differences between the
levels of individual esters in the two fractions were observed.
With much improved analytical technology in the late 1980s,
Arrendale et al. (103), in their study on the long-chained ali-
phatic ester fraction in tobacco, were able to identify not only
many of the esters identified earlier in tobacco and smoke by
Rodgman et al. but also many more higher molecular weight
esters. Logic would dictate that if every ester identified in the
Rodgman et al. study was present in both tobacco and smoke
then every ester identified by Arrendale et al. (103) in tobacco
would also be in smoke. Inclusion of the esters newly identi-
fied by Arrendale et al. in the smoke list results in a substan-
tial increase in the number of smoke components.
Examination of the esters listed in Table V-3 indicates that
most of the esters identified in tobacco smoke are found in
the particulate phase. An ester that exists predominantly in
the vapor phase of tobacco smoke and was identified in ciga-
rette MSS vapor phase by Laurene (2310) in 1959 and Grob
(1413) in 1962 was the methyl ester of acetic acid. Since then,
acetic acid methyl ester has been identified in cigarette MSS
vapor phase in over fifty different studies.
Because many esters have an aroma or taste acceptable
to the consumer, the list of individual compounds used as
tobacco ingredients by U.S. tobacco manufacturers contains
numerous esters. Such a list was prepared by Doull et al.
(1053) from information provided by the U.S. tobacco product
manufacturers. A detailed examination of the Doull et al. list
by Rodgman (3266) revealed that many of the added ingre-
dients had been identified in additive-free tobacco and/or its
smoke.
381
11/13/08 5:15:21 PM
 382 The Chemical Components of Tobacco and Tobacco Smoke
As Rodgman noted, the compounds added as ingredi-
ents to cigarette tobacco may fall into one of the following
categories:
• It is a component of one or more of the tobacco types
(flue-cured, Oriental, burley, Maryland) commonly
used in cigarette blends.
• It is a component of cigarette MSS.
• It is a component of both tobacco and tobacco smoke.
• It is not a component of either the tobaccos or
their smoke.
An ingredient compositionally similar to but not identical
with a tobacco leaf or smoke component may be categorized
in two ways: It is either an isomer or a homolog of a com-
pound identified in natural tobacco leaf and/or its smoke. As
noted, there are compounds used as cigarette ingredients that
do not fall into any of the first three categories listed.
In the broad spectrum of chemistry, biochemistry, and biol-
ogy, cases exist where the properties of one homolog vary sig-
nificantly from those of another or where the properties of one
isomer differ significantly from those of another. For exam-
ple, whether classified as a “Group 2A carcinogen” by the
International Agency for Research on Cancer (IARC) (1868a),
or a significant carcinogen in cigarette MSS (1727), or overall
as a borderline carcinogen by others (983), the specific tum-
origenicity of mouse skin-painted or subcutaneously injected
benz[a]anthracene (B[a]A) is insignificant compared to that
of its homolog, 7,12-dimethylbenz[a]anthracene (DMB[a]A),
one of the four most potent tumorigenic polycyclic aromatic
hydrocarbons (PAHs) known (983). The isomeric C20H12 PAHs
benzo[e]pyrene (B[e]P) and benzo[a]pyrene (B[a]P) differ
markedly in their specific tumorigenicities in studies involv-
ing mouse skin painting or subcutaneous injection (983). B[e]P
under the usual laboratory test conditions is found to be
essentially nontumorigenic on skin painting or subcutaneous
© 2009 by Taylor & Francis Group, LLC
78836_C005.indd 382
injection, whereas the isomeric B[a]P under the same condi-
tions is one of the most potent tumorigens known.
Of the 460 individual ingredients listed by Doull et al.
[1053, see Table 1 in (3266)], 117 (25%) are esters (Table V-1)
and all have been approved for use by the U.S. Food and Drug
Administration or by the Flavor and Extract Manufacturers
Association (FEMA). Of the 117 esters listed by Doull et al.,
46 (39%) have been identified in untreated cigarette tobacco
and/or its smoke (indicated by + in Table V-1) and 18 are
either an homolog (indicated by H in Table V-1) or an iso-
mer (indicated by I in Table V-1) of a known tobacco and/or
smoke component.
Doull et al. (1053) also listed 146 mixtures reportedly used
by U.S. manufacturers as flavoring ingredients in tobacco
products [see Table 2 in (3266)]. Many of these mixtures are
obviously multicomponent items and detailed analyses of
several of them (cardamom, cocoa, coffee, davana, licorice)
indicated the presence of esters [see Table 3 in (3266)] listed
by Doull et al. (1053). A similar situation exists with regard
to flavorful mixtures used on tobacco products by non-U.S.
manufacturers. Some thirty-four such mixtures are used on
tobacco products by non-U.S. manufacturers [172a, 174a,
174b, 174c, see Table 7B in (3266)].
Compounds (forty-eight in number) other than those in
the Doull et al. list are used in tobacco products by man-
ufacturers in countries other than the United States [172a,
174a, 174b, 174c, see Table 7A in (3266)]. Among the forty-
eight esters, are nineteen (21%) that have been identified in
untreated cigarette tobacco and/or its smoke (indicated by +
in Table V-2).*
Table V-3 lists the esters identified to date in tobacco and/
or tobacco smoke.
* Inadvertently, two esters (methyl anthranilate and methyl 2-octynate)
already included in Table 1 in (3266) were included in Table 7A in
(3266).
11/13/08 5:15:22 PM
 The Esters 383

Table V-1
Esters Used as Tobacco Ingredients by U.S. Tobacco Product Manufacturers (1053)
Identified In
CAS No. Chemical Abstracts Nomenclature Smoke Tobacco

123-86-4 Acetic acid, butyl ester + +

151-05-3 Acetic acid, 1,1-dimethyl-2-phenylethyl ester — —
115-95-7 Acetic acid, 3,7-dimethyl-1,6-octadien-6-yl ester — +
105-87-3 Acetic acid, 3,7-dimethyl-2,6-octadien-1-yl ester — —
141-78-6 Acetic acid, ethyl ester + +
112-06-1 Acetic acid, heptyl ester H Ha
3681-71-8 Acetic acid, 3-hexen-1-yl ester — —
142-92-7 Acetic acid, hexyl ester — +
123-92-2 Acetic acid, 3-methylbutyl ester — —
80-26-2 Acetic acid, 2-(4-methyl-3-cyclohex-1-yl)-2-propyl ester + +
89-48-5 Acetic acid, 5-methyl-2-(1-methylethyl)-cyclohexanyl ester — —
140-39-6 Acetic acid, 4-methylphenyl ester — —
110-19-0 Acetic acid, 2-methylpropyl ester — —
143-13-5 Acetic acid, nonyl ester — H
2442-10-6 Acetic acid, 1-octen-3-yl ester — —
24851-98-7 Acetic acid, 2-pentyl-3-oxo-1-cyclopentyl-, methyl ester — —
93-92-5 Acetic acid, 1-phenethyl ester — +
103-45-7 Acetic acid, 2-phenethyl ester + +
103-54-8 Acetic acid, 3-phenyl-2-propenyl ester — —
122-72-5 Acetic acid, 3-phenylpropyl ester — —
76-49-3 Acetic acid, endo-1,7,7-trimethylbicyclo[2,2,1]heptan-2-yl ester — —
125-12-2 Acetic acid, exo-1,7,7,-trimethylbicyclo[2,2,1]heptan-2-yl ester — —
141-97-9 Acetoacetic acid, ethyl ester — —
122-43-0 Benzeneacetic acid, butyl ester H H
101-97-3 Benzeneacetic acid, ethyl ester — +
102-22-7 Benzeneacetic acid, 3,7-dimethyl-2,6-octadieny-1-yl ester — —
5421-17-0 Benzeneacetic acid, hexyl ester — —
101-41-7 Benzeneacetic acid, methyl ester + +
102-19-2 Benzeneacetic acid, 3-methylbutyl ester — —
101-94-0 Benzeneacetic acid, 4-methylphenyl ester — —
102-13-6 Benzeneacetic acid, 2-methylpropyl ester — —
102-20-5 Benzeneacetic acid, phenylethyl ester; — H
104-21-2 Benzenemethanol, 4-methoxy-, acetate + —
122-91-8 Benzenemethanol, 4-methoxy-, formate — —
102-17-0 Benzenemethanol, 4-methoxy-, phenylacetate — —
93-89-0 Benzoic acid, ethyl ester + +
93-58-3 Benzoic acid, methyl ester + +
120-51-4 Benzoic acid, phenylmethyl ester + +
134-20-3 Benzoic acid, 2-amino-, methyl ester — +
118-61-6 Benzoic acid, 2-hydroxy-, ethyl ester — +
119-36-8 Benzoic acid, 2-hydroxy-, methyl ester — +
87-19-4 Benzoic acid, 2-hydroxy-, 2-methylpropyl ester — —
118-55-8 Benzoic acid, 2-hydroxy-, phenyl ester — —
118-58-1 Benzoic acid, 2-hydroxy-, phenylmethyl ester — +
121-98-2 Benzoic acid, 4-methoxy-, methyl ester — —
94-46-2 Benzoic acid, 3-methylbutyl ester — +
106-65-0 Butanedioic acid, dimethyl ester + —
109-21-7 Butanoic acid, butyl ester H H
10094-34-5 Butanoic acid, 1,1-dimethyl-2-phenylethyl ester — —
106-29-6 Butanoic acid, 3,7-dimethyl-2,6-octadien-1-yl ester — —
141-16-2 Butanoic acid, 3,7-dimethyl-6-octenyl ester — —
105-54-4 Butanoic acid, ethyl ester + +
106-27-4 Butanoic acid, 3-methylbutyl ester — —
540-18-1 Butanoic acid, pentyl ester — —
103-52-6 Butanoic acid, phenylethyl ester H H
103-37-7 Butanoic acid, phenylmethyl ester + +

(Continued)

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 384 The Chemical Components of Tobacco and Tobacco Smoke

Table V-1 (Continued)

Esters Used as Tobacco Ingredients by U.S. Tobacco Product Manufacturers (1053)
Identified In
CAS No. Chemical Abstracts Nomenclature Smoke Tobacco
7452-79-1 Butanoic acid, 2-methyl-, ethyl ester I Ib
10032-15-2 Butanoic acid, 2-methyl-, hexyl ester — —
109-19-3 Butanoic acid, 3-methyl-, butyl ester H H
1009-20-6 Butanoic acid, 3-methyl-, 3,7-dimethyl-2,6-octadieny-1-yl ester —
108-64-5 Butanoic acid, 3-methyl-, ethyl ester + +
556-24-1 Butanoic acid, 3-methyl-, methyl ester — +
659-70-1 Butanoic acid, 3-methyl-, 3-methylbutyl ester — —
55066-56-3 Butanoic acid, 3-methyl-, 4-methyylphenyl ester — —
140-26-1 Butanoic acid, 3-methyl-, phenethyl ester — +
140-27-2 Butanoic acid, 3-methyl-, 3-phenyl-2-propenyl ester — —
10544-63-5 2-Butenoic acid, ethyl ester — H
110-40-7 Decanedioic acid, diethyl ester — —
110-38-3 Decanoic acid, ethyl ester — +
106-33-2 Dodecanoic acid, ethyl ester — +
77-83-8 Ethyl methylphenylglycidate — —
105-86-2 Formic acid, 3,7-dimethyl-2,6-octadien-1-yl ester — —
33467-73-1 Formic acid, 3-hexenyl ester — +
110-45-2 Formic acid, 3-methylbutyl ester — —
638-49-3 Formic acid, pentyl ester — —
614-99-3 2-Furancarboxylic acid, ethyl ester H —
611-13-2 2-Furancarboxylic acid, methyl ester + +
126-14-7 α-D-Glucopyranoside, β-D-fructofuranosyl-, octaacetate — —
106-30-9 Heptanoic acid, ethyl ester — +
628-97-7 Hexadecanoic acid, ethyl ester + +
123-66-0 Hexanoic acid, ethyl ester + +
2198-61-0 Hexanoic acid, 3-methylbutyl ester — —
123-68-2 Hexanoic acid, 2-propenyl ester — —
123-29-5 Nonanoic acid, ethyl ester — +
112-63-0 9,12-Octadecadienoic acid (Z,Z), methyl ester + +
111-61-5 Octadecanoic acid, ethyl ester — +
301-00-8 9,12,15-Octadecatrienoic acid, methyl ester + +
111-62-6 9-Octadecenoic acid, ethyl ester — +
106-32-1 Octanoic acid, ethyl ester — +
2035-99-6 Octanoic acid, 3-methylbutyl ester — —
638-25-5 Octanoic acid, pentyl ester — —
111-12-6 2-Octynoic acid, methyl ester — —
539-82-2 Pentanoic acid, ethyl ester + +
539-88-8 Pentanoic acid, 4-oxo-, ethyl ester — H
102-76-1 1,2,3-Propanetriol, triacetate + —
105-53-3 Propanedioic acid, diethyl ester H H
105-37-3 Propanoic acid, ethyl ester + +
122-63-4 Propanoic acid, phenylmethyl ester — —
103-56-0 Propanoic acid, 3-phenyl-2-propenyl ester — —
7492-70-8 Propanoic acid, 2-butoxy-, butyl ester — —
97-64-3 Propanoic acid, 2-hydroxy-, ethyl ester + —
97-89-2 Propanoic acid, 2-methyl-, 3,7-dimethyl-6-octenyl ester — —
65416-14-0 Propanoic acid, 2-methyl-, 2-methyl-4-oxo-4H-pyran-3-yl ester — —
103-93-5 Propanoic acid, 2-methyl-, 4-methylphenyl ester — —
109-15-9 Propanoic acid, 2-methyl-, octyl ester — —
103-48-0 Propanoic acid, 2-methyl-, phenylethyl ester H H
103-36-6 2-Propenoic acid, 3-phenyl-, ethyl ester + —
103-26-4 2-Propenoic acid, 3-phenyl-, methyl ester H —
7779-65-9 2-Propenoic acid, 3-phenyl-, 3-methylbutyl ester H —
122-67-8 2-Propenoic acid, 3-phenyl-, 2-methylpropyl ester H —
103-53-7 2-Propenoic acid, 3-phenyl-, phenylethyl ester H —

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 The Esters 385

Table V-1 (Continued)

Esters Used as Tobacco Ingredients by U.S. Tobacco Product Manufacturers (1053)
Identified In
CAS No. Chemical Abstracts Nomenclature Smoke Tobacco
103-41-3 2-Propenoic acid, 3-phenyl-, phenylmethyl ester + —
122-69-0 2-Propenoic acid, 3-phenyl-, 3-phenyl-2-propenyl ester + —
122-68-9 2-Propenoic acid, 3-phenyl-, 3-phenylpropyl ester — —
93-60-7 3-Pyridinecarboxylic acid, methyl ester + +
124-06-1 Tetradecanoic acid, ethyl ester — +
10580-24-2 Undecanoic acid, butyl ester — H
a H = a homolog of an identified tobacco and/or smoke component
b I = an isomer of an identified tobacco and/or smoke component

Table V-2
Esters Used as Tobacco Ingredients by Tobacco Product Manufacturers Outside of the U.S.
Identified In
CAS No. Chemical Abstracts Nomenclature Smoke Tobacco

141-12-8 Acetic acid, 3,7-dimethyl-2,8-octadien-1-yl ester — —

150-84-5 Acetic acid, 3,7-dimethyl-6-octen-1-yl ester — —
2497-18-9 Acetic acid, 2-hexen-1-yl ester — +
126-64-7 Benzoic acid, 3,7-dimethyl-1,6-octadien-6-yl ester — —
87-20-7 Benzoic acid, 2-hydroxy-, 3-methylbutyl ester — +
539-90-2 Butanoic acid, 2-methylpropyl ester — —
76-50-6 Butanoic acid, 3-methyl-, endo-1,7,7-trimethylbicyclo[2,2,1]heptan-2-yl ester — +
103-38-8 Butanoic acid, 3-methyl-, phenylmethyl ester — +
16409-46-4 Butanoic acid, 3-methyl-, 5-methyl-2-(1-methylethyl)-cyclohexanyl ester, — —
104-57-4 Formic acid, phenylmethyl ester — +
540-07-8 Hexanoic acid, pentyl ester — —
591-68-4 Pentanoic acid, butyl ester — —
7549-33-9 Propanoic acid, anisyl ester — —
105-68-0 Propanoic acid, 3-methylbutyl ester — —
103-28-6 Propanoic acid, 2-methyl-, phenylmethyl ester — +
78-35-3 Propanoic acid, 2-methyl-, 3,7-dimethyl-1,6-octadien-6-yl ester — —
97-62-1 Propanoic acid, 2-methyl-, ethyl ester — —
103-59-3 Propanoic acid, 2-methyl-, 3-phenyl-2-propen-1-yl ester — —
110-27-0 Tetradecanoic acid, 1-methylethyl ester — —

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 386 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3
Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke
Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

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 The Esters 387

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 388 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C005.indd 388 11/13/08 5:15:28 PM

 The Esters 389

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 390 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Esters 391

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 392 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Esters 393

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 394 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Esters 395

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 396 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Esters 397

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 398 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C005.indd 398 11/13/08 5:15:54 PM

 The Esters 399

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C005.indd 399 11/13/08 5:15:59 PM

 400 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Esters 401

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 402 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Esters 403

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C005.indd 403 11/13/08 5:16:08 PM

 404 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Esters 405

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 406 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Esters 407

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 408 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Esters 409

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 410 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Esters 411

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 412 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Esters 413

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 414 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Esters 415

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 416 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Esters 417

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 418 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Esters 419

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 420 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Esters 421

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C005.indd 421 11/13/08 5:16:52 PM

 422 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C005.indd 422 11/13/08 5:16:54 PM

 The Esters 423

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C005.indd 423 11/13/08 5:16:57 PM

 424 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C005.indd 424 11/13/08 5:16:59 PM

 The Esters 425

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C005.indd 425 11/13/08 5:17:02 PM

 426 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C005.indd 426 11/13/08 5:17:04 PM

 The Esters 427

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C005.indd 427 11/13/08 5:17:06 PM

 428 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C005.indd 428 11/13/08 5:17:08 PM

 The Esters 429

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C005.indd 429 11/13/08 5:17:16 PM

 430 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C005.indd 430 11/13/08 5:17:17 PM

 The Esters 431

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 432 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Esters 433

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 434 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C005.indd 434 11/13/08 5:17:26 PM

 The Esters 435

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C005.indd 435 11/13/08 5:17:29 PM

 436 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C005.indd 436 11/13/08 5:17:31 PM

 The Esters 437

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 438 The Chemical Components of Tobacco and Tobacco Smoke

Table V-3 (Continued)

Esters in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 6 The Lactones
At various periods during the past fifty years, lactones in
tobacco and tobacco smoke, particularly those in tobacco
smoke, were discussed with regard to their toxicity, tumorige-
nicity, and genotoxicity. However, examination of the numer-
ous lists of tobacco and tobacco smoke components classified
as toxic, tumorigenic, and/or genotoxic reveals that seldom is
a lactone included. The first significant list, derived from the
1986 International Agency for Research on Cancer (IARC)
monograph on tobacco smoke (1870), was published in 1986
by Hoffmann and Wynder (1808). Over the next two decades,
the Hoffmann-Wynder list was followed by successive similar
but not identical lists by Hoffmann and Hecht (1727) in 1990,
Hoffmann et al. (1773) in 1993, the Occupational Safety and
Health Administration (OSHA) (2825) in 1994, Hoffmann
and Hoffmann (1740, 1741, 1743) in 1997, 1998, and 2001,
and Fowles and Bates (1217) in 2001 [see a summary of all
these lists in Table 2 in Rodgman (3265)].
Based on its February 1985 meeting on tobacco smok-
ing, the IARC Working Group wrote in 1986 [see p. 107 in
(1870)]:
About 80 lactones have been identified in tobacco smoke.
These compounds, especially the γ-butyrolactones, and others,
have alkylating potential and some have been reported to be
carcinogenic in laboratory animals [Lawley (6A12)]. [see also
Appendix 2, pp. 387–394) in (1870)]. Quantitatively, about
half the lactones in the smoke consist of γ-butyrolactone
[IARC (6A10)] (about 10 μg/cigarette) and its deriva-
tives; δ-valerolactone and some alkylated and unsaturated
δ-valerolactones, as well as coumarin [see pp. 427–430 in
Wynder and Hoffmann (4332)], 6-methylcoumarin, and 3,4-
dihydrocoumarin have also been isolated [Schumacher et al.
(3553)]. The occurrence of coumarin derivatives in smoke
could be due to pyrolysis of polyphenols with a coumarin
structure … or of plant extracts added to tobacco to enhance
flavour [see pp. 427–430 in Wynder and Hoffmann (4332)].
Coumarin itself is carcinogenic to rats after oral administra-
tion [IARC (6A10)].
In its monograph, IARC made no comment on the ten
lactones, including coumarin, that Lawley listed as inac-
tive in oncogenesis tests [see Table XXVII in (6A12)], citing
the 1965 study on coumarin by Dickens and Jones (6A06).
IARC also failed to mention the 1984 listing by Slaga and
DiGiovanni (3685) of the report by Wattenberg et al. (4149d),
who described the anticarcinogenicity of coumarin towards
the potent tumorigenic polycyclic aromatic hydrocarbons
(PAHs) benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]
anthracene (DMB[a]A).
At the time of the writing of the IARC 1986 monograph
on tobacco smoking, over 100 lactones had been identified in
tobacco smoke.
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78836_C006.indd 439
The information on pages 387–394 in Appendix 2 in
(1870), particularly the information provided by the IARC
Working Group on lactones on page 391, is:
Degree of Evidence in
Compound Animals (and Humans)
5. Lactones
Coumarin Limited evidence
γ-Butyrolactone No evidence
In the cited Figure 5 [see page 93 in (1870)], only the fol-
lowing five lactones (substituted coumarins) of the nearly
two dozen identified in tobacco and/or tobacco smoke were
depicted, namely, scopoletin (7-hydroxy-6-methoxy-2H-1-ben-
zopyran-2-one), scopolin [7-(β-D-glucopyranosyloxy)-6-met-
hoxy-2H-1-benzopyran-2-one], esculetin (6,7-dihydroxy-2H-1-
benzopyran-2-one), cichoriin [7-(β-D-glucopyranosy-loxy)-
6-hydroxy-2H-1-benzopyran-2-one], and scopoletin-β-gentio-
bioside.
Two lactones that received some attention with regard to
tobacco and smoke were aflatoxins, B1 and B2, primarily afla-
toxin B1, the more toxic of the two. In 1970, Kaminski et al.
(2024) examined the butts, ashes, and mainstream smoke
(MSS) vapor phase and particulate phase from machine-
smoked commercial nonfilter cigarettes treated with afla-
toxin B1. In six separate smoking experiments, no trace of
aflatoxin B1 was detected in any of the fractions examined.
In their 1967 examination of several samples of leaf tobacco,
including three types of good-grade tobaccos and heavily
molded flue-cured tobacco, and of cigarette smoke conden-
sate (CSC), Tso and Sorokin (3986) failed to detect aflatoxin
B1. They also reported that no aflatoxin B1 was found in the
CSC from cigarettes enriched with authentic aflatoxin B1
prior to smoking. They concluded that the added aflatoxin
B1 was changed or decomposed during the smoking process.
Later, Tso (3970) again reported the results of this aflatoxin B1
study at the 1967 World Conference on Smoking and Health.
In his 2000 review of scientific publications on aflatoxin B,
tobacco, and tobacco smoke, Massey (2484) concluded that
aflatoxin B was not a contamination issue on tobaccos and,
even if present, would decompose in the burning cigarette
and would not transfer to smoke.
As noted in the quotation from the 1986 IARC mono-
graph, orally administered coumarin (2H-1-benzopyran-2-
one) had been reported as carcinogenic in rats. The results
reported from several studies on the tumorigenicity of cou-
marin eventually resulted in coumarin being removed from
439
11/13/08 7:07:38 PM
 440 The Chemical Components of Tobacco and Tobacco Smoke
5 4
6 3
7
O O
8
I II
HO O O
V IV
COOH
OH
III
Figure VI-1  Relationships between coumarin, its derivatives, and dicumarol.
the flavor formulations used throughout the tobacco industry
on cigarette and pipe tobacco. Coumarin was considered by
the consumer as a significantly acceptable contribution to
tobacco smoke. Coumarin was identified by Schumacher and
Vestal as a minor component of untreated Oriental tobacco
in the early 1960s (3560).
The initial concern in the early 1960s about the addition of
coumarin {I} to tobacco products was whether or not it was con-
verted during the smoking process to dicumarol (3,3’-methylene-
bis[4-hydroxy-2H-1-benzopyran-2-one]) {II} (Figure VI-1). Di-
cumarol is a powerful anticoagulant that had been identified in
sweet clover hay (6A21).
In previous metabolic studies, it had been reported that
coumarin was not a precursor of dicumarol {II} (6A03,
6A15) or of o-coumaric acid [3-(2-hydroxyphenyl)-2-prope-
noic acid] {III} (6A21). {III} was known to be a precursor of
dicumarol via 4-hydroxycoumarin {IV}. Laboratory animals
(rats, rabbits) fed coumarin excreted 4-hydroxycoumarin
{IV} (6A04). Between 70% and 90% of coumarin adminis-
tered to humans resulted in excretion of 7-hydroxycoumarin
{V} (6A17), a coumarin derivative never indicted as danger-
ous to any species or proposed as a dicumarol precursor.
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78836_C006.indd 440
OH OH
H2
C
O OO O
OH
O O
O O
OH O
COOH
OH OH COOH
Newell reported in 1963 that (1) inclusion in cigarette
tobacco of 3-14C-coumarin {I} gave no dicumarol {II} in
either the MSS or the sidestream smoke (SSS) and (2) inclu-
sion in cigarette tobacco of unlabeled dicumarol gave no
dicumarol {II} in either the MSS or the SSS (2757). Of the
3-14C-coumarin applied to the tobacco blend, Newell reported
that 60% appeared unchanged in the MSS and SSS.
To assess the claims of the possible adverse effect of
including coumarin in flavor formulations, several reports
and memoranda were written in the late 1970s about the
coumarin situation in an obvious attempt to put the issue in
perspective. In 1978, Buchner (6A05) listed several of the
authorities that incorrectly cited negative tumorigenicity
results as positive, for example, in 1976, the National Institute
for Occupational Safety and Health (NIOSH) (6A16) incor-
rectly cited results published in 1955 by Roe and Salaman
(6A20). Much weight was given to the reported findings of
Griepentrog (6A02, 6A07), the only findings on the induction
of bile duct carcinomas in coumarin-fed rats. Buchner (6A05)
summarized many of the results of studies that raised ques-
tions about the classification of coumarin as a carcinogen,
for example, the negative tumorigenicity results reported by
11/13/08 7:07:39 PM
 The Lactones 441
Hagan et al. (6A08) and Hazleton et al. (6A09). He also cited
several genotoxicity studies in which coumarin was found to
be inactive against human chromosomes (6A22) and against
Salmonella typhimurium strains TA 1535, TA 1537, TA 98,
and TA 100 in the Ames test [Buchner, private communica-
tion, see Reference 26 in (6A22)].
Paralleling the report by Buchner were several memoranda
on coumarin by Rodgman in 1978 (6A18) and 1982 (6A19) in
which the problems of misinterpretation of data and contrary
data pertinent to coumarin were presented. Included in the
memoranda were the negative mutagenicity results obtained
in Ames tests with five strains (TA 1535, TA 1537, TA 1538,
TA 98, TA 100) of Salmonella typhimurium on coumarin
conducted in-house by Lee (6A13) at R.J. Reynolds Research
and Development. His results were confirmed on a coded
coumarin sample among a set of coded samples tested at a
contract laboratory (6A14).
Despite the controversies over the tumorigenicity of cou-
marin, its use in tobacco flavor formulations was subsequently
discontinued throughout the tobacco industry worldwide.
In its 2000 evaluation of the tumorigenicity of coumarin
(2H-1-benzopyran-2-one), IARC (6A11) noted the following
as of 21 August, 2000:
Coumarin is a natural product occurring in the essential oils
of a large number of plants, such as cinnamon, cassia, lavender
and woodruff. It is used for its fragrance in many personal
care products (perfumes, deodorants, soaps) and in tobacco,
in household and industrial products to mask unpleasant
odours and, in some countries, as a flavouring agent in food
and beverages. It has also been used to treat several medi-
cal conditions. Exposure to coumarin may occur from its
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78836_C006.indd 441
production, its natural presence in many plants and essential
oils, and its several industrial, medical and consumer uses.
According to IARC, no data were available to its Working
Group on the carcinogenicity of coumarin in humans. After
assessment of various studies in which coumarin was admin-
istered to laboratory animals, IARC concluded that the
evidence was limited in laboratory animals on the carcino-
genicity of coumarin. IARC described its overall evaluation
of coumarin as a carcinogen as follows: “Coumarin is not
classifiable as to its carcinogenicity to humans.”
In 1998, Abbott (6A01) described the results of the exami-
nation of numerous food additives by the World Health
Organization. The food additives in this particular study
comprised a series of so-called aliphatic lactones. Among
the lactones discussed were several that not only are used
as foodstuff additives but also occur in tobacco and/or its
smoke and several that are used as tobacco additives. The
results of several toxicological studies (acute toxicity, short-
and long-term toxicity, carcinogenicity) and genotoxic
studies on the lactones were described in detail by Abbott.
Table VI-1 presents the results listed by Abbott on those lac-
tones that are used in tobacco products.
Table VI-2 lists the tobacco and/or smoke lactones that,
according to the Doull et al. listing (1053), are or have been used
recently as components in flavor formulations for tobacco.
The number of lactones identified to date in tobacco and/
or tobacco smoke is 304. Of these, 162 have been identified
in tobacco smoke, 201 in tobacco, and 59 in both tobacco
and tobacco smoke. Table VI-3 lists the lactones identified in
tobacco and tobacco smoke to date.
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78836_C006.indd 442

442
Table VI-1
Some Biological Properties of Lactones Used as Additives in Foodstuffs as Well as in Tobacco Products (6A01)
Lactone Flavor Short-term
Smoke or Tobacco Formulation Acute Toxicity, Toxicity, NOELb,
CAS No. CAS Nomenclature Common Name Genotoxicity a
Component Additive LD50, mg/kg mg/kg/day

104-50-7 2(3H)-Furanone, 5-butyldihydro- γ-octalactone + + >5000 (rat)c

96-48-0 2(3H)-Furanone, dihydro- γ-butyrolactone + + negative 1245 (mouse) 300 (rat)
175 (mouse)
695-06-7 2(3H)-Furanone, dihydro-5-ethyl- γ-hexalactone + + >5000 (rat)
104-67-6 2(3H)-Furanone, dihydro-5-heptyl- γ-undecalactone - + 6 negative 18500 (rat) >14 (rat)
2 positive
706-14-9 2(3H)-Furanone, dihydro-5-hexyl- γ-decalactone} + + >5000 (rat)
108-29-2 2(3H)-Furanone, dihydro-5-methyl- γ-valerolactone} + + >5000 (rat) >50 (rat)
2305-05-7 2(3H)-Furanone, dihydro-5-octyl- γ-dodecalactone} - + >5000 (rat)
104-61-0 2(3H)-Furanone, dihydro-5-pentyl- γ-nonalactone} + + 3 negative 9780 (rat) >72 (rat)
3 positive 3440 (guinea pig)
105-21-5 2(3H)-Furanone, dihydro-5-propyl- γ-heptalactone + + negative >5000 (rat)

The Chemical Components of Tobacco and Tobacco Smoke

28664-35-9 2(5H)-Furanone, 3-hydroxy-4,5-dimethyl- - +
698-10-2 2(5H)-Furanone, 5-ethyl-3-hydroxy-4-methyl- - + >1.3 (rat)
591-12-8 2(3H)-Furanone, 5-methyl- α-angelica lactone + + 2800 (mouse) >17 (rat)
7779-50-2 Oxacycloheptadec-7-en-2-one ‑ +
106-02-5 Oxacyclohexadecan-2-one ω-pentadecalactone + + 2 negative
27593-23-3 2H-Pyran-2-one, 6-pentyl- 6-amyl-α-pyrone - +
3301-94-8 2H-Pyran-2-one, tetrahydro-6-butyl- δ-nonalactone} - +
713-95-1 2H-Pyran-2-one, tetrahydro-6-heptyl- δ-dodecalactone - +
710-04-3 2H-Pyran-2-one, tetrahydro-6-hexyl- δ-undecalactone} - +
823-22-3 2H-Pyran-2-one, tetrahydro-6-methyl- δ-hexalactone + -
705-86-2 2H-Pyran-2-one, tetrahydro-6-pentyl- δ-decalactone} - + >5000 (rat)
698-76-0 2H-Pyran-2-one, tetrahydro-6-propyl- δ-octalactone} + + >5000
a References to the various genotoxicity systems used may be found in Abbott [see Table 6 in (6A01)].
b NOEL = no observed effect level
c References to procedures used may be found in Abbott [see Table 3 in (6A01)]
11/13/08 7:07:41 PM

© 2009 by Taylor & Francis Group, LLC

 The Lactones 443

Table VI-2
Tobacco and/or Smoke Lactones Used in Flavor Formulations
Identified In
CAS No. Chemical Abstracts Nomenclature As Listed by Doull et al. (1053) Smoke Tobacco
50-81-7 L-Ascorbic acid {L-gulofuranolactone, 3-oxo-} ascorbic acid + +
96-48-0 2(3H)-Furanone, dihydro- 4-hydroxybutanoic acid lactone + +
104-50-7 2(3H)-Furanone, dihydro-5-butyl- γ-octalactone - +
695-06-7 2(3H)-Furanone, dihydro-5-ethyl- γ-hexalactone - +
104-67-6 2(3H)-Furanone, dihydro-5-heptyl- γ-undecalactone - Ha
706-14-9 2(3H)-Furanone, dihydro-5-hexyl- γ-decalactone - +
108-29-2 2(3H)-Furanone, dihydro-5-methyl- γ-valerolactone + +
2305-05-7 2(3H)-Furanone, dihydro-5-octyl- γ-dodecalactone - H
104-61-0 2(3H)-Furanone, dihydro-5-pentyl- γ-nonalactone - +
105-21-5 2(3H)-Furanone, dihydro-5-propyl- γ-heptalactone – +
591-12-8 2(3H)-Furanone, 5-methyl- 4-hydroxy-3-pentenoic acid lactone + +
27538-09-6 3(2H)-Furanone, 3-ethyl-4-hydroxy-5-methyl- b 3-ethyl-4-hydroxy-5-methyl-3(2H)- - -
furanoneb
551-08-6 1(3H)-Isobenzofuranone, 3-butylidene- 3-butylidenephthalide - H
564-20-5 Naphtho[2,1-b]furan-2(1H)-one, decahydro-3a,6,6,9a-tetramethyl- sclareolide + +
7779-50-2 Oxacycloheptadec-7-en-2-one ω-6-hexadecenlactone - H
106-02-5 Oxacyclohexadecan-2-one ω-pentadecalactone - +
3301-94-8 2H-Pyran-2-one, tetrahydro-6-butyl- b δ-nonalactoneb - H
713-95-1 2H-Pyran-2-one, tetrahydro-6-heptyl- δ-dodecalactone - H
710-04-3 2H-Pyran-2-one, tetrahydro-6-hexyl- δ-undecalactone - H
2721-22-4 2H-Pyran-2-one, tetrahydro-6-nonyl- b tetradecalactoneb - H
705-86-2 2H-Pyran-2-one, tetrahydro-6-pentyl- δ-decalactone - +
698-76-0 2H-Pyran-2-one, tetrahydro-6-propyl- δ-octalactone - +
a H = homolog of an identified tobacco and/or smoke component
b This lactone is not included in the Doull et al. list (1053) but is included in flavor formulations used by cigarette manufacturers outside of the U.S. [see
Table 7A in (3266)]

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 444 The Chemical Components of Tobacco and Tobacco Smoke

Table VI-3
Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke
Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

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 The Lactones 445

Table VI-3 (Continued)

Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 446 The Chemical Components of Tobacco and Tobacco Smoke

Table VI-3 (Continued)

Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Lactones 447

Table VI-3 (Continued)

Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 448 The Chemical Components of Tobacco and Tobacco Smoke

Table VI-3 (Continued)

Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Lactones 449

Table VI-3 (Continued)

Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 450 The Chemical Components of Tobacco and Tobacco Smoke

Table VI-3 (Continued)

Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Lactones 451

Table VI-3 (Continued)

Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 452 The Chemical Components of Tobacco and Tobacco Smoke

Table VI-3 (Continued)

Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Lactones 453

Table VI-3 (Continued)

Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 454 The Chemical Components of Tobacco and Tobacco Smoke

Table VI-3 (Continued)

Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Lactones 455

Table VI-3 (Continued)

Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 456 The Chemical Components of Tobacco and Tobacco Smoke

Table VI-3 (Continued)

Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Lactones 457

Table VI-3 (Continued)

Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 458 The Chemical Components of Tobacco and Tobacco Smoke

Table VI-3 (Continued)

Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Lactones 459

Table VI-3 (Continued)

Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 460 The Chemical Components of Tobacco and Tobacco Smoke

Table VI-3 (Continued)

Lactones Identified In Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C006.indd 460 11/13/08 7:08:33 PM

 7 Anhydrides
The number of anhydrides identified in tobacco and tobacco
smoke is small. In 1988, Roberts (3215) reported that there
were only ten anhydrides identified in tobacco, ten identified
in tobacco smoke, and four in both tobacco and tobacco smoke.
The number of anhydrides in tobacco and tobacco smoke has
not changed substantially since that time. There are presently
thirteen anhydrides identified in tobacco, thirteen in tobacco
smoke, and six in both tobacco and tobacco smoke.
In his 1984 review of the carcinogenesis induced by alky-
lating agents, Lawley (Table XXV, p. 434 in 7A04) tabulated
the findings of Dickens and Jones on a study of the tumori-
genicity (sarcogenicity) of maleic anhydride (7A01) and 2,3-
dimethylmaleic anhydride and succinic anhydride (7A02)
administered by subcutaneous injection to Wistar rats.
In its 1986 monograph, the International Agency for
Research on Cancer (IARC) wrote very little on the few
anhydrides in tobacco smoke [see p. 107 in (1870)]. IARC
commented:
At least eight acid anhydrides have been found in cigarette
smoke, including maleic anhydride and succinic anhydride
and their alkylated derivatives [Schumacher et al. (3553),
Newell et al. (2769)]. These smoke constituents are of par-
ticular concern because of their alkylating potential. Maleic
anhydride, 2,3-dimethylmaleic anhydride and succinic anhy-
dride have produced local tumours in one experiment in rats
[Dickens and Jones (7A01, 7A02), IARC (7A03)].
An inserted comment in the IARC monograph referred
the reader to Appendix 2, pages 389–394 in (1870), which
listed the components in tobacco smoke that had been evalu-
ated for carcinogenicity in the IARC monograph series. The
tumorigenicity of succinic anhydride was listed as:
Degree of Evidence in
Compound Animals (and Humans)
7. Agricultural chemicals and derivatives
Succinic anhydride Limited evidence
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It is obvious from the review by Lawley (7A04) and the
data in the Dickens and Jones reports (7A01, 7A02) that the
anhydrides are sarcogens, not carcinogens, that is, they do
not fit the definition of a carcinogen, a factor that induces a
carcinoma.
At R.J. Reynolds Tobacco Co. (RJRT) R&D, two anhy-
drides, 3,4-diethyldihydro-2,4-furandione (diethylsucccinic
anhydride) and 3,4-dimethyldihydro-2,4-furandione (dim-
ethylsucccinic anhydride) were identified by Jones and
Latimer during their research on Oriental tobacco composi-
tion. The two anhydrides were listed in their 1943 report on
the Oriental tobacco components they identified through the
end of 1942 (1980).
In a subsequent RJRT research effort in 1963 and 1964,
several anhydrides (see Table VII-1) were isolated from
tobacco smoke and identified by Fredrickson (1233, 1235)
during his study of the composition of burley tobacco smoke
condensate. Two decades later, several additional anhydrides
(see Table VII-1) were identified as components of Oriental
tobacco by Schumacher (3543).
Table VII-1 lists the twenty anhydrides identified to date
in tobacco and/or tobacco smoke. None of the anhydrides
listed in Table VII-1 was included in any of the many publi-
cations issued between 1986 and 2001 in which the toxicants
in tobacco and/or tobacco smoke were listed (1217, 1727,
1740, 1741, 1743, 1744, 1773, 1808, 2825).
No anhydride was included in the 1994 Doull et al. list
(1053) on compounds in flavor formulations used on tobacco
products by members of the U.S. tobacco industry.
461
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Table VII-1
Anhydrides in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Anhydrides 463

Table VII-1 (CONTINUED)

Anhydrides in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 8 Carbohydrates and Their Derivatives
The four macromolecules that have been called the “build-
ing blocks of life” are carbohydrates, proteins, lipids, and
nucleic acids. Tso (3873) estimated that as much as 75% of
all the carbon from CO2 that is reduced by plants enters into
some form of carbohydrate for at least a brief period of time.
Via numerous metabolic pathways these carbohydrates are
converted into hundreds of functional molecules necessary
to sustain life.
There are 279 components in tobacco and/or tobacco
smoke that may be considered either as a complete carbo-
hydrate or one in which a carbohydrate is linked to another
structure, such as a glycoside. This number is greater than the
156 listed by Tso in his 1990 book [see Table 1.38 in (3873)]
because of our inclusion of the carbohydrate-combined com-
ponents. The following indicates the difference in numbers:
Tobacco
Reference Total Smoke Tobacco
Table 1.38
Tso in (3873) 156 30 138
Carbohydrates Table VIII-3 279 35 271
A great number of carbohydrate-linked components,
mostly in tobacco, involve the linkage of a carbohydrate to a
2H-1-benzopyran-2-one or 4H-1-benzopyran-4-one, which
may not only be hydroxylated, for example, 6-(β-D-glucopy-
ranosyloxy)-7-hydroxy-2H-1-benzopyran-2-one (esculin), but
also may have one or more hydroxyphenyl links, for example,
3-[(6-deoxy-α-L-mannopyranosyl)oxy]-2-(3,4-dihydroxyphenyl)-
5,7-dihydroxy-4H-1-benzopyran-4-one (quercitrin), 3-[[6-
O-(6-deoxy-α-L-mannopyranosyl)-β-D-glucopyranosyl]
oxy]-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4H-1-benzo-
pyran-4-one (rutin), and 3-(β-D-glucopyranosyloxy)-5,7-
dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one
(kaempferol glycoside). Components such as these were clas-
sified as polyphenols. Tobacco components such as the latter
three may be the precursors of part of the phenols yield in
tobacco smoke. Snook et al. (8A08) determined the levels of
rutin and kaempferol glycoside in sixty-two different species
of Nicotiana. Their levels ranged from <0.005 to 1.6% for
rutin and <0.005 to 0.16% for the kaempferol glycoside. There
are, of course, in tobacco several carbohydrate-linked benzo-
pyranones that lack an hydroxyphenyl group, for example,
6-(β-D-glucopyranosyloxy)-7-hydroxy-2H-1-benzopyran-2-
one (esculin) and 7-(β-D-glucopyranosyloxy)-6-methoxy-
2H-1-benzopyran-2-one (scopolin).
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As indicated in Table VIII-1, only a few tobacco and/or
tobacco smoke carbohydrates are used in the flavor formula-
tions used by cigarette manufacturers in the United States
(1053) and in other countries (3266). None of those used in
that way is linked to a noncarbohydrate entity.
The use of tobacco containing various carbohydrate addi-
tives, such as the various sugars listed in Table VIII-1, has
been the subject of much discussion recently in attempts to
link such additives to medical problems induced by cigarette
smoke. The major concern was the generation of carbonyl
compounds such as formaldehyde and acetaldehyde.
Although Baker (8A02), in his letter to the editor of
Food and Chemical Toxicology, agrees with the statements
of Talhout et al. (3865b) that addition of sugars to tobacco
results in increased yields of formaldehyde in the main-
stream smoke (MSS), he also provided numerous references
[Baker (8A01), Baker and Bishop (172a, 172b), Baker et al.
(172c, 174a, 174b, 174c, 8A03), Baker and Smith (174e), Gori
and (1332), Massey (2484a), Rodgman (3264), Rustemeier et al.
Smoke (3370), Seeman et al. (3579, 8A06), Thornton and Massey
(3913), Zilkey et al. (4418)] and much discussion to coun-
12 ter the assertions by Talhout et al. (3865b) that sugar addi-
27 tion had an adverse effect on the biological properties of the
MSS. Not included in Baker were the facts that (1) Doull et
al. (1053), in their detailed 1994 assessment of 599 additives
used by members of the U.S. tobacco industry in cigarette
manufacture, reported no significant biological problem from
the use of sugars in the flavor formulations and (2) Dalhamn
et al. (892) had reported in 1968 that a significant percent-
age of water-soluble MSS vapor-phase components, such
as formaldehyde, acetaldehyde, and other carbonyls, never
reached the respiratory tract cilia of the smoker because of
their solution in the fluids coating the oral cavity. The find-
ings of Dalhamn et al. (892) were a confirmation of those
by Rodgman et al. (3306), Industrial Bio-Test Laboratories,
an independent contract laboratory (8A04), and the repeated
assertions by Wynder and Hoffmann that such would be the
case with water-soluble ciliastats (4330, 4332).
In their mid-1960s publications, Wynder and Hoffmann
commented several times on the fact that most of the known
ciliastatic components of MSS demonstrated to be cilia-
static in various in vitro systems were water soluble and this
property would markedly influence their fate and behavior
during and after inhalation. Wynder and Hoffmann (4330)
noted:
As far as human smoking habits are concerned, it remains
also to be estimated to which extent volatile smoke compo-
nents reach the bronchial tree. Preliminary studies indicate
that a significant proportion of the gaseous components is
being retained within the oral cavity.
465
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 466 The Chemical Components of Tobacco and Tobacco Smoke

Table VIII-1
Tobacco and/or Smoke Carbohydrates Used in Flavor Formulations
Identified in
As Listed by Smoke Tobacco
CAS No. Chemical Abstracts Nomenclature
Doull et al. (1053)
57-48-7 D-Fructose sugars + +
59-23-4 D-Galactose sugars + +
50-99-7 α-D-Glucose sugars + +
57-50-1 α-D-Glucopyranoside, β-D-fructofuranosyl- {sucrose} sugars + +
50-99-7 α-D-Glucose sugars + +
31103-86-3 Mannose sugars + +
50-70-4 Sorbitola glucitol - +
a  orbitol (glucitol)) is not included in the Doull et al. list (1053) but is included in flavor formulations used by cigarette manufacturers
S
outside of the U.S. [see Table 7A in (3266)].

Later, Wynder and Hoffmann [see p. 542 in (4332)] wrote:
Water-soluble volatile components, which are primarily
responsible for the results of the acute in vitro short-term
cilia toxicity tests, are, to a large extent, removed when ciga-
rette smoke contacts the saliva in the mouth and the abun-
dant secretions of the trachea and main bronchi.
They added [see p. 646 in (4332)]:
In man’s manner of smoking, however, volatile components are
retained to a significant degree in the oral cavity and may, there-
fore, be far less important than when tested experimentally.
Baker (8A02), in the letter to the editor of Food and
Chemical Toxicology in which he responded to the assertions
of Talhout et al. (3865b), noted several early studies cited
by Talhout et al., those of Thornton and Massey (3913) and
Shelar et al. (8A07) in which high levels of a carbohydrate
(sugar) were added to the tobacco, resulting in a significant
increase in the MSS yield of several carbonyl compounds,
namely formaldehyde, acetaldehyde, and acrolein. However,
the added carbohydrate greatly exceeded the amount usually
added in an industrial situation.
As noted by Baker (8A02), Talhout et al. (3865b) com-
mented on the effect on MSS carbonyl component yields
produced by additions to tobacco of 12% of three sugars but
they did not describe the effect of the additions of 4% of each
sugar, an addition level that more closely resembled that used
commercially. Table VIII-2 lists the changes reported by
Shelar et al. (8A07) in per cigarette MSS yield of formalde-
hyde, acetaldehyde, acetone, and acrolein by addition of 4%
fructose, glucose, or sucrose to two different burley samples.
Not discussed by either Baker (8A02) or Talhout et al. (3865b)
was a 1970 study by Best (297) in which a flue-cured tobacco
sample was treated with sugar to raise its level from 12.6% to
21.0%. Even though the sugar addition to the flue-cured tobacco
represented a 66% increase, the MSS yields of carbonyl com-
ponents increased: Formaldehyde from 35.4 μg/cigarette to
48.8 μg/cigarette, a 37.8% increase; acetaldehyde from 998 μg/
cigarette to 1020 μg/cigarette, a 2.2% increase; acrolein from
124 μg/cigarette to 131 μg/cigarette, a 5.6% increase.
In his review of the genotoxicity of tobacco smoke and
tobacco smoke condensate, DeMarini (933) described in
detail the 1979 findings of Mizusaki et al. (2568) on the effect
of the cigarette smoke condensate (CSC) from high-sugar
tobacco (20% to 30%) vs. the CSC from low-sugar tobacco

Table VIII-2
Effect of Sugars Added to Burley Tobacco on Mainstream Smoke Aldehyde and Ketone Yields (8A07)
Per Cigarette MSS Yield
Formaldehyde Acetaldehyde Acetone Acrolein
Burley 1 16.0 507 269 118
+ 4% fructose 18.2 (13.8%) 591 (16.6%) 333 (23.8%) 135 (14.4%)
+ 4% glucose 15.7 (-2%) 553 (9.1%) 335 (24.5%) 123 (4.2%)
+ 4% sucrose 20.4 (27.5%) 574 (13.2%) 364 (35.3%) 139 (17.8%)
Burley 2 11.2 578 306 118
+ 4% fructose 12.0 (7.1%) 652 (12.8%) 330 (7.8%) 130 (10.2%)
+ 4% glucose 18.6 (66.1%) 567 (-2%) 216 (-29.5%) 93 (-21.2%)
+ 4% sucrose 18.2 (62.5%) 561 (-3%) 270 (-12%) 109 (-7.7%)

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 Carbohydrates and Their Derivatives 467
(5%) in the Ames test (Salmonella typhimurium strain
TA 1538). The high-sugar tobacco CSC was much less muta-
genic than the low-sugar tobacco CSC. DeMarini (933) also
summarized the results of a study by Sato et al. (8A05) in
which various sugars were added to the tobacco in high-“tar”
and low-“tar” cigarettes, the CSCs collected, and tested for
mutagenicity in the Ames test with Salmonella typhimurium
TA 98 and TA 100, with and without activation. The sugars
tested included glucose, fructose, galactose, lactose, sucrose,
and sorbitol. The mutagenicity of the CSC from the sugar-
treated high-“tar” cigarettes was reduced 35% from the muta-
genicity observed for the CSC from the untreated tobacco
cigarette. The mutagenicity of the CSC from the low-“tar”
cigarettes was reduced 36% from mutagenicity of the CSC
from the untreated tobacco cigarette.
In the National Cancer Institute study of the third set of
cigarettes, Gori (1332) reported the effect of adding invert
sugar at a level approximating that used commercially to
the Standard Experimental Blend III (SEB III) [see Table 8,
p. 99, cigarette 81 in (1332)] on the per cigarette MSS yields
of numerous smoke components, including formaldehyde,
acetaldehyde, and acrolein [see Table 8, p. 59 in (1332)]. The
© 2009 by Taylor & Francis Group, LLC
78836_C008.indd 467
multiple samples of SEB III yielded an average of 33.8 μg/
cigarette of formaldehyde, 1212 μg/cigarette of acetaldehyde,
and 110 μg/cigarette of acrolein. Cigarette 81, fabricated from
SEB III with added invert sugar, yielded 32.3 μg/cigarette
of formaldehyde, 1090 μg/cigarette of acetaldehyde, and 113
μg/cigarette of acrolein. Dermal assays were initiated with
100 ICR Swiss female mice in each group. Multiple samples
of CSC from SEB III at 12.5 mg and 25.0 mg doses produced
twenty-seven and forty-seven tumor-bearing animals (TBA),
respectively [see Table 2, p. 86 in (1332)], whereas the CSC
from the invert sugar-treated SEB III at 12.5 mg and 25.0
mg doses produced nineteen and forty-one TBA, respectively
[see Table 3, p. 87, cigarette 81 in (1332)]. However, the CSCs
studied would be devoid of formaldehyde, acetaldehyde, and
acrolein because of their vaporization during the collection,
solution preparation, and administration of the CSCs.
Table VIII-3 lists the carbohydrates and their derivatives
identified to date in tobacco, tobacco smoke, and tobacco
substitute smoke. Of the 279 identified carbohydrates listed,
most of them are tobacco components: 271 have been identi-
fied in tobacco vs. only 35 in smoke; 27 have been identified
in both tobacco and smoke.
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 468 The Chemical Components of Tobacco and Tobacco Smoke

Table VIII-3
Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carbohydrates and Their Derivatives 469

Table VIII-3 (continued)

Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 470 The Chemical Components of Tobacco and Tobacco Smoke

Table VIII-3 (continued)

Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carbohydrates and Their Derivatives 471

Table VIII-3 (continued)

Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 472 The Chemical Components of Tobacco and Tobacco Smoke

Table VIII-3 (continued)

Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carbohydrates and Their Derivatives 473

Table VIII-3 (continued)

Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 474 The Chemical Components of Tobacco and Tobacco Smoke

Table VIII-3 (continued)

Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carbohydrates and Their Derivatives 475

Table VIII-3 (continued)

Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 476 The Chemical Components of Tobacco and Tobacco Smoke

Table VIII-3 (continued)

Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carbohydrates and Their Derivatives 477

Table VIII-3 (continued)

Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 478 The Chemical Components of Tobacco and Tobacco Smoke

Table VIII-3 (continued)

Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carbohydrates and Their Derivatives 479

Table VIII-3 (continued)

Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 480 The Chemical Components of Tobacco and Tobacco Smoke

Table VIII-3 (continued)

Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carbohydrates and Their Derivatives 481

Table VIII-3 (continued)

Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 482 The Chemical Components of Tobacco and Tobacco Smoke

Table VIII-3 (continued)

Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carbohydrates and Their Derivatives 483

Table VIII-3 (continued)

Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 484 The Chemical Components of Tobacco and Tobacco Smoke

Table VIII-3 (continued)

Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Carbohydrates and Their Derivatives 485

Table VIII-3 (continued)

Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 486 The Chemical Components of Tobacco and Tobacco Smoke

Table VIII-3 (continued)

Carbohydrates in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 9 Phenols and Quinones
IX.A Phenols
Examination of the extensive literature on the composition of
tobacco smoke reveals that considerable effort was expended
in the early 1960s in defining the nature of the phenolic com-
ponents of tobacco smoke. Subsequently, even though the
identity of many phenols in tobacco smoke are now known,
research has indicated their number identified in tobacco
smoke is much fewer than the number of identified polynu-
clear aromatic hydrocarbons (PAHs).
With the tremendous effort expended on the identifica-
tion of PAHs and some of their nitrogen analogs in tobacco
smoke, what series of events triggered the interest in and the
emphasis on phenols in tobacco smoke in the early 1960s?
The reports by Wynder et al. (4306a, 4306c) in the early
1950s that cigarette smoke “tar” or cigarette smoke condensate
(CSC) was tumorigenic to mouse skin prompted an intense
search for the responsible component(s). Initially, the PAHs
were selected for investigation because of the wealth of chemi-
cal and biological data generated on a great number of them
following the synthesis of dibenz[a,h]anthracene (DB[a,h]A)
in 1929 (760, 1184), the isolation of benzo[a]pyrene (B[a]P)
from coal tar in 1932 (796a, 797), and the demonstration of
the potent tumorigenicity of both of them to mouse skin (194,
2078). Almost immediately after the report by Wynder et al.
(4306a) of the mouse skin-painting results with tobacco “tar,”
the PAHs were proposed by some investigators to be the major
tumor initiators in CSC. Because of its level in CSC and its
potency in mouse-skin tumorigenesis, B[a]P was defined as
the most significant of the PAHs in tobacco smoke.
However, it was soon recognized that neither the B[a]
P content nor its tumorigenicity could explain the biologi-
cal response observed in the mouse skin-painting bioassay.
Similarly, neither the total content of the PAHs tumorigenic to
mouse skin nor their summed tumorigenicities could explain
the observed biological response. In fact, it was pointed out
repeatedly over the next several decades that the levels of
B[a]P and other tumorigenic PAHs in CSC accounted for less
than 3% of the observed tumorigenicity [Wynder and Wright
(4353, 4354), Wynder and Hoffmann (4307, 4308, 4312, 4317,
4319, 4332, 4342), Druckrey (1056), Roe (3310, 3311), USPHS
(3999, 4005, 4009, 4010), Lazar et al. (2320), Stedman (3797),
Selikoff et al. (3584a), Coultson (830)].
As early as the mid-1950s, Wynder and Wright (4353)
noted that the concentration of B[a]P in cigarette tar was
insufficient to account for its observed carcinogenicity to
mouse epidermis: “The concentration in which benzo[a]
pyrene seems to be in cigarette tar is insufficient to account
for the observed carcinogenic activity to mouse epidermis.”
At the 1957 Blatnik Committee hearings, Wynder reported
Wright’s opinion (4282a) on the subject as well as his own
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78836_C009.indd 487
(4296). Wynder noted that much attention had been directed
at the PAH B[a]P. So much in fact that, as he stated, B[a]
P had become an issue in itself because it was one of the
known tumorigenic substances and everyone tried to blame
everything on it alone. During his testimony, he also noted
that his Sloan Kettering group had repeatedly stated that the
amount of B[a]P in tobacco “tar” was insufficient to explain
the animal results published by his group. He added that
cigarette “tar” contained numerous other B[a]P-related com-
pounds much more active than B[a]P and they most likely
accounted for the majority of the activity, and it was more or
less academic whether it was B[a]P or a dibenzopyrene or a
dibenzanthracene or a substituted B[a]P because they were
all formed in the same manner during the tobacco smoking
process. That same year, Wynder and Wright (4354) wrote
that, to that date, no carcinogens had been identified in large
enough quantities in tobacco “tar” or its fractions to account
for the observed activity in mouse skin-painting studies:
We have demonstrated experimentally … that 0.0001 per cent
or even 0.0005 per cent benzopyrene in acetone will not pro-
duce any tumors in the present experimental mouse or rabbit
groups. Thus, there is conclusive proof that the animal results
cannot be solely due to the benzopyrene content of tobacco .
The benzopyrene content of the total tar as well as the
active fractions is far too low to account alone for the posi-
tive results [in laboratory animal]. So far, no carcinogens
have been identified in large enough quantity in tobacco tar
or its fractions to account for the observed activity.
These Wynder-Wright results led to an intensive but unsuc-
cessful eighteen-month search for a “supercarcinogenic” PAH
by Wright. The absence of such a PAH was subsequently con-
firmed by the USDA group at Athens, Georgia [Snook (3732),
Snook et al. (3756–3758)] by their identification of over 500
PAHs in the PAH fraction from cigarette mainstream smoke
(MSS), an identification procedure that completely accounted
for the fraction in the cigarette smoke studied.
In 1959, unable to explain the bioassay (mouse skin-paint-
ing) results with CSC on the basis of either its B[a]P con-
tent (less than 2% explainable) or its total tumorigenic PAH
content (less than 3% explainable), Wynder and Hoffmann
(4307) added the concept of promotion by low molecular
weight phenols to the concept of tumor initiation by PAHs in
an attempt (unsuccessful) to explain the bioassay results.
A similar comment that the amount of tumorigenic PAHs
found in CSC could not by themselves account for the total
biological activity observed was included in a more detailed
publication (4307). They also stated (4308) that the higher
PAHs played an important role in the carcinogenicity of
CSC but when the various known concentrations of the
487
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 488 The Chemical Components of Tobacco and Tobacco Smoke

carcinogenic PAHs, as estimated in CSC, were summed, it
was obvious that they could not account for the established
carcinogenicity of the CSC nor of its isolated PAH fraction.
Several carcinogenic higher aromatic polycyclic hydrocar-
bons [are] present in tobacco smoke condensate. They include
benzo[a]pyrene …, benzo[e]pyrene …, chrysene …, benz[a]
anthracene …, dibenz[a,h]anthracene …, and dibenzo[a,i]
pyrene … From the amount in which these materials have
been found in tobacco smoke condensate it was evident that
these, by themselves, could not account for the total biologi-
cal activity observed.
In 1960, Van Duuren et al. (4027) reported the identification
of several aza-arenes (dibenz[a,h]acridine, dibenz[a,j]acridine,
dibenzo[c,g]carbazole) not only structurally similar to some of
the known tumorigenic PAHs in CSC but also reported to be
tumorigenic under certain conditions to mouse skin. Adding
this class of tumorigenic cigarette smoke components to the
assessment of the tumorigenicity of CSC failed to account for
more than a few percent of the observed response.
However, it should be noted that Candeli et al. (587) could
not confirm the findings of Van Duuren et al. on the pres-
ence of these three aza-arenes in cigarette MSS. During the
next three decades, other research groups, as shown in Table
IX.A-1, in Germany, Japan, and the United States were also
unable to confirm the presence in cigarette MSS of dibenz[a,h]
acridine, dibenz[a,j]acridine, and dibenzo[c,g]carbazole.
Wynder and Hoffmann (4312) wrote that the PAHs in
CSC accounted for not more than 3% of the total biological
activity observed in mouse-skin bioassays:
The polynuclear aromatic hydrocarbons are mainly formed
during the combustion of tobacco. The tobacco of our stan-
dard cigarettes contains only very minute quantities of
benzo(a)pyrene (0.02 ppm). A bioassay indicates that these
polycyclic hydrocarbons of the condensate by themselves,
however, can account for not more than 3 per cent of the
total biological activity.
They also wrote (4313) that the established carcinogenic-
ity of CSC to mouse epidermis could to a great extent be
accounted for on the basis of initiating carcinogens, largely
PAHs, and promoting substances, a major group of which
was the phenols. This statement was not true in 1961, nor is
it true now.
Wynder and Hoffmann (4314), unable to explain the mouse
skin-painting bioassay results with CSC on the basis of its con-
tent of tumorigenic PAHs and aza-arenes, promoting and/or
cocarcinogenic phenols, and promoting and/or cocarcino-
genic nontumorigenic PAHs, added the concept of ciliastasis
in an attempt (unsuccessful) to explain cigarette smoke tum-
origenicity in smokers’ lungs.
In their lengthy 1964 review of tobacco carcinogenesis,
Wynder and Hoffmann (4319) stated that no one could deny
that tobacco products were tumorigenic even though no single
component in tobacco smoke could by itself or jointly with
other components account for the observed tumorigenic activ-
ity of such tobacco products to the skin of laboratory animals:
It is furthermore true that none of the agents is carcino-
genic in the concentrations in which they are present in
tobacco products.

Table IX.A-1
Dibenz[a,h]acridine (I), Dibenz[a,j]acridine (II), and 7H-dibenzo[c,g]carbazole (III) in Nicotine Pyrolysates
(Pyr) and Mainstream Cigarette Smoke Condensate
Dibenz[a,h]acridine Dibenz[a,j]acridine 7H-Dibenzo[c,g]carbazole
Investigators Pyr CSC Pyr CSC Pyr CSC
Van Duuren et al. (4027) yes yes yes yes no yes
Candeli et al. (587), Wynder and Hoffmann (4319, 4332) NE no NE yes NE NE
Kaburaki et al. (2006) no NE no NE NE NE
Schmeltz et al. (3499) no NE no NE no NE
Schmeltz et al. (3512) no no no no no no
Snook (3733) NE no NE no NE no
Snook et al. (3750) NE no NE no NE no
Grimmer et al. (1409) NE no NE no NE no
Kamata et al. (2021) NE no NE no NE NE
Sasaki and Moldoveanu (3414) NE no NE no NE NE
Rustemeier et al. (3370) NE no NE yes NE NE

yes = Compound identified.

no = Compound not found or identified.
NE = Substrate not examined for compound in question.

Examination of these results indicates that Van Duuren et al. (4027) reported the identification of the three N-heterocyclic compounds (I, II, and III) in
MSS CSC and two of them (I and II) in a nicotine pyrolysate; whereas, Candeli et al. (587) failed to identify I but did identify II in MSS CSC. The 1963
Candeli et al. findings on II in MSS CSC were not confirmed in 1979 by investigators (3512) from the same laboratory: Hoffmann was a participant in
both the 1963 and 1979 studies. Two studies (3499, 3512) confirmed the 1960 report by Van Duuren et al. that 7H-dibenzo[c,g] carbazole (III) was not
present in a nicotine pyrolysate.

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 Phenols and Quinones 489
Wynder and Hoffmann (4332) expressed similar views
on the tumorigenicity of tobacco smoke components in their
1967 book, but they continued to maintain that the PAHs in
cigarette smoke were important as tumor initiators:
While BaP and other carcinogenic PAH can by themselves
account for only a small portion of the total tumorigenic
activity of cigarette smoke condensate, probably less than
2%, they are, nevertheless, of obligatory importance as
tumor initiators.
The next year, Wynder and Hoffmann (4342) wrote,
“Carcinogenic polynuclear hydrocarbons in the concentra-
tions present in tobacco ‘tar’ clearly do not, by themselves,
account for the observed carcinogenicity.”
On several occasions, the U.S. Surgeon General in his
periodic reports on smoking and health discussed the rela-
tionship between the levels of PAHs in cigarette smoke, their
tumorigenic potency to mouse skin, and the observed biolog-
ical response with CSC in mouse skin-painting bioassays.
The results of a number of such assays [mouse skin-painting]
present a puzzling anomaly: the total tar from cigarettes has
about 40 times the carcinogenic potency of the benzo(a)
pyrene present in the tar. The other carcinogens known
to be present in tobacco smoke are, with the exception of
dibenzo(a,i)pyrene, much less potent than benzo(a)pyrene
and they are present in smaller amounts. Apparently, there-
fore, the whole is greater than the sum of the known parts.
[see p. 58 in (3999)]
Benzo(a)pyrene is present in much larger concentrations
than is any other carcinogenic polycyclic hydrocarbon. The
inability to account for the carcinogenicity of the tobacco
products, except to a very minor degree, by the amount of
benzo(a)pyrene present was unanticipated. Both Druckrey
(1056) and Wynder (4300) emphasized that the benzo(a)pyrene
concentration of various tobacco and smoke preparations is
only sufficient to account for a very small part of the carcino-
genicity of these materials [see pp. 144–145 in (3999)].
PAH alone, however, account for only a small portion of
the carcinogenicity of tobacco “tar” … The levels of carci-
nogenic PAH in tobacco smoke are well below their practi-
cal threshold as complete mouse skin carcinogens … (see
4005).
The contribution of BaP or PAH in general to mouse skin
carcinogenesis by cigarette smoke condensate cannot be
fully measured at this time. Wynder and Hoffmann [4332]
found a correlation between BaP levels and carcinogenicity
of smoke condensates from several types of cigarettes. A
much larger series of experimental cigarettes was studied
in the smoking and health program of the National Cancer
Institute. No significant dependence of carcinogenic potency
on BaP content was observed [Gori (1329, 1330, 1332, 1333),
National Cancer Institute (2683)]. [See (4009).]
The carcinogenic activity of the particulate matter of
tobacco smoke in epithelial tissues of laboratory animals is
greater than the sum of the effects of the known carcinogens
present [(see 4010); and the comment in the 1964 Advisory
Committee Report to the Surgeon General: “Apparently,
therefore, the whole is greater than the sum of the known
parts” (3999)].
© 2009 by Taylor & Francis Group, LLC
78836_C009.indd 489
In 1980, Coultson (830) commented on the decades of
attention on B[a]P in cigarette MSS and its supposed rele-
vance in cigarette smoke-induced cancers:
Whether it’s benzo[a]pyrene or not, nobody really knows.
More work has been done on benzo[a]pyrene to prove it to be
the causative agent in cigarette smoking than I think on any
other chemical for any disease that I know. And yet the point
is, you can’t prove it.
The failure of PAHs to explain no more than a few per-
cent of the tumorigenicity of CSC led to the inclusion of the
concept of promotion in the overall equation. As noted previ-
ously, Wynder and Hoffmann (4313) asserted that the estab-
lished carcinogenicity of CSC on mouse epidermis could to
a great extent be accounted for on the basis of initiating car-
cinogens, largely PAHs, and promoting substances, a major
group of which was the phenols. Their assertion was incor-
rect in 1961, and it is incorrect today.
In his listing of reported identified tobacco smoke compo-
nents (Table IX.A-2), Kosak (2170) listed published reports on
two simple phenols, the early reports on phenol by Wenusch
(4202) and Ikeda (1857) and on catechol (1,2-benzenediol) by
Kissling (2107) and Wenusch (4202), but he questioned the iden-
tification of phenol. Kosak also cited earlier reports by Thoms
(3912) and McNally (2524) who mentioned the presence of
“phenols” in tobacco smoke and Roffo (3324) who mentioned
the presence of phenolic acids. However, it should be remem-
bered that Roffo’s 1939 studies dealt with a destructive distillate
from tobacco, not with tobacco smoke generated in a tobacco
smoking process simulating that used by human smokers.
Table IX.A-3 summarizes 1954 listing by Kosak of phe-
nolic components reported in tobacco smoke, the year of the
report, and the investigators involved.
However, critical examination of the chronology of the
pre-1954 investigations of phenolic compounds in tobacco
smoke reveals that Kosak’s 1954 publication suffers from
several deficiencies with regard to reports on this class of
tobacco smoke components. The examination indicates that
his manuscript was submitted to the journal Experientia in
September 1953, accepted for publication shortly thereafter,
and appeared in a February 1954 issue of the journal. One
of the significant omissions was the report by Rayburn and
his colleagues at the Research Department of the American
Tobacco Company: At the 6th Tobacco Chemists’ Research
Conference (TCRC) in December 1952, Rayburn (3089)
described the unequivocal identification of four low molecular
weight phenols in the MSSs from a series of cigarettes, each
member of the series fabricated from one of the four major
tobacco types (flue-cured, burley, Maryland, Oriental). The
phenols identified were phenol, guaiacol (2-methoxyphenol),
o-cresol (2-methylphenol), and m-cresol (3-methylphenol).
The next year, these results were published by Rayburn et al.
in the journal Analytical Chemistry (3090).
In Table IX.A-4 literature references are listed for
phenolic components in tobacco smoke cited by Kosak
(2170) plus several pertinent references not included in
his publication.
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 490 The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-2
Tobacco Smoke Components Listed by Kosak (2170)
Class Component Class Component Class Component
Hydrocarbons Hentriacontane (?) Ketones 3-Pentanone Acids Formic acid
Acetylene 4-Heptanone Acetic acid
“Unsaturated hydrocarbons” 17-Tritriacontanone (?) Butyric acid
Azulene 2,3-Butanedione Valeric acid
Phenanthrene (?) “Higher” ketones (?) Caproic acid
Anthracene (?) C7 and C8 aliphatic acids (?)
Benzopyrene (?) Succinic acid (?)
“Condensed aromatics” (?) Fumaric acid (?)
Citric acid (?)
Benzoic acid (?)
Phenolic acids (?)
Alcohols and Methanol Alkaloids Nicotine Miscellaneous Levoglucosand
Phenols Glycerol Pyridyl ethyl ketone Components “Phytosterol” (?)
Diethylene glycola Myosmine C10H14O (a furan ?)
Ethylene glycola Nicotyrine “Resins” (?)
Phenol (?) α-Socratinec “Resin acids” (?)
Catechol (?) β-Socratinec
γ-Socratinec
Obelinc
Lohitamc
Anodminc
Lathraeinc
Poikilinec
Gudhamc
Aldehydes Formaldehyde Other Pyrrole (?) Inorganic Components Ammonia
Acetaldehyde N-containing “Pyrroles” (?) Carbon monoxide
Butyraldehyde components “N-Methyl- Carbon dioxide
Acrolein (?) pyrrolidines” (?) Hydrogen cyanide
Benzaldehyde Pyridine Hydrogen sulfide
2-Furaldehyde (?) b “Picoline” (?) Thiocyanic acid (?)
“Lutidine” (?) Oxygen
“Collidine” (?) Arsenic e
“Pyridine bases” (?) “Acetates” (?)
Methylamine (?) “Chlorides” (?)
“Chlorophyll degradation “Cyanides” (?)
products” (?) “Nitrates” (?)
“Uric acids” (?)
a In smoke because of transfer of an humectant added to tobacco.
b The question mark indicates that Kosak did not consider the evidence in the literature to be definitive proof of the identity of the component.
c Subsequent study demonstrated this component was not a well-defined compound but an artifact, a mixture, or an ammonium salt [see discussion by
Johnstone and Plimmer (1971)].
d 1,6-Anhydro-β-D-glucopyranose.
e Probably present as As2O3..

The report of the possible presence of phenol-like com-
pounds in Oriental tobacco by Jones and Latimer (1980) at
RJRT R&D eventually prompted a research project to syn-
thesize a series of phenols in an attempt to find one or more
that would impart a pleasant leather-like aroma to cigarette
smoke (3235a, 3240a). Some twenty phenols were syn-
thesized. However, none was ever used commercially as a
tobacco flavorant or in any extensive in-house panel tests, for
the following reasons.
During the course of his initial research project (3235a,
3240a) at RJRT R&D, Rodgman suggested the possibility of
the conversion of several of the phenols to a quinone during the
smoking process. This suggestion, coupled with the reports by
Takizawa (3865a) that several simple quinones such as p-ben-
zoquinone (2,5-cyclohexadiene-4-dione), 1,2-naphthoquinone
(1,2-naphthalenedione), and 1,4-naphthoquinone (1,4-naph-
thalenedione) were tumorigenic to mouse skin, raised serious
questions about the addition of phenols to the tobacco blend.

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 Phenols and Quinones 491

OH
Table IX.A-3
R6 R2
Phenolic Components of Tobacco Smoke Listed
by Kosak (2170)
R5 R3
Year Investigator Component
1904 Thoms (3912) “phenols” R4
1919 Kissling (2107) catechol
1932 McNally (2524) “phenols” Figure IX.A-1  A substituted phenol.
1939 Roffo (3324) phenolic acids
1939 Wenusch (4202) catechol If neither R2 nor R6 is hydrogen, that is, when R2 ≠ H and
1939 Wenusch (4202) phenol R6 ≠ H, no promoting effect is observed.
1947 Ikeda (1857) phenol
The coupling of the findings reported by Boutwell et al.
(414) on the promoting effects of low molecular weight phe-
nols on PAHs in the mouse skin-painting bioassay with the
The biological findings on p-benzoquinone were subsequently failure to explain the tumorigenicity of CSC on the basis of
confirmed by Tiedemann (3916a). Takizawa (3865a) reported its PAH content subsequently triggered extensive research
that neither of the higher molecular weight quinones 9,10-anthr- both within and outside of the tobacco industry on several
aquinone (9,10-anthracenedione) or 9,10-phenanthrenequinone aspects of the phenols in tobacco smoke.
(9,10-phenanthrenedione) was tumorigenic to mouse skin.
Rodgman also communicated to management the sub- 1. Identification and quantitation of phenols in
stance of the early reports by Boutwell et al. (414), subse- cigarette MSS: To date, the number of phenols
quently amplified by Boutwell and Bosch (414), that when identified in tobacco smoke exceeds 400 (see
certain low molecular weight phenols were applied to mouse Table IX.A-22). While the number of phenols iden-
skin in sequence with a level of a tumorigenic PAH such as tified is significantly fewer than the number of
B[a]P either insufficient to induce tumors or sufficient to PAHs identified in cigarette MSS, the number of
induce tumors in only a small percentage of the treated ani- identified tobacco smoke phenols is much greater
mals the phenols enhanced (or promoted) the tumorigenic than that identified in any other consumer product
effect of the PAH, that is, the percent tumor-bearing animals such as tea, coffee, or cocoa, again a reflection of
(% TBA) was much higher than that anticipated on the basis the intense scrutiny directed at tobacco smoke vs.
of the PAH dose administered. that directed at any other consumer product.
The effectiveness of the promotion of the tumorigenic- 2. Bioassays to determine contribution of phenols to
ity of a tumorigenic PAH by a phenol is dependent on the CSC tumorigenicity: Determination of the biologi-
substituents R2 and R6 on the C2 and C6 carbons, the carbon cal relationship, if any, between the phenol fraction
atoms adjacent to the carbon to which the hydroxyl group from cigarette MSS or its individual components
is attached (Figure IX.A-1). If R2 = H or R6 = H or if R2 = and the PAH fraction from cigarette MSS or its
R6 = H, then the phenol will exert a promoting effect, the individual components needed to be conducted.
effect being greatest when both substituents R2 = R6 = H. Was the biological relationship between phenol and

Table IX.A-4
Studies of Phenolic Components of Tobacco Smoke Omitted from the 1954 Listing by Kosak (2170)
Year Investigator Component
1871 Vohl and Eulenberg (4065) phenol
1876 Ludwig (2408) phenol
1904 Thoms (3912) “phenols”
1919 Kissling (2107) 1,2-dihydroxybenzene (catechol)
1932 McNally (2524) “phenols”
1939 Roffo (3324) phenolic acids
1939 Wenusch (4202) phenol, 1,2-dihydroxybenzene (catechol)
1947 Ikeda (1857) phenol
1950 Molinari (2605) phenol, 1,2-dihydroxybenzene (catechol)
1952 Rayburn (3089) phenol, 2-methoxyphenol (guaiacol), 2-methylphenol (o-cresol), 3-methylphenol (m-cresol)
1953 Rayburn et al. (3090) phenol, 2-methoxyphenol (guaiacol), 2-methylphenol (o-cresol), 3-methylphenol (m-cresol)
1954 Kosak (2170) list of tobacco smoke components

Note: Entries in bold print refer to items included by Kosak (2170).

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 492 The Chemical Components of Tobacco and Tobacco Smoke
the tumorigenic PAHs one of promotion, cocar-
cinogenesis, inhibition, or anticarcinogenesis?
3. Determination of the nature of the precursors in
tobacco of the phenols in cigarette MSS: The studies
in the mid-1960s to identify the major precursors in
tobacco of the phenols in tobacco smoke paralleled
the studies in the late 1950s and early 1960s on the
precursors in tobacco of the PAHs in tobacco smoke.
4. The effect of cigarette design parameters on deliv-
ery of MSS phenols: Determinations of which
cigarette design parameters enabled significant
control of the levels of phenols in MSS needed to
be conducted.
In the following paragraphs, each of the topics listed
above is discussed in considerable detail with an attempt to
put in perspective the relationships between isolation/identi-
fication, precursor definition, bioassay results, and delivery
control pertinent to the phenols in cigarette MSS.
IX.A.1 Identification and Quantitation
of Phenols in Cigarette MSS
In their reviews of phenolic components of tobacco smoke,
Wynder and Hoffmann (4319, 4332) concluded their report on
the first successful isolation of phenols from tobacco smoke
by Vohl and Eulenberg (4065) and Ludwig (2408) with the
comment: “Since that time, publications have dealt sporadi-
cally with smoke phenols.”
From the early 1950s through 1967, over 110 reports
dealing with phenols in smoke were presented at scientific
meetings and/or published in peer-reviewed journals. Such a
number can hardly be considered as sporadic!
Many of the studies in the 1950s dealt with the identifica-
tion and quantitation of various low molecular weight phenols
in cigarette MSS [see the studies on phenol, the methylphe-
nols (the cresols), 2-methoxyphenol (guaiacol), the dimeth-
ylphenols (the xylenols) by Rayburn (3089), Rayburn et al.
(3090), Commins and Lindsey (786–789, 789a), Izawa et al.
(1906), and on scopoletin by Yang et al. (4373–4375)].
Not only was a variety of separation techniques employed
to obtain the phenols but also a variety of analytical tech-
niques was employed for the quantitation. Examples of these
methods follow.
Diazotization with p-nitroaniline, Rayburn et al. (3090)
paper chromatography, UV
absorption spectrophotometry
Methylation, paper Commins and Lindsey (786)
chromatography, UV absorption
spectrophotometry
Formation of 2,4-dinitrobenzoates Izawa et al. (1906)
Formation of phenylazobenzene Izawa et al. (1906)
sulfonic acid derivatives
Methylation, gas chromatography Carruthers and Johnstone (615)
Gas chromatography, internal Hoffmann and Wynder (1789),
standard addition Crouse et al. (851), Spears (3764)
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78836_C009.indd 492
Gas chromatography Oakley et al. (2820)
4-Aminoantipyrine treatment, Lorentzen and Neurath (2397)
colorimetry
Glass capillary gas Smith and King (3716)
chromatography
Diazotization with p-nitroaniline, Smith and King (3717, 3718)
colorimetry
Thin layer chromatography Smith and Sullivan (3719)
Derivatization, colorimetry Knoop and Rosene (2142a)
In 1959, Johnstone and Plimmer (1971) cataloged the six-
teen tobacco smoke phenols listed in Table IX.A-5.
Examination of the chronology of the published reports
on phenols in tobacco smoke reveals the escalation (see
Table IX.A-6) of the scientific publications/presentations
between 1952 and 1964, the year of the Advisory Committee’s
Report on Smoking and Health to the U.S. Surgeon General
(3999). This escalation was similar to but not as extensive as
the increase from 1953 to 1964 in the number of presenta-
tions/publications pertinent to PAH in tobacco smoke.
In January 1964, the Advisory Committee on Smoking
and Health submitted its report to the U.S. Surgeon General
(3999). Because of the widespread dissemination of the con-
tents of this report, its January 1964 publication provides an
appropriate point in time to assess the situation with regards to
prior research publications on phenolic compounds in tobacco
smoke. Table IX.A-6 summarizes chronologically some of
the various reports issued between 1952 and 1964 on tobacco
smoke phenols. Of the eighty-two reports cited in Table IX.A-6
from 1952 through 1964, eighty were issued from 1955 through
1964. If, because of the early 1964 issuance of the Advisory
Committee’s Report, the publications on tobacco smoke phe-
nols in 1964 are omitted from the listing, the number from
1953 through 1963 becomes sixty-five. As noted previously in
the discussion of the early studies of PAHs, a similar assess-
ment of publications on PAHs in tobacco smoke indicated that
some 213 reports were issued from 1953 through 1964. If the
publications on tobacco smoke PAHs in 1964 are omitted, the
number from 1953 through 1963 becomes 200.
During the first decade of research on tobacco smoke,
effort was divided between the identifications of the various
phenolic compounds and improvements of their quantitation
in cigarette MSS.
Less than a decade after the 1959 review by Johnstone and
Plimmer, Stedman (3797) tabulated the reports in which the
identifications of fifty-four phenols in tobacco smoke were
described (Table IX.A-7).
In their 1980 review, Ishiguro and Sugawara (1884) listed
over 150 phenolic compounds that had been identified as
tobacco smoke components.
By the mid-1990s, over 270 completely identified pheno-
lic compounds were reported as tobacco smoke components
(Table IX.A-22). It should be noted that, despite repeated
criticisms of the publication policy of the R.J. Reynolds
Tobacco Company on tobacco smoke composition, seventy
of the phenolic compounds listed in Table IX.A-22 were first
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 Phenols and Quinones 493

Table IX.A-5
Tobacco Smoke Phenols Cataloged by Johnstone and Plimmer (1971)
Phenol
1,2-Benzenediol {catechol}
1,3-Benzenediol {resorcinol}
1,4-Benzenediol {hydroquinone}
2H-Benzopyran-6-one, 7-hydroxy-
6-methoxy- {scopoletin}
Ethanone, 1-(3-hydroxyphenyl)-
{3’-hydroxyacetophenone}
Ethanone, 1-(4-hydroxyphenyl)-
{4’-hydroxyacetophenone}
1-Naphthalenol {1-naphthol}
2-Naphthalenol {2-naphthol}
Phenol
Phenol, 2,4-dimethyl- {2,4-xylenol}
Phenol, 3,5-dimethyl- {3,5-xylenol}
Phenol, 2-dimethoxy- {guaiacol}
Phenol, 2-methyl- {o-cresol}
Phenol, 3-methyl- {m-cresol}
Phenol, 4-methyl- {p-cresol}
Phenol. 2,4,6-trimethyl- {mesitol}
References
Molinari (2605, 2607), Bonnet and Neukomm (396), Carruthers and Johnstone (615)
Commins and Lindsey (789, 789a)
Bonnet and Neukomm (396)
Yang et al. (4373-4375)
Carruthers and Johnstone (615)
Carruthers and Johnstone (615)
Commins and Lindsey (789, 789a)
Commins and Lindsey (789, 789a)
Vohl and Eulenberg (4065), Ludwig (2408), Rayburn (3089), Rayburn et al. (3090),
Commins and Lindsey (789, 789a), Bonnet and Neukomm (396), Carruthers and Johnstone (615)
Wynder and Wright (4354)
Carruthers et al. (616), Clemo (765)
Rayburn (3089), Rayburn et al. (3090)
Rayburn (3089), Rayburn et al. (3090), Commins and Lindsey (789, 789a), Carruthers and Johnstone (615)
Rayburn et al. (3089), Commins and Lindsey (789, 789a), Carruthers and Johnstone (615)
Commins and Lindsey (789, 789a), Carruthers and Johnstone (615)
Bonnet and Neukomm (396)

Table IX.A-6
Publications/Presentations (1952–1964) Pertinent to Identification of Phenolic Components of Tobacco Smoke
Number
Year In Year Accumulated Investigator(s)

1952 1 1 Rayburn (3089)

1953 1 2 Rayburn et al. (3090)
1955 1 3 Wright and Wynder (4353)
1956 5 8 Commins and Lindsey (786–789, 789a)
1957 3 11 Bonnet and Neukomm (396), Landahl and Tracewell (2261), Wynder and Wright (4354)
1958 11 22 Bonnet (392), Carruthers et al. (616), Clemo (765), Rowland (3347), Weaving (4156),
Wender et al. (4164), Yang et al. (4373–4375)
1959 8 29 Dieterman et al. (969), Doll (1025), Izawa et al. (1906), Onishi (2858), Reid (3096),
Rodgman and Cook (3271), Roe et al. (3314)
1960 3 33 Carruthers and Johnstone (615), Rodgman and Cook (3280, 3286), Weaving (4158),
Yang et al. (4376)
1961 8 41 Cundiff (859), Herrmann (1625), Hoffmann and Wynder (1789), Latimer (2274), Rodgman
and Cook (3286), Wynder and Hoffmann (4311–4313)
1962 7 48 Kato and Shibayama (2044), P. Lorillard Co. R&D (2399), Rodgman and Cook (3286),
Schmeltz et al. (3488), Wynder and Hoffmann (4314), Yang and Wender (4377, 4378)
1963 17 65 Crouse et al. (851), Hoffmann et al. (1766), Hoffmann and Wynder (1791), Kato et al.
(2045), Laurene (2295, 2295a), Laurene et al. (2311, 2312), Lorentzen and Neurath (2397),
Osman et al. (2876), Rodgman and Cook (3286), Rodgman and Mims (3305), Spears
(3764, 3765), Unghvary et al. (3995), Wender and Yang (4163), Wynder and Hoffmann
(4317)
1964 17 82 Ehmke and Neurath (1115), Elmenhorst (1129), Esterle and Campbell (1164), Knoop and
Rosene (2142a), Mann et al. (2451), Oakley et al. (2820), Pyriki and Moldenauer (3043),
Rodgman and Cook (3286), Seehofer et al. (3574), Smith and King (3716, 3717)

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 494 The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-7
Tobacco Smoke Phenols Cataloged by Stedman (3797)
1. Acetic acid, 2-hydroxyphenyl- 28. Ethanone, 1-(2-hydroxyphenyl)- acetophenone, 2’-hydroxy-
2. Acetic acid, 3-hydroxyphenyl- 29. Ethanone, 1-(3-hydroxyphenyl)- acetophenone, 3’-hydroxy-
3. Acetic acid, 4-hydroxyphenyl- 30. Ethanone, 1-(4-hydroxyphenyl)- acetophenone, 4’-hydroxy-
4. Benzaldehyde, 3,4-dihydroxy- protocatechualdehyde 31. 1-Naphthalenol 1-naphthol
5. Benzaldehyde, 3,5-dimethoxy- syringaldehyde 32. 2-Naphthalenol 2-naphthol
4-hydroxy-
6. Benzaldehyde, 2-hydroxy- salicaldehyde 33. Phenol
7. Benzaldehyde, 3-hydroxy- 34. Phenol, 2,6-dimethoxy-
8. Benzaldehyde, 4-hydroxy- 35. Phenol, 2,3-dimethyl- 2,3-xylenol
9. Benzaldehyde, 4-hydroxy- vanillin 36. Phenol, 2,4-dimethyl- 2,4-xylenol
3-methoxy-
10. 1,2-Benzenediol catechol 37 . Phenol, 2,5-dimethyl- 2,5-xylenol
11. 1,3-Benzenediol resorcinol 38. Phenol, 2,6-dimethyl- 2,6-xylenol
12. 1,4-Benzenediol hydroquinone 39. Phenol, 3,4-dimethyl- 3,4-xylenol
13. Benzoic acid, 3,4-dihydroxy- protocatechuic acid 40. Phenol, 3,5-dimethyl- 3,5-xylenol
14. Benzoic acid, 3,5-dimethoxy- syringic acid 41. Phenol, 2-ethyl-
4-hydroxy-
15. Benzoic acid, 2-hydroxy- salicylic acid 42. Phenol, 3-ethyl-
16. Benzoic acid, 3-hydroxy- 43. Phenol, 4-ethyl-
17 Benzoic acid, 4-hydroxy- 44. Phenol, 2-methoxy- guaiacol
18. Benzoic acid, 3-hydroxy- isovanillic acid 45. Phenol, 2-methoxy-
4-methoxy-
19. Benzoic acid, 4-hydroxy- vanillic acid 46. Phenol, 4-methoxy-
3-methoxy-
20. 2H-1-Benzopyran-6-one, 6,7- esculetin 47. Phenol, 2-methoxy-4-(1-propenyl)- isoeugenol
dihydroxy-
21. 2H-1-Benzopyran-6-one, 7-hydroxy- scopoletin 48. Phenol, 2-methoxy-4-(2-propenyl)- eugenol
6-methoxy-
22. Cinnamic acid, 3,4-dihydroxy- caffeic acid 49. Phenol, 2-methyl- o-cresol
23. Cinnamic acid, 3,4-dihydroxy-, chlorogenic acid 50. Phenol, 3-methyl- m-cresol
3-ester with 1,3,4,5-tetrahydroxycy
clohexanecarboxylic acid
24. Cinnamic acid, 3,4-dihydroxy-, neochlorogenic acid 51. Phenol, 4-methyl- p-cresol
5-ester with 1,3,4,5-
tetrahydroxycyclohexane-
carboxylic acid
25. Cinnamic acid, 3,5-dimethoxy- sinapic acid 52. Phenol, 5-methyl-2-(1-methylethyl)- thymol
4-hydroxy-
26. Cinnamic acid, 4-hydroxy- coumaric acid 53. Phenol, 2,4,6-trimethyl- mesitol
27. Cinnamic acid, 4-hydroxy- ferulic acid 54. Propanoic acid, 3-hydroxyphenyl-
3-methoxy-
55. Propanoic acid, 4-hydroxyphenyl-

reported as tobacco smoke components by R.J. Reynolds
Tobacco Company R&D personnel and the identities of an
additional twenty-five phenolic smoke components reported
by others were confirmed.
As shown by the citations included in Table IX.A-8, the
Tobacco Chemists’ Research Conference over the years has
been a significant forum for the dissemination of new and
meaningful information pertinent to phenolic components in
tobacco smoke.
While the nature and levels of the low molecular weight
phenols in tobacco smoke were being defined in the late
1950s and early 1960s, additional research permitted the
identification of several more complex phenolic compo-
nents of tobacco smoke, for example, the naphthalenols by
Commins and Lindsey (789, 789a), hydroxybenzopyranones
such as scopoletin by Yang et al. (4373–4375) and Wender
et al. (4164), esculetin by Dietermann et al. (969), α-tocopherol
by Rodgman and Cook (3271), hydroxycinnamic acids by
Yang and Wender (4376), hydroxyphenylacetic acids by Yang
and Wender (4377) and Wender and Yang (4163), and sev-
eral hydroxybenzaldehydes by Yang and Wender (4379). In
contrast to the low molecular weight phenols, many of these
more complex phenols are also present at more than trace
amounts in tobacco. A series of low molecular weight, vola-
tile phenols were identified in the tobacco type Latakia by
Irvine and Saxby (1876, 1877a) at much greater levels than
volatile phenols are found in other tobacco types such as flue-
cured and burley.

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 Phenols and Quinones 495

Table IX.A-8
Presentations at Tobacco Chemists’ Research (TCRC) and Tobacco Science
Research Conferences (TSRC) on Phenolic Components of Tobacco Products
TCRC Investigator(s) TCRC Investigator(s)

• Isolation, Identification, Quantitation of Phenols in Tobacco Products

6th Rayburn (3089) 34th Carmella et al. (600)
12th Rowland (3347) 34th Schlotzhauer et al. (3462)
16th Davis and George (911a) 35th Carmella et al. (598)
16th Schmeltz et al. (3488) 36th Lee et al. (2329)
17th Burdick et al. (526) 36th Snook and Chortyk (3737)
18th Ayres and Thornton (127) 37th Carmella et al. (599)
18th Esterle and Campbell (1164) 39th Adams et al. (30)
18th Knoop and Rosene (2142a) 40th McWilliams et al. (2526)
18th Mann et al. (2451) 42nd Nanni et al. (2681a)
18th Rodgman and Cook (3280) 42nd Risner and Cash (3172)
19th Ayres and Thornton (128) 42nd Snook et al. (3754)
19th Spears et al. (3767) 43rd Risner and Cash (3174)
20th Kallianos et al. (2016) 45th Lee et al. (2330a)
20th Schlotzhauer et al. (3468) 46th Prakasch and Ireland (2983)
21st Kallianos et al. (2017) 46th Risner (3166)
22nd Benner et al. (276) 48th Wilson (4268)
22nd Leach and Alford (2321) 50th Green and Rodgman (1373)
23rd Benner et al. (275) 50th Risner (3170)
24th Miller et al. (2554) 51st Risner and Nelson (3170)
25th Singer and Hoffmann (3674) 51st Zhangyu et al. (4412)
27th Thacker and Martin (3894) 52nd Risner and Cash (3174)
28th Guerin et al. (1450) 53rd Forehand et al. (1213)
29th Newell et al. (2769) 54th Wooten et al. (4279)
29th Roberts and Watts (3228) 55th Li et al. (2361)
29th Schumacher et al. (3553) 55th Purkis et al. (3007)
30th Chamberlain et al. (664) 56th Honglin et al. (1825)
30th Kallianos (2614) 56th Reffick et al. (3093)
31st Hecht et al. (1561) 57th Volgger et al. (4067)
31st Schlotzhauer et al. (3474) 57th Warren (4137)
32nd Cornell et al. (828) 58th Hwang et al. (1854)
32nd Heckman and Best (1587) 58th Little et al. (2379)
32nd Snook et al. (3744) 58th Loureau et al. (2400a)
32nd Snook et al. (3746) 58th Sheng et al. (3646)
33rd Snook et al. (3751) 59th Hwang et al. (1853a)

• Precursor, Biological, and Other Studies on Phenols in Tobacco Products

19th Chortyk et al. (725a) 28th Hecht et al. (1582)
19th Spears et al. (3767) 29th Brunnemann et al. (496)
22nd Bell et al. (246) 31st Hardy and Hobbs (1501)
23rd Benner et al. (275) 37th Brunnemann et al. (499)
23rd Burton et al. (539) 48th Wilson (4268)
23rd Colucci et al. (783b) 50th Hu (1840a)
23rd Lakritz et al. (2253) 52nd Leffingwell and Alford (2339)
25th Rathkamp et al. (3087) 54th Doolittle et al. (1051)
26th Artho et al. (105) 59th Dyakonov et al. (1077a)
28th Baggett and Morie (156) 59th Hwang et al. (1853a)

Eventually, several hydroxyphenyl alcohols and hydroxy-
benzyl alcohols were identified in tobacco and tobacco
smoke by Hecht et al. (1561). These identifications were soon
followed by the identification of a series of phenolic acids
from tobacco by Snook et al. (3749, 3751). Table IX.A-5 sum-
marizes the studies on phenols in tobacco smoke up to 1964.
In Table IX.A-9, studies on phenols in tobacco smoke from
1964 to date are summarized.
IX.A.2 Bioassays to Determine the Contribution
of Phenols to Cigarette Smoke
Condensate Tumorigenicity
At several scientific meetings in the mid-1950s, Boutwell et
al. (414) described their preliminary findings on the promot-
ing effect of phenol on the specific tumorigenicity of 7,12-
dimethylbenz[a]anthracene (DMB[a]A) when the application

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 496 The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-9
Reports of Research Pertinent to Phenolic Compounds in Tobacco and Tobacco Smoke, 1964 to 2005
Year Investigator(s)

1964 Ehmke and Neurath (1115), Elmenhorst (1129), Esterle and Campbell (1164), Knoop and Rosene (2142a), Mann et al. (2451), Oakley et al.
(2820), Pyriki and Moldenauer (3043), Rodgman (3251), Rodgman and Cook (3286), Seehofer et al. (3574), Smith and King (3716, 3717),
Smith and Sullivan (3719), Testa et al. (3890), USPHS (3999), Wynder and Hoffmann (4319)

1965 Bock et al. (358), Chortyk et al. (725a), Cuzin et al. (884), Kaburaki et al. (1996, 1997), Kato et al. (2043, 2046), LeRoux (2351), Lipp (2374,
2376, 2377), Rodgman and Cook (3286), SEITA (3602), Smith and King (3718), Spears et al. (3767), Steck and Wender (3792), Steck et al.
(3793), Testa et al. (3891), Waltz and Häusermann (4121), Waltz et al. (4123, 4124), Wynder and Hoffmann (4330)

1966 Bell et al. (248), Chortyk et al. (726), Kallianos et al. (2016), Mokhnachev and Latayeva (2577), Mold et al. (2594), Müller and Moldenhauer
(2653), Schlotzhauer et al. (3468), Shamberger (3625), Touey and Kiefer (3937), Van Duuren et al. (4037)

1967 Hoffmann and Wynder (1797), Kallianos et al. (2017), Lyerly and Gilleland (2413a), Mokhnachev and Latayeva (2578), Müller and
Moldenhauer (2653), Schlotzhauer et al. (3468), Schmeltz et al. (3486), Wynder and Hoffmann (4332)

1968 Avetyam et al. (125), Bell et al. (246), Benner et al. (274), Chamberlain and Stedman (666), Colucci and Sizemore (783a), Dalhamn (891a),
Hoffmann and Wynder (1798), Irvine and Saxby (1876), Kaburaki et al. (1994, 1995), Kallianos et al. (2016), Leach and Alford (2321),
Schmeltz and Schlotzhauer (3497), Stedman (3797), Van Duuren et al. (4036), Wynder and Hoffmann (4342, 4346)

1969 Benner et al. (275, 276), Burton et al. (539), Colucci et al. (783b), Georgiev (1284a), Green et al. (1377, 1378), Grob and Völlmin (1427),
Irvine and Saxby (1877a), Lakritz et al. (2253), Leach et al. (2322), Wynder and Hoffmann (4344, 4346)

1970 Green et al. (1377), Grob and Völlmin (1426), Kaburaki et al. (2006), Kushnir et al. (2245), Laurene et al. (2306), Martin and Thacker (2478),
Miller et al. (2554), Reynolds (3111), Testa (3884), Viart (4050), Wynder and Hoffmann (4346a)

1971 Green and Schumacher (1375), Hoffmann and Wynder (1800), Kaburaki et al. (2005), Miller et al. (2554), Rathkamp et al. (3087), Royal
College of Physicians (3363), Shigematsu et al. (3650), Singer and Hoffmann (3674), Van Duuren et al. (4035)

1972 Artho et al. (105), Bock (352), Elmenhorst (1132), Hoffmann and Wynder (1802, 1803), Klimisch and Reese (2125), Schmeltz et al. (3499),
Schumacher et al. (3557), USPHS (4003)

1973 Baggett and Morie (155), Benner et al. (278), Derreux et al. (952), Diffee (970), Morie and Sloan (2635), Rathkamp et al. (3088), Thacker and
Martin (3894), Van Duuren et al. (4029)

1974 Akin and Chamberlain (39a), Baggett and Morie (156), Green and Best (1356), Guerin et al. (1449), Hecht et al. (1582), Heckman (1586),
Klus and Kuhn (2137), Lloyd and Miller (2387, 2388), Newell et al. (2767), Schmeltz et al. (3484), Schumacher et al. (3553)

1975 Baggett and Morie (156), Brunnemann et al. (496), Hecht et al. (1583), Malaterre et al. (2447), Newell et al. (2769, 2777), Roberts and Watts
(3228), Schmeltz et al. (3484), Schumacher et al. (3553)

1976 Best et al. (312), Brunnemann et al. (497), Chamberlain et al. (664), Green et al. (1375b), Hoffmann et al. (1780), Ishiguro et al. (1878a,
1879, 1886), Kallianos (2014), Kensler (2082), Mauldin (2506), Miller et al. (2543), Moates (2570), Newell et al. (2761, 2762, 2765, 2766),
Patterson et al. (2904), Sakuma et al. (3395), Testa and Hys (3892), Van Duuren and Goldschmidt (4028)

1977 Brunnemann et al. (514), Hardy and Hobbs (1501), Harrell (1530), Hecht et al. (1561), Schlotzhauer et al. (3474), Schmeltz and Hoffmann
(3491), Schmeltz et al. (3512), Schumacher et al. (3553), Walters (4113)

1978 Chamberlain et al. (663), Cornell et al. (828), Green et al. (1371), Hecht et al. (1561), Heckman and Best (1587), Ishiguro and Sugawara
(1881–1883), Newell et al. (2769), Schlotzhauer (3447), Schlotzhauer et al. (3474), Snook et al. (3744, 3746, 3753), Van Duuren et al. (4038)

1979 Chamberlain et al. (652), Green et al. (1367), Schmeltz et al. (3512), Snook and Fortson (3745), Snook et al. (3751), USPHS (4005)

1980 Ishiguro and Sugawara (1884), Martin and Gilleland (2476), Mokhnachev and Mironenko (2579), Sakuma et al. (3402), Schlotzhauer et al.
(3452), Snook et al. (3747), Van Duuren (4026), Wattenberg et al. (4149c)

1981 Hecht et al. (1562), Heckman and Best (1587), Morée-Testa (2615), Schlotzhauer and Chortyk (3453), Shelar and Colby (3641–3643), Snook
et al. (3748, 3749), USPHS (4009)

1982 Hwang et al. (1854a), Sakuma et al. (3400), Schlotzhauer et al. (3462), Snook and Chortyk (3737, 3738), USPHS (4010)

1983 Brunnemann et al. (499), Hoffmann et al. (1736), Yoshida and Fukuhara (4386)

1984 Adams et al. (28), Jeanty et al. (1926)

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 Phenols and Quinones 497

Table IX.A-9 (Continued)

Reports of Research Pertinent to Phenolic Compounds in Tobacco and Tobacco Smoke, 1964 to 2005
Year Investigator(s)

1985 Adams et al. (30), Eaker and Hutcherson (1091), Eble et al. (1105), Sakuma et al. (3392), Snook et al. (3743)

1986 Grimmer et al. (1409), IARC (1871), LaVoie et al. (2314a, 2314b), McWilliams et al. (2526), Risner (3159)

1987 Adams et al. (31), Grimmer et al. (1409), Melikian et al. (2527f)

1988 Nanni et al. (2681), Risner (3161), Risner and Cash (3171, 3172)

1989 Melikian et al. (2527c, 2527d), Risner and Cash (3173, 3174), Schmidt and Hecker (3519a), Snook et al. (3754)

1990 Martin et al. (2480), Melikian et al. (2527g), Nanni et al. (2681), Risner and Cash (3173)

1991 Risner (3165)

1992 Prakash and Ireland (2983), Risner (3166), Zhao and Zhou (4414)

1994 Risner et al. (3168), Wilson (4268)

1996 Green and Rodgman (1373), Hu (1840a), Risner (3170)

1997 Borgerding et al. (420), Risner and Nelson (1970), Zhangyu et al. (4412)

1998 Hecht et al. (1572), Hoffmann and Hoffmann (1741), Leffingwell (2339), Nelson et al. (2691)

1999 Baker (172), Forehand et al. (1213), Hirose et al. (1656a), Leffingwell (2338), Omori et al. (2857),

2000 Fowles et al. (1217), Hajaligol and Fisher (1485), Wooten et al. (4279)

2001 Hoffmann and Hoffmann (1743), Li et al. (2361), Wooten et al. (4277)

2002 Carmines (603), Lauterbach (2313a), Reddick et al. (3093), Smith et al. (3712)

2003 Chen and Moldoveanu (688), Dagnon and Edreva (890), Volgger et al. (4067), Warren (4137)

2004 Gregg et al. (1386), Hwang et al. (1854), Little et al. (2379), Loureau et al. (2400a), Zha and Moldoveanu (4407)

2005 Little et al. (2379a), Uchii and Sato (3990a)

2006 Larkins (2262a)

of the PAH to mouse skin was followed by an application
of phenol. Subsequently, Boutwell and Bosch (414) reported
that phenol and many substituted phenols enhanced or pro-
moted the specific tumorigenicity of PAHs. However, they
reported that 1,2-benzenediol (catechol) exhibited no tumor-
promoting activity. Later, 1,2-benzenediol (catechol) was
found to be the most plentiful low molecular weight phenol
in cigarette MSS [Kallianos et al. (2016), Schlotzhauer et
al. (3462), Schlotzhauer and Chortyk (3453), Morée-Testa
(2615), Risner and Cash (3171–3174), Risner (3165),] and was
reported [Van Duuren et al. (4029)] to be a cocarcinogen for
PAHs, not a promoter.
Coincident with the phenol studies of Boutwell et al. (414)
and during the time that much effort was being expended to
resolve the question about the presence of PAHs in tobacco
smoke, Gwynn and Salaman (1463b) reported the promoting
effect of CSC.
Two years later, Gellhorn (1281) reported that whole CSC
acted as a promoting agent for several tumorigenic PAHs
applied to mouse skin.
The next year, Roe et al. (3314) reported that the phenolic
fraction from CSC exerted a significant promoting effect on
the specific tumorigenicity of PAHs. They theorized:
Cigarette smoke condensate may be richer in tumour-pro-
moting substances than in tumour-initiating substances.
Phenolic compounds may be responsible for much of its pro-
moting activity.
As noted previously, Wynder and Hoffmann (4307),
unable to explain the bioassay (skin painting) results with
CSC on the basis of either its B[a]P content (less than 2%
tumor-bearing animals explainable) or its total tumorigenic
PAH content (less than 3% tumor-bearing animals explain-
able), added the concept of promotion, particularly that
attributed to low molecular weight phenols, in an attempt
(unsuccessful) to explain the bioassay results in laboratory
animals. They amplified their theory in a more detailed
publication (4307). They also stated (4308) that the higher
molecular weight PAHs played an important role in the
carcinogenicity to mouse skin of CSC but when the vari-
ous known concentrations of the carcinogenic PAHs as

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 498 The Chemical Components of Tobacco and Tobacco Smoke

estimated in CSC were summed, it was obvious that these
smoke components acting either individually or in concert
could not account for the established carcinogenicity to
mouse skin of the CSC nor of its isolated PAH fraction.
Because of the inability to explain the mouse skin-painting
bioassay results with CSC on the basis of its PAH content and
because of the presumed biological relationship between the
phenol fraction and/or its individual components and the PAH
fraction and/or its individual components, the findings reported
by Boutwell et al. (414), Gwynn and Salaman (1463b), Gellhorn
(1281), and Roe et al. (3314) stimulated extensive research on
the nature and levels of the phenols in cigarette MSS in the late
1950s to early 1960s. Over the next few years, the results from
different laboratories of the bioassays involving tobacco smoke
phenols varied considerably. The variations raised the ques-
tion as to whether the relationship between the tobacco smoke
phenols and PAHs was one of promotion, cocarcinogenesis,
inhibition, or anticarcinogenesis.
From the results of their studies on the administration of
B[a]P plus phenol and the administration of DMB[a]A plus
phenol, Wynder and Hoffmann (4313) concluded:
[Our results] show that promoting substances present in
tobacco smoke can increase and accelerate the tumor yield of
carcinogenic polynuclear hydrocarbons that by themselves
are not present in sufficient concentration to yield any tumors
or yield them only after a prolonged latent period.
In 1958, Wynder et al. (4355) proposed the use of the level
of B[a]P in CSC as an “indicator” or “marker” of the specific
tumorigenicity (mouse skin) of CSC as well as an “indicator”
or “marker” of its levels of tumorigenic PAHs with four or
more rings. When the low molecular weight phenols in tobacco
smoke attracted considerable attention because of their claimed
contribution to the specific tumorigenicity of CSC, Hoffmann
et al. (1766) and Wynder and Hoffmann (4317) extended the
“indicator” concept to phenol, designating it as an “indicator”
or “marker” for the promoting low molecular weight volatile
phenols in cigarette MSS. Just as the concept of B[a]P as an
“indicator” or “marker” of CSC specific tumorigenicity and
tumorigenic higher PAHs content was subsequently shown to
be incorrect, so was the concept of phenol as an “indicator” or
“marker” of phenols-induced promoting activity of CSC and
promoting phenols content shown to be incorrect. The phenol
“indicator” situation is discussed below.
Table IX.A-10 summarizes some of the diversity observed
in the bioassay results on the properties pertinent to the tum-
origenicity of PAHs of several phenol components of tobacco

Table IX.A-10
Variation in Bioassay Results with Phenols or Phenol-Containing Materials
Effect on Specific Tumorigenicity of Polycyclic Aromatic Hydrocarbons
Phenol Promotion Cocarcinogenicity Inhibition or Anticarcinogenesis
CSC a yes:
Gwynn and Salaman, (1463b),
Gellhorn (1281)
Phenolic fraction from CSC a yes:
Roe et al. (3314)

Phenols yes:
Boutwell et al. (414)
Phenol yes: no: yes:
Wynder and Hoffmann, Van Duuren et al. (4029) Van Duuren et al. (4029, 4035)
(4313, 4317), Hoffmann and
Wynder (1791), Hoffmann et al.
(1736)
1,2-Benzenediol no: yes:
{catechol} Van Duuren and Goldschmitt Van Duuren et al. (4029), Van
(4028) Duuren and Goldschmitt (4028),
Hecht et al. (1562), Hoffmann
et al. (1736)
1H-1-Benzopyran-6-ol, 3,4-
dihydro-2,5,7,8-tetramethyl-2-
(4,8,12-trimethyltridecyl)-
{α-tocopherol} yes:
Shamberger (3625), Slaga and Bracken
(3684), Viaje et al. (4049a), Shklar
(3655a), Weerapradist and Shklar
(4159a), Toth and Patil (3927a),
Mirvish (2559b)
a CSC = cigarette smoke condensate

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 Phenols and Quinones 499
smoke (phenol, catechol, and α-tocopherol), the phenolic
fraction from CSC, and CSC itself.
Although much attention and effort were devoted to the
supposed deleterious effects of various tobacco smoke com-
ponents such as the PAHs, the aza-arenes, and the low molec-
ular weight phenols, very little was reported about the tobacco
smoke components with properties that offset the supposed
tumorigenicity or promoting effects of the compound classes
mentioned. One of the first examples of cigarette MSS com-
ponents inhibiting the action of a “tumorigen” was described
by Wynder and Hoffmann (4311). This finding was an out-
growth of their studies on the effect of organic solvent extrac-
tion of tobacco on the PAH content of the extracted tobacco
smoke. Lam (2255) and Wynder (4294) in the mid-1950s
proposed that the precursors in tobacco of PAHs in ciga-
rette MSS were the saturated aliphatic hydrocarbons; Wright
(4282a) and Wynder et al. (4355, 4356) proposed the phyto-
sterols as the PAH precursors, and Wright (4282) also pro-
posed the terpenoid compounds as major PAH precursors.
These compounds are removable almost totally or to a sub-
stantial degree by extraction of tobacco with organic solvents
such as hexane or pentane. Cigarettes fabricated from the
extracted tobacco yielded lower quantities in MSS of PAHs
such as B[a]P that were known under certain laboratory con-
ditions to produce tumors on the shaved backs of susceptible
strains of mice. Skin-painting studies with mainstream CSC
collected by smoking cigarettes made with the control and
extracted tobaccos gave a lower percentage of TBA in the
extracted tobacco CSC group. However, the decrease in %
TBA was much less than the percent decrease in the level
in the CSC of tumorigenic PAHs such as B[a]P (4282, 4294,
4307, 4355, 4356).
One explanation for this difference was that the solvent
extraction removed nearly all the aliphatic saturated hydro-
carbons from the tobacco and, thus, they were either absent
from the MSS from the extracted-tobacco cigarettes or present
at extremely low levels. Wynder and Hoffmann [see pp. 330–
331 in (4319) and pp. 370–371 in (4332)] reported that this
aliphatic saturated hydrocarbon fraction (constituting about
3% of the mainstream CSC) inhibited the activity of tum-
origenic PAHs, including B[a]P. The components in the ali-
phatic hydrocarbon fraction ranged from pentadecane (C15)
to pentatriacontane (C35). Each hydrocarbon was present as
the normal, iso, and anteiso isomers. The C27 to C33 hydro-
carbons constituted about 80% of the saturated hydrocarbon
fraction; with C31 (n-hentriacontane) and C33 (n-tritriacontane)
hydrocarbons usually being the most plentiful components
in the fraction. Subsequent study with improved analytical
methodology demonstrated the presence of trace amounts of
additional isomeric aliphatic saturated hydrocarbons with as
many as forty carbons.
Studies with B[a]P and the C31 and C35 saturated hydro-
carbons (SHC), where the SHC:B[a]P ratio was 200:1 and 100:1,
showed that both saturated hydrocarbons exerted a significant
inhibiting effect at both levels on the specific tumorigenicity of
B[a]P in mouse skin-painting experiments [4311, 4314, see also
pp. 330–331 in (4319) and pp. 370–371 in (4332)].
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78836_C009.indd 499
When the saturated hydrocarbon content (normally
about 3% of the particulate phase) of mainstream CSC was
increased from 3% to 4% (an overall 33% increase) by addi-
tion of the saturated hydrocarbon fraction isolated from CSC,
the specific tumorigenicity of the CSC decreased, the % TBA
decreased from 40% to 24%. The MSS of a cigarette deliver-
ing 20 mg of CSC contains about 0.6 mg (600,000 ng) of this
saturated hydrocarbon fraction and 10 ng of B[a]P, an SHC:
B[a]P ratio of 60,000:1, far in excess of the 200:1 or 100:1
SHC: B[a]P ratio that produced the significant inhibition of
the specific tumorigenicity of B[a]P reported in the mouse
skin-painting bioassay (4314, 4319, 4332).
Other MSS components may have also influenced the PAH
and mouse skin-painting results obtained with control tobacco
CSC vs. the CSC from organic solvent-extracted tobacco. The
extraction of tobacco with a solvent such as hexane not only
removed the saturated aliphatic hydrocarbon inhibitors from
the tobacco, thus making impossible their transfer to MSS
when such tobacco is smoked, but also removed other com-
ponents such as β-sitosterol (4356), α-tocopherol (vitamin E)
(3271, 3347), indole (3279), and α- and β-4,8,13-duvane-1,3-
diol (3221, 3361, 3389), thus preventing their transfer to MSS
during the smoking process. Subsequently, these tobacco com-
ponents, now known to transfer from the tobacco rod to MSS
during the smoking process and presumably to sidestream
smoke (SSS) during cigarette smolder, have been shown to
behave as anticarcinogens for several of the reported tobacco
smoke “tumorigens,” such as the PAHs, the N-nitrosamines,
and ethyl carbamate. Neither the presence of several of these
tobacco and MSS components nor their anticarcinogenic or
inhibitory activity vs. known tumorigens was known in the
late 1950s or early 1960s.
Despite the emphasis on the contribution of CSC components
to its specific tumorigenicity when administered to laboratory
animals via skin painting, the inhibition of tumorigenesis by
CSC and several of its components was not completely ignored
during the 1960s. In addition to the role of saturated aliphatic
hydrocarbons in the inhibition of the specific tumorigenicity of
CSC reported by Wynder and Hoffmann [4311, 4314, see also
pp. 330–331 in (4319) and pp. 370–371 in (4332)], other studies
pertinent to the antitumorigenicity of tobacco smoke included
an earlier one in 1958 by Hoffman and Griffin (1672a) plus
later ones in the mid-1960s by Homburger and his colleagues
(1823, 1823b, 1824) as well as one reported in the late 1970s by
Chamberlain et al. (663) at the USDA.
Comparison of the list of the 5200 or so identified compo-
nents in tobacco smoke with extensive lists presented by Fay
et al. (1177a) and Slaga and DiGiovanni (3685) of compounds
and elements reported to possess inhibitory or anticarcino-
genic action in carcinogenesis-type experiments in laboratory
animals reveals not only that tobacco smoke contains numer-
ous anticarcinogens but also that the levels in tobacco smoke
of many of them far exceed those of the levels of the reported
tobacco smoke “tumorigens” (3255a). The levels of many of
the anticarcinogens in tobacco smoke vs. those of the reported
smoke “tumorigens” are far in excess of the ratio needed for
the anticarcinogenicity to be effective. Table IX.A-11, adapted
11/13/08 5:22:39 PM
 500 The Chemical Components of Tobacco and Tobacco Smoke
Table IX.A-11
Inhibitors and Anticarcinogens in Tobacco Smoke
Tobacco Smoke Component Class (examples)
Hydrocarbons, saturated (e.g., C31H64, C35H72)
Hydrocarbons, unsaturated (D-limonene)
Hydrocarbons, monocyclic aromatic (benzene)
Hydrocarbons, aromatic, polycyclic (naphthalene, anthracene, phenanthrene,
fluoranthene, pyrene, benzo[e]pyrene, benzo[b]triphenylene)
Lactones (coumarin, α-angelica lactone)
Alcohols (ethanol, n-butanol, tert-butanol, cholesterol, β-sitosterol,
α- and β-4,8,13-duvane-1,3-diol
Purines (caffeine, theobromine)
Indoles (indole, indole-3-acetonitrile)
Miscellaneous components (maleic anhydride, aconitic acid, selenium,
carbon disulfide)
Phenols (phenol, caffeic acid, ferulic acid, gallic acid; 2-hydroxycinnamic
acid; 4-methoxyphenol; α-tocopherol) (see Table IX.A-9)
a NNK = 4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone
b NNN = N’-nitrosonornicotine
from Rodgman (3255a), lists tobacco smoke components
reported to be inhibitory or anticarcinogenic to several of the
“tumorigens” reported to be present in tobacco smoke.
Hoffmann et al. (1766) reported that the results from
their study of the levels of several selected components in
the MSSs from different tobacco products gave suggestive
support to the hypothesis that B[a]P and phenol may serve as
“indicators” of the specific tumorigenic activities (initiation,
promotion) of tobacco “tars.” During the next decade, the
hypothesis that phenol was an “indicator” of the low molecu-
lar weight, promoting phenols was reiterated numerous times
by Wynder and Hoffmann (4319, 4330, 4332, 4342, 4344,
4346, 4346a). However, as research on the biological effects
of phenols in tobacco smoke escalated, it became obvious
that the promoting effect of the low molecular weight phenols
on the specific tumorigenicity of PAHs in tobacco smoke was
not as definitive as Wynder and Hoffmann and other investi-
gators asserted. The discovery that a large percentage of the
volatile phenols are removed from MSS by the plasticized
filter tip led to differences of opinion on the promoting action
of the volatile phenols.
Numerous statements in Hoffmann-Wynder presentations
and publications described their conclusions with respect to
volatile phenols removal vs. tumorigenicity of the phenols-
depleted CSC. Examples of their statements follow.
In their 1967 book, Wynder and Hoffmann [(4340), see
p. 626 in (4332)] stated:
It should be noted, however, that a reduction of phenols in
tobacco smoke condensate has not led to a concomitant
reduction of tumorigenicity in the corresponding “tars.”
In 1968, Wynder and Hoffmann (4342) again discussed phe-
nols as promoters:
© 2009 by Taylor & Francis Group, LLC
78836_C009.indd 500
Tumorigen Suppressed
B[a]P
NNKa, dibenzo[a,i]pyrene
B[a]P, DB[a,h]A
B[a]P, DB[a,h]A, DMB[a]A
B[a]P, DMB[a]A
NNNb, DMB[a]A
ethyl carbamate, N-nitrosamines, DMB[a]A
B[a]P
B[a]P, DMB[a]A, 1,2-dimethylhydrazine
B[a]P, N-nitrosamines, 1,2-dimethylhydrazine, DMB[a]A, 1,2-dihydro-
3-methylbenz[e]aceanthrylene (3-methylcholanthrene)
Volatile phenols represent one type of tumor promoter in
tobacco smoke. In mouse-skin carcinogenesis, however, they
evidently do not play an essential role as such, since a sig-
nificant reduction of phenols in the smoke condensate is not
accompanied by a similar reduction in carcinogenic activity
of the “tar” [4332].
A year later, Wynder and Hoffmann [see p. 298 in (4344)]
wrote:
The only known group of promoters in tobacco smoke are
the volatile phenols. Their reduction of up to 80% by selec-
tive filtration, however, did not lead to a reduction of tumor
promoting activity.
In the same article, they added [p. 299 in (4344)]:
A reduction of phenol in tobacco smoke through the use of
filters, however, does not alter the complete tumorigenic
activity of “tar” obtained from such cigarettes. This infers
that a selected reduction of volatile phenols will not reduce
the tumor-promoting activity of such “tar.”
In the written introduction to their presentation at the 28th
TCRC in 1974, Hecht et al. (1582) stated the following and
cited Wynder and Hoffmann (4332) as their source:
Phenol and some substituted phenols are weak promoters,
but they alone contribute only a small part of the promot-
ing activity, since selective filtration of phenol does not
change significantly the biological activity of the resulting
condensate.
In their discussion of tumor promoters and the complexity
of CSC, Van Duuren et al. (4035) reported:
Phenol, which is a weak tumor-promoting agent, is indeed
an inhibitor of tumorigenesis when applied simultaneously
with benzo[a]pyrene.
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 Phenols and Quinones 501

Table IX.A-12
Tobacco Smoke Phenols with Anticarcinogenic or Antipromoting Properties
Phenolic Smoke Component
Benzoic acid, 3,4,5-trihydroxy- {gallic acid}
1H-1-Benzopyran-6-ol, 3,4-dihydro-2,5,7,8-
tetramethyl-2-(4,8,12-
trimethyltridecyl)- {α-tocopherol}
Phenol
Phenol, 4-methoxy-
2-Propenoic acid, 3-(3,4-dihydroxyphenyl)-,
cis-{cis-caffeic acid}
2-Propenoic acid, 3-(3,4-dihydroxyphenyl)-,
trans-{trans-caffeic acid}
2-Propenoic acid, 3-hydroxy-4-methoxy-
phenyl)-, trans- {ferulic acid}
Reference to Identification Reference to Anticarcinogenesis (AC)
in Tobacco Smoke or Antipromotion (AP)
Kröller (2195) (AC) Mirvish et al. (2559c)
Rodgman and Cook (3271, 3286), (AC) Shamberger (3625), Slaga and Bracken
Rodgman (3251) (3684), Viaje et al. (4049a), Shklar (3655a),
Weerapradist and Shklar (4159a), Toth and
Patil (3927a), Mirvish (2559b)
Vohl and Eulenberg (4065), Ludwig (2408), (AP) Van Duuren et al. (4035)
Ikeda (1857)
Spears (3764) (AC) Wattenberg et al. (4149c)
Yang et al. (4376), Yang and Wender (4377), (AC) Wattenberg et al. (4149c), Wattenberg
Wender and Yang (4163) (4149b)
Yang et al. (4376), Yang and Wender (4377), (AC) Wattenberg et al. (4149c), Wattenberg
Wender and Yang (4163) (4149b)
Yang and Wender (4377) (AC) Wattenberg (4149b)

Van Duuren et al. also noted that rutin, a tobacco com-
ponent, also inhibited B[a]P carcinogenesis in the mouse
skin-painting bioassay. From the results of their biological
experiments on cocarcinogenesis (simultaneous and repeated
application of an agent, in this case 1,2-benzenediol [cate-
chol]), with B[a]P, Van Duuren et al. (4029) deduced that 1,2-
benzenediol (catechol) showed remarkable cocarcinogenic
activity with B[a]P. They reported:
Phenol has been regarded as an important “tumor promoter”
in cigarette smoke condensate … [but our] work indicates
it is inactive in cocarcinogenesis and, indeed, has a slightly
inhibitory effect on benzo[a]pyrene carcinogenesis.
Later, Van Duuren and Goldschmidt (4028) demonstrated
the cocarcinogenicity of 1,2-benzenediol (catechol) when
applied as a 2% solution to mouse skin three times weekly
with a solution of 0.005% B[a]P. They contrasted the remark-
able cocarcinogenic activity of 1,2-benzenediol (catechol)
with its inactivity as a tumor promoter for B[a]P.
Hecht et al. (1562) described the importance of 1,2-ben-
zenediol (catechol) as a tobacco smoke cocarcinogen. They
also noted that the levels of 1,2-benzenediol (catechol) in
MSS was reduced by prior extraction of the tobacco with
hexane-ethanol or by inclusion of reconstituted tobacco sheet
(RTS) in the tobacco blend.
While Wynder and Hoffmann wrote at length about the
promoting effect of low molecular weight phenols and the
phenol fraction of CSC on PAH tumorigenicity, it is interest-
ing to note their change in emphasis in 1986. In a 1986 article
(1808), the Hoffmann-Wynder discussion dealt primarily
with the nature of tumor initiators (PAHs) and cocarcinogens
(catechols), with no mention of the phenolic promoters they
had discussed repeatedly for more than two decades since the
early 1960s! In that same year, the IARC published its mono-
graph on tobacco smoking to which Wynder and Hoffmann
had contributed substantial information on tobacco smoke
chemistry. In its monograph, IARC defined the phenols as
a major group of promoting agents in tobacco smoke (1870),
but IARC made no mention of the Wynder-Hoffmann obser-
vation of a lack of effect on specific tumorigenicity of the
almost complete removal of the phenols from MSS.
Although much was written during the 1950s, 1960s, and
1970s about the supposed adverse effect, that is, the promot-
ing effect of phenolic compounds in tobacco smoke on its
specific tumorigenicity in laboratory animals, significant
properties, for example, their anticarcinogenicity and/or anti-
promoting effects, of several specific tobacco smoke phenols
have generally been overlooked. Phenolic compounds in
tobacco smoke known to possess either of these properties
are listed in Table IX.A-12.
In addition to the known antitumorigenic and antipromot-
ing effects of CSC and several specific components in it, it
has also been shown by Lee et al. (2327a, 2327b, 2337c) that
cigarette MSS possesses antimutagenic properties that offset
the mutagenicity in the Ames test (Salmonella typhimurium)
of several N-nitrosamines and several of the N-heterocyclic
amines defined as “cooked food” mutagens.
IX.A.3 Determination of the Nature of
the Precursors in Tobacco of the
Phenols in Mainstream Smoke
Resolution of the question of the presence of tetracyclic and
higher PAHs, particularly B[a]P, in tobacco smoke was fol-
lowed chronologically by studies to determine the source
of the PAHs in tobacco smoke. When the PAH-containing

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 502 The Chemical Components of Tobacco and Tobacco Smoke
environmental pollutants from lighting sources (matches,
hydrocarbon-fueled cigarette lighters, etc.) were discarded
in the early 1950s as significant contributors to the PAHs
in tobacco smoke, particularly cigarette MSS, the contribu-
tion of tobacco itself to the PAHs in smoke was questioned:
What were the components in tobacco that, during the
smoking process, could act as significant precursors of the
PAHs in its smoke? The investigation sequence was essen-
tially the same with the reported tumorigenic aza-arenes
in tobacco smoke. Initially, the identifications of the aza-
arenes were resolved. Subsequently, studies were conducted
to define the precursors in tobacco of the aza-arenes identi-
fied in tobacco smoke. As noted previously, however (see
Table IX.A-1 and accompanying text), the results reported
on numerous studies between 1963 and 1992 have raised
other serious questions concerning the presence of the
aza-arenes dibenz[a,h]acridine, dibenz[a,j]acridine, and
7H-dibenzo[c,g]carbazole in tobacco smoke and their sup-
posed generation from nicotine.
The difference in the levels of simple phenols in tobacco
smoke vs. their levels in the major tobacco types (flue-cured,
burley, Maryland tobaccos), which collectively constitute the
major proportion of American cigarette tobacco blends, sug-
gested that the simple phenols in cigarette MSS were present
not as a result of their significant direct transfer per se from
the tobacco but as a result of their pyrosynthesis from pre-
cursors comprising one or more tobacco components. Long
before the concern expressed that the simple phenols pos-
sessed promoting activity that enhanced the tumorigenicity
of tumorigenic PAHs (414) and the concern expressed by
Roe et al. (3314) and Wynder and Hoffmann (4307) about the
presence of the simple phenols in tobacco smoke, Wenusch
(4202) had suggested that the major sources in tobacco of the
tobacco smoke phenols were its lignin and complex carbohy-
drate and polyphenol components.
In contrast to flue-cured, burley, and Maryland tobaccos,
highly aromatic tobaccos such as Latakia were reported
to contain significant levels of free simple phenols (1876,
1877a). As the complexity of the phenols increased, the like-
lihood of their presence in tobacco increased and many were
found in smoke as a result of direct transfer, for example, the
high molecular weight phenol, 3,4-dihydro-2,5,7,8-tetram-
ethyl-2-(4,8,12-trimethyltridecyl)-1H-1-benzopyran-6-ol
(α-tocopherol), first identified as a tobacco leaf component
by Rowland (3347) and as a tobacco smoke component by
Rodgman and Cook (3271), 6,7-dihydroxy-2H-1-benzopy-
ran-6-one (esculetin) identified in tobacco and its smoke
by Dieterman et al. (969). In the early 1960s, Herrmann
(1625, 1626) reviewed various studies on the phenols, phe-
nolic acids, and related compounds identified in tobacco and
tobacco smoke.
Examination of the chronology of the investigation of
phenolic components of tobacco smoke reveals an interest-
ing situation. In the early 1960s, substantial research was
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78836_C009.indd 502
conducted on the phenols in tobacco smoke, their identifica-
tion, their quantitation, and their major precursors in tobacco.
When the promoting effect of the low molecular weight
monohydric phenols was seriously questioned, the effort on
phenols waned for some years but accelerated again when
the claims on the co-carcinogenicity of the dihydric phenols,
particularly 1,2-benzenediol (catechol), surfaced. This situa-
tion triggered examination of the levels of the benzenediols
in tobacco smoke and their possible precursors in tobacco.
Table IX.A-13 summarizes some of the studies conducted to
define the nature of the major precursors in tobacco of the
phenolic components of tobacco smoke.
Zane and Wender (4403) described their pyrolysis (pyroly-
sis temperature that of a Bunsen burner flame) of the tobacco
components rutin, quercitin, and chlorogenic acid. In addition
to nonphenolic compounds, each pyrolysate was reported to
contain 1,2-benzenediol (catechol) with lesser amounts of
4-methyl-1,2-benzenediol, 1,3-benzenediol (resorcinol).
The amounts of phenol and 4-methylphenol (p-cresol) in
the pyrolysates obtained under various conditions from sev-
eral major tobacco components (cellulose, pectin, and lignin),
a tobacco additive (invert sugar), several individual tobacco
types (flue-cured tobacco, cased burley tobacco, Maryland
tobacco), and a tobacco substitute (spinach) were reported by
Rodgman and Mims (3305) and Rodgman and Cook (3286).
Table IX.A-14 summarizes the results.
Spears et al. (3767) and Bell et al. (248) determined the
generation of phenol when flue-cured and burley tobaccos
and various tobacco components (glucose, sucrose, starch,
cellulose, and pectin) were pyrolyzed at various temperatures
in an air or nitrogen atmosphere. In each instance, phenol
was generated.
In their study of tobacco lignin as a phenols precursor,
Kato et al. (2043) examined the residue resulting from heating
tobacco stalk lignin at 450 to 500°C for two hours. They iden-
tified the following phenols: phenol, 2-methoxyphenol (gua-
iacol), 2-methylphenol (o-cresol), 3-methylphenol (m-cresol),
4-methylphenol (p-cresol). Kato et al. (2046) also conducted
a comparative thermal analysis of tobacco stalk-derived cel-
lulose, holocellulose, and lignin subjected to similar heating.
In a continuation of the pyrolysis study by Chortyk
et al. (725a, 726) on the possible contribution of the tobacco
pigment to the PAH content of tobacco smoke composition,
Schlotzhauer et al. (3468) examined the pyrogenesis of phe-
nols from high molecular weight components of tobacco,
specifically the tobacco pigment and the biopolymers lignin,
cellulose, and pectin. They (3468) reported that the phenol
amounts (phenol, 3- and 4-methylphenol [m- and p-cresol])
found in the pyrolysates from Oriental tobacco and the high
molecular weight tobacco components (pigment, lignin, pectin,
and cellulose) pyrolyzed at 700°C/nitrogen atmosphere were
generated in the following sequence:
Oriental tobacco > pigment > lignin ≥ pectin >> cellulose
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 Phenols and Quinones 503

Table IX.A-13
Precursors in Tobacco of Phenols in Tobacco Smoke
Tobacco Smoke Phenol Tobacco Leaf Precursor References



 lignin Rodgman and Mims (3305), Kato et al. (2043, 2046), Schlotzhauer et al. (3456, 3462,
3468), Higman et al. (1647), Carmella et al. (598)



 sugars Spears et al. (3767), Bell et al. (248), Higman et al. (1647), Carmella et al.
(598, 602), Schlotzhauer et al. (3462)
Phenol 

Methylphenols {cresols} 


 polysaccharides (cellulose, Kato et al. (2043, 2046), Spears et al. (3767), Bell et al. (248), Schlotzhauer et al.
starch, pectin) (3456, 3462, 3468), Higman et al. (1647), Brunnemann et al. (496, 497), 1975,
1976, Carmella et al. (598, 601, 602)

Dimethylphenols {xylenols}  protein Higman et al. (1647)

Benzenediols {catechol,  amino acids Higman et al. (1647)
resorcinol, hydroquinone}  



 extracted tobacco Rodgman and Cook (3277), Rodgman and Mims (3305), Severson et al. (3616),
Carmella et al. (600), Schlotzhauer et al. (3453, 3462)

 tobacco pigment Schlotzhauer et al. (3468)


 tobacco extracts Schlotzhauer et al. (3456), Severson et al. (3616)




 rutin Zane and Wender (4403), Spears et al. (3767), Bell et al. (248), Brunnemann et al.
(496, 497), Carmella et al. (598), Schlotzhauer et al. (3462)

 quinic acid a Ayres and Thornton (127a)

 chlorogenic acid Zane and Wender (4403), Brunnemann et al. (496, 497), Carmella et al. (598, 600,
602), Schlotzhauer et al. (3462)
a Quinic acid = 1,3,4,5-tetrahydroxycyclohexanecarboxylic acid
b Chlorogenic acid = 3-(3,4-dihydroxyphenyl)-2-propenoic acid, 3-ester with 1,3,4,5-tetrahydroxycyclohexanecarboxylic acid

In a study of the effect of steady-state pyrolysis of tobacco vs.
pulsed pyrolysis simulating the puffing sequence in a smoked
cigarette, Patterson et al. (2904) reported that the pulsed pyrol-
ysis procedure gave much higher levels of the low molecular
weight phenols (phenol, 2-, 3-, and 4-methylphenol [o-, m-,and
p-cresol], 2-, 3-, and 4-ethylphenol, 2,4-, and 2,5-dimethylphe-
nol [2,4- and 2,5-xylenol], and 2-methoxyphenol [guaiacol]) in
the pyrolysate than did the steady-state pyrolysis.
The report of the significant cocarcinogenicity of 1,2-ben-
zenediol (catechol) by Van Duuren and Goldschmidt (4028)

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 504 The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-14
Pyrolysis of Tobacco, Tobacco Components, and Spinach: Phenol Content
of Pyrolysate
Phenol, µg/g Pyrolyzed
Material Pyrolyzed Atmosphere T°C Phenol 4-Methylphenol (p-Cresol)

Individual Component
Cellulose nitrogen 550 460 215
Cellulose nitrogen 650 350 110
Pectin nitrogen 550 310 130
Lignin nitrogen 550 2370 2330
Lignin air 550 440 460
Invert sugar nitrogen 550 140 50

Tobaccos and Spinach

Flue-cured nitrogen 550 730 310
Burley, cased nitrogen 550 620 390
Maryland nitrogen 550 470 150
Spinach nitrogen 550 360 280

and the subsequent confirmation of its cocarcinogenicity by
Hecht et al. (1562) triggered considerable interest in the source
in tobacco of 1,2-benzenediol (catechol) in tobacco smoke.
In the early 1980s, Schlotzhauer et al. (3462) and
Schlotzhauer and Chortyk (3453) at the USDA, in their study
of the precursors in tobacco of phenols in tobacco smoke,
investigated the pyrolysis of various solvent-extracted frac-
tions from tobacco plus the tobacco residue after extraction.
The extracted tobacco residue, the ethanol extract, and the
methanol extract were the major sources of benzenediols
(catechol, resorcinol, and hydroquinone). From these results,
it was proposed that chlorogenic acid in tobacco was a major
precursor of the benzenediols, particularly 1,2-benzenediol
(catechol), in tobacco smoke. The extracted tobacco residue
was also reported as the major source of the monohydric phe-
nols (phenol, cresols, xylenols, and guaiacols).
Figure IX.A-2 illustrates the possible relationship between
1,2-benzenediol (catechol) and several complex tobacco phe-
nols subsequently studied as its precursor.
In a continuation of their study of the conversion of various
tobacco components to catechol, Schlotzhauer et al. (3462)
examined the phenols formed during the pyrolysis of a vari-
ety of tobacco components, including chlorogenic and caffeic
acids, rutin and quercetin, cellulose and lignin, and fructose
and sucrose (Table IX.A-15). They reported that chlorogenic
acid, usually the most abundant polyphenol in tobacco, pro-
duced the highest levels of 1,2-benzenediol (catechol) and
4-ethyl-1,2-benzenediol (4-ethylcatechol) during pyrolysis.
In addition, the tobacco biopolymer lignin was also reported
to be a significant source of 1,2-benzenediol (catechol). Their
examination of the phenols generation by pyrolysis of several
different flue-cured and burley tobaccos indicated that the
flue-cured tobaccos produced significantly higher levels of
the phenols than did the burley tobaccos. A similar situation
is obtained when the MSS phenols from cigarettes fabricated
from all flue-cured and all burley tobaccos are compared on
a milligram of phenol per milligram of CSC basis [Wynder
and Hoffmann (4317, 4332)].
Because they considered 1,2-benzenediol (catechol) a
“major constituent of tobacco smoke,” a component they
considered an important contributor to the biological proper-
ties of smoke, Hoffmann and his colleagues at the American
Health Foundation conducted an extensive study in the early
1980s on the pyrosynthesis of 1,2-benzenediol (catechol)
during the tobacco smoking process. The goal of the study
was to determine the major precursor(s) in tobacco of the
1,2-benzenediol (catechol) in MSS. Initial experiments by
Carmella et al. (600) involved the sequential extraction of
tobacco with hexane, chloroform, benzene, and methanol,
followed by pyrolysis of the material extracted by each sol-
vent and determination of the 1,2-benzenediol (catechol)
in the pyrolysate. Only the pyrolysates from the methanol
extract and the residual extracted tobacco indicated the pres-
ence of 1,2-benzenediol (catechol) precursors.
From the results of a study in which Kentucky reference
1R1 cigarettes were “spiked” with increasing levels of chlo-
rogenic acid (the 3-ester of 3,4-dihydroxycinnamic acid with
1,3,4,5-tetrahydroxycyclohexane-carboxylic acid), smoked
under standard conditions, and the MSS analyzed for 1,2-
benzenediol (catechol), Carmella et al. (598) concluded that,
under their experimental conditions, chlorogenic acid was not
a major precursor in tobacco of 1,2-benzenediol (catechol) in
tobacco smoke. This finding was the opposite of that reported
by Schlotzhauer et al. (3453, 3462).
In a subsequent study by Carmella et al. (602), tobacco was
extracted sequentially with hexane then aqueous methanol.

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 Phenols and Quinones 505

O
OH
O HO COOH
OH
HOOC 2
3
4 OH
1 5 HO
OH
OH
Chlorogenic acid;
3-O-caffeoylquinic acid trans-Caffeic acid
CAS No. 327-97-9 CAS No. 4361-87-9
Cyclohexanecarboxylic acid, 3-[[3-(3,4- 2-Propenoic acid, 3-(3,4-dihydroxyphenyl)-
dihydroxyphenyl)-1-oxo-2-propenyl]oxy]-
1,4,5-trihydroxy-\

HO HO

O OH O OH
HO HO

ruffinose O HO

O OH O OH
Rutin Quercitin
CAS No. 153-18-4 CAS No. 117-39-5
4H-1-Benzopyran-4-one, 3-[[6-O-(6-deoxy-α- 4H-1-Benzopyran-4-one, 2-(3,4-
L-mannopyranosyl)-β-D-glucopyranosyl]oxy]- dihydroxyphenyl)-3,5,7-trihydroxy-
2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-

Figure IX.A-2  Potential precursors in tobacco of 1,2-benzenediol (catechol) in tobacco smoke.

The major components of the aqueous methanol extract were
identified as fructose, glucose, sucrose, and chlorogenic acid.
Contributions of each of these tobacco components plus the
contributions of the tobacco components cellulose and rutin
to the 1,2-benzenediol (catechol) level in cigarette MSS were
determined in a “spiking” experiment in which cigarettes
were “spiked” with each of the components mentioned, two
of which were radiolabeled (fructose and cellulose). The
minimum contributions of these components to the 1,2-
benzenediol (catechol) level in MSS were: cellulose, 7% to
12%; total of the sugars, glucose, fructose, and sucrose, 4%;
chlorogenic acid, 13%; rutin, less than 1%. Carmella et al.
considered that a significant portion of the unaccounted for
1,2-benzenediol (catechol) was formed from the other biopo-
lymers, pectin, starch, and hemicellulose. It would appear that
these 1984 results on the involvement of chlorogenic acid as a

Table IX.A-15
Pyrolysis of Tobacco Components: Generation of Phenols
Tobacco Component Pyrolyzed
Phenol Chlorogenic Caffeic Acid Rutin Quercetin Lignin Cellulose Fructose Sucrose
Phenol × — — — × — — —
Phenol, 2-methoxy- a — — — — × — — —
Phenol, 2-methoxy- — — — — × — — —
4-(1- propenyl)-b
1,2-Benzenediol c × × × × × — — —
1,2-Benzenediol, — — × × × — — —
4-methyl-
1,2-Benzenediol, × — × — — — — —
4-ethyl-
1,2-Benzenediol, — — × — — — — —
4-propyl-
Furfuralsd × — … — — × × ×
a Guaiacol
b Isoeugenol
c Catechol

d Furfural and/or 5-(hydroxymethyl)furfural

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 506 The Chemical Components of Tobacco and Tobacco Smoke
1,2-benzenediol (catechol) precursor differed from those pre-
sented previously by the same investigators [Carmella et al.
(602) vs. Carmella et al. (598) who earlier stated in 1981:
The results under these experimental conditions [a “spiking”
experiment] suggest that chlorogenic acid is not a major pre-
cursor of catechol in cigarette smoke.
Carmella et al. (601) reported that cellulose in tobacco was
a major precursor of 1,2-benzenediol (catechol) in tobacco
smoke. Comparison of the pyrogenesis of 1,2-benzenediol
(catechol) from cellulose and carboxymethylcellulose sug-
gested that the 1,2-benzenediol (catechol) level in tobacco
smoke might be reduced by modification of the tobacco
cellulose. Subsequently, Carmella et al. (599) reported that
carboxymethylation of the cellulose in tobacco reduced the
1,2-benzenediol (catechol) in the MSS from 252 to 162 µg/
cigarette, a 36% reduction.
In addition to investigations of the possible precursors
in tobacco of phenols in cigarette MSS, the contribution of
several tobacco additives to phenols in MSS was studied.
Many years before the advent of the use of expanded tobacco
and filter-tip perforations in the design of low- to medium-
“tar” cigarettes, Kato and Shibayama (2044) reported that
vanillin (4-hydroxy-3-methoxybenzaldehyde) incorporated
in the tobacco blend by many manufacturers as a flavorant
was converted to phenol during the smoking process and
therefore should not be used as a cigarette tobacco flavorant.
Contradictory results were reported in a subsequent study at
RJRT R&D by Eble et al. (1105) with radiolabeled vanillin.
They reported that no radiolabeled phenol was detected in
the cigarette MSS and concluded that vanillin did not gen-
erated phenol during the smoking process. The difference
between the Kato and Shibayama 1962 results and the Eble
et al. 1985 results was readily explained by the difference in
the experimental conditions used in the two studies: Kato and
Shibayama (2044) used continuous draw in their smoking
regime, that is, no alternating puff and smoldering period,
whereas Eble et al. (1105) used the intermittent-puff regime
and smoking procedure defined in the U.S. FTC “tar” and
nicotine procedure (35-ml puff-volume, 2-sec puff-duration,
1 puff/min, 25°C, 60% relative humidity, etc.).
Many flavoring materials have been proposed for use as
flavoring materials in tobacco smoking products. Leffingwell
et al. (2341) reported that these range from individual chemi-
cal compounds to a variety of natural herbs, essential oils,
and extracts. Many of the proposed flavoring additives for
tobacco smoking products have been included in commercial
Table IX.A-16
Smoke Chemistry Data: NCI Study of Cocoa Addition (1332)
Code No. Filler
83 SEB III
82 SEB III + 1% cocoa
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78836_C009.indd 506
products, but many have not. Among the naturally occurring
mixtures used historically were deer tongue, tonka bean,
and vanilla extract (2341). In the early 1970s, Higman et al.
(1649) investigated the pyrolysis of these three historically
used tobacco additives to determine their possible contribu-
tions to the composition of cigarette smoke. In addition to
numerous monocyclic and PAHs and their monocyclic and
polycyclic nitrogen analogs, all three pyrolysates contained
phenol, cresols, and xylenols. The deer tongue and tonka
bean pyrolysates also contained naphthols and coumarin.
With regard to the use of these three materials as tobacco
additives, the authors noted:
The contribution of such additives [tonka bean, deer tongue,
vanilla extract] to the chemical and biological effects of ciga-
rette smoke would be in proportion to the amounts of such
additives used and also to the pyrolytic-distillation pattern to
which the additive is subjected in the thermal flow environ-
ment of the burning cigarette.
The report by Gori (1332) and the National Cancer
Institute (2683) on the results obtained in the NCI Smoking
and Health Program on “less hazardous” cigarettes (1329,
1330, 1332, 1333, 2683) led to an initial concern about the
contribution of cocoa added to tobacco to the chemical and
biological properties of the smoke from cigarettes containing
cocoa-treated tobacco. Subsequent examination of the bio-
logical data indicated that the initial concern was unfounded.
Schlotzhauer (3447) at the USDA research center in Athens,
Georgia, reported the results of his analysis of the pyrolysis
of cocoa powder and its possible contribution to the phenols
content of smoke from cigarettes made with cocoa-treated
tobacco. Pyrolysis of cocoa at various temperatures (350°,
450°, 550°, 650°, and 750°C) yielded phenol, the three dim-
ethylphenols (o-, m-, and p-cresol), several dimethylphenols
(xylenols), and 1,2-benzenediol (catechol). From his results,
Schlotzhauer concluded:
Addition of cocoa powder to tobacco products in the quanti-
ties normally utilized for flavoring purposes would not …
be expected to significantly enhance the phenolic content of
tobacco smoke.
Results of the study indicate that the levels of phenols
derived from pyrolysis of cocoa should not significantly
enhance the phenol content of tobacco smoke …
As shown in Table IX.A-16, comparison of the MSS phe-
nol data from the NCI study on cocoa-free (Sample Code 83)
vs. cocoa-treated (Sample Code 82) (1332, 2683) confirms
the view expressed by Schlotzhauer (3447).
Relative to “dry” Condensate, µg/g
Phenol o-Cresol m- and p-Cresol
4.33 0.68 1.98
4.46 0.75 2.02
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 Phenols and Quinones 507
Over a decade later in 1990, Roemer and Hackenberg
(3314a) reported the results of mouse skin-painting bioassays
in which the CSCs from cigarettes containing various levels of
cocoa were tested. The CSCs from cigarettes containing differ-
ent levels of cocoa (0, 1%, and 3%) were studied for their spe-
cific tumorigenicity. Their results contradicted those reported
by Gori (1332) for the NCI less hazardous cigarette study. The
1% and 3% addition levels of cocoa were equivalent to and
three times, respectively, the level of cocoa usually added to
commercial cigarettes. Roemer and Hackenberg noted:
We found no evidence for indicating an enhancement of the
biological activity of cigarette smoke condensates derived
from cigarettes to which 1 and 3% cocoa was added.
Additional details pertinent to cocoa are summarized by
Rodgman (3264).
IX.A.4 The Effect of Cigarette Design Parameters
on Yield of Mainstream Smoke Phenols
Despite the controversy over the biological properties of the
phenols in tobacco smoke, that is, were they promoters of the
tumorigenicity of the PAHs in the mouse skin-painting bio-
assay or cocarcinogens for the PAHs in that bioassay? Or were
they noncontributors or minor contributors to the bioassay
results? The next step after identification, refinement of quanti-
tation procedures, and resolution of the question of precursors
was the determination of which cigarette design parameters
would permit control of the levels of phenols in MSS.
Of course, the first method discovered to control the MSS
levels of phenols was their selective filtration by the plasti-
cized cellulose acetate filter tip.
The extensive research on phenols in tobacco smoke
eventually led to the resolution of the question of whether
selective filtration of a particular component or class of com-
ponents in cigarette MSS was possible. Despite listing effec-
tive filtration as an important means to reduce cigarette MSS
particulate matter, Wynder and Hoffmann in 1961 (4311)
categorized “selective filtration” of a particular component
or class of components in cigarette MSS as an impossibility.
However, the next year, because of their findings with low
molecular weight phenols in the MSS of filter-tipped ciga-
rettes, Wynder and Hoffmann (4314) reversed their previ-
ously expressed assertion on the impossibility of “selective
filtration.” They reported that the levels of MSS low molecu-
lar weight phenols were significantly reduced (75% to 90%)
by the plasticized cellulose acetate filter tip.
It was determined by numerous investigators that highly
volatile, low molecular weight phenols such as phenol and the
isomeric methylphenols (the cresols) were selectively filtered
from cigarette MSS. That the filter-tip plasticizer (usually
triacetin) played a significant role in the selective filtration
was demonstrated in the early 1960s by Lorillard (2399),
Laurene (2295, 2295a, 2298), Laurene et al. (2311, 2312),
Spears (3765), and Hoffmann and Wynder (1791). Brown and
Williamson patented the use of Carbowax® as an alterna-
tive filter-tip additive for selective filtration of low molecular
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78836_C009.indd 507
weight phenols. Low molecular weight phenol levels in MSS
were reduced 75% to 90% by the selective filtration of triace-
tin- or Carbowax®-treated cellulose acetate. Because of the
volatility of the low molecular weight phenols, an equilibrium
exists between these components of the tobacco smoke aero-
sol vapor phase and of the tobacco smoke aerosol particulate
phase. Thus, these components are substantially partitioned
between the particulate phase and vapor phase of cigarette
MSS aerosol. The selective filtration (75% to 90%) occurs
by removal from the smoke stream of significant amounts
of low molecular weight phenols in the aerosol vapor phase.
During the brief time of the MSS transit through the plasti-
cized filter tip, removal of the phenols from the vapor phase
results in vaporization of the phenols from the particles in
attempt to reestablish the original particulate phase-vapor
phase equilibrium.
Subsequently, it was determined by Fredrickson (1236)
in the mid-1960s and by Morie and Sloan (2635) and
Brunnemann et al. (514) in the 1970s that similar selective
filtration occurred with volatile N-nitrosamines such as
N-dimethylnitrosamine and N-diethylnitrosamine with 70%
to 80% of the volatile N-nitrosamines being removed from
MSS by a plasticized cellulose acetate filter tip.
The discovery in the early 1960s of the selective filtration
of the low molecular weight phenols from cigarette MSS was
subsequently confirmed by numerous investigators through-
out the world. As shown by the citations in Table IX.A-17, the
selective filtration of phenols from cigarette MSS was exten-
sively studied from the early 1960s to the mid-1970s. A few
additional studies have been described from the mid-1970s
to date.
From these studies, it was also reported by Laurene et al.
(2311, 2312) that the effectiveness of the selective filtration of
plasticized filter-tip cigarettes decreased during the shelf life
of the cigarette.
Discovery of the extensive partitioning of low molecular
weight phenols between the particulate and vapor phases of
cigarette MSS necessitated modifications to the methods for
determining them. Although several low molecular weight
PAHs such as naphthalene (mol wt 128) and its alkyl deriva-
tives also show some partitioning between the particulate and
vapor phases, the high molecular weight PAHs [anthracene
and phenanthrene (mol wt 178), B[a]A (mol wt 228), DB[a,h]
A (mol wt 278), B[a]P (mol wt 252)] exist almost exclusively
in the particulate phase. Before the extent of this partitioning
and the selective filtration of low molecular weight phenols
had been determined, most early studies dealt with analysis
for the per cigarette yield of the low molecular weight phe-
nols in the particulate phase. Thus, the relationships between
the per cigarette levels of the tumorigenic PAHs and these
phenols in mainstream CSC and the proposed promotion
of the specific tumorigenicity of the PAHs by the phenols
required reassessment.
This research observation-based comment raises the ques-
tion about the repeated assertion of the importance of the
promoting activity of phenol and other low molecular weight
phenols, particularly in their supposed enhancement of the
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 508 The Chemical Components of Tobacco and Tobacco Smoke
Table IX.A-17
Studies on the Selective Filtration of Phenolic Compounds in Cigarette
Mainstream Smoke
Year Investigator(s)
1962 Davis and George (911a)
Lorillard (2399)
1963 Hoffmann and Wynder (1791)
Laurene (2295, 2295a)
Laurene et al. (2311, 2312)
Spears (3765)
Waltz and Häusermann (4118)
1964 Esterle and Campbell (1164)
Pyriki and Moldenhauer (3043)
Seehofer et al. (3574)
Testa et al. (3890)
1965 Cuzin et al. (884)
George (1282a)
Kaburaki et al. (1996)
Laurene (2298)
LeRoux (2351)
Lipp (2376, 2377)
SEITA (3602)
Waltz and Häusermann (4121)
1966 Kallianos et al. (2016)
Müller and Moldenhauer (2653)
Touey and Kiefer (3937)
specific tumorigenicity of PAHs. What kind of tobacco smoke
promoter is it that exerts so little effect that, in its absence,
the specific tumorigenicity in the mouse skin-painting bioas-
say of the CSC remains essentially unaltered?
Table IX.A-18 illustrates the effect of several tobacco
expansion procedures and inclusion of the expanded tobacco
in the cigarette blend on the MSS phenol yield.
Brunnemann et al. (496, 497) confirmed the previous find-
ing of Waltz et al. (4123) that 1,2-benzenediol (catechol) was
the phenol usually present at the highest yield in cigarette
MSS. Brunnemann et al. determined that the level of 1,2-
benzenediol (catechol) in the MSS of a nonfiltered cigarette
varied from 160 to 500 µg/cigarette. The level of 1,2-ben-
zenediol (catechol) in the MSS from a filter-tipped ciga-
rette varied from 60 to 200 µg/cigarette. They also reported
that 1,2-benzenediol (catechol) and its derivatives were not
selectively reduced by commercial cigarette filter tips as
were many low molecular weight monohydric (one hydroxyl
group) phenols.
In 1953, when reconstituted tobacco sheet (RTS) was
introduced into its cigarette products by R.J. Reynolds
Tobacco Company as a cigarette design technology, little was
known about either the nature or yields of phenols in ciga-
rette MSS (see Table IX.A-4). Also, the promoting activity
of low molecular weight phenols to the specific tumorigenic-
ity of PAHs had not been reported by Boutwell et al. (414).
Until the early to mid-1960s, the contribution of RTS to MSS
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78836_C009.indd 508
Year Investigator(s)
1967 George and Keith (1284)
Müller and Moldenhauer (2653)
Waltz et al. (4122)
1968 George (1283)
Kallianos et al. (2016)
1969 Georgiev (1284a, 1284b)
1970 Reynolds (3111)
1972 Artho et al. (105)
1974 Baggett and Morie (156)
1975 Baggett and Morie (156)
Brunnemann et al. (496)
1976 Brunnemann et al. (497)
Kensler (2082)
1980 Mokhnachev and Mironenko (2579)
1994 Wilson (4268)
composition dealt primarily with the decrease in the yields
of the MSS PAHs, particularly B[a]P, and the decrease in
the specific tumorigenicity (mouse skin) of the CSC as the
percent inclusion of the RTS in the blend was increased [see
pp. 531–532 in (4332)].
Reports presented during the “less hazardous” cigarette
workshop held at the 1967 World Conference on Smoking
and Health were published the next year as an NCI mono-
graph edited by Wynder and Hoffmann (4343). Moshy and
Halter presented data on the effect of inclusion of experimen-
tal RTS in a blend. They wrote (2647a):
It is apparent from the data [presented] that selective reduc-
tions of up to 45% for benzo[a]pyrene and up to 87% for phenol
were achieved with some of the experimental tobacco leaves.
At the same conference, Hoffmann and Wynder (1798)
also discussed the percent reduction of the PAH content, spe-
cifically the B[a]P content, of the cigarette CSC by inclusion
of RTS in the cigarette tobacco blend. Although analytical
data on the decrease in TPM, B[a]P, and phenol yields were
presented graphically, they had no comment on the signifi-
cant percent reduction in the phenol content of the MSS, a
percent reduction that exceeded that of the B[a]P content.
In the NCI Smoking and Health Program on the “less
hazardous” cigarette, the substantial lowering of the yields
of phenol and the 2-, 3-, and 4-methylphenols (o-, m-, and
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 Phenols and Quinones 509

Table IX.A-18
Effect of Tobacco Expansion on Levels of Mainstream Smoke Phenols
RJRT-Expanded Tobacco Study (3254)
Tobacco Blend Composition Mainstream Smoke Level
% Control Blend b % RJRT-Expanded Blend µg/cig mg/g WTPM a
100 0 117 3.36
90 10 106 (9) c 3.73 (-11)
75 25 95 (19) 3.36 (0)
50 50 72 (38) 2.76 (18)
0 100 45 (62) 2.16 (36)

% Flue-Cured % RJRT-Expanded
Flue-Cured
100 0 126 3.09
0 100 70 (44) d 2.99 (3)
NCI “Less Hazardous” Cigarette Study (1330, 2683)
Mainstream Smoke Level, mg/g WTPMa
Tobacco Code No. Phenol o-Cresol m- + p-Cresol
SEBII b 42 3.83 0.62 2.04
SEBII 42 3.66 0.55 1.78
SEBII 44 3.90 0.63 1.56
SEBII 45 3.81 0.59 1.65
SEBII Avg 3.80 0.60 1.76
RJRT-expanded SEBII 48 2.56 (33) c 0.36 (40) 1.10 (40)
PM-expanded SEBII 49 2.93 (23) 0.40 (33) 1.37 (26)
NCSU-freeze dried SEBII 50 3.47 (9) 0.49 (18) 1.61 (13)
a WTPM = wet total particulate matter
b SEBII = the Standard Experimental Blend used in the second phase of the NCI “Less Hazardous” Cigarette Study.
c The number in parenthesis is the % decrease of the MSS yield of phenols in the MSS from the expanded or freeze-dried SEBII

vs. that in the MSS from the control SEBII.

p-cresols) in the MSS from RTS (paper process) cigarettes
vs. the tobacco blend (SEBI) was recorded (1329).
At RJRT R&D, Newell et al. (2765) reported the results of
a detailed study of the effect of increasing the level of RTS
(G7) on the composition of cigarette MSS. Decreased MSS
yields of the PAHs, nicotine, and phenols plus increased
yields in carbon monoxide, aldehydes, ketones, and low
molecular weight acids were observed.
In 1979, the U.S. Surgeon General (4005) reported the
beneficial effects of inclusion of RTS on the MSS composi-
tion (B[a]P, phenols, specific tumorigenicity):
Cigarette fillers low in wax layer components, either by use
of tobacco stems, reconstituted tobacco sheet, or tobacco
extracted with a hexane-ethanol mixture, delivered smoke
significantly reduced in catechols … Although it has not been
directly established that a selective reduction in catechol leads
to a significant reduction of the tumorigenic potential of ciga-
rette smoke, it is of interest that all those tars or whole smokes
of cigarettes which are low in catechol also have a significant
lower tumorigenic activity [Gori (1329, 1330, 1332)].
These comments on the relationship between RTS and
the 1,2-benzenediol (catechol) yield in MSS are of interest
because examination of the MSS data from the four sets of
experimental cigarettes [Gori (1329, 1330, 1332, 1333), NCI
(2683)] reveal that no analysis for 1,2-benzenediol (catechol)
was conducted on any of the cigarette samples in the study,
that is, the 100 or so experimental cigarettes or the standard
SEBI, SEBII, SEBIII, or SEBIV cigarettes and the Kentucky
1R1 reference cigarette.
In the late 1950s and the 1960s, one of the methods stud-
ied to control the pyrosynthesis of PAHs from tobacco during
the smoking process was the addition of various materials
(inorganic or organic) to the tobacco in attempts to control
its combustion and lower the per cigarette PAHs yields, par-
ticularly the B[a]P yield, in the tobacco smoke [Alvord and
Cardon (56, 57), Lindsey et al. (2370), Rodgman (3246, 3254),
Bentley and Burgan (286), Candeli et al. (589), Wynder and
Hoffmann (4311, 4317, 4319, 4332), Cuzin et al. (885), deS-
ouza and Scherbak (953), Pyriki et al. (3046), Hoffmann and
Wynder (1797, 1798)].
The most effective additives in PAHs reduction were the
nitrates. The following explanation of their effectiveness
was offered. When heated, the nitrates generate nitric oxide
(NO), an odd-electron compound, capable of “scavenging”
free radicals thermally generated from tobacco components

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 510 The Chemical Components of Tobacco and Tobacco Smoke
during the smoking process, thus interrupting the free radi-
cal reactions postulated as contributing to one of the mecha-
nisms important in the generation of PAHs in tobacco smoke
[see Badger and Spotswood (152), Badger (139a, 140), Badger
et al. (141, 142, 147)].
However, in addition to lowering the levels of PAHs in
tobacco smoke, addition of nitrates or the use of high-nitrate
tobacco affected MSS yield and composition in other ways. In
the 1950s and early 1960s, the reductions in the MSS yields
of “tar,” nicotine, and PAHs in general and B[a]P in particu-
lar were viewed as desirable achievements. When concern
was expressed about the supposed promoting action of the
low molecular weight phenols, the reduction of their levels
in MSS by nitrate addition to the tobacco was also viewed
positively. These decreases were, however, accompanied by
an increase in the level of NO in the smoke. Subsequently,
two reported observations did much to dampen the enthusi-
asm for nitrate addition to the tobacco and/or the use of high-
nitrate tobaccos in the blend:
• The identification of various volatile and tobacco-
specific N-nitrosamines in tobacco and its smoke
and the positive dependence of their levels in
both tobacco and smoke on the nitrate level of the
tobacco [Morie and Sloan (2635), Tso et al. (3985),
Brunnemann et al. (499)].
• The identification of a series of nitrophenols, many of
which are known to be highly toxic, in the MSS from
cigarettes fabricated with nitrate-treated tobacco and/
or with high-nitrate tobaccos in the blend [Kallianos
et al. (2016), Klus and Kuhn (2137)].
Table IX.A-19 summarizes some of the studies on the
use of nitrate addition to tobacco and/or use of high-nitrate
tobacco to reduce the yields of PAHs in cigarette MSS. Also
noted in Table IX.A-19 are some of the other compositional
changes observed in MSS yield and composition. In most
instances, the yields of MSS PAHs in general and B[a]P were
reduced although an occasional exception was observed, for
example, in the NCI Smoking and Health Program on “less
hazardous” cigarettes the MSS B[a]P yield increased with
nitrate addition but the B[a]A yield decreased (1329). Benner
et al. (274) reported that a comparison of the low molecular
weight phenols in the MSS from high- and low-nitrate tobac-
cos showed little difference in the yields of phenol per milli-
gram total particulate matter (TPM) but significant decreases
in the yields of the methylphenols (the cresols) per milligram
TPM. Benner et al. (276, 277) also reported that treatment of
tobacco with an alternative combustion modifier (3:7 boric
acid:sodium tetraborate decahydrate) increased the levels of
low molecular weight phenols in cigarette MSS, an increase
that was paralleled by the increase in low molecular weight
phenols in the pyrolysates from cellulose or lignin treated
with the same boric acid-tetraborate modifier.
In the mid-1970s, Brunnemann et al. (497) described an
improved method for the quantitation of 1,2-benzenediol (cat-
echol) in tobacco smoke and a possible way to reduce its MSS
level. The procedure they described involved extraction of
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78836_C009.indd 510
tobacco with a hexane-ethanol azeotrope which removed from
the tobacco what Brunnemann et al. defined as “waxes.” They
noted:
Compared to the corresponding control cigarette, the dry
TPM [from a cigarette filled with reconstituted tobacco from
which the “wax” layer had been removed by hexane-ethanol
azeotrope extraction] had been reduced by 44%, the nicotine
by 47% and catechol by 85%. This demonstrates a strong,
selective reduction of catechols in the smoke by the removal
of the “wax” layer.
Additional impetus to study the level and source of 1,2-
benzenediol (catechol) in tobacco smoke was provided by
Hecht et al. (1562), who asserted that 1,2-benzenediol (cat-
echol) was an important tobacco smoke cocarcinogen. They
also noted that the levels of 1,2-benzenediol (catechol) in
cigarette MSS were reduced by prior extraction of the tobacco
with a hexane-ethanol azeotrope or by inclusion of RTS in
the tobacco blend.
From the results of their study of cellulose vs. carboxy-
methylcellulose as a precursor of 1,2-benzenediol (catechol)
in tobacco smoke, Carmella et al. (599, 601) reported that the
carboxymethylation of tobacco cellulose significantly reduced
the level of 1,2-benzenediol (catechol) in tobacco smoke.
Wynder and Hoffmann asserted that cigarette MSS yield
and composition were controllable in a beneficial way by
increasing the number of cuts per inch in the tobacco blend
filler. Results obtained in the NCI program on the “less
hazardous” cigarette and reported in 1976 by Gori (1329) and
1980 by NCI (2683) were contradictory to the unpublished
results obtained in 1963 by Hoffmann and Wynder and later
reported by Wynder and Hoffmann [see p. 318 in (4319),
pp. 529–531 in (4332), (4330)]. In the NCI study, important
analytes such as B[a]P, B[a]A, phenol, and the three meth-
ylphenols (cresols) showed no consistent relationship between
their MSS yields and width of cut of the cigarette tobacco
filler. The mouse skin-painting bioassay also showed no con-
sistency between % TBA and the CSCs generated from ciga-
rettes with fillers of different cut widths.
In their report of the results of an unpublished study by
Hoffmann and Wynder of the effect of width of cut of the ciga-
rette filler, Wynder and Hoffmann reported that increasing the
number of cuts per inch (decreasing the cut width) decreased the
per cigarette MSS yield of TPM and B[a]P. They did not report
on the effect of cut width on phenols delivery. However, they
did report that the specific tumorigenicity of the CSCs from
cigarette fabricated with tobacco at 20, 30, and 50 cuts per inch
decreased as the number of cuts per inch increased [see p. 318
in (4319), pp. 529–531 in (4332), (4330)]. Subsequently, Wynder
and Hecht (4306d) tabulated the effect on chemical and bio-
logical properties of change in cut width as: “insignificant” for
the change in per cigarette MSS yields of carbon monoxide,
“tar,” nicotine, and B[a]P, as “insignificant” for the change in
MSS ciliatoxicity, as “insignificant” for the change in specific
tumorigenicity (mouse skin) of the CSC, and “unknown” for
the changes in tumor promoting effect. Their table was used
essentially unchanged by the Surgeon General in his 1979
report on smoking and health (4009).
11/13/08 5:22:50 PM
 Phenols and Quinones 511

Table IX.A-19
Studies Involving Nitrate Addition to Tobacco
Nitrate Change in CSC
Identity Amount Added, % B[a]P Level Tumorigenicity Comments References

Mg (NO3)2.6H2O 5.0 decrease 

2.0 decrease Rodgman and Cook (3269)
Al (NO3)3.9H2O 2.0 decrease 
KNO3 2.0 decrease 
4.0 decrease 
Cu (NO3)2 5.0 decrease Bentley and Burgan (286)
2.5 decrease 
1.0 decrease 
NaNO3 5.0 decrease 
Cu (NO3)2.5 H2O 5.0 decrease decrease Wynder and Hoffmann (4312)
Cu (NO3)2.5 H2O 5.0 decrease decrease Wynder and Hoffmann (4317)

Cu (NO3)2.5 H2O decrease Pyriki et al. (3046)

KNO3 MSS 1,2-benzenediol Kallianos et al. (2016)
(catechol) yield/cig
inversely related to
tobacco nitrate level,
4-nitro-1,2-benzenediol
yield/cig related to
tobacco nitrate level
NaNO3 8.3 decrease decrease TPM/cig decreased, Hoffmann and Wynder (4332)
phenol/cig yield
decreased, phenol/mg
of CSC decreased, no
N-nitrosamines detected
in nitrate-enhanced
tobacco cigarettes
NaNO3 3.0 decrease decrease 
8.3 decrease decrease  Hoffmann and Wynder (1798)
KNO3 2.5 decrease decrease 
0.1% vs. 1.66% decrease methylphenols (cresols) Benner et al. (274)
nitrate tobacco yields/mg TPM
inversely related to
tobacco nitrate level;
little difference in
phenol/mg TPM
delivery
KNO3 1.3 ND ND yields of a series of Klus and Kuhn (2137)
nitrophenols identified
in MSS from nitrate-
treated and high-nitrate
tobacco cigarettes
directly proportional to
nitrate content of filler
KNO3 2.8 increase decrease increased nitrate gave Gori (1329)
decreased phenol/mg
TPM and methylphenols
(cresols) levels/mg
TPM, NO increased
relative to TPM
2.3 decrease decrease

(Continued)

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 512 The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-19 (Continued)

Studies Involving Nitrate Addition to Tobacco
Nitrate Change in CSC
Identity Amount Added, % B[a]P level Tumorigenicity Comments References
NO3 addition decrease decrease nitrate addition and/or Wynder and Hecht (4306d)
use of high-nitrate
tobacco classified as
“only of academic
interest” because of
undesirable
N-nitrosamine-nitrate
relationship.
NO3 addition decrease decrease Surgeon General USPHS (4005)
reiterated Wynder-Hecht
(4306d) comment.
decrease decrease despite decreases in Brunnemann and Hoffmann
TPM, B[a]P, phenols, (480, 486)
CSC tumorigenicity, use
of low-nitrate tobacco
or nitrate removal
recommended because
of undesirable
N-nitrosamine-nitrate
relationship.
NaNO3 0.7 to 2.5 decrease decrease MSS 1,2-benzenediol Adams et al. (28)
(catechol) level
inversely related to
nitrate content of filler;
MSS volatile and
tobacco-specific
N-nitrosamine levels
proportional to nitrate
content of filler

In the NCI Smoking and Health Program on “less hazard-
ous” cigarettes [Gori (1329), NCI (2683)] the effects of cut
width on cigarette smoke properties (chemical composition,
biological properties) were not as pronounced as the effects
reported in Wynder and Hoffmann [see p. 318 in (4319), pp.
529–531 in (4332), (4330)]. Examination of the summary of
these studies in Table IX.A-20 reveals the lack of confirma-
tion of the Hoffmann-Wynder results. In fact, the proposal
that cut width would be a significant technology in the design
of a “less hazardous” cigarette was similar to many of the
proposals from the so-called cigarette design experts not
associated with the tobacco industry. Of the numerous tech-
nologies proposed during the decade-long NCI study, only
those eight technologies proposed by U.S. tobacco company
and/or tobacco supplier R&D personnel were eventually clas-
sified as significant by the NCI (2683), Gori (1332, 1333), the
U.S. Surgeon General (4005, 4009), and other anti-tobacco-
smoking investigators such as Hoffmann and Hoffmann
(1740).
The effectiveness of the various methods proposed to con-
trol the yield of the supposed promoting low molecular phe-
nols may be summarized as:
Tobacco extraction with wax-dissolving nonpolar organic
solvents (hexane, pentane) to remove PAH precursors does
indeed result in reduced levels of PAHs, including B[a]P, in
cigarette MSS. However, the solution of what was considered
by some as a possible PAH problem is accompanied by the
creation of two alternative problems, both of which might be
criticized from a scientific point of view. For example, extrac-
tive removal of the nonpolar organic solvent-soluble mate-
rial results in an increase in the percentage of the organic
solvent-insoluble biopolymers (the major phenols precursors
cellulose, pectins, starch, and lignin) in the extracted tobacco
residue. Smoking of the extracted residue in cigarette form
yields higher levels of low molecular weight phenols in the
MSS (3277, 3305). In addition, nitrates in the tobacco are
not removed by solution in nonpolar organic solvents, so
their percentages in the extracted tobacco residue increase.

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 Phenols and Quinones 513
Table IX.A-20
Effect of Cut Width on Mainstream Smoke Properties
PAHa, µg/g.
Tobacco, cuts/in Condensate, mg/cig B[a]P
Hoffmann and Wynder [see p. 318 in (4319), pp. 529–531 in (4332), (4330)]
8 29.1 1.27
20 27.3 1.25
30 25.4 1.30
50 24.4 0.94
60 23.0 0.91
Gori (1329), NCI (2683)
20 32.6 0.91
32 30.2 0.72
60 29.6 0.86
a PAH = polycyclic aromatic hydrocarbon, B[a]P = benzo[a]pyrene;
B[a]A = benz[a]anthracene, % TBA = % tumor-bearing animals
b 2-Methylphenol, 3-methylphenol, 4-methylphenol = o-, m-, and p-cresol, respectively
c Painting dose = 50 mg of cigarette smoke condensate/day
d Painting dose = 25 mg of cigarette smoke condensate/day
Experimental results reported by Morie and Sloan (2635),
Tso et al. (3985), and Brunnemann et al. (499) indicated that
smoking of this increased-nitrate-level extracted residue in
cigarette form would yield higher levels of N-nitrosamines
in the MSS.
Tobacco extraction with a hexane-ethanol azeotrope selec-
tively reduced the levels of 1,2-benzenediols (catechols) in the
cigarette MSS. Tobacco extraction with a polar organic sol-
vent system (aqueous ethanol or aqueous methanol) removes
chlorogenic acid, a known major precursor of 1,2-benzene-
diol (catechol), a phenol categorized as a cocarcinogen.
Because nitrate addition to tobacco resulted in reduction of
the cigarette MSS deliveries of “tar,” nicotine, PAHs includ-
ing B[a]P, and the low molecular weight phenols, nitrate addi-
tion and/or use of high-nitrate tobacco was considered to be
the way to introduce the most effective combustion modifier.
However, while apparently solving several problems concern-
ing MSS yield and composition, nitrate addition caused sev-
eral alternate problems. Once the levels of N-nitrosamines
and nitrogen oxides (NO) in tobacco smoke were shown to be
positively correlated to the nitrate content of the tobacco filler,
nitrate addition and the use of high-nitrate tobaccos were
eventually viewed as undesirable technologies. In addition,
higher nitrate tobacco fillers, whether a result of nitrate addi-
tion or inclusion of high-nitrate tobaccos, generated a series
of nitrophenols, many of which are known to be highly toxic.
From a comparison of the pyrogenesis of 1,2-benzenediol
(catechol) from cellulose vs. carboxymethylcellulose, it was
reported that the carboxymethylation of tobacco cellulose
significantly reduced the level of 1,2-benzenediol (catechol)
in tobacco smoke (599, 601).
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78836_C009.indd 513
Phenol, mg/g
B[a]A Phenol 2-Methylphenolb 3- and 4-Methylphenolb % TBA
27
16
13
1.40 4.35 0.78 1.85 46c
33d
1.20 3.95 0.72 1.83 44.6c
45.0d
1.31 4.17 0.63 1.92 39c
39d
Of the various technologies proposed to control the levels
of phenols in cigarette MSS, selective filtration appears to
be the most effective and most efficient. A significant por-
tion (65% to 75%) of the low molecular weight monohydric
phenols in cigarette MSS is removed from the smoke stream
by a cellulose acetate filter tip plasticized with triacetin. As
the cigarette ages, the plasticizer is slowly absorbed by the
cellulose acetate fiber and the effectiveness of the selective
filtration gradually decreases with time. The one drawback
with selective filtration is that it does not occur with dihy-
dric phenols such as 1,2-benzenediol (catechol) in the MSS,
that is, 1,2-benzenediol and its homologs are not selectively
removed from MSS by a plasticized filter tip.
Many of the complex tobacco-only phenolic components
have interesting structures in that they contain a cyclohexan-
ecarboxylic acid moiety linked to one of the following: (1)
a 4-hydroxyphenyl group, for example, p-coumaroylquinic
acid, (2) a 3,4-dihydroxyphenyl group, for example, chloro-
genic acid, or (3)) a 3-methoxy-4-hydroxyphenyl group, for
example, 3-O-feruloylquinic acid. In each case, one can theo-
rize that during the tobacco smoking process the complex
tobacco phenol could sequentially yield a substituted 2-pro-
penoic acid, a substituted benzaldehyde, a substituted ben-
zoic acid, and a simple phenol. Table IX.A-21 summarizes
the possible sequence of the pyrogenesis of such components.
Each of the compounds listed as tobacco smoke components
in Table IX.A-21 has been identified in cigarette MSS.
A similar situation exists with a series of components in
which a variously substituted 4H-1-benzopyranone is linked to a
4-hydroxyphenyl group, such as, kaempferol, or a 3,4-dihydroxy-
phenyl group, for example, quercitin, quercitrin, and rutin.
11/13/08 5:22:54 PM
 514 The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-21
Theoretical Relationship between Phenols in Tobacco and Several Phenols in Tobacco Smoke Phenols

In Table IX.A-22, the various phenolic components of
tobacco and tobacco smoke are listed, with appropriate refer-
ences to the identifications for each. Many of the references
cited contain additional references pertinent to the phenolic
component in question. The many references cited in Table
IX.A-22 include a variety of topics pertinent to the particular
phenol. They cover the following topics:
1. The isolation and/or identification of the phenol
from tobacco and/or smoke
2. Methods to quantitate the phenolic component in
tobacco and/or smoke
3. Determination of the precursors in tobacco of the
phenolic compound in smoke
4. Cigarette design technologies to decrease the per
cigarette MSS yield of the phenolic compound
5. The biological properties of the phenolic
compound
6. Discussions by personnel from governmental agen-
cies, medical institutions, etc., on the biological
problems pertinent to a given phenolic compound
While 558 phenolic components have been completely
or partially identified in tobacco and tobacco smoke, 244

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 Phenols and Quinones 515

Table IX.A-22
Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 516 The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Phenols and Quinones 517

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 518 The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Phenols and Quinones 519

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 520 The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Phenols and Quinones 521

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 522 The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Phenols and Quinones 523

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 524 The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Phenols and Quinones 525

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 526 The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Phenols and Quinones 527

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 528 The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Phenols and Quinones 529

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 530 The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C009.indd 530 11/13/08 5:23:36 PM

 Phenols and Quinones 531

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 532 The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C009.indd 532 11/13/08 5:23:38 PM

 Phenols and Quinones 533

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 534 The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Phenols and Quinones 535

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 536 The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Phenols and Quinones 537

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 538 The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Phenols and Quinones 539

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 540 The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Phenols and Quinones 541

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 542 The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Phenols and Quinones 543

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 544 The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Phenols and Quinones 545

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 546 The Chemical Components of Tobacco and Tobacco Smoke

Table IX.A-22 (Continued)

Phenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Phenols and Quinones 547

were identified in tobacco only, 444 in tobacco smoke only,
and 130 were identified in both tobacco and smoke. For the
tobacco smoke components partially identified, the nature
and/or position of an alkyl substitute was not defined by the
investigator.
IX.B  Quinones
Even in the mid-1950s when knowledge of the composition of
tobacco smoke was extremely limited and only a few phenols
were known to be present in tobacco smoke, it was suggested
that several of the phenols might be converted to the corre-
sponding quinone during the smoking process.
This suggestion, coupled with the mouse skin-painting
bioassay results reported by Takizawa (3865a) that sev-
eral simple quinones such as 2,5-cyclohexadiene-1,4-dione
(p-benzoquinone), 1,2-naphthalenedione (1,2-naphthoqui-
none), and 1,4-naphthalenedione (1,4-naphthoquinone) were
tumorigenic to mouse skin, raised serious questions about the
desirability of adding phenols to the tobacco blend to enhance
the odor and flavor of its smoke. Despite the many studies
in which benzene was used as the solvent for testing of the
tumorigenicity of PAHs, benzene seldom induced tumors in
the skin-painted solvent-control group of laboratory animals
[Hartwell (1543, 1544), Shubik and Hartwell (3664, 3665),
Thompson et al. (3908)]. Similarly, naphthalene was found to
be nontumorigenic in skin-painting studies.
The mouse skin-painting bioassay results with 2,5-cyclo-
hexadiene-1,4-dione (p-benzoquinone) were subsequently
confirmed by Tiedemann (3916a). Neither of the higher
molecular weight tricyclic quinones 9,10-anthracenedione
(9,10-anthraquinone) (3865a) or 9,10-phenanthrenedione (9,
10-phenanthrenequinone) (3865a) was reported to be tumori-
genic to mouse skin.
In the early days of the studies on the specific tumorige-
nicity of various classes of compounds to mouse skin, inves-
tigators were intrigued by the activities exhibited by aromatic
hydrocarbons, their dihydric phenols, and the quinones cor-
responding to the dihydric phenols. The results of mouse
skin-painting bioassays with various aromatic hydrocarbons
ranging in complexity from monocyclic to hexacyclic, their
dihydric phenols, and the corresponding quinones are sum-
marized in Table IX.B-1.
From the studies on the chemical relationship between
aromatic hydrocarbons and their quinones, the theory of
the oxidation-reduction potential of quinones was proposed.

Table IX.B-1
Comparison of the Tumorigenicities of Aromatic Hydrocarbons, their Diols (Phenols),
and their Diones (Quinones)
Hydrocarbon Diol Dione
Benzene – 1,4-benzenediol – 2,5-cyclohexadiene-1,4-dione +
(hydroquinone) (p-benzoquinone)
– 1,2-benzenediol – 3,5-cyclohexadiene-1,2-dione ?
(catechol) (o-benzoquinone)
Naphthalene (1,2-naphthoquinone) – 1,2-naphthalenediol +
1,2-naphthalenedione
1,4-naphthalenediol – 1,4-naphthalenedione +
(1,4-naphthoquinone)
Anthracene – 9,10-anthracenediol – 9,10-anthracenedione –
(9,10-anthraquinone)
(9,10-phenanthraquinone) –
Phenanthrene – 9,10-phenanthrenediol – 9,10-phenanthrenedione
Chrysene 5,6-chrysenediol – 5,6-chrysenedione –
(5,6-chrysenequinone)
6,12-chrysenediol – 6,12-chrysenedione
Benz[a]anthracene ± 7,12-benz[a]anthracenediol – 7,12-benz[a]anthracenedione –
(7,12-benz[a]anthraquinone)
Dibenz[a,h]anthracene ± 7,14-dibenz[a,h]anthracenediol – 7,14-dibenz[a,h]anthracenedione –
(7,14-dibenz[a,h]anthraquinone)
Benzo[a]pyrene + benzo[a]pyroquinone –
Dibenzo[b,def]chrysene + 7,14-dibenzo[b,def]chrysenedione –

– = negative response in mouse skin-painting bioassay

+ = positive response in mouse skin-painting bioassay
± = equivocal response in mouse skin-painting bioassay

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 548 The Chemical Components of Tobacco and Tobacco Smoke
A prime proponent of this theory was Fieser (1180b), who
reported the reduction potentials of the following quinones:
• Several anthracenediones other than 9,10-an-
thracenedione [Conant and Fieser (790b), Fieser
(1180a-1)].
• 9,10-Phenanthrenedione (9,10-phenanthraquinone)
[Fieser (1180a-2)].
• 2,5-Cyclohexadiene-1,4-dione ( p-benzoquinone)
[Fieser (1180a-3)].
• Several naphthalenediones other than the 1,2- and
1,4-naphthalenediones [Fieser (1180a-4)].
• 7,12-Benz[a]anthracenedione (7,12-benz[a]anthra-
quinone), 7,14-dibenz[a,h]anthracenedione (7,14-
benz[a,h]anthraquinone), 5,6-chrysenedione
(5,6-chrysenequinone), 6,12-chrysenedione (6,12-
chrysenequinone) [Fieser and Dietz (1180a-5)].
• 3,5-Cyclohexadiene-1,2-dione (o-benzoquinone)
and 1,2-naphthalenedione (1,2-naphthoquinone
[Fieser and Peters (1180a-6)].
• 9,10-Anthracenedione (9,10-anthraquinone) [Fieser
and Peters (1180a-7)]
• 1,4-Naphthalenedione (1,4-naphthoquinone) [Fieser
and Fieser (1180a-8)].
After the first demonstrations by Kennaway and Hieger
(2078) of the tumorigenicity to mouse skin of DB[a,h]A, a PAH
synthesized by Fieser and Dietz (1184), and of B[a]P by Barry et
al. (194), the coal tar component isolated from coal tar and subse-
quently synthesized by Cook et al. (796a, 797), the tumorigenic-
ity of a great number of PAHs and their derivatives was studied.
Soon observed was the pronounced contrast between the
gradation in specific tumorigenicities in the mouse skin-
painting bioassay from the nontumorigenicity of the mono-
and bicyclic aromatic hydrocarbons benzene and naphthalene,
respectively, to the potent tumorigenicities of the pentacyclic
aromatic hydrocarbons DB[a,h]A and B[a]P vs. the tumorige-
nicities of the quinones 2,5-cyclohexadien-1,4-dione (p-ben-
zoquinone), 1,2-naphthalenedione (1,2-naphthoquinone), and
1,4-naphthalenedione (1,4-naphthoquinone) and the nontum-
origenicities of dibenzanthraquinone and benzopyroquinone.
Neither the tricyclic aromatic hydrocarbons anthracene and
phenanthrene nor their corresponding quinones have elicited
tumors in the mouse skin-painting bioassay. The tumorige-
nicities of the tetracyclic hydrocarbons benz[a]anthracene
and chrysene have been classified as extremely weak or
equivocal. None of their quinones has shown tumorigenic-
ity in the mouse skin-painting bioassay (see Table IX.B-1).
Initially it was found that the higher the tumorigenic potency
of the quinones, particularly the benzoquinones and the naph-
thoquinones, the higher was the reduction potential of the
quinone. In essence, the oxidation-reduction potential theory
was eventually used in an attempt to relate the oxidation-re-
duction potential of the hydrocarbon-quinone system to the
specific tumorigenicity observed in the mouse skin-painting
bioassays for PAHs and their quinones.
© 2009 by Taylor & Francis Group, LLC
78836_C009.indd 548
Although none of the diols (phenols) listed in Table IX.B-1
was found to be tumorigenic, in subsequent research deal-
ing with the metabolism of tumorigenic PAHs, it was found
that some of the dihydrodiols and dihydrodiol epoxides were
tumorigenic to mouse skin [see review by Dipple et al. (983)].
However, it is obvious from examination of the structures of
the dihydrodiols and dihydrodiol epoxides that none of these
metabolites is a phenol.
As the laboratory data and understanding of chemical car-
cinogenesis increased dramatically pre- and post-World War
II, exceptions to the theory of oxidation-reduction potential
resulted in its being supplanted by other more meaningful
theories, for example, the relationship between electronic
configuration, the activity of the so-called K region, and the
inactivity of the so-called L region in aromatic compounds,
particularly PAHs, and their tumorigenicity [see reviews by
Coulson (829), Pullman and Pullman (3003)]. The interest in
the theory of the electronic configuration-tumorigenesis rela-
tionship of PAHs was such that the 1953 review by Coulson
was selected as the introductory chapter in Volume 1 of the
newly instituted publication, Advances in Cancer Research.
It is interesting to note that even in the early 1950s, the
idea of the involvement of a hydroxylated PAH metabolite
in tumorigenesis was already being discussed. For example,
Pullman and Pullman (3003) wrote:
It is nevertheless generally admitted that [dihydro]diols
are probably intermediates in the metabolism of aromatic
hydrocarbons
Although their speculation as to the precise nature of its
involvement was somewhat in error, the Pullmans (3003) did
propose that a dihydroepoxide might also be involved in the
metabolism of PAHs, the metabolite-cellular component inter-
action, and the tumorigenicity attributed to some of the PAHs.
The oxidation-reduction potential of the aromatic hydrocar-
bon-quinone system and its possible involvement in cigarette
smoke was revisited some years later. Schmeltz et al. (3510)
reported that cigarette smoke condensate (CSC) possessed
reducing properties sufficient to reduce 2,5-cyclohexadiene-1,4-
dione (1,4-benzoquinone; p-benzoquinone) to 1,4-benzenediol
(hydroquinone). This CSC-induced reduction apparently did
not occur with 9,10-anthracenedione (9,10-anthraquinone).
Compared to the number of polycyclic aromatic hydro-
carbons (PAHs) and phenols identified in tobacco smoke,
the number if quinones identified is low despite the fact that
many of the phenols after their pyrogenesis during the smok-
ing process could realistically yield quinones. Table IX.B-2
lists the forty-eight quinones identified to date in tobacco and
tobacco smoke. Of the forty-eight, thirty-three were identi-
fied in smoke, twenty-one in tobacco, and only six in both. In
his 1954 review of tobacco smoke components identified to
that date, Kosak (2170) listed no quinone.
In view of tobacco smoke composition findings after the
mid-1950s, the suggestion in the late 1950s by Rodgman that
phenols were inappropriate additives for cigarette smoke flavor
11/13/08 5:24:14 PM
 Phenols and Quinones 549

enhancement might have been an example of excessive cau-
tion. His suggestion was based on two factors, the promoting
effect of phenols reported in 1955, 1956, and 1959 by Boutwell
and his colleagues (414) plus the possible conversion during the
smoking process of substituted phenols to corresponding qui-
nones, several of which had been reported to be tumorigenic
by Takizawa (3865a) and Tiedemann (3916a). Obviously, the
latter situation occurred infrequently. The great discrepancy
between the large number of phenols and the small number
of quinones identified in tobacco smoke suggests that the
phenol-quinone conversion does not occur in many instances
or, if it does occur, the conversion results in the generation of
extremely low levels of the quinone. As noted elsewhere, it
has been estimated from examination of the many peaks and
shoulders in the detailed glass capillary gas chromatograms
from tobacco smoke and/or its fractions that the number of
tobacco smoke components exceeds the number of identified
tobacco smoke components by factors ranging from 10 to 25,

Table IX.B-2
Quinones Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 550 The Chemical Components of Tobacco and Tobacco Smoke

Table IX.B-2 (continued)

Quinones Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Phenols and Quinones 551

Table IX.B-2 (continued)

Quinones Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 552 The Chemical Components of Tobacco and Tobacco Smoke

Table IX.B-3
Chronology of Identification of Quinones in Tobacco and/or Smoke
Year Event
1924–1934 Fieser and his colleagues investigated the reduction of quinones and generated the theory of the oxidation-reduction
potential of quinones. The reduction of the following quinones was studied: Several anthracenediones other than
9,10-anthracenedione [Conant and Fieser (790b), Fieser (1180a)], 9,10-phenanthrenedione (9,10-phenanthraquinone)
(1180a), 2,5-cyclohexadiene-1,4-dione (p-benzoquinone) [Fieser (1180a)], several naphthalenediones other than the
1,2- and 1,4-naphthalenediones [Fieser (1180a)], 3,5-cyclohexadiene-1,2-dione (o-benzoquinone) and 1,2-
naphthalenedione (1,2-naphthoquinone) [Fieser and Peters (1180a)], 9,10-anthracenedione (9,10-anthraquinone)
[Fieser and Peters (1180a)], 1,4-naphthalenedione (1,4-naphthoquinone) [Fieser and Fieser (1180a)] 7,12-benz[a]-
anthracenedione (7,12-benz[a]anthraquinone), 7,14-dibenz[a,h]anthracenedione (7,14-benz[a,h]anthraquinone),
5,6-chrysenedione (5,6-chrysene-quinone), 6,12-chrysenedione (6,12-chrysenequinone) [Fieser and Dietz (1180a)].
Later, the theory of the oxidation-reduction potential of quinones was advanced to explain the differences in
tumorigenicity of the various quinones and their aromatic hydrocarbons sources.
1940–1941 Takizawa (3865a) reported that several simple quinones [2,5-cyclohexadiene-1,4-dione (p-benzoquinone), 1,2-
naphthalenedione (1,2-naphthoquinone), 1,4-naphthalenedione (1,4-naphthoquinone)] were tumorigenic in mouse
skin-painting experiments.
1942 Fieser (1180b) reviewed the theory of the oxidation-reduction potential of quinones. Because some nontumorigenic
aromatic hydrocarbons (benzene, naphthalene) yielded tumorigenic quinones, some nontumorigenic aromatic
hydrocarbons yielded nontumorigenic quinones, and some tumorigenic aromatic hydrocarbons (dibenz[a,h]
anthracene) yielded nontumorigenic quinones, attempts were made to correlate the relationship between aromatic
hydrocarbons, their quinones, the reduction potential of quinones, and the tumorigenicities (mouse skin) of the
aromatic hydrocarbons vs. the tumorigenicities of their quinones.
1953 Tiedemann (3916a) confirmed the finding of Takizawa on the tumorigenicity of 2,5-cyclohexadiene-1,4-dione
(p-benzoquinone) to mouse skin.
1953–1955 The theory of oxidation-reduction potential of quinones was supplanted by other more meaningful theories, e.g., the
relationship between electronic configuration, the activity of the so-called K region, and the inactivity of the so-called
L region in aromatic compounds, particularly PAHs, and their tumorigenicity [see reviews by Coulson (829) and
Pullman and Pullman (3003)].
1954 Kosak (2170) in his compilation of tobacco smoke components reported in the literature did not list a quinone.
1957 Bonnet and Neukomm (396) suspected the presence of 2,5-cyclohexadiene-1,4-dione (p-benzoquinone) in cigarette
mainstream smoke because of the identification of 1,4-benzenediol (hydroquinone) when the smoke was collected
under reducing conditions. Under similar reducing conditions, they were unable to identify 1,4-napthalenediol,
concluding that 1,4-napthalenedione (1,4-naphthoquinone) was not present in the smoke.
1959 Bentley and Berry (282) in their compilation of identified tobacco smoke components listed the report of 2,5-
cyclohexadiene-1,4-dione (p-benzoquinone) by Bonnet and Neukomm (396).
1959 In their review of tobacco and tobacco smoke composition, Johnstone and Plimmer (1971) listed no quinone in
tobacco or tobacco smoke.
1961 Onishi et al. (2860) reported the presence of 9,10-anthracenedione (9,10-anthraquinone) in tobacco smoke.
1965 Kröller (2195) reported the presence of 9,10-anthracenedione (9,10-anthraquinone) and 9,10-phenanthrenedione
(9,10-phenanthraquinone) in tobacco smoke.
1965 To estimate the 1,4-benzenediol (hydroquinone) in tobacco smoke, Testa et al. (3891) used air oxidation to convert
the 1,4-benzenediol (hydroquinone) to 2,5-cyclohexadiene-1,4-dione (p-benzoquinone) which was subsequently
derivatized and estimated. No effort was made to determine whether any 2,5-cyclohexadiene-1,4-dione
(p-benzoquinone) was already present in the smoke prior to the air oxidation.

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 Phenols and Quinones 553

Table IX.B-3 (continued)

Chronology of Identification of Quinones in Tobacco and/or Smoke
Year Event

1968 In his review of tobacco and tobacco smoke composition, Stedman (3797) listed only two quinones, 9,10-
anthracenedione (9,10-anthraquinone) in tobacco and 2,3,6-trimethyl-1,3-naphthalenedione (2,3,6-trimethyl-1,4-
naphthoquinone) in tobacco smoke. He discussed the Bonnet and Neukomm (396) report. Because of the uncertainty
of the Bonnet and Neukomm data and additional data from Testa et al. (3891), Stedman did not include 2,5-
cyclohexadiene-1,4-dione (p-benzoquinone) as a tobacco smoke component. He also did not include the reports of the
presence of 9,10-anthracenedione (9,10-anthraquinone) [Onishi et al. (2960), Kröller (2195)] or 9,10-
phenanthrenedione (9,10-phenanthraquinone) (2195) in tobacco smoke
1968–1969 Bell et al. (246, 247) reported the presence of several alkylated 9,10-anthracenediones in tobacco smoke.
1969–1978 RJRT R&D personnel identified numerous previously unidentified alkylated 2,5-cyclohexadiene-1,4-diones and
9,10-anthracenediones in tobacco smoke [Green et al. (1360, 1378), Schumacher et al. (3553), Heckman (1586),
Newell et al. (2769)].
1976–1977 Schmeltz et al. (3510) identified several previously unidentified alkylated 2,5-cyclohexadiene-1,4-diones and
9,10-anthracenediones in tobacco smoke.
1978–1980 Snook et al. (3747, 3748) identified a series of alkyl-, dialkyl-, trialkyl-, and tetraalkyl-1,4-naphthalenediones.in
tobacco smoke.

for example, see Wakeham (4103). It is possible that quinones
contribute to some of the extremely minor chromatographic
peaks representing components as yet unidentified.
Table IX.B-3 lists the chronology of some of the major
events pertinent to the identification of quinones in tobacco
smoke. It is obvious that the number of significant events
for these quinones is substantially less than those cata-
loged for the PAHs, the aza-arenes, the phenols, and the
N-nitrosamines. More than likely, the difference is a direct
reflection of the concern expressed relative to the tumori-
genicity in laboratory animals of the various classes of
compounds.

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 10 The Ethers
Assessment of the chronology of the number of ethers iden-
tified in tobacco and tobacco smoke provides another excel-
lent example of the effect of the advancements in analytical
technology on our ability to identify components in a com-
plex mixture. In his 1954 review of the components identified
to that date in tobacco smoke, Kosak (2170) lists only two
ethers, 2-furancarboxaldehyde (furfural) and 1,6-anhydro-β-D-
glucopyranose (levoglucosan). Johnstone and Plimmer (1971)
did not list ethers as a specific class of components in tobacco
or tobacco smoke but did mention the identification of several
under different headings in their 1959 review, for example,
furan, 2-methylfuran, 2-furancarboxaldehyde (furfural) and
two of its derivatives, 3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,
12-trimethyltridecyl)-2H-1-benzopyran-6-ol (α-tocopherol)
and 3,4-dihydro-2,7,8-trimethyl-2-(4,8,12,16,20,24,28,32-octa-
methyl-3,7,11,15,19,23,27,31-tritriacontaoctaenyl)-2H-1-benzo-
pyran-6-ol (solanachromene), the monosaccharides glucose
and fructose, the disaccharide sucrose, the trisaccharides
raffinose and planteose, and the tetrasaccharide stachyose.
Overall, fewer than thirty ethers are listed by Johnstone and
Plimmer (1971).
From 1959 to date the number of ethers identified in
tobacco and tobacco smoke has increased over 30-fold to
992, 506 of which have been identified in tobacco smoke,
659 in tobacco, and 173 in both tobacco and tobacco smoke.
In his 1968 review, Stedman (3797) tabulated the pres-
ence of five cyclic ethers in tobacco smoke, that is, furan,
methylfuran, 2,5-dimethylfuran, tetrahydrofuran, and tet-
rahydropyran. Currently, the identified ethers with a furan
nucleus exceed 275, those with a pyran nucleus exceed 225.
The methoxy and ethoxy ethers number over 260, phenoxy
ethers number 20.
© 2009 by Taylor & Francis Group, LLC
78836_C010.indd 555
One of the types of ethers that received considerable atten-
tion were the ethers derived from the cyclotetradecanols (see
Figure X-1). Because of their unusual structure, none of them
was counted in the furan or pyran nucleus group. Over twen-
ty-five of these ethers have been identified in tobacco and
tobacco smoke (9, 12, 3351, 3352, 3360, 3361, 4089–4091).
As noted by Rodgman (3266), many components, includ-
ing a number of ethers, used by the tobacco industry in its fla-
vor formulations [see listing by Doull et al. (1053)] are known
components of additive-free tobacco and/or its smoke. Thus,
such additives are not strangers to tobacco and/or its smoke
but their addition increases the consumer acceptable flavor.
Table X-1 lists some of the tobacco and/or tobacco smoke ether
components that have been or are used in flavor formulations.
In Table X-2 are listed the various ethers identified to date
in tobacco, tobacco smoke, and tobacco substitute smoke. Of
the 992 ethers identified to date, 506 have been reported in
smoke, 659 in tobacco, and 173 in both.
Overall Summary of Oxygen-Containing
Components of Tobacco and/or
Smoke: Chapters 2 through 10
Table X-3 summarizes the distribution in our catalogs in
Chapters 2 through 10 of the O-containing components iden-
tified in tobacco and/or tobacco smoke. As we have noted in
the introductions to each of the nine chapters, the numbers
for the various classes of O-containing components have
escalated tremendously since the last published review by
Stedman (3797) in 1968 on tobacco and tobacco smoke com-
ponents identified to that date.
555
11/13/08 5:24:58 PM
 556 The Chemical Components of Tobacco and Tobacco Smoke

CH3 H3C CH3 CH3

H 3C H3C
OH CH3 CH3 OH
10 6 13 9 H3C 10 6
H 3C 12 11 10 8
8 14 8
11 9 7 5 11 9 7 5
CH3 O OH O CH3
2 4 1 7 12 2 4
1 3 6 1
4 5 HO
3 2 3
CH3 CH3 O CH3
O
1,5,11-Trimethyl-8-(1- 8-Hydroxy-4,8,14-trimethyl-11-(1- 1,5,11-Trimethyl-8-(1-
methylethyl)-15- methylethyl)-15- methylethyl)-15-
oxabicyclo[10.2.1]pentadeca- oxabicyclo[12.1.0]pentadeca-4,9- oxabicyclo[9.3.1]pentadeca-2,6-
2,6,10-trien-5-ol, dien-6-one diene-5,12-diol,

Figure X-1  Cembranoid ethers identified in tobacco and/or tobacco smoke.

Table X-1
Tobacco and/or Smoke Ethers Used in Flavor Formulations
Identified In
CAS No. Chemical Abstracts Nomenclature As Listed by Doull et al. (1053) Smoke Tobacco
120-14-9 Benzaldehyde, 3,4-dimethoxy-; veratraldehyde Ia I
121-32-4 Benzaldehyde, 3-ethoxy-4-hydroxy- ethylvanillin + +
10031-82-0 Benzaldehyde, 4-ethoxy- p-ethoxybenzaldehyde Hb H
121-33-5 Benzaldehyde, 4-hydroxy-3-methoxy- vanillin + +
123-11-5 Benzaldehyde, 4-methoxy p-methoxybenzaldehyde + +
151-10-0 Benzene, 1,3-dimethoxy- m-dimethoxybenzene I I
150-78-7 Benzene, 1,4-dimethoxy- p-dimethoxybenzene
104-46-1 Benzene, 1-methoxy-4-(1-propenyl)- anethole + +
1076-56-8 Benzene, 3-methoxy-1-methyl-4-(1-methylethyl)- 4-isopropyl-3-methoxy-1-methylbenzene ‑ +
105-13-5 Benzenemethanol, 4-methoxy- anisyl alcohol ‑ +
104-21-2 Benzenemethanol, 4-methoxy-, acetate anisyl acetate + +
104-93-8 Benzene, 1-methoxy-4-methyl- p-methylanisole + ‑
104-45-0 Benzene, 1-methoxy-4-propyl- dihydroanethole H ‑
623-15-4 3-Buten-2-one, 4-(2-furanyl)- 4-(2-furyl)-3-buten-2-one + +
100-06-1 Ethanone, 1-(4-methoxyphenyl)- acetanisole + +
1193-79-9 Ethanone, 1-(2-furanyl 5-methyl)- 2-acetyl-5-methylfuran + +
611-13-2 2-Furancarboxylic acid, methyl ester methyl 2-furoate + +
93-18-5 Naphthalene, 2-ethoxy- β-naphthyl ethyl ether ‑ +
470-82-6 2-Oxabicyclo[2.2.2]octane, 1,3,3-trimethyl- eucalyptol + +
91-10-1 Phenol, 2,6-dimethoxy- 2,6-dimethoxyphenol + +
7786-61-0 Phenol, 4-ethenyl-2-methoxy- 2-methoxy-4-vinylphenol + +
123-07-9 Phenol, 4-ethyl- p-ethylphenol + +
90-05-1 Phenol, 2-methoxy- guaiacol + +
93-51-6 Phenol, 2-methoxy-4-methyl- 2-methoxy-4-methylphenol + +
122-84-9 2-Propanone, 1-(4-methoxyphenyl)- 1-(p-methoxyphenyl)-2-propanone I ‑
a I = compound is an isomer of an identified component
b H = compound is a homolog of an identified component

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 The Ethers 557

Table X-2
Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke
Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

(Continued )

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 558 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Ethers 559

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 560 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Ethers 561

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 562 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Ethers 563

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 564 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Ethers 565

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 566 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Ethers 567

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 568 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Ethers 569

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 570 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Ethers 571

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 572 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Ethers 573

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 574 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Ethers 575

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 576 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Ethers 577

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 578 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 The Ethers 579

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 579 11/13/08 5:25:52 PM

 580 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C010.indd 580 11/13/08 5:25:55 PM

 The Ethers 581

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 581 11/13/08 5:25:56 PM

 582 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 582 11/13/08 5:26:00 PM

 The Ethers 583

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 583 11/13/08 5:26:01 PM

 584 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 584 11/13/08 5:26:04 PM

 The Ethers 585

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C010.indd 585 11/13/08 5:26:06 PM

 586 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 586 11/13/08 5:26:09 PM

 The Ethers 587

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C010.indd 587 11/13/08 5:26:10 PM

 588 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 588 11/13/08 5:26:14 PM

 The Ethers 589

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 589 11/13/08 5:26:15 PM

 590 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 590 11/13/08 5:26:18 PM

 The Ethers 591

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 591 11/13/08 5:26:19 PM

 592 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 592 11/13/08 5:26:22 PM

 The Ethers 593

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 593 11/13/08 5:26:24 PM

 594 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 594 11/13/08 5:26:27 PM

 The Ethers 595

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 595 11/13/08 5:26:28 PM

 596 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 596 11/13/08 5:26:32 PM

 The Ethers 597

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 597 11/13/08 5:26:33 PM

 598 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 598 11/13/08 5:26:36 PM

 The Ethers 599

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 599 11/13/08 5:26:37 PM

 600 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 600 11/13/08 5:26:41 PM

 The Ethers 601

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 601 11/13/08 5:26:42 PM

 602 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 602 11/13/08 5:26:46 PM

 The Ethers 603

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C010.indd 603 11/13/08 5:26:53 PM

 604 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C010.indd 604 11/13/08 5:26:55 PM

 The Ethers 605

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C010.indd 605 11/13/08 5:26:56 PM

 606 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 606 11/13/08 5:27:00 PM

 The Ethers 607

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C010.indd 607 11/13/08 5:27:01 PM

 608 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 608 11/13/08 5:27:04 PM

 The Ethers 609

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C010.indd 609 11/13/08 5:27:05 PM

 610 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 610 11/13/08 5:27:09 PM

 The Ethers 611

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C010.indd 611 11/13/08 5:27:10 PM

 612 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C010.indd 612 11/13/08 5:27:13 PM

 The Ethers 613

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C010.indd 613 11/13/08 5:27:14 PM

 614 The Chemical Components of Tobacco and Tobacco Smoke

Table X-2 (Continued)

Ethers in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

Table X-3
Distribution of Identified Oxygen-Containing Components between Tobacco
and Tobacco Smoke
Component Table Totala Smoke Tobacco Smoke and Tobacco
Alcohols Table II.A-5 1462 531 1152 221
Phytosterols and derivatives Table II.B-2 111 44 102 35
Aldehydes Table III-12 263 143 199 79
Ketones Table III-13 1090 656 647 213
Carboxylic acids Table IV.A-3 745 354 614 223
Amino acids Table IV.B-7 103 30 102 29
Esters Table V-3 1030 617 924 511
Lactones Table VI-2 304 162 201 59
Anhydrides Table VII-1 20 13 13 6
Carbohydrates Table VIII-3 279 35 271 27
Phenols Table IX.A-22 558 444 244 130
Quinones Table IX.B-2 48 33 21 6
Ethers Table X-2 992 506 659 173
Totals 7005 3568 5149 1712
a  olyfunctional O-containing compounds are counted in each functional group, e.g., propanoic acid, 2-hydroxy- (lactic
P
acid) appears in the alcohol catalog and the acid catalog; benzoic acid, 4-hydroxy-3-methoxy- (vanillic acid) appears
in the acid catalog, the phenol catalog, and the ether catalog.

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78836_C010.indd 614 11/13/08 5:27:15 PM

 11 Nitriles
The nitriles in tobacco and tobacco smoke provide another
excellent example of the escalation of the number of identified
components. From the listing in 1954 by Kosak (2170) who
recorded only the simplest nitrile, that is, hydrogen cyanide
(HCN), in tobacco smoke to those cataloged in Table XI-2
which includes the simplest “nitrile,” hydrocyanic acid (HCN)
plus 140 nitriles identified to date in tobacco and/or tobacco
smoke. HCN was first identified in tobacco smoke in 1828 by
Vogler (4062). Examination of Table XI-2 indicates the list-
ing of seven partially identified nitrile isomers plus thirteen
cyano group-containing pesticides used in tobacco agronomy.
In the latter case, many were identified in tobacco only but
several identified in tobacco were also found to transfer intact
to smoke, for example, Cypermethrin® (52315-07-8).
In their 1959 review of tobacco and tobacco smoke com-
ponents, Johnstone and Plimmer (1971) listed the following
four components containing a –C≡N group: hydrogen cya-
nide, cyanogen, thiocyanic acid, and thiocyanogen. No alkyl
nitriles were listed.
With the advent of gas chromatography, Grob used his
gas chromatographic knowledge and skill to identify a series
of nitriles in tobacco smoke in 1962 (1413) and 1965 (1416,
1417). His 1965 findings were accompanied by similar find-
ings reported in 1965 by Newsome et al. (2782). Many of the
nitriles identified in their studies were discussed by Wynder
and Hoffmann in their 1967 book [see pp. 450–451 in (4332)].
They also discussed the reports by Campbell et al. (582) and
McKee et al. (2519b) on the indication that acetonitrile in
the body fluids was indicative of exposure to tobacco smoke
because no other respiratory exposure was known. Table XI-1
lists some of the nitriles identified in the early 1960s.
In his 1968 review on tobacco and tobacco smoke com-
position, Stedman (3797) listed fifteen nitriles, including
HCN, as chemical components of tobacco smoke. Many of
the nitriles listed were those identified by Grob (1412, 1413,
1416, 1416a, 1419) in his gas chromatographic studies of
tobacco smoke. Stedman also listed 2-pyridinecarbonitrile
and 3-pyridinecarbonitrile (nicotinonitrile) as pyrolysis prod-
ucts of various alkaloids.
In addition to HCN, cyanogen, thiocyanic acid, and thio-
cyanogen, Schmeltz and Hoffmann, in their 1977 review of
N-containing components of tobacco and tobacco smoke,
listed thirty-one nitriles [see Table IX in (3491)]. Ishiguro
and Sugawara, in their 1980 catalog (1884) of the chemical
© 2009 by Taylor & Francis Group, LLC
78836_C011.indd 615
components of tobacco smoke, listed thirty nitriles in addi-
tion to HCN, cyanogen, thiocyanogen, and thiocyanic acid.
In its 1986 monograph on tobacco smoking, the Interna-
tional Agency for Research on Cancer (IARC) wrote very lit-
tle about nitriles in tobacco smoke. IARC categorized HCN
as one of the most toxic agents in the vapor phase of tobacco
smoke and noted its presence in smoke was dependent on the
level of nitrate, proteins, and amino acids in tobacco [see p.
96 in (1870)]. IARC also listed cyanogen as a tobacco smoke
component. In its summary of its evaluation for carcinoge-
nicity of chemical components identified in tobacco smoke,
IARC did classify 2-propenenitrile (acrylonitrile) with suf-
ficient evidence for carcinogenicity in animals but limited
evidence in humans [see p. 392 in (1870)]. The per cigarette
MSS yield of 2-propenenitrile (acrylonitrile) was listed at 3.2
to 15 μg, based on data provided by Wynder and Hoffmann
from their 1982 publication (4348a). In a publication issued
shortly after the IARC 1986 monograph on tobacco smok-
ing, Hoffmann and Wynder estimated the number of tobacco
smoke components to be approximately 3900, of which the
number of nitriles was listed at 105 [see Table 1 in (1808)].
They listed HCN as a major toxic agent in nonfiltered cig-
arette smoke [see Table  2 in (1808)] and 2-propenenitrile
(acrylonitrile) as a biologically active agent in MSS [see
Table 13 in (1808)]. It is interesting to note that despite the
considerable contribution of Wynder and Hoffmann to the
subject of smoke components and their biological properties
in the IARC 1986 monograph on tobacco smoking that only
HCN, cyanogen, and 2-propenenitrile (acrylonitrile) of the
105 nitriles noted by Hoffmann and Wynder (1808) appeared
in the IARC monograph (1870).
In many of the publications issued between 1990 and 2001
in which various tumorigens in tobacco smoke, particularly
cigarette smoke, were listed, 2-propenenitrile (acrylonitrile)
was included [Hoffmann and co-authors (1727, 1740, 1741,
1743, 1744, 1783), Fowles and Bates (1217), OSHA (2825)]. In
2003, these lists were discussed in detail by Rodgman (3265).
HCN and cyanogen, while not listed as tumorigens, were
listed in many instances as biologically active toxicants. In
many cases, acetonitrile was listed as a vapor-phase com-
ponent of tobacco smoke. For example, in their 1997 and
2001 articles, Hoffmann and Hoffmann (1740, 1743) and
Hoffmann et al. (1744) listed HCN, acetonitrile, 2-pro-
penenitrile (acrylonitrile), and ten unnamed nitriles as
615
11/13/08 5:28:29 PM
 616 The Chemical Components of Tobacco and Tobacco Smoke

Table XI-1
Nitriles Identified and/or Discussed in Tobacco Smoke by the Mid-1960s
CAS No. Nitrile References by Mid-1960s
75-05-8 Acetonitrile Grob (1413, 1416), Newsome et al. (2782), Wynder and Hoffmann (4319, 4332)
140-29-4 Benzeneacetonitrile {α-tolunitrile} Grob (1427)
100-47-0 Benzonitrile Grob (1426)
109-74-0 Butanenitrile Grob (1416, 1417, 1422), Wynder and Hoffmann (4332)
625-28-5 Butanenitrile, 3-methyl- {isovaleronitrile} Grob (1416, 1417), Wynder and Hoffmann (4332)
4786-20-3 2-Butenenitrile {crotononitrile} Newsome et al. (2782), Wynder and Hoffmann (4332)
628-73-9 Hexanenitrile {capronitrile} Grob (1416, 1417, 1422), Wynder and Hoffmann (4332)
107-12-0 Propanenitrile Grob (1413, 1416, 1422), Newsome et al. (2782), Wynder and Hoffmann (4319, 4332)
78-82-0 Propanenitrile, 2-methyl- {isobutyronitrile} Grob (1413, 1416, 1422), Newsome et al. (2782), Wynder and Hoffmann (4319, 4332)
107-13-1 2-Propenenitrile {acrylonitrile} Grob (1413, 1416, 1422), Newsome et al. (2782), Wynder and Hoffmann (4319, 4332)
126-98-7 2-Propenenitrile, 2-methyl- {methacrylonitrile} Grob (1413, 1416, 1422), Newsome et al. (2782), Wynder and Hoffmann (4319, 4332)
110-59-8 Pentanenitrile {valeronitrile} Grob (1416, 1417, 1422), Wynder and Hoffmann (4332)
542-54-1 Pentanenitrile, 4-methyl- {isocapronitrile} Grob (1416, 1417), Wynder and Hoffmann (4332)
100-54-9 3-Pyridinecarbonitrile {nicotinonitrile} Grob (1426)

cigarette MSS vapor-phase components but they listed only
2-propenenitrile (acrylonitrile) as a carcinogen. HCN was
listed as a major toxic agent in cigarette smoke in their 2001
article (1743).
Because of its inclusion in so many of the Hoffmann co-
authored lists, 2-propenenitrile (acrylonitrile) was among the
forty or so smoke components that subsequently became clas-
sified as a “Hoffmann analyte.” While it did not use the term
“Hoffmann analyte” in its 2000 report, the Department of
Health (Canada) proposed that analytical data on over forty
components from tobacco smoke should be a requirement
to enable the department to assess the health hazard of a
cigarette product marketed in Canada (11A01). In its list, the
Department of Health (Canada) included 2-propenenitrile
(acrylonitrile) and HCN. Examination of the Department
of Health (Canada) list reveals that most of its components
appear in the biologically active component lists in the pub-
lications co-authored by Hoffmann (1727, 1773, 1808, 1740,
1741, 1743, 1744).
Table XI-2 lists the 141 nitriles identified to date in tobacco
products. Of the 141, 131 have been identified in smoke, 23 in
tobacco, and 13 in both.

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78836_C011.indd 616 11/13/08 5:28:30 PM

 Nitriles 617

Table XI-2
Nitriles in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke
Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

(Continued )

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78836_C011.indd 617 11/13/08 5:28:31 PM

 618 The Chemical Components of Tobacco and Tobacco Smoke

Table XI-2 (CONTINUED)

Nitriles in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C011.indd 618 11/13/08 5:28:32 PM

 Nitriles 619

Table XI-2 (CONTINUED)

Nitriles in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C011.indd 619 11/13/08 5:28:34 PM

 620 The Chemical Components of Tobacco and Tobacco Smoke

Table XI-2 (CONTINUED)

Nitriles in Tobacco,Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C011.indd 620 11/13/08 5:28:35 PM

 Nitriles 621

Table XI-2 (CONTINUED)

Nitriles in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C011.indd 621 11/13/08 5:28:37 PM

 622 The Chemical Components of Tobacco and Tobacco Smoke

Table XI-2 (CONTINUED)

Nitriles in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C011.indd 622 11/13/08 5:28:40 PM

 Nitriles 623

Table XI-2 (CONTINUED)

Nitriles in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C011.indd 623 11/13/08 5:28:42 PM

 624 The Chemical Components of Tobacco and Tobacco Smoke

Table XI-2 (CONTINUED)

Nitriles in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C011.indd 624 11/13/08 5:28:44 PM

 Nitriles 625

Table XI-2 (CONTINUED)

Nitriles in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C011.indd 625 11/13/08 5:28:45 PM

 12 Acyclic Amines
The great diversity and number of the N-containing com-
ponents in tobacco and tobacco smoke make it difficult to
categorize them and catalog the members in each category.
Examination of past reviews indicates that their authors had
the same problems even when the numbers of components in
the various categories were much fewer than they are now. The
categorization used herein is an attempt to present a simpli-
fied but complete system for the reader. Because of its nature,
tobacco and its smoke contain a multitude of N-containing
components distributed among various categories. The sim-
plest categories, of course, are the nitriles and the acyclic or
aliphatic amines. The latter category also includes individual
amino acids and their complexes (proteins, polypeptides),
many of which possess a nonsubstituted amino group. More
complex are the pentacyclic and hexacyclic N-containing
components plus those that are combinations of more than one
of each type, that is, linked pentacyclic structures (porphyrin),
linked hexacyclic structures (2,3′-bipyridine), or a linked pen-
tacyclic and hexacyclic structure [3-(1-methyl-2-pyrrolidinyl)-
pyridine (nicotine)]. Even more complex are those structures
in which two or more cyclic units are fused with at least one
containing N in its cycle, that is, the aza-arenes. Also pertinent
to tobacco smoke chemistry are the components possessing a
combination of an amino group with an aza-arene structure
such as occurs in the N-heterocyclic amines.
All categories mentioned, except the amino acids, include
components comprising carbon, hydrogen, and nitrogen.
However, several other categories, like the amino acids
and the N-nitrosamines, include oxygen in the molecule,
for example, the amides {I}, imides {II}, and lactams {III}
(Figure XII-1). Herein, the amines will be discussed and
cataloged. Subsequently, the other categories mentioned
will be discussed and cataloged, that is, amides, imides,
and lactams, components with five-membered N-containing
rings, six-membered N-containing rings, and combinations
of them, the aza-arenes, and the N-heterocyclic amines. The
amino acids were discussed and cataloged previously. Other
components, similar to the N-heterocyclic amines in which
an amino group is attached to a fused N-containing system,
have been identified in tobacco and/or smoke, for example,
1H-purin-6-amine (adenine).
Because of the multitude of nicotine-related alkaloids,
amino acids, and proteins in tobacco, diligent research
eventually led to the identification of a host of alkyl amines
in tobacco and smoke. In addition to ammonia, the only
alkylamine listed as a tobacco smoke component in 1954 by
Kosak (2170) was methylamine, but he questioned its identifi-
cation even though he cited the 1904 report by Thoms (3912)
and the 1930 report by Koperina (2161) on its identification.
© 2009 by Taylor & Francis Group, LLC
78836_C012.indd 627
A similar Koperina report (2162) appeared in a 1931 mono-
graph edited by Shmuk on tobacco research (3655c).
In their 1959 review, Johnstone and Plimmer (1971) listed
ammonia and trimethylamine as identified tobacco and
smoke components and methylamine, dimethylamine, and
ethylamine as identified tobacco smoke components. Nearly
a decade later, in addition to the amino acids, Stedman listed
over forty components with either a free or substituted amino
group [see Table XI in (3797)]. In their 1977 tabulations of ali-
phatic and aromatic amines, Schmeltz and Hoffmann listed
nearly eighty components almost equally divided between
aliphatic and aromatic amines [see Tables I and II in (3491)].
Many of those they listed were identified in tobacco in the
late 1960s by Irvine and Saxby (1877) and in tobacco smoke
by Pailer et al. (2882, 2883, 2889).
Ishiguro and Sugawara (1884) had a few more amines than
those listed in the Schmeltz-Hoffmann compilation because
they included as aliphatic amines several cyclic amines
and their alkyl derivatives, such as pyrrolidine and piperi-
dine. However, this need not be considered a discrepancy.
Examination of the structures of N-ethylethanamine (dieth-
ylamine) {IV} vs. pyrrolidine {V} or N-(1-methylethyl)-2-
propanamine {VI} vs. 2,5-dimethylpyrrolidine {VII} reveals
the structural similarities (Figure XII-2).
While Tso (3973) in his 1990 book listed numerous nicotine
alkaloid-related amines as identified tobacco components, his
list also included ammonia but very few alkylamines and no
aromatic aniline-related amines in tobacco [see Table 27-1,
Part IV in (3973)].
In addition to the simplest amine of all, ammonia, included
in Table XII-1 for the sake of completeness are hydroxylam-
ine and hydrazine and several alkylhydrazine derivatives.
The source of many of the amines, including the alkylam-
ines in tobacco and/or its smoke, is the disintegration of vari-
ous proteins, individual amino acids, and nicotine-related
alkaloids (2001, 3477, 4275a) during tobacco growth or the
smoking process (3972). Obviously, a portion of those amines
identified in both tobacco and tobacco smoke occur in the
smoke because of their transfer from the tobacco during the
smoking process. The various benzenamine (aniline)-related
components in tobacco are considered to arise from enzy-
matic or microbial disintegration of the amino acids phenyla-
lanine or tyrosine (3491). Schmeltz et al. (3499) reported that
the benzenamine-related amines were not generated from
nicotine during the tobacco smoking process.
In its 1986 monograph on tobacco smoking, the
International Agency for Research on Cancer (IARC) [see
pp. 107–109 in (1870)] noted that about 200 amines had
been identified in tobacco smoke, based on its citation of the
627
11/24/08 12:24:30 PM
 628 The Chemical Components of Tobacco and Tobacco Smoke

R R1

N O O
N N O
R2 R R
O
I II III

Figure XII-1  Oxygenated N-containing components of tobacco and tobacco smoke.

N N N N
H H H H
IV V VI VII
Ethanamine, N-ethyl- Pyrrolidine 2-Propanamine, N-(1- Pyrrolidine, 2,5-dimethyl-
109-89-7 123-75-1 methylethyl)- 3378-71-0
108-18-9

Figure XII-2  Structural similarities of alkylamines and pyrrolidines.

1977 review by Schmeltz and Hoffmann (3491), the 1982
review by Dube and Green (1067), and the report by Heckman
and Best (1587). IARC described the per cigarette smoke
yield of several alkylamines, noting that the most plentiful
was methylamine. Citing the data presented by Patrianakos
and Hoffmann (2900), IARC also discussed the per cigarette
mainstream and sidestream smoke yields of several aromatic
amines including eleven benzenamines, the 1-and 2-naphtha-
lenamines, and the [1,1’-biphenyl]-2-, 3-, and 4-amines (the
aminobiphenyls). IARC noted that it had previously evalu-
ated the carcinogenicity of several tobacco smoke aromatic
amines, namely, 1- and 2-naphthalenamine, [1,1’-biphenyl]-
4-amine, benzenamine (aniline), 2-methylbenzenamine
(o-toluidine), N-phenyl-2-naphthalenamine, and 2-methoxy-
benzeneamine (o-anisidine). Table XII-1 summarizes the
IARC categorization of several amines, including hydrazine
and 1,1-dimethylhydrazine, identified in tobacco smoke [see
Appendix 2 in (1870)].
The IARC monograph (1870) is based on the findings
of its 1985 Working Group. Despite its review of the litera-
ture to 1985, the IARC had no comment about the numer-
ous reports (1835a, 2491a, 2492, 2849, 2849a, 2949b, 3829a,
3862b, 3862c, 3862d, 3865b, 4365a, 4388) issued from 1975
to 1985 on the isolation initially from cooked food and sub-
sequently from tobacco smoke of the tumorigenic and highly
mutagenic N-heterocyclic amines.

Table XII-1
IARC Evaluation of Carcinogenicity of Various Aromatic Amines in Tobacco Smoke (1870)
Degree of Evidence in
CAS No. Amine Yield, ng/cig Animals Humans
62-53-3 Benzenamine {aniline} 102, 364 a Limited evidence —
95-53-4 Benzenamine, 2-methyl 30-337b
{o-toluidine; 2-toluidine} 32, 162a Sufficient evidence Inadequate evidence
104-94-9 Benzenamine, 4-methoxy- {p-anisidine} present Sufficient evidence —
92-67-1 [1,1’-Biphenyl]-4-amine 2-5.6 c Sufficient evidence Sufficient evidence
{4-aminobiphenyl} 2.4, 4.6 a
302-01-2 Hydrazine 24-43 b Sufficient evidence Inadequate evidence
57-14-7 Hydrazine, 1,1-dimethyl- present b Sufficient evidence —
134-32-7 1-Naphthalenamine 4.3, 2.5 a Inadequate evidence Inadequate evidence
91-59-8 2-Naphthalenamine 1-334 b Sufficient evidence Inadequate evidence
1.0, 1.7 a
135-88-6 2-Naphthalenamine, N-phenyl- present Inadequate evidence Inadequate evidence
a Data cited by IARC (1870) from Patrianakos and Hoffmann (2900); first value is for a U.S. 85-mm non-filtered cigarette, second value is
for a French 70-mm non-filtered cigarette.
b Data cited by Hoffmann and Hoffmann (1741, 1743, 1744).
c Data cited by Hoffmann and Hoffmann (1743, 1744).

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 Acyclic Amines 629
There are several interesting aspects to the 1984 American
Chemical Society monograph on chemical carcinogens edited
by Searle (3568):
• Despite a voluminous review by Dipple et al. (983)
on PAHs and the tumorigenicity of many of them,
no mention was made of a tumorigenic or carcino-
genic PAH in tobacco smoke.
• The only significantly tumorigenic, carcinogenic,
or biologically active tobacco and tobacco smoke
components discussed in the 1400-page mono-
graph were the N-nitrosamines [see pp. 839–844
in Preussmann and Eisenbrand (2990)]. Much of
the data cited by Dipple et al. were those previ-
ously presented by Hoffmann and his colleagues
(514, 1680, 1685).
• In two chapters on the tumorigenicity of aro-
matic amines, neither Garner et al. (1275a) nor
Parkes and Evans (12A02) mention the presence in
tobacco smoke of the aromatic amines categorized
as significant tumorigens or carcinogens, namely,
2-naphthalenamine, [1,1’-biphenyl]-4-amine, and
2-methylbenzenamine (o-toluene). Garner et al.
[see Table I in (1275a)] tabulated the tumorigenic-
ity results of studies on many substituted benze-
namines (anilines). The data indicated that several
appeared to be as tumorigenic as or even more tum-
origenic than 2-methylbenzenamine (o-toluidine),
a tobacco smoke component listed as a significant
tumorigen (1217, 1727, 1740, 1741, 1743, 1744, 1773,
1808, 2825). Each of them has been identified as a
tobacco smoke component, for example, 3-methyl-
benzeneamine (m-toluidine), 4-methylbenzeneam-
ine (p-toluidine), and 2,4,6-trimethylbenzenamine
(mesitylamine), but none was listed as a significant
tumorigen.
• Despite the number of reports issued after 1975
on N-heterocyclic amines, Garner et al. (1275a)
did not mention their presence in tobacco smoke.
They commented, “A multitude of new aromatic
amine or heterocyclic amino compounds will most
© 2009 by Taylor & Francis Group, LLC
78836_C012.indd 629
likely be discovered in the foreseeable future, such
as those found in cooked foods” [Yamazoe et al.
(4370a), Takeda et al. (12A03)].
Several of the components listed in Table XII-1 have been
included in many of the lists of carcinogens, tumorigens,
or biologically active components in cigarette smoke pre-
sented by Fowles and Bates (1217), Hoffmann and colleagues
(1727, 1740, 1741, 1743, 1744, 1773, 1808), and OSHA (the
Occupational Safety and Health Administration) (2825).
Based on these lists, the per cigarette yields proposed by
some authorities, such as the Department of Health (Canada)
(12A01), to be determined of the “Hoffmann analytes” among
the amines include 1-naphthalenamine, 2-naphthalenamine,
[1,1’-biphenyl]-3-amine, [1,1’-biphenyl]-4-amine, 2-methyl-
benzenamine (o-toluidine), and ammonia.
The primary goal in Table XII-2 is the listing of those
tobacco and/or smoke components that are acyclic amines. In
some cases, an amino group, either unsubstituted (-NH2) or sub-
stituted {VIII}, may be linked to a cyclic N-containing structure,
R1
-N
R 2
VIII
for example, 2-pyridinamine, 2-amino-1,7-dihydro-6H-purin-6
-one (guanine), but the reason for inclusion of the component in
Table XII-2 is that part of the molecule is an acyclic amine.
For the sake of completeness, several components
have been included in Table XII-2 because they possess
the amine function (-NH 2) but are not linked to a carbon
atom, for example, ammonia, hydrazine, and hydroxylam-
ine. None of them fits the definition of an amide, imide,
or lactam. Other components included in Table XII-2 for
the sake of completeness are the amino acids with acy-
clic unsubstituted or substituted amine groups, the acyclic
N-nitrosamines, and the N-heterocyclic amines. With the
inclusion in Table XII-2 of the various items just men-
tioned, the number of acyclic amines and their derivatives
total 469, with 259 identified in smoke, 316 in tobacco,
and 106 in both tobacco and smoke.
11/24/08 12:24:31 PM
 630 The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2
Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke
Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

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 Acyclic Amines 631

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C012.indd 631 11/24/08 12:24:31 PM

 632 The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C012.indd 632 11/24/08 12:24:32 PM

 Acyclic Amines 633

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C012.indd 633 11/24/08 12:24:33 PM

 634 The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C012.indd 634 11/24/08 12:24:34 PM

 Acyclic Amines 635

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C012.indd 635 11/24/08 12:24:35 PM

 636 The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C012.indd 636 11/24/08 12:24:36 PM

 Acyclic Amines 637

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C012.indd 637 11/24/08 12:24:37 PM

 638 The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C012.indd 638 11/24/08 12:24:38 PM

 Acyclic Amines 639

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C012.indd 639 11/24/08 12:24:39 PM

 640 The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C012.indd 640 11/24/08 12:24:40 PM

 Acyclic Amines 641

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C012.indd 641 11/24/08 12:24:41 PM

 642 The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C012.indd 642 11/24/08 12:24:42 PM

 Acyclic Amines 643

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C012.indd 643 11/24/08 12:24:43 PM

 644 The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C012.indd 644 11/24/08 12:24:43 PM

 Acyclic Amines 645

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C012.indd 645 11/24/08 12:24:45 PM

 646 The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C012.indd 646 11/24/08 12:24:45 PM

 Acyclic Amines 647

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C012.indd 647 11/24/08 12:24:46 PM

 648 The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C012.indd 648 11/24/08 12:24:47 PM

 Acyclic Amines 649

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C012.indd 649 11/24/08 12:24:48 PM

 650 The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C012.indd 650 11/24/08 12:24:49 PM

 Acyclic Amines 651

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C012.indd 651 11/24/08 12:24:50 PM

 652 The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C012.indd 652 11/24/08 12:24:51 PM

 Acyclic Amines 653

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C012.indd 653 11/24/08 12:24:52 PM

 654 The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C012.indd 654 11/24/08 12:24:53 PM

 Acyclic Amines 655

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C012.indd 655 11/24/08 12:24:54 PM

 656 The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C012.indd 656 11/24/08 12:24:55 PM

 Acyclic Amines 657

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C012.indd 657 11/24/08 12:24:56 PM

 658 The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C012.indd 658 11/24/08 12:24:57 PM

 Acyclic Amines 659

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C012.indd 659 11/24/08 12:24:58 PM

 660 The Chemical Components of Tobacco and Tobacco Smoke

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C012.indd 660 11/24/08 12:24:59 PM

 Acyclic Amines 661

Table XII-2 (continued)

Amines Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C012.indd 661 11/24/08 12:25:00 PM

 13 Amides
In his 1954 compilation of smoke components, Kosak (2170)
listed no amide identified to that date. In their 1959 review
of tobacco and tobacco smoke components, Johnstone and
Plimmer (1971) described the identification of asparagine
and glutamine in tobacco and glutamine and nicotinamide in
tobacco smoke. The latter were identified in smoke by Buyske
et al. (562). In its 1963 monograph on tobacco and smoke com-
ponents, Philip Morris (2939) listed the amides, asparagine,
glutamine, citrulline, and nicotinamide, as tobacco components
but only glutamine and nicotinamide as smoke components.
Stedman (3797) in his 1968 review of tobacco and smoke
components listed asparagine, citrulline, and glutamine as
amino-acid related components, not as amides [see Table
XIV in (3797)]. Nicotinamide and N-methylnicotinamide
were not listed specifically as amides but as alkaloid deriva-
tives [see Table XI in (3797)]. Cotinine was also listed in the
same table.
Ishiguro and Sugawara (1884) in their 1980 monograph
on tobacco smoke components listed a total of seventy-two
amides, imides, and lactams (forty-nine amides, seven imides,
sixteen lactams) [see Table I-15 in (1884)]. The reference for
all but two of the compounds listed (formamide, urethane)
was Schumacher et al. (3553). Several amides, imides, and
lactams were listed by Ishiguro and Sugawara in other tables,
for example, asparagine and glutamine under amino acids
[Table I-19 in (1884)], cotinine and norcotinine under alka-
loids, caffeine under N-polycyclics (excluding alkaloids).
Citing publications by Schmeltz and Hoffmann (3491),
Schumacher et al. (3553), and Heckman and Best (1587), the
International Agency for Research on Cancer (IARC) in its
1986 monograph on tobacco smoking stated [see p. 109 in
(1870)] that there was a large spectrum of amides, imides,
and lactams in tobacco smoke (including some fifty aliphatic
amides). While the IARC commented on the Johnston et al.
1973 report on the per cigarette yields of formamide, acet-
amide, and propanamide, it did not mention that Johnston
et al., in their 1973 report (1965), had noted that only three
amides, glutamine, asparagine, and nicotinamide, had been
identified in tobacco smoke at that time. The IARC expressed
concern about the twenty-four secondary amides identified in
smoke, particularly N-methylformamide, N-methylacetamide,
N-methylpropanamide, and N-methylnicotinamide, because
of their propensity to generate tumorigenic nitrosamides.
Despite the fact that these secondary amides have been
identified in tobacco smoke and are known to readily form
N-nitrosamides, no such N-nitroso compound has been identi-
fied to date in tobacco smoke [Rodgman and Green (3300)].
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78836_C013.indd 663
IARC also mentioned the two lactams N-methyl-2-
pyrrolidone and N-methyl-2-piperidone and the urethanes,
but made no textual comment about their biological effect.
Of the fifty-three amides identified in tobacco smoke by
Schumacher et al. (3553), thirty-two were new to tobacco
smoke composition. Their contribution in this regard was the
result of the use of an analytical technology that permitted
the fractionation and identification of many components in
the water-soluble portion of cigarette smoke condensate.
In his study of the composition of smoke from an all-
burley tobacco cigarette, Heckman (1586) identified six-
teen amides, ranging in complexity from acetamide to
N′-formylnornicotine.
Although 186 amides are cataloged in Table XIII-1, it
should be realized that the number of amides in tobacco far
exceed the number of amides listed for tobacco and tobacco
smoke. Each of the many thousands of enzymes, proteins, and
proteinaceous components in tobacco possesses many amido
linkages. Nearly 500 of the well-characterized enzymes and
proteins are cataloged in Table XXII-2 in Chapter XXII, but
that number is only a small fraction of the great number of
such components in tobacco.
IARC had little to say about the possible ill effects of any
of the amides in tobacco smoke. However, it did note in an
appendix to its monograph [Appendix 2, pp. 389–394 in (1870)]
that sufficient evidence existed for the initiating and cocarci-
nogenic activity in animals of urethane (ethyl carbamate) and
the evidence was limited for acetamide. IARC listed the per
cigarette yields of acetamide and urethane. In the first listing
of tumorigens, carcinogens, and toxicants in tobacco smoke,
by Hoffmann and Wynder in 1986 (1808), only urethane was
included. Urethane was included in several subsequent lists,
those by Hoffmann and Hecht (1727), Hoffmann et al. (1773),
and Hoffmann and Hoffmann (1740). In their 1997 list (1740),
Hoffmann and Hoffmann added acrylamide (2-propenamide)
as present in cigarette smoke but no per cigarette yield was
included. In their next three lists of tumorigens, carcinogens,
and toxicants in tobacco smoke issued between 1998 and
2001, Hoffmann and Hoffmann (1741, 1743, 1744) listed per
cigarette yields of acetamide and urethane and the presence
of acrylamide. Other listings of tumorigens, carcinogens, and
toxicants in tobacco and tobacco smoke by the Occupational
Safety and Health Administration (OSHA) (2825) in 1994
and Fowles and Bates (1217) in 2001 included urethane but
not acetamide or acrylamide. The various degrees of inclu-
sion in the many lists issued between 1986 and 2001 were
summarized by Rodgman (3265).
663
11/13/08 5:31:16 PM
 664 The Chemical Components of Tobacco and Tobacco Smoke

Acetamide, acrylamide, and urethane were not included
in most of the requirements for “Hoffmann analyte” data
as an indication of cigarette smoke hazard, for example, the
Department of Health (Canada) proposal in 2000 (25A06).
One other aspect of interest concerning amides is that sev-
eral (asparagine, glutamine, and urea) appear on the Doull
et al. list of individual compounds used in cigarette manu-
facture by U.S. companies (1053). The Doull et al. list also
includes the imide 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,
6-dione (caffeine).
Although they are on the borderline of the definition of
an amide, urethane plus urea and several of its derivatives
have been included in Table XIII-1. Because each possesses
structure I, each was included as an amide for the sake of
completeness, for example, urea is H2N-CO-NH2 and ethyl
urethane is H2N-COO-C2H5. Several of the urea derivatives
are compounds used in tobacco agronomy.
H
N
R1
O
R2
I
The number of compounds in Table XIII-1 totals 212, of
which 191 are amides. The remaining components include
urethane plus urea and several of its derivatives. Of the 212
compounds, 127 were identified in tobacco, 118 in tobacco
smoke, and 33 were identified in both tobacco and smoke.

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 Amides 665

Table XIII-1
Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C013.indd 665 11/13/08 5:31:19 PM

 666 The Chemical Components of Tobacco and Tobacco Smoke

Table XIII-1 (continued)

Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C013.indd 666 11/13/08 5:31:20 PM

 Amides 667

Table XIII-1 (continued)

Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C013.indd 667 11/13/08 5:31:21 PM

 668 The Chemical Components of Tobacco and Tobacco Smoke

Table XIII-1 (continued)

Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C013.indd 668 11/13/08 5:31:22 PM

 Amides 669

Table XIII-1 (continued)

Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C013.indd 669 11/13/08 5:31:24 PM

 670 The Chemical Components of Tobacco and Tobacco Smoke

Table XIII-1 (continued)

Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C013.indd 670 11/13/08 5:31:32 PM

 Amides 671

Table XIII-1 (continued)

Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C013.indd 671 11/13/08 5:31:33 PM

 672 The Chemical Components of Tobacco and Tobacco Smoke

Table XIII-1 (continued)

Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C013.indd 672 11/13/08 5:31:37 PM

 Amides 673

Table XIII-1 (continued)

Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C013.indd 673 11/13/08 5:31:40 PM

 674 The Chemical Components of Tobacco and Tobacco Smoke

Table XIII-1 (continued)

Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C013.indd 674 11/13/08 5:31:41 PM

 Amides 675

Table XIII-1 (continued)

Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C013.indd 675 11/13/08 5:31:44 PM

 676 The Chemical Components of Tobacco and Tobacco Smoke

Table XIII-1 (continued)

Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C013.indd 676 11/13/08 5:31:46 PM

 Amides 677

Table XIII-1 (continued)

Amides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C013.indd 677 11/13/08 5:31:49 PM

 14 Imides

In his 1954 compilation of tobacco smoke components, Kosak
(2170) listed no imide identified in tobacco smoke to that date.
Ishiguro and Sugawara, in their 1980 monograph on tobacco
smoke components, listed a total of seventy-two amides, imi-
des, and lactams, including seven imides [see Table I-15 in
(1884)]. Their reference for all the imides listed was that of
Schumacher et al. (3553). Ishiguro and Sugawara did not list
caffeine as an imide but listed it under N-polycyclics (exclud-
ing alkaloids) [see Table I-14 in (1884)].
In its 1986 monograph on tobacco smoking, the Inter-
national Agency for Research on Cancer (IARC) stated that
there was a large spectrum of amides, imides, and lactams in
tobacco smoke (including some fifty aliphatic amides) [see
p. 109 in (1870)]. The basis for the IARC comments were the
1977 review of N-containing components in tobacco and
tobacco smoke by Schmeltz and Hoffmann (3491) and the
smoke composition publication in 1977 of Schumacher et al.
(3553) and in 1981 by Heckman and Best (1587).
Of the twenty-four imides identified in tobacco smoke by
Schumacher et al. (3553), six were new to tobacco smoke com-
position. Many of the previously identified imides were deriva-
tives of 1H-pyrrole-2,5-dione (maleimide), 2,5-pyrrolidinedione
(succinimide), and 1H-isoindole-1,3(2H)-dione (phthalimide).
The use of a recently developed analytical technology that per-
mitted the fractionation and identification of components in the
water-soluble portion of cigarette smoke condensate (CSC) was
a key factor in their mid-1977 study. In a detailed study of the
ether-soluble portion from the same CSC studied by Schumacher
et al., Newell et al. (2769) identified five imides. In his earlier
study of the composition of smoke from an all-burley tobacco
cigarette, Heckman (1586) identified fifteen imides.
Examination of the structures of several of the CSC com-
ponents indicates that the decision of their categorization is
somewhat difficult. In Figure XIV-IA, representative struc-
tures for an amide, an imide, and a lactam are presented. To
which of these categories—amide, imide, or lactam—should
the smoke component 1-acetyl-3-ethyl-1,5-dihydro-4-methyl-
2H-pyrrol-2-one {I} be assigned? Its structure is depicted in
Figure XIV-IB. In Structure {II} of Figure XIV.B, the amide
configuration is shown. Structures {III} and {IV} show the
imide and lactam configurations, respectively. This same
situation is present with several other smoke components.
Although there may be some disagreement on the preciseness
of our selection, for completeness sake such components are
listed in each chapter in its major catalog table. As a result,
the total number of components in each of the major catalog
tables may be slightly inflated.
In addition to several amides (asparagine, glutamine,
urea), Doull et al. lists the imide 3,7-dihydro-1,3,7-trimethyl-
1H-purine-2,6-dione (caffeine) among individual compounds
used in cigarette manufacture by U.S. companies (1053).
The seventy-nine imides identified in tobacco and tobacco
smoke are cataloged in Table XIV-1. Of the seventy-nine
imides reported, thirty-nine have been identified in tobacco,
fifty-nine in tobacco smoke, and nineteen in both tobacco and
smoke.

R1 R2
N
O N O N O
H H
O R
Amide Imide Lactam
configuration configuration configuration

Figure XIV-1A  The amide, imide, and lactam configurations.

H3C C2H5 H3C C2H5 H3C C2H5 H3C C2H5

N O O O N O
N N

O CH3 O CH3
O CH3 H 3C O

I II III IV
2H-Pyrrol-2-one, 1-acetyl-3-ethyl-1,5-dihydro-4-methyl-
(CAS No. 61892-80-6)

Figure XIV-1B  The amide {II}, imide {III}, and lactam {IV} configurations in 1-acetyl-3-ethyl-1,5-dihydro-4-methyl-2H-pyrrol-2-one {I}.

679

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 680 The Chemical Components of Tobacco and Tobacco Smoke

Table XIV-1
Imides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C014.indd 680 11/13/08 5:32:35 PM

 Imides 681

Table XIV-1 (continued)

Imides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 682 The Chemical Components of Tobacco and Tobacco Smoke

Table XIV-1 (continued)

Imides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Imides 683

Table XIV-1 (continued)

Imides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 684 The Chemical Components of Tobacco and Tobacco Smoke

Table XIV-1 (continued)

Imides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C014.indd 684 11/13/08 5:32:40 PM

 Imides 685

Table XIV-1 (continued)

Imides Identified in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 15 N-Nitrosamines
The introduction to this chapter on N-nitrosamines (NNAs)
in tobacco and tobacco smoke is a considerably abbreviated
but updated version of the lengthy unpublished 1993 memo-
randum by Rodgman (3256). Omitted from this outline are
several sections covered in detail in (3256). These include
much of the discussion on the early studies of the biological
properties of NNAs [see pp. 117–178 in (3256)] and studies
on alternate sources of exposure to NNAs [see pp. 107–116
in (3257)].
The numerous publications during the past two decades
on the identification, quantitation, and bioassay of NNAs,
particularly those found in tobacco-related entities [tobacco,
mainstream smoke (MSS), sidestream cigarette smoke (SSS),
and environmental tobacco smoke (ETS)] raise the question
as to why this class of tobacco/tobacco smoke components
has received such emphasis. Since the early 1950s, several
classes of compounds in tobacco smoke have been proposed
as prime contributors to cancer of the respiratory tract in
smokers. The events that triggered detailed examination of
the composition of cigarette MSS included:
1. The results of retrospective studies that were
interpreted as indicating an association between
cigarette smoking and carcinoma of the lung in
smokers [Levin et al. (2355), Mills and Porter
(2556), Schrek et al. (3529), Wynder and Graham
(4306b), Doll and Hill (1027), McConnell et al.
(2525), Sadowky et al. (3375a)]. Subsequently, the
results from additional retrospective studies and
several prospective studies on smoking and respi-
ratory tract cancer bolstered the evidence for this
association.
2. Bioassay results from studies (4306a, 4306c) in
which carcinomas were produced in susceptible
mouse strains at the site of repeated skin paint-
ing with massive doses of cigarette smoke con-
densate (CSC) prepared in a manner supposedly
simulating the human smoking process (the puff
frequency used was a 2-sec puff each 20 sec vs.
the usually accepted routine of a 2-sec puff each
60 sec). Between 1953 and late 1966, the major
skin-painting studies involving CSC administered
to various laboratory animal species numbered
about sixty (4332).
Despite numerous statements to the contrary—that the
data from mouse skin-painting experiments with CSC were
not extrapolable from mouse skin to the human lung, some
authorities continued to imply that such data were meaningful
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in terms of respiratory tract cancer in smokers. For example,
Wynder (4292) wrote:
The mouse skin test cannot give definitive proof for a human
carcinogen, although it has long been used as a reliable tool
for testing of carcinogenic materials … The animal data
must be considered, not as a proof for the human experience,
but as a tool with which to work toward the isolation and
identification of carcinogenic agent(s). At this time we can
only assume, on the basis of the combined human and ani-
mal data, that these carcinogens are the same for man and
for mice.
In 1956, Wynder (4295) stated:
We believe that no animal data can be used to establish a
causative role in cancer in man. Such proof can come only
from human epidemiologic data … animal evidence by
itself can never establish a human carcinogen nor can it ever
disprove it … For example, if we suspect tobacco as a car-
cinogen to man, animal experimentation can determine the
specific parts of tobacco which are carcinogenic to animals.
Once identified, we can only assume that the specific car-
cinogens are the same to which man also responds and intro-
duce preventive measures accordingly.
Despite comments such as these and additional ones in
later publications, animal experimentation, particularly
mouse skin-painting studies, constituted a substantial part
of the bioassays on tobacco smoke. Such bioassays are not
only expensive but also extremely time consuming (18 to 24
months). Because of the absence of a positive response in
studies of tobacco smoke inhalation by laboratory animals,
mouse skin-painting with CSC was selected as the bioas-
say of choice in the massive decade-long (1970–1980) study
conducted by the National Cancer Institute (NCI) on “less
hazardous” cigarettes, a study that involved nearly 100 test
cigarettes and 30 standard or reference cigarettes (1329,
1330, 1332, 1333, 2683).
Successively after the late 1950s, various classes of smoke
components were proposed as either the cause of (as tumor
initiators) or contributors to (as promoters, cocarcinogens,
ciliastats) lung cancer in smokers:
1. Polycyclic aromatic hydrocarbons (PAHs)
2. Their polycyclic nitrogen analogs, the aza-arenes,
reported to be carcinogenic to mouse skin
3. Low molecular weight phenols reported to be pro-
moters of tumorigenic PAHs
4. Aldehydes and ketones reported to be ciliastatic in
in vitro ciliated systems
687
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 688 The Chemical Components of Tobacco and Tobacco Smoke
5. Aromatic amines
6. Metallic items (210Po, Ni)
7. Other miscellaneous compounds, such as ethyl
urethan
One by one the claims for involvement of each of these
classes of compounds were either discounted or seriously
questioned [Rodgman (3255, 3257), Rodgman et al. (3307)].
PAHs were described as the only major tumor initiators in
mouse skin carcinogenesis [Wynder and Hoffmann (4332)]:
The many detailed data obtained in studies of tobacco car-
cinogenesis on mouse skin exclude with some certainty the
major tumor initiators other than the PAH type play a role in
this assay system.
Benzo[a]pyrene (B[a]P), because of its potency in skin-
tumor carcinogenesis and per cigarette MSS yield, was
considered the major PAH of concern in tobacco smoke. In
1981, the Surgeon General commented on PAHs [see p. 36
in (4009)]:
BaP appears to be the most important single member of this
class of compounds, taking into consideration both its con-
centration and its relative carcinogenic potency.
It was obvious that additional mechanisms were needed to
explain the observed biological effect since (1) B[a]P in CSC
acting alone accounted for less than 2% of the observed bio-
logical response in mouse skin-painting studies, (2) the total
PAH fraction accounted for less than 3% of the observed bio-
logical response in mouse skin-painting studies, (3) no “super-
carcinogenic” PAH was found in CSC (3756–3758, 4282),
and (4) inclusion of tumorigenic aza-arenes in CSC explained
very little more of the unexplained tumorigenicity.
The first additional explanation of the observed effect in
skin-painting studies with CSC involved the mechanisms of
promotion and cocarcinogenesis of tobacco smoke compo-
nents. The smoke components first classified as promoters
were the low molecular weight phenols because of their
known promotion of such potent tumorigenic PAHs as B[a]P
and dibenz[a,h]anthracene (DB[a,h]A) (414).
However, the significance of the promoting/cocarcino-
genic effect of tobacco smoke phenols on PAH tumorigenic-
ity [Wynder and Hoffmann (4309, 4317, 4344)] was offset by
the following observations:
1. Removal of a substantial amount (70% to 85%)
of the low molecular weight phenols from CSC
by selective filtration of the MSS did “not change
significantly the biological activity of the resulting
condensate” [Wynder and Hoffmann, see p. 626 in
(4332), Hecht et al., see p. 2 in presentation manu-
script (1582, 1583)].
2. Low molecular weight phenols inhibited the tum-
origenicity of B[a]P [Van Duuren et al. (4029,
4035)].
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3. Inclusion of known initiators, promoters, and
cocarcinogens in tobacco smoke in the calcula-
tion of its tumorigenicity explained less than 5%
of the observed biological effect in skin-painting
studies.
The failure of several groups of investigators [Candeli et
al. (587), Kaburaki et al. (2006), Schmeltz et al. (3499, 3512),
Snook (3733), Snook et al. (3750), Grimmer et al. (1409), Kamata
et al. (2021), Sasaki and Moldoveanu (3414), Rustemeier et al.
(3370)] to reproduce the findings of Van Duuren et al. (4027)
on the presence and/or levels of the aza-arenes dibenz[a,h]
acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole in
tobacco smoke was discussed by Rodgman [3255, 3260, see
Table 4 in (3265)] and Baker (172).
The failure to explain the observed tumorigenicity of CSC
in the mouse-skin bioassay by consideration of the following
tobacco smoke systems led to the inclusion of ciliastasis by
various water-soluble vapor-phase (VP) tobacco smoke com-
ponents in an attempt to explain the causation of respiratory
tract cancer in smokers:
1. The levels in CSC of mouse-skin tumorigenic
PAHs, acting individually or in concert, could not
account for the response in CSC-painted animals.
2. The CSC levels of mouse-skin tumorigenic PAHs
plus the promoting/cocarcinogenic phenols, acting
individually or in concert, could not account for
the observed response in CSC-painted animals.
3. The CSC levels of mouse-skin tumorigenic PAHs
plus promoting/cocarcinogenic phenols and non-
tumorigenic PAHs, acting individually or in con-
cert, could not account for the observed response
in CSC-painted animals.
4. Inclusion of tumorigenic aza-arenes in the calcula-
tion could not account for the observed biological
response.
In fact, when the levels of the known tumorigenic, promot-
ing, and cocarcinogenic components of tobacco smoke and
their activity toward mouse skin are included in the assess-
ment, less than 5% of the observed biological response in the
CSC-painted animals can be explained!
To circumvent this failure to explain the observations
with CSC-treated laboratory animals and attempt to explain
the epidemiological findings in human smokers, ciliastasis
was introduced as an additional mechanism involved in the
causation of smokers’ lung cancer. In a variety of in vitro
systems, ciliastasis was produced by cigarette MSS VP and
by individual MSS VP components (hydrogen cyanide, form-
aldehyde, acetaldehyde, acetone, phenol). It was proposed
that ciliastasis occurred in the smokers’ respiratory tract and
significantly diminished the lung clearance mechanism of
the cilia, thus permitting tobacco smoke particulate-phase
particles (and their included “tumorigens”) to remain on the
lung surface and initiate the cellular changes required for
tumor development. However, this proposal was seriously
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 N-Nitrosamines 689
compromised by the demonstration in intact animals as well
as in human smokers that a large proportion (60% to 75%)
of the in vitro ciliastats (all water-soluble) in the inhaled
smoke failed to reach the ciliated tissue in the respiratory
tract because of solution in the aqueous secretions coating
the oral cavity tissues [Rodgman et al. (3306), Dalhamn et al.
(892, 893)].
Prior to the emphasis on NNAs, the class of tobacco smoke
components subjected to the most study was the PAHs, with
particular emphasis on the CSC compound considered the
most potent, B[a]P. Although the NNAs identified in tobacco
and/or tobacco smoke number fewer than sixty, the number
of PAHs either identified or partially identified* exceeds 500
[Severson et al. (3619), Snook et al. (3756-3758), Rodgman
and Perfetti (3306a)].
The role played by the PAHs, particularly B[a]P, in induc-
tion of skin carcinoma in skin-painted laboratory animals
was seriously questioned because of the demonstrations
by Roe (3310, 3311) that a 10-fold increase and by Lazar
et al. (2320) that a 30-fold increase in the B[a]P level of CSC
failed to produce an increase in its tumorigenicity to mouse
skin. This lack of correlation between levels of PAHs [B[a]
P, benz[a]anthracene (B[a]A)] in CSC and percent tumor-
bearing animals was demonstrated in the NCI “less hazard-
ous” cigarette study [Gori (3329, 3230, 3232, 3233), National
Cancer Institute (2683)]. The results were acknowledged in
the U.S. Surgeon General’s 1981 report [see p. 36 in (4009)]:
The contribution of BaP or PAH in general to mouse skin
carcinogenesis by cigarette smoke condensate cannot be
fully measured at this time. Wynder and Hoffmann (4332)
found a correlation between BaP levels and carcinogenic
activity of smoke condensates from several types of ciga-
rettes. A much larger series of experimental cigarettes was
studied in the smoking and health program of the National
Cancer Institute. No significant dependence of carcinogenic
potency on BaP was observed [Gori (3329, 3230, 3232, 3233),
NCI (2683)].
It should be noted that in the NCI “less hazardous”
cigarette study, neither the tobaccos used in the nearly 100
experimental cigarettes and thirty standard and reference
cigarettes nor the MSSs generated from them were analyzed
for NNAs.
Despite observations that NNAs in CSC or NNAs indi-
vidually induce few, if any, tumors at the application site in
mouse skin-painting studies with CSC, they are one of the
two classes of tobacco product components to which the pro-
health forces continue to devote their major efforts. In 1990,
Hoffmann and Hecht (1727) noted:
Mouse skin is particularly responsive to PAH tumorigenesis.
It is not equally responsive to other important classes of car-
cinogens such as N-nitrosamines …
* The partial identification of a PAH refers to the instances where the posi-
tions of alkyl substituents and/or their precise identity are uncertain, for
example, a trimethyl vs. an ethylmethyl derivative.
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78836_C015.indd 689
As noted in 1984 by Hoffmann et al. (1696), three types
of NNAs are formed in tobacco processing and during the
tobacco smoking process: volatile N-nitrosamines (VNAs),
tobacco-specific N-nitrosamines (TSNAs), and nonvolatile
N-nitrosamines. The latter include N-nitrosodiethanolamine
(NDELA) and N-nitrosoproline (NPRO). Recently, several
N-nitrosamino acids were identified in tobacco. The major
NNAs identified in tobacco and/or tobacco smoke are listed
in Table XV-1.
In the mid-1960s, Fredrickson (1236), using a laboratory
procedure that precluded artifactual formation of NNAs,
identified several volatile NNAs in cigarette MSS. He also
reported that volatile NNAs, like the low molecular weight
phenols, are selectively removed from MSS by plasticized
(triacetin) cellulose acetate filters. Per cigarette MSS volatile
NNA yields are reduced by 75% to 80% in this manner, a
value similar to that observed with the selective filtration of
low molecular weight phenols. This diminution of volatile
NNA yields was confirmed several years later by Morie and
Sloan (2635) and Brunnemann et al. (514).
TSNAs, because of their low volatility, occur predomi-
nantly in the MSS particulate phase and behave similarly to
other particulate-phase components such as the PAHs, that is,
they are not selectively reduced by filtration with plasticized
cellulose acetate. However, Hoffmann et al. (1685) noted that
MSS TSNA yields are reduced by any technology designed
to reduce the MSS particulate phase, such as increased fil-
tration efficiency, increased air dilution (filter-tip perforation,
paper porosity), and tobacco expansion.
The precursors in tobacco of the NNAs in tobacco smoke
have been studied extensively. Tobacco protein is reported
by Brunnemann et al. (511) to be the major precursor of the
volatile NNAs and N-nitrosoproline (NPRO). Based on these
findings, Hoffmann et al. (1696) wrote:
The protein fraction of tobacco appears to represent the major
precursor group of the carcinogenic volatile nitrosamines in
smoke. In addition, Tso et al. (3985) had previously reported
that the volatile NNAs in smoke are proportional to the
nitrate content of the tobacco filler, an observation also made
by Morie and Sloan (2635).
Precursors of TSNAs in tobacco and smoke are nicotine,
nornicotine, anabasine, and anatabine [Hecht et al. (1564),
Adams et al. (29)]. Both nicotine and nornicotine are con-
sidered precursors of N’-nitrosonornicotine (NNN). Direct
transfer of TSNAs from tobacco to the smoke accounts for
about 40% of NNN and 30% of 4-(N-methylnitrosamino)-1-
(3-pyridinyl)-1-butanone (NNK) in MSS. The remainder of
these two TSNAs in the MSS is formed during the smoking
process [Hoffmann et al. (1734), Hecht et al. (1564)]. Like the
levels of the volatile NNAs in MSS, the yields of the TSNAs
in MSS are proportional to the nitrate content of the tobacco
filler (3985).
PAHs are ubiquitous. They are present in the atmosphere
as components of a variety of dusts, soots, tars, oils, engine
exhaust gases; in water; in many commonly consumed food-
stuffs, particularly those that are heated, roasted, or broiled
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 690 The Chemical Components of Tobacco and Tobacco Smoke
Table XV-1
Major N-Nitrosamines in Tobacco and/or Tobacco Smoke
Chemical Name Abbreviation
Volatile N-nitrosamines
1-Butanamine, N-butyl-N-nitroso- NDBA
1-Butanamine, N-methyl-N-nitroso- NBMA
Ethanamine, N,1-dimethyl-N-nitroso-
Ethanamine, N-ethyl-N-nitroso- NDEA
Ethanamine, N-methyl-N-nitroso- NEMA
Methanamine, N-methyl-N-nitroso- NDMA
Morpholine, 4-nitroso- NMOR
Piperidine, 1-nitroso- NPIP
Propanal, 3-(methylnitrosamino)-
1-Propanamine, N,2-dimethyl-N-nitroso-
1-Propanamine, N-ethyl-2-methyl-N-nitroso-
1-Propanamine, N-ethyl-N-nitroso-
1-Propanamine, N-methyl-N-nitroso
1-Propanamine, N-nitroso-N-propyl- NDPA
Propionitrile, 3-(methylnitrosamino)-
Pyrrolidine, 1-nitroso- NPYR
Nonvolatile N-nitrosamines
Diethanolamine, N-nitroso- NDELA
2-Pyrrolidinecarboxylic acid, 1-nitroso- NPRO
Tobacco-Specific N-nitrosamines
2,3’-Bipyridine, 1-nitroso-1,2,3,6-tetrahydro- NAT
Butanal, 4-(N-methylnitrosamino)-4-(3-pyridinyl)-
Butanoic acid, 4-(N-methylnitrosamino)-4-(3-pyridinyl)- iso-NNAC
1-Butanol, 4-(N-methylnitrosamino)-1-(3-pyridinyl)- NNAL
1-Butanol, 4-(N-methylnitrosamino)-4-(3-pyridinyl)- iso-NNAL
1-Butanone, 4-(N-methylnitrosamino)-1-(3-pyridinyl)- NNK
Pyridine, 3-(1-nitroso-2-piperidinyl)- NAB
Pyridine, 3-(1-nitroso-2-pyrrolidinyl)- NNN
N-Nitrosamino Acids, Esters, Nitriles
Acetic acid, 2-(methylnitrosamino)- NSAR
Acetic acid, 2-(methylnitrosamino)-, methyl ester
Butanoic acid, 4-(methylnitrosamino)- NMBA
Butanoic acid, 4-(methylnitrosamino)-, methyl ester
Hexanoic acid, 2,6-di-(methylnitrosamino)-
Pentanoic acid, 2,5-di-(methylnitrosamino)-
2-Piperidinecarboxylic acid, 1-nitroso-
Propanoic acid, 3-(methylnitrosamino)- NMPA
Propanoic acid, 3-(methylnitrosamino)-, methyl ester
Propanoic acid, 2-(methylnitrosamino)-3-phenyl-
2-Pyrrolidinecarboxylic acid, 1-nitroso-, methyl ester
[Rodgman (15A48), Grasso (1345), Maga (2438)] and in ETS.
Similarly, exposure to NNAs is widespread. Volatile NNAs
are not only components of MSS, SSS, and ETS, they are
also present in a variety of foodstuffs and beverages. Sen et
al. (15A52) noted:
Nitrosopyrrolidine , which is a potent liver carcinogen [in
[a]
laboratory animals], has been shown to be formed during the
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78836_C015.indd 690
Common Name
N-nitrosodibutylamine
N-nitrosobutylmethylamine
N-nitrosoisopropylmethylamine
N-nitrosodiethylamine
N-nitrosoethylmethylamine
N-nitrosodimethylamine
N-nitrosomorpholine
N-nitrosopiperidine
3-(methylnitrosamino)propionaldehyde
N-nitrosoisobutylmethylamine;
N-nitrosomethyl(2-methylpropyl)amine
N-nitrosoethylisobutylamine;
N-nitrosoethyl(2-methylpropyl)amine
N-nitrosoethylpropylamine
N-nitrosomethylpropylamine
N-nitrosodipropylamine
3-(methylnitrosamino)propionitrile,
N-nitrosopyrrolidine
N-nitrosodiethanolamine
N-nitrosoproline;
2-pyrrolidinecarboxylic acid, 1-nitroso-
N’-nitrosoanatabine
4-(N-methylnitrosamino)-4-(3-pyridinyl)-butanal
4-(N-methylnitrosamino)-4-(3-pyridinyl)- butanoic acid
4-(N-methylnitrosamino)-1-(3-pyridinyl)-butanol
4-(N-methylnitrosamino)-4-(3-pyridinyl)- butanol
4-(N-methylnitrosamino)-1-(3-pyridinyl)-butanone
N’-nitrosoanabasine
N’-nitrosonornicotine
N-nitrosarcosine; N-methyl-N-nitrosoglycine
4-(methylnitrosamino)butanoic acid
4-(methylnitrosamino)butanoic acid, methyl ester
2,6-di-(methylnitrosamino)hexanoic acid
2,5-di-(methylnitrosamino)pentanoic acid
1-nitroso-2-piperidinecarboxylic acid
3-(methylnitrosamino)propanoic acid;
N-methyl-N-nitroso-β-alanine
3-(methylnitrosamino)propanoic acid, methyl ester
2-(methylnitrosamino)-3-phenylpropanoic acid
1-nitroso-2-pyrrolidinecarboxylic acid, methyl ester;
N-nitrosoproline, methyl ester
frying of bacon, and to be present in sausage, corned beef,
luncheon meat, fried pig liver, cooked and uncooked cod fish
and finned herring.
[a]As noted previously, NPYR is a tobacco smoke component.
The magnitude of the occurrence of NDMA in beer
was studied by Spiegelhalder (15A54) in a survey of many
German beers: 70% of the sample showed NDMA at a mean
11/13/08 7:14:50 PM
 N-Nitrosamines 691
concentration of 2.7 ppb with a maximum of 68 ppb. Barley
malt was considered the NNA source. In 1988, Maga (2438)
reviewed some forty publications on NNAs in common food-
stuffs, beverages, and spices.
The generation of NNAs by the reaction of ingested
nitrates with body chemical components was discussed in a
survey by the Office of Technology Assessment (15A38):
Nitrate and nitrate salts naturally occur in vegetable, fish and
meats, are in food for their preservative properties and are
present in pesticide and drug residues in food. They react
with other chemicals in the body to produce NNAs and
N-nitrosamides.
In their 1990 list of forty-three “tumorigenic agents in
tobacco and tobacco smoke,” a list cited frequently in reports
issued by various governmental agencies (EPA, USPHS),
Hoffmann and Hecht (1727) included five volatile NNAs
(NDMA, NDEA, NEMA, NPYR, and NMOR), one nonvol-
atile NNA (NDELA), and three TSNAs (NNN, NNK, and
NAB). Repeatedly since the mid-1980s, Hoffmann and his
colleagues have published detailed reviews on NNAs, par-
ticularly TSNAs, their levels in tobacco, MSS, SSS, and ETS,
and their supposed involvement in cancer induction in tobacco
users plus many reports on other aspects of NNAs [Hecht et al.
(15A18), Hoffmann et al. (1688, 1698, 1731, 1745, 1746,
1750, 1770–1772, 1774–1776), Hecht and Hoffmann (1571,
1571a, 15A19, 15A20), Hoffmann and Hecht (1725, 1727),
Brunnemann et al. (459, 477), Brunnemann and Hoffmann
(483, 484, 486, 487), Djordjevic et al. (977, 1013, 1015–1017),
Andersen et al. (76), Rivenson et al. (3182), Prokopczyk et al.
(2994, 2997)].
In addition to the studies by Hoffmann et al., a great
number of conference presentations and journal publications
on NNAs, particularly TSNAs, have been provided by other
investigators. A representative sample includes the contribu-
tions by Brown et al. (437), Bush et al. (557), d’Andres et
al. (895), de Roton et al. (951), Katsuya et al. (2050–2052),
Moldoveanu et al. (2599), Nestor et al. (2700), Peele et al.
(2917), Risner et al. (3176a), Risner and Wendelboe (3177),
Tricker (3953), and Tricker et al. (3944–3948).
Finally, with regard to NNAs it should be noted that CSCs
from tobaccos grown under high-nitrate fertilization regimes
produce fewer tumor-bearing animals than do the CSCs from
tobaccos grown under low-nitrate fertilization regimes even
though high-nitrate tobaccos usually show higher levels of
both volatile NNAs and TSNAs and their smokes contain
higher levels of these compounds than do low-nitrate tobac-
cos. The responses observed in mutagenicity testing (Ames
test with Salmonella typhimurium) are the opposite of those
observed in mouse skin-painting studies. Nitrate addition, use
of high-nitrate tobacco, and/or use of tobacco stems, which
are generally much higher in nitrate than laminae, result in
reduced levels of MSS total particulate matter (and “tar”)
and in mainstream CSCs with reduced levels of phenols
and PAHs, including B[a]P, plus increased levels of NNAs
[Wynder and Hoffmann (4312, 4317), Hoffmann and Wynder
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78836_C015.indd 691
(1797, 1798, 1801, 1802), Rathkamp and Hoffmann (3081,
3082), Hoffmann et al. (1783), Brunnemann and Hoffmann
(480), Adams et al. (28)].
XV.A Volatile N-Nitrosamines
The volatile NNAs in tobacco smoke, usually reported as
tobacco smoke components that contribute to the health prob-
lems related to smoking, particularly the cigarette smoke-
respiratory tract cancer problem, are the first seven listed in
Table XV-2.
Table XV-3 summarizes much of the early research on the
volatile N-nitrosamines.
Almost a decade after the proposal by Boyland et al. (422,
423, 15A00) that the TSNAs NNN and NAB might be pres-
ent in tobacco and tobacco smoke, NNN was identified in
cigarette MSS by Klus and Kuhn (2136). This and subsequent
identification of other TSNAs in tobacco and smoke resulted
in a gradual decrease in the research effort on volatile NNAs
and a significant increase in the research effort on TSNAs.
XV.B Nonvolatile N-Nitrosamines
As noted in Table XV-1, N-nitrosodiethanolamine (NDELA)
and N-nitrosoproline (NPRO) are classified as nonvolatile
NNAs in tobacco and tobacco smoke. In bioassays in labora-
tory animals, N-nitrosoproline (NPRO) is the only tobacco/
tobacco smoke NNA to give negative responses.
The one considered the more controversial of the two is
NDELA. Prior to its identification in tobacco in 1977 and
smoke in 1981, its biological properties in laboratory animals
and other test systems had been studied for over a decade.
Druckrey et al. (1058) reported that NDELA was an hepatic
carcinogen in rats. In its review of biological data generated
in NNA studies, the IARC (1866) reported that this com-
pound induced tracheal carcinomas in the hamster. Lijinsky
et al. (15A35) reported that NDELA induced carcinoma of
the liver and kidney in rats. McMahon et al. (2521) reported
that NDELA was mutagenic when tested in modifications of
the Ames test with Salmonella typhimurium.
In 1977, Schmeltz et al. (3480) isolated NDELA from
tobacco and identified it. In 1981, Brunnemann and Hoffmann
(479) reported that cigarettes fabricated from tobaccos treated
with the diethanolamine salt of maleic hydrazide delivered 10
to 40 ng/cigarette of NDELA in the MSS. These two studies
were conducted when it was permissible to treat tobacco with
the diethanolamine salt of maleic hydrazide, a sucker growth
inhibitor. Previously reported findings on the tumorigenicity
in laboratory animals of NDELA and its level in cigarette
MSS eventually led to the banning by the Environmental
Protection Agency (EPA) (1147) of the use on tobacco of
maleic hydrazide-diethanolamine salt in the United States
and acceptance of the maleic hydrazide-potassium salt as
replacement for the maleic hydrazide-diethanolamine salt.
In his response to the Environmental Protection Agency’s
draft document (1148) on ETS, Rodgman (3255) criticized
the inclusion by EPA of NDELA as a tumorigenic agent
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78836_C015.indd 692

692
Table XV-2
Summary of Lists of Tumorigenic N-Nitrosamines in Tobacco and Tobacco Smoke
Mainstream Smoke Delivery/Cigarette Reported by
1986 1986 1990, 1993 1994 1997 1998 2001 2001 2001
Hoffmann & Hecht Hoffmann & Hoffmann & Hoffmann & Hoffmann Fowles &
Hoffmann & (1727), Hoffmann OSHA Hoffmann Hoffmann Hoffmann et al. Bates
N-Nitrosamine IARC (1870) Wynder (1808) et al. (1773) (2825) (1740) (1741) (1743) (1744) (1217)

N-Nitrosodimethylamine 1-200 ng 1-180 ng 0.1-180 ng 10-40 ng 0.1-180 ng 2-180 ng 2-180 ng 2-1000 ng 24.4 ng
N-Nitrosoethylmethylamine 0.1-10 ng 1-40 ng 3-13 ng NL 3-13 ng 3-13 ng 3-13 ng 3-13 ng 6.0 ng
N-Nitrosodiethylamine ND-10 nga 0.1-28 ng ND-25 ng ND-25 ng ND-2.8 ng ND-2.8 ng ND-2.8 ng ND-2.8 ng 8.3 n
N-Nitrosodi-n-propylamine ND-1 ng NL NL P, NYL NL ND-1.0 ng ND-1.0 ng ND-1.0 ng NL
N-Nitrosodi-n-butylamine ND-3 ng NL NL P, NYL NL ND-30 ng ND-30 ng ND-30 ng 12 ng
N-Nitrosopyrrolidine 2-42 ng 2-110 ng 1.5-110 ng 6-30 ng 3-60 ng 3-110 ng 3-110 ng 3-110 ng 113 ng
N-Nitrosopiperidine ND-9 ng ND-9 ng NL P, NYL e NL ND-9 ng ND-9 ng ND-9 ng NL

The Chemical Components of Tobacco and Tobacco Smoke

N-Nitrosodiethanolamine b ND-90 ng ND-40 ng ND-36 ng 20-70 ng ND-68 ng ND-68 ng ND-68 ng ND-68 ng 30 ng
N-Nitrososarcosine NL c NL NL NL ND ND NL NL NL
N’-Nitrosonornicotine 0.13-2.5 µg 0.12-3.7 µgd 0.12-3.7 µg 0.2-3.0 µg 0.12-3.7 µg 120-3.7 µg 0.12-3.7 µg 0.12-3.7 µg 1.90 µg
4-(N-Methylnitrosamino)- 0.08-0.77 µg 0.12-0.95 µg 0.08-0.77 µg 0.1-1.0 µg 0.08-0.77 µg 0.08-0.77 µg 0.08-0.77 µg 0.08-0.77 µg 300 µg
1-(3-pyridyl)-1-butanone
N’-Nitrosoanabasine ND-200 ng 40-400 ng 0.14-4.6 µg NL 0.14-4.6 µg ND-150 ng NL NL 19 ng
N’-Nitrosoanatabine ND-3.7 µg NL NL NL NL NL NL NL 72.2 µg
N-Nitrosomorpholine NL NL ND in MSS NL ND in MSS ND in MSS NL NL NYL
a ND = not detected.
b A component listed in bold is no longer relevant (3300)
c NL = not listed as a tumorigenic or carcinogenic component of cigarette MSS.

d A range listed in bold type contains a numerical error and/or a unit error (ng vs. µg).

e P = present; NYL = no yield level listed for cigarette MSS.

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 N-Nitrosamines 693

Table XV-3
A Brief Chronology of the Research on Volatile N-Nitrosamines From 1937 to 1990
Year Investigation

1937 Freund (15A13) reported the acute toxicity of NDMA in humans accidentally exposed to the reagent.
1954 Barnes and Magee (192) reported the hepatotoxicity of N-nitrosodialkylamines in several laboratory animal species.
1956 Magee and Barnes (2441a) reported that almost all rats fed a diet containing 50 ppm of NDMA developed malignant liver tumors
within less than a year.
1960 Zak et al. (15A59) reported that feeding and daily oral dosing of rats with NDMA resulted in induction of lung tumors which
adenomas, not the lung tumor type - squamous cell carcinoma - reported in various epidemiological studies to be associated with
cigarette smoking.
1960 Rodgman (15A49) proposed that NNAs were likely cigarette MSS components.
1960 Tindall (15A55)] patented the preparation of NNAs from methyl nitrite and secondary amines.
R1 R1
N-H + CH3-ONO N-NO + CH3OH

R2 R2

The demonstration of the presence of methyl nitrite in tobacco smoke [Laurene (2293), Philippe and Hackney (2841), Laurene
et al. (2310)] led to the suggestion by Rodgman (15A49) that this was their mode of formation in tobacco smoke. This
mechanism of formation of volatile NNAs was also proposed by Wynder and Hoffmann [see p. 437 in (4332)]:
An opportunity for the formation of nitrosamines is the interaction of methyl nitrite and secondary amines. It could be
demonstrated in these laboratories, that at least in the presence of water, methyl nitrite and diethylamine form DENA.
This proposal was subsequently negated when Vilcins and Lephardt (4058) demonstrated that methyl nitrite does not exist in the
smoke within the cigarette or in the smoke at the instant it issues from the mouth-end of the cigarette but begins to form artifactually
immediately after the smoke exits the mouth-end of the cigarette. As the level of the methyl nitrite in the aging smoke increases, its
methanol level decreases. This artifactual formation of methyl nitrite was recognized by Brunnemann and Hoffmann (480):
Being aware of the artifactual formation of nitrogen dioxide and methyl nitrite by aging of smoke we prefer to report
nitrogen oxides in cigarette smoke as NO [nitric oxide].
1961 Druckrey et al. (1059) reported the results of their study on the formation, chemical structure, and tumorigenicity of NNAs. This
publication did not deal with the possible presence in tobacco smoke of the NNAs but their findings probably led to the1962
publication by Druckrey and Preussmann (1057).
1962 Druckrey and Preussmann (1057) theorized that the conditions in a burning cigarette were appropriate for the generation of
NNAs, i.e., present in the reaction mixture were secondary amines, water, and nitrogen oxides.
1962 Data reported by Dontenwill and Mohr (15A09) indicated that NDEA had an organ-specific effect in the tracheobronchial tree
of hamsters.
1962 Pasternak (15A40) and Rapoport (15A45) reported the mutagenicity of NNAs in pre-Ames (Salmonella typhimurium) test
systems. Numerous reports describing the mutagenicity of NNAs were issued over the next few years. The test systems used
included Drosophila melanogaster, Escherichia coli, Neurospora crassa, Saccharomyces cerevisiae, among others [see
review by Magee and Barnes (2442)].
1963- Herrold (15A24) studied the tumorigenicity of NDEA. Herrold and Dunham (15A25) studied the tumorigenicity of
1964 subcutaneously injected NDMA and reported that intratracheal or intragastric administration of NDEA to laboratory animals
resulted in a large number of respiratory tract tumors.
1963 Boyland et al. (15A01) discussed the possibility of the presence of NNAs in tobacco smoke, particularly “in the acidic
environment of the cigarette smoke” (pH ≤ 6.7) as opposed to the alkaline environment (pH ≥ 7.0) of cigar and pipe smoke.
1964 Boyland et al. (422, 423) suggested that it was possible, because of the formation of NNAs by the reaction of NOx with secondary
amines, that cigarette MSS could contain NAB and NNN because of the presence in tobacco MSS of nornicotine and anabasine. They
reported that NAB, when administered orally to rats, produced numerous esophageal tumors in the treated animals.
1964 Neurath et al. (2751) reported the isolation and identification of N-nitroso-n-butylmethylamine and the isolation of two
unidentified NNAs in cigarette MSS.
1964 Boyland et al. (422, 423) suggested that it was possible, because of the formation of NNAs by the reaction of NOx with secondary
amines, that cigarette MSS could contain NAB and NNN because of the presence in tobacco MSS of nornicotine and anabasine.
They reported that NAB, when administered orally to rats, produced numerous esophageal tumors in the treated animals.

(Continued )

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 694 The Chemical Components of Tobacco and Tobacco Smoke

Table XV-3 (Continued)

A Brief Chronology of the Research on Volatile N-Nitrosamines From 1937 to 1990
Year Investigation

1964 Serfontein and Hurter (3595) reported the identification of NNAs in the MSS from South African cigarettes. Serfontein (15A53)
reported the identification of N-nitrosopiperidine (NPIP). Robertson (15A47), President of the National Cancer Association of
South Africa, commented on Serfontein and Hurter’s report of the identification of NNAs in cigarette MSS:
The significance of this discovery lies in the fact that although the nitrosamine compound is known as a carcinogen, this is
the first time that it has been established beyond doubt that various nitrosamines occur in cigarette smoke.
1964- Serfontein and Hurter (3596-3598) developed a thin-layer chromatographic method for separation and analysis of extremely
1966 small amounts of NNAs and noted that “the method has been successfully applied to the analysis of nitrosamines in cigarette
smoke.” In a detailed account of the identification of NNAs in CSC, they reported:
In the course of initial scanning experiments, strong evidence was obtained by means of gas chromatographic analysis of the
neutral fraction of cigarette smoke condensate…that various nitrosamines [N-nitrosodimethylamine (NDMA),
N-nitrosodiethylamine (NDEA), and N-nitrosopiperidine (NPIP)] were present in cigarette smoke in measurable quantities.
They estimated the level of NPIP to range from 1 to 5 μg/cig.
1965 Neurath et al. (2750) discounted their reported 1964 findings (2751) on the identification of MSS NNAs because of their artifactual
formation during their collection and analytical procedure. However, with a modified analytical and collection procedure, NDMA (4
ng/cig) and (NPYR) (4 ng/cig) were identified in MSS. The previously reported N-nitroso-n-butylmethylamine (NBMA) was found
in the part of the collection system where artifactual formation was possible.
Artifactual formation of NNAs during smoke generation, separation, and analysis was a recognized problem since the first
NNA identification in MSS (573, 2750, 2751, 15A10, 15A33) and resulted in much debate. Krull et al. (15A33) discussed the
artifactual generation of NNAs during their determination. Subsequent research eventually resolved the question concerning the
presence or absence of NNAs in tobacco and/or tobacco smoke. However, some artifactual formation did occur, resulting in
inflated values for NNAs in MSS and SSS [Caldwell and Conner (572-574)].
1965 Eisenstark et al. (15A11), nearly a decade before Ames’ 1973 presentation on the use of Salmonella typhimurium to test for
mutagenicity, described the high mutagenicity obtained with NNAs in tests with Salmonella typhimurium. Several potent NNAs
became positive standards, e.g., N-methyl-N’-nitro-N-nitrosoguanidine in the Ames test with Salmonella typhimurium.
1965- Besides identifying several volatile NNAs in burley tobacco MSS with a procedure that precluded artifactual formation,
1967 Fredrickson (1236) demonstrated that MSS volatile NNA yields were significantly reduced (60-85%) by a plasticized cellulose
acetate filter, a finding later confirmed (514, 1761, 2635). This reduction of volatile NNA yields by selective filtration paralleled
that observed for phenols (2312, 4312). Concern over phenols and their promotion effect diminished after reports of removal of
significant amounts of them from MSS by selective filtration. While concern about volatile NNAs did diminish, a new NNA
concern arose: One involving TSNAs, a class of NNAs newly identified in tobacco and tobacco smoke, namely NNN and NAB.
1967 In their NNA review, Magee and Barnes (2442), cf. Barnes and Magee (192) noted:
It is too early to be able to suggest with any confidence the part nitrosamines might play in the etiology of human cancer. In a
whole range of experimental animals tumors can be produced in a number of different sites which bear in some cases a
striking pathological resemblance to cancers seen in man. However, the species, the nature of the nitroso compound, and the
dose and route by which it is administered can all play a part in determining the nature of the malignant lesion produced.
1967 Brune and Henning (15A02) reported the induction of eyelid carcinoma in mice treated with methylbutyl-N-nitrosamine
1967 Wynder and Hoffmann noted [see p. 436 and p. 628 in (4332)]:
To date, we lack a method of quantitative determination of nitrosamines in tobacco smoke although a few good
quantitative techniques have emerged. Since the presence of nitrosamines in cigarette smoke bears considerable
implications in tobacco carcinogenesis, it is hoped that further and more detailed studies will also be initiated by other
groups to clarify fully this important factor… A most important question, however, is whether nitrosamines are indeed
formed during smoking of tobacco and whether the induction of papillary tumors in the respiratory tree of hamsters bears
any relation to the induction of human bronchiogenic cancer.
They concluded [p. 639 in (4332)]:
At this time one cannot deny the potential of tobacco smoke to form nitrosamines; however, we are not convinced that
these agents actually exist in the cigarette smoke inhaled by man.
1967 Hoffmann and Wynder (1797) and Rathkamp and Hoffmann (3081, 3082) demonstrated that addition of nitrates to tobacco
decreased the per cigarette yields of TPM, promoting/cocarcinogenic phenols, and tumorigenic PAHs (including B[a]P) in MSS
and the tumorigenicity of the mainstream CSC to mouse skin. Later, Brunnemann et al. (471, 499) reported that increased levels
of tobacco nitrate increased MSS yields of both volatile NNAs and TSNAs, resulting in recommendations to reduce the nitrate
levels in tobacco stems and ribs.

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 N-Nitrosamines 695

Table XV-3 (Continued)

A Brief Chronology of the Research on Volatile N-Nitrosamines From 1937 to 1990
Year Investigation

1968 Montesano and Saffiotti (15A37) studied the carcinogenic response of the respiratory tract of Syrian golden hamsters to different
doses of NDEA. They also summarized over two dozen previous studies with NDEA.
1968 In their review of the identification and quantitation of NNAs in MSS, Johnson et al. (1952) wrote:
It is possible…that little or no nitrosamines are present in cigarette smoke under normal conditions of smoking. Because of
the importance of these compounds and the known high incidence of lung cancer, the establishment of their presence in
smoke is of importance in the health of man… Even if the nitrosamines are identified and unequivocally established as
being present in cigarette smoke at a certain level then it must be investigated whether they contribute to the total toxic
activity of tobacco smoke.
1970 Volatile NNA tumorigenicity in laboratory animals was repeatedly cited with the implication that this property was extrapolable
to man because of cigarette smoke NNAs. In laboratory animals, NNAs are organ-specific tumorigens and seldom have been
shown to induce carcinoma at the painting site in mouse skin-painting experiments. Hoffmann and Wynder (15A29) noted:
We…need to consider that nitrosamines have so far not been reported to be carcinogenic to man.
1971 Hoffmann and Vais (1784) reported NDMA and NEMA in unaged MSS from an 85-mm nonfiltered U.S. blend cigarette: NDMA
and NEMA yields were 80 and 30 ng/cig, respectively. NDEA and NDBA were not detected. The properties of an NNA thought
to be NPIP did not match those of an authentic sample.
1972 The chapter in the 1972 Surgeon General’s report (4003) dealing with the harmful components of tobacco smoke noted that the
reports describing the presence of various NNAs in cigarette smoke were published after the June 1970 conference on which the
chapter was based.
1973 Morie and Sloan (2636) reported the substantial reduction of the volatile NNA N-nitrosodimethylamine (NDMA) by plasticized
cellulose acetate filters vs. the negligible reduction obtained with paper filters. Substantial selective filtration of NDMA was
demonstrated by the 85% reduction in its delivery vs. the 36% reduction observed in the delivery of total particulate matter with
the plasticized cellulose acetate filter. Minimal selective filtration was obtained with the paper filter: 66% reduction in NDMA vs.
55% reduction in total particulate matter, cf. Fredrickson (1236).
1974 Hoffmann et al. (1761) confirmed the findings of Hoffmann and Vais (1784) on NNAs in cigarette MSS. They reported
84 ng/cig of NDMA, 30 ng/cig of NEMA, and less than 5 ng/cig of NDEA in the MSS of a nonfiltered U.S. blend cigarette. They
also reported that selective filtration produced a 60 to 85% reduction of volatile NNAs by use of a plasticized cellulose acetate
filter, cf. Fredrickson (1236), Morie and Sloan (2636).
1974 Barnes (191) [the co-discoverer with Magee of the tumorigenicity of NNAs (Magee and Barnes (2441a)] stated:
Preoccupation with the occurrence and behavior of minute amounts of nitrosamines in the human environment will
probably divert skills from more profitable studies of the behavior of nitrosamines in experimental systems… If [this
essay] leaves the reader with the impression that nitrosamines have a much greater potential as research tools than they
have as health hazards, it will have served its purpose.
1976 Magee et al. (2443) wrote:
That a wide range of species is susceptible to the carcinogenic action of nitrosamines suggests that man is probably not
resistant…Many N-nitroso compounds are powerfully carcinogenic in experimental animals, and, although there is no
proof, it is highly probable that they are also carcinogenic in man.
1977 Brunnemann et al. (514) reported that the volatile NNA levels in MSS and SSS were lower than previously reported, attributing
the lower levels to the avoidance of artifactual formation of NNAs during smoke collection and analysis. They wrote:
In fact, several of the cigarettes which were machine smoked earlier and analyzed without precautions, when smoked by us
under the same conditions but with precautions, yielded 25 to 100% lower values for DMN [N-nitrosodimethylamine] and
NPY [N-nitrosopyrrolidine] for the mainstream smoke…The nitrate content of the tobacco appears to be a determining
factor for the concentration of volatile nitrosamines in the smoke. Selective removal of these nitrosamines does occur with
cellulose acetate filter tips but not with charcoal filter tips.
They determined the levels of volatile NNA for unaged MSS and SSS from 17 commercial and experimental cigarettes
(Table XV-3).
Level Found, ng/cig
Volatile NNA MSS SSS
NDMA 1.7 - 97 680 - 1770
NEMA 0.1 - 9.1 9 - 75
NDEA 0 - 4.8 8 - 73
NPYR 0 - 4.8 8 - 73

(Continued )

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 696 The Chemical Components of Tobacco and Tobacco Smoke

Table XV-3 (Continued)

A Brief Chronology of the Research on Volatile N-Nitrosamines From 1937 to 1990
Year Investigation

1977 The Royal College of Physicians (3364) reported that N-nitroso compounds were, along with the PAHs, the chief initiators of
cancer in tobacco smoke. The College noted:
The NNAs in food and drink are regarded as a potential health hazards at concentrations as low as one part per billion.
N’-Nitrosonornicotine has been identified in both tobacco smoke and unburnt tobacco, the concentration in the latter being
2,000 to 9,000 parts per billion…concentrations much higher than those of other nitroso compounds found in meat, fish, or
beverages. Its presence may be of great biological importance and could explain the correlation between tobacco chewing
and the development of cancer of the mouth.
1978 The problem of the artifactual formation of volatile NNAs during smoke collection and analysis was discussed previously by Neurath
(2750, 2751) and by Fredrickson (1236). It was once again revisited. Krull et al. (15A33) described the problem of artifactual formation
of NNAs during the collection, fractionation, and analysis of cigarette smoke and proposed methodology to reduce the problem. This
problem resurfaced several times in the next decade in the determination of both volatile NNAs [Eisenbrand et al. (15A10); Caldwell and
Conner ( 572, 573)] and TSNAs in tobacco smoke (572, 573); preventative measures were described.
1978 Brunnemann and Hoffmann (477) described the results of their measurements of volatile NNAs in indoor air containing ETS.
1979 In the 1979 U.S. Surgeon General report [see p. 107 in (4005)], it was noted:
The N-nitrosamine formation in tobacco smoke is determined by the nitrate content of the tobacco… More importantly…
selective removal (70 to 80 percent) of volatile nitrosamines from the smoke can be achieved by cellulose filters [sic]a… At
present, it has not been demonstrated that a significant reduction of volatile N-nitrosamines will lead to a significant reduction
of the tumorigenic potential of cigarette smoke.
a This should read “cellulose acetate.”
It was also stated that NNAs are animal carcinogens with the ability to induce pulmonary tumors (adenomas).
1979 Rinkus and Legator (3157) listed numerous tobacco and cigarette smoke components as mutagenic in the Salmonella
typhimurium system. Among these were the following volatile NNAs [excluding (NMOR)] known to occur in tobacco smoke:
NDMA, NDEA, NPYR, NDBA, NDPA, NMOR, NPIP.
1980 In discussing “The Less Harmful Cigarette,” Hoffmann et al. (1783) included a table which showed that nitrate fertilization of
tobacco [which leads to increased NNAs formation] has led to significant reductions in MSS levels of “tar”, nicotine, and B[a]P
as well as in the specific tumorigenicity of the “tar” administered via skin painting to laboratory animals. They wrote that “the
reduction of the tar content of cigarettes [sic] was an important step in reducing the hazards of cigarette smoking.”
1980 Hoffmann et al. (1711) noted:
In the mainstream smoke of a cigarette, these carcinogens [the volatile N-nitrosamines] can be reduced significantly by
utilization of tobacco low in nitrate content and acetate filter tips that selectively retain volatile N-nitrosamines.
They also stated that “most present-day commercial filter cigarettes are effectively reducing volatile NNAs.” This effective
reduction in volatile NNAs in cigarette MSS has not lessened during the intervening years from 1980 to date!
1980 Brunnemann et al. (467) presented additional data on the levels of NNAs in MSS and SSS, cf. Brunnemann et al., (457). The SSS
levels exceeded those in the MSS. Much of the MSS and sidestream data for NNAs were summarized by Hoffmann et al. (1685).
1980 Bartsch et al. (203) listed numerous NNAs as mutagenic in the Ames Salmonella typhimurium test system. The following volatile
NNAs reported as tobacco and/or smoke components were included: NDMA, NDEA, NMPA, NDPA, NDBA, NPYR, NMOR, and
NPIP. NNN was also tested.
1980 Rühl et al. (3366) reported the levels of volatile NNAs and TSNAs in the MSSs and SSSs from American, German, and French
cigarettes.
1981 In the 1981 Surgeon General’s report (4009) on smoking vs. health, volatile NNAs were discussed as “organ-specific
carcinogens.” The Surgeon General, citing Brunnemann et al. (514), noted: “The volatile nitrosamines…can be selectively
reduced by filtration…” [cf. Fredrickson (1236), Morie and Sloan (2636)].
1982 In the 3rd Annual Report on Carcinogens by the National Technical Information Service (2686), it was noted: “there is sufficient
evidence for the carcinogenicity of N-nitrosodimethylamine (NDMA) in experimental animals.” Similar comments were made about
NPYR (MSS yield estimated as being as much as 113 ng/cig) and NDEA (MSS, 8 ng/cig; SSS yield, about ten times that in MSS).
1982 Hoffmann and Wynder (1807a) included a table which indicated that nitrate fertilization (known to increase the levels of NNAs
in the tobacco and the smoke from it) significantly reduced the biologically activity (carcinogenicity) of CSC to mouse skin. The
PAH levels in the CSC were also reported to be reduced.
1982 In contrast to suggestions made in the late 1950s/early 1960s to control the pyrogenesis of PAHs by reduction of the tobacco wax
components, e.g., long-chained saturated hydrocarbons such as n-hentriacontane, and/or the use of high-nitrate tobacco,
Brunnemann and Hoffmann (480) recommended the following approaches - the direct opposite of the earlier suggestions from
the Wynder and Hoffmann laboratory - to control both the PAHs and the NNAs in tobacco smoke:

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 N-Nitrosamines 697

Table XV-3 (Continued)

A Brief Chronology of the Research on Volatile N-Nitrosamines From 1937 to 1990
Year Investigation

Selective filtration is highly effective in removing volatile N-nitrosamines from the smoke stream, but is ineffective for the
selective reduction of tobacco-specific nitrosamines. Selective reduction of nitrate in tobacco stems offers one possible
approach, but additional means of reducing nitrogen oxides and N-nitrosamines without diminishing PAH reduction need
to be found. Selection of tobacco with high levels of long chain hydrocarbons (e.g. hentriacontane C31H64) may be helpful.
These 1982 suggestions for the design of a “less hazardous” cigarette were in direct contradiction to those offered two decades
previously when the main emphasis was not on NNAs (their presence in tobacco smoke was, at best, theoretical in the early
1960s) but on the tetracyclic and higher PAHs, particularly B[a]P, because of the known effect of it and other PAHs on the skin
of laboratory animals.
1982 The 1982 report of the Surgeon General (4010), citing the studies of Magee et al. (2443) and the IARC (1866), concluded:
More than 50 of the approximately 100 NNAs which have been tested have various degrees of carcinogenic potency in laboratory
animals… There is a lack of direct evidence that these compounds are also human carcinogens. Nonetheless, many scientists
concur with the [IARC] that, for practical purposes, these nitrosamines should be regarded as carcinogenic in humans.
It was noted that NDMA and NPYR were the most plentiful NNAs in cigarette smoke. NDMA is listed in this report as a “toxic
and tumorigenic agent” in the vapor phase of cigarette smoke. Both NEMA (MSS delivery, 1 to 40 ng/cig) and NDEA (MSS
delivery, 0.1 to 28 ng/cig) were reported as “among the most potent environmental carcinogens” of the NNAs.
1982 Stehlik et al. (3812) determined the levels of NDMA in the air of cigarette smoke-filled rooms.
1983 In his concluding remarks at the 1983 NNA conference (published in 1984), Magee (2441) stated:
A major component of this evidence [that N-nitroso compounds probably can cause human cancer] is the large number of
species known to be susceptible to cancer induction by nitrosamines… The question of whether any human cancer has
been caused by nitrosamines remains open, but several relevant and interesting presentations were given during the
meeting… Following up the well-established relationship between cigarette smoking and the incidence of human lung
cancer, these workers [Hoffmann, Hecht, Castonguay, and their colleagues] presented persuasive evidence for a
relationship between the use of chewing tobacco and snuff and human cancer…A role for nitrosamines in the causation of
human cancer has not been established, but it should not be excluded and merits further study.
1984 Although their data showed that an increase in the nitrate content of cigarette tobacco reduced the levels of FTC “tar”, nicotine,
carbon monoxide, catechol, and B[a]P, Adams et al. (28) emphasized that significantly higher yields of volatile NNAs and
TSNAs were found in the MSS of an 85-mm nonfiltered cigarette. They concluded:
The findings of this study support the recommendation that the nitrate content of tobacco products should be reduced.
[Cf. 1967/1970 studies and comments by Hoffmann and Wynder (1797, 1798) and Rathkamp and Hoffmann (3081, 3082) that
use of high-nitrate tobacco was beneficial in that it reduced the levels of CSC PAHs and CSC tumorigenicity to mouse skin. Also,
the findings of Brunnemann et al. (481, 482) that addition of stems, high in nitrate, did not reduce “tar”, nicotine, or carbon
monoxide yields.]
1984 Despite three decades of a variety of claims against the PAHs and their role in carcinoma induction in laboratory animals
skin-painted with CSC and their alleged role in carcinoma induction in cigarette smokers, it is interesting to note that in the
American Chemical Society monograph (2nd edition) edited by Searle (3568), the only class of compounds in tobacco or
cigarette smoke discussed with regard to their tumorigenicity in laboratory animals was the NNAs. Even though several chapters
were written by experts in the fields of PAH, their nitrogen analogs, and aromatic amines, no mention was made throughout this
two-volume 1400-page monograph of the numerous PAHs in tobacco or cigarette smoke, their levels, or their role in respiratory
tract cancer attributed by some to the PAHs in cigarette smoke. The only class of tumorigens discussed was the NNAs and
TSNAs. Most of the data cited were those of Hoffmann and his colleagues.
1984 The Preussmann and Eisenbrand summary (2990) of research on NNAs in tobacco and tobacco smoke was, according to their
article, taken largely from a 1982 review by Hoffmann et al. Preussmann and Eisenbrand commented:
Although Hoffmann et al. have clearly demonstrated the effectiveness of cellulose acetate filters in model experiments, the
values for U.S. commercial cigarettes are about the same for filter as for nonfilter cigarettes; the reductive effect of filters
in practice may be counteracted by variations in tobacco composition between the two types of cigarettes… In conclusion,
tobacco and tobacco smoke represent the largest nonocccupational source of exposure for preformed nitrosamines.
1984 Matsushita and Mori (2495) determined the levels of nitrogen dioxide and volatile NNAs in indoor air and cigarette SSS.
1984 Preussmann (15A43) tabulated the ranges of the reported levels of a variety of NNAs in tobacco and in cigarette MSS and SSS.
1986 The IARC (170) concluded that NDMA, NDEA, NPYR, and NEMA were tumorigenic to laboratory animals and that NDMA
was one of the two most abundant volatile NNAs in cigarette MSS.
1987 Klus et al. (15A32) reported the levels of several volatile NNAs in ETS in several real life situations.

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 698 The Chemical Components of Tobacco and Tobacco Smoke

Table XV-3 (Continued)

A Brief Chronology of the Research on Volatile N-Nitrosamines From 1937 to 1990
Year Investigation

1987 The RTECS (Registry of Toxic Effects of Chemical Substances) (3095) reviewed the studies in which lung tumors were observed
in laboratory animals treated with an NNA by a variety of administration routes. The RTECS categorized the positive inhalation
findings involving NNAs as “equivocal.” E.g., the dose level used (200000 ng/m3) for NDMA in the inhalation experiments was
significantly greater than the NDMA level observed (10 to 240 ng/m3) in ETS exposure.
1989- Caldwell and Conner (573) reported:
1990
The methodology previously reported [by others] leads to significant overestimation of N-nitrosamine concentrations in
cigarette smoke.
The overestimations were true for both volatile and tobacco-specific NNAs in MSS and SSS for the Kentucky Reference
Cigarette 1R4F: MSS data indicated that the levels were 380% high for NPYR and 83%, 38%, 27%, and 19% for NAB, NAT,
NNK, and NNN, respectively. Thus, it is probable that many of the previously reported levels of NNAs in MSS and SSS,
tabulated in various articles [cf. Adams et al. (31), Hoffmann and Hecht (1727)] and cited by EPA (1148) and the U.S. Surgeon
General (4005, 4009, 4010, 15A57) are incorrect.
Hoffmann and Hecht (1727) did not acknowledge that the MSS levels listed for volatile NNAs and the TSNAs were likely to be
incorrect (and high) because of the artifactual formation of both types during MSS (and SSS) collection for analysis as reported
by Caldwell and Conner (572-574). EPA (1148) accepted without question the MSS volatile NNA and TSNA yields listed by
Hoffmann and Hecht (1727) whose data were cited by the U.S. Surgeon General (4012). The levels of various NNAs reported in
foodstuffs and beverages are also possibly in error because of artifactual formation of NNAs during the isolation procedure and
subsequent quantitation.
1990 In their list of 43 “tumorigenic agents” in tobacco and/or smoke, Hoffmann and Hecht (1727) included the following volatile
NNAs: NDMA, NDEA, NEMA, and NPYR. Little comment was made about these four volatile NNAs and their supposed
tumorigenicity to smokers. However, they did note that IARC (1870) had evaluated the bioassay data from laboratory animals
exposed to these NNAs and considered the data sufficient to classify all four as tumorigenic to animals. IARC did not express an
opinion as to whether these four were tumorigenic to humans.
Brunnemann et al. (1459, 460, 462) summarized data from several publications on the levels of various volatile NNAs (NDMA
and NPYR) in indoor air at various sites (trains, offices, coffee shops, dance halls).

in tobacco and/or smoke. EPA had based its assessment of Hoffmann et al. (1696) had predicted that the NDELA
this compound on the Hoffmann-Hecht list of forty-three level in tobacco would decrease:
“tumorigenic agents in tobacco and tobacco smoke” (1727).
Rodgman’s reasoning was as follows: Since the dietha- At present, NDELA [N-nitrosodiethanolamine] levels are
nolamine salt had not been used in the United States for relatively high in U.S. brands (290–300 mg/kg) but they are
expected to decrease, since the herbicide was banned from
nearly a decade, the level of this nitrosamine should now be
use on tobacco as of October 1981 (1147).
substantially reduced in tobacco as well as in MSS and SSS
from cigarettes containing such tobacco.
In 1982, the U.S. Surgeon General concluded (4010) that
The chronological pattern of decrease in levels of NDELA
NDELA was a carcinogen, noting not only did NDELA
might parallel those reported for the decrease in levels of
induce carcinomas in treated laboratory animals (carcinoma
arsenic and DDT in tobacco (and its smoke) when arseni-
of the liver and kidneys in rats, carcinoma of the trachea in
cals and DDT were no longer used on tobacco in the United
hamsters) but also it was present in tobaccos treated with the
States. For example, in 1952, arsenicals were removed from
diethanolamine salt of maleic hydrazide.
the list of recommended and permissible insecticides for
In the National Technical Information Service 3rd Annual
tobacco. By 1968, the arsenic content of U.S.-grown tobacco
Report on Carcinogens (2686), it was concluded that there
had decreased to 0.5–1.0 μg/g from the 1951 level of about
was sufficient evidence to classify NDELA as a carcinogen
50 μg/g of tobacco (1870, 4005); arsenic levels reported in
in laboratory animals.
1975 by Griffin et al. (1391) were 0.5 to 0.9 μg/g of tobacco.
In its review of tumorigenic components of tobacco and
Similarly, discontinuance of the use of chlorinated insecti-
tobacco smoke, the IARC (1870) noted for NDELA:
cides such as DDT in U.S. tobacco culture in the late 1960s
resulted in a gradual and substantial reduction of DDT resi-
Its presence in tobacco products has been related to the use of
dues in leaf tobacco. Between 1968 and 1974, the residual the sucker growth inhibitor, maleic hydrazide when formu-
DDT level in American flue-cured tobacco decreased rapidly lated with the diethanolamine salt (“MH-30” or “MH-40”)
and substantially (1870, 4005) from 52 μg/g in 1968 to 6 μg/g …; in the USA, that formulation has been replaced by
in 1970, and to 0.23 μg/g in 1974. the potassium salt … Tobaccos grown in a pesticide-free

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 N-Nitrosamines 699
NO NO
H H
N N N N
OH HO OH O O
HO
II I III IV
Figure XV-1  N-Nitrosodiethanolamine (NDELA) and N-nitro-
somorpholine (NMOR).
environment and smoke generated from such tobaccos are
devoid of N-nitroso-diethanolamine [NDELA].
Hoffmann and Hecht (1727) included five volatile NNAs
[NDMA, NDEA, NEMA, NPYR, NMOR] and the nonvola-
tile NDELA in their list of forty-three “tumorigenic agents in
tobacco and tobacco smoke.” They noted that NMOR had not
been reported as a tobacco smoke component. Possible rela-
tionships between diethanolamine {I}, NDELA {II}, morpho-
line {III}, and NMOR {IV} are illustrated in Figure XV-1. It
is possible that as the NDELA level in tobacco has declined,
the levels of morpholine and NMOR also have declined.
More recent major efforts in the NNA-tobacco area have
been devoted to the study of TSNAs and N-nitrosamino acids
rather than to the NDELA/NMOR question.
Tobacco products and smoke, however, are not the only
source of exposure to NDELA. As noted previously, it is
highly likely that the current levels of NDELA in tobacco
products is approaching zero because of the discontinued
use of the diethanolamine salt of maleic hydrazide in U.S.
tobacco agronomy. However, consumer exposure to NDELA
from nontobacco sources is possible. Studies of NDELA-
contaminated cosmetics indicated substantial levels of
NDELA have been identified in cosmetics, for example, Fan
et al. (15A12) detected NDELA in twenty-seven of twenty-
nine products tested at levels ranging from 1 to 48,000 ppb;
Klein et al. (15A31) detected it in five of ten cosmetic products
(range = 20 to 4113 ppb). Hecht (15A15) found no NDELA in
the products but did find N-nitrosomethyldodecylamine in six
of seven cosmetics containing laurylamine (dodecylamine).
NDELA is readily absorbed through the skin after applica-
tion of NDELA-contaminated cosmetics and is detected
in cosmetic users’ urine, [see Preussmann and Eisenbrand
(2990)].
The other nonvolatile NNA is NPRO (see Table XV-1). It
was not included by Hoffmann and Hecht (1727) in their list of
forty-three “tumorigenic agents in tobacco and tobacco smoke”
or any of the subsequent lists tabulated in Table XV-2.
Scott et al. (3566) and Brunnemann et al. (511) reported
that cigarette and chewing tobaccos differed in their NPRO
levels: Cigarette tobacco contained ≈2 ppm (less than 1%
of free proline was nitrosated), chewing tobacco contained
about 35 ppm (up to 40% of free proline was nitrosated).
They reported that the NPRO level is dependent on proline
level, nitrate level, and curing method.
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78836_C015.indd 699
Brunnemann et al. (509) reported the measurement of the
endogenous formation of NPRO in smokers and nonsmokers
on a controlled diet, relatively low in proline and ascorbic
acid. The NPRO in urine was determined in 24-h urine sam-
ples on days 3, 6, 9, and 12. Different groups in the study were
administered proline and/or ascorbic acid at appropriate times
during the experiment. Ascorbic acid intake reduced urinary
levels of NPRO. Differences in NPRO excretion by smokers
and nonsmokers on the controlled diet, ascorbic acid supple-
ment, no proline supplement were not statistically significant.
The results of numerous studies on the in vivo formation of
NNAs were presented at the 1983 IARC conference [O’Neill
et al. (15A39)]. Many dealt with the in vivo generation of
NPRO in nitrite- and proline-treated mammalian species,
including humans. Numerous investigations have been con-
ducted on NPRO because of its presence not only in tobacco
and tobacco smoke but also in a variety of consumer prod-
ucts (meat, bacon, ham, chicken, fish, toast, biscuits, corn-
flakes, beer) [Brunnemann et al. (509), Hansen et al. (15A14),
Pensabene et al. (15A41), Pollock (15A42), Sen and Seaman
(15A50), Sen et al. (15A51)].
In the IARC monograph (1870), it was noted that NPRO
was detected in cigarette smoke at extremely low levels (<1
ng/cigarette) by Brunnemann et al. (511) despite the fact it is
readily detected in tobaccos. Hoffmann et al. (1696) listed
the levels of NPRO in various tobacco products (cigarette
tobaccos, little cigars, cigars, chewing tobaccos, snuff). The
reported values ranged from a low of 450 to a high of 22000
ng/g of tobacco (dry weight).
XV.C Tobacco-Specific N-Nitrosamines
A year after the proposal by Druckrey and Preussmann
(1057) that the conditions in a smoked cigarette were appro-
priate for the generation of NNAs, Boyland et al. (422, 423,
15A01) speculated that it was possible, because of the forma-
tion of NNAs by the reaction of nitrogen oxides with second-
ary amines, that cigarette MSS could contain NNN and NAB
because of the presence of the secondary amines nornico-
tine and anabasine in tobacco and smoke. They also reported
that oral administration of NAB to rats induced esophageal
tumors. After nearly a decade of investigation on the volatile
NNAs in tobacco smoke, attention was turned to the higher
molecular weight NNAs.
Figure XV-2 shows the relationships among the nicotine-
related alkaloids — nornicotine {V}, nicotine {VI}, anata-
bine {VII}, anabasine{VIII} — and the NNAs {IX, XI-XVII}
and cotinine {X}. Table XV-4 summarizes some of the early
research on the TSNAs.
Between the early 1980s and 2004, a substantial number of
studies were devoted to some aspect of the TSNAs in tobacco
and/or its smoke. Included were conference presentations
and journal publications in which were discussed analyti-
cal technology, artifactual TSNA generation during collec-
tion and analysis, quantitation, adverse biological effects and
their inhibition, and effect on various biological systems and
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 700 The Chemical Components of Tobacco and Tobacco Smoke

LEGEND

V Nornicotine
VI Nicotine
R N R N N VII Anatabine {1,2,3,6-tetrahydro-2,3'-bipyridine}
R R N
H H H VIII Anabasine {3-(2-piperidinyl)pyridine}
V VI VII VIII IX N´-Nitrosonornicotine {NNN}
R= X Cotinine
XI N´-Nitrosoanatabine {NAT}
N XII N´-Nitrosoanabasine {NAB}
R N R N O XIII 4-(N-Methylnitrosamino)-1-(3-pyridinyl)-1-
R N R N
IX X XI XII butanone {NNK}
NO NO NO XIV 4-(N-Methylnitrosamino)-1-(3-pyridinyl)-1-
butanol {NNAL}
CH2OH CH=O COOH XV 4-(N-Methylnitrosamino)-4-(3-pyridinyl)-4-
N butanol {iso-NNAL}
N
R O R OH N R N N XVI 4-(N-Methylnitrosamino)-4-(3-pyridinyl)butanal
R R
NO NO NO XVII 4-(N-Methylnitrosamino)-4-(3-
NO NO
pyridinyl)butanoic acid {iso-NNAC}
XIII XIV XV XVI XVII

Figure XV-2  Tobacco-specific N-nitrosamines.

Table XV-4
A Brief Chronology of the Research on Tobacco-Specific N-Nitrosamines
Year Investigation

1964 Boyland et al. (422, 423) suggested that, because of the possibility of the formation of NNAs by the reaction of NOx with
secondary amines, cigarette MSS could contain NAB and NNN generated from nornicotine and anabasine in tobacco MSS.
NAB, when administered orally to rats, induced esophageal tumors in the treated animals.
1973 At the Austria Tabakwerke A.G., Klus and Kuhn (2136) detected 40 ng/cig of NNN in the MSS from cigarettes made with
nornicotine-rich tobacco (1.95% nornicotine). However, they failed to detect NNN in the MSS from a blended commercial
cigarette. They concluded:
From the biological and toxicological points of view, the expected quantity of nornicotine nitrosamine developed from a
commercial cigarette containing an average of 0.04% nornicotine is almost meaningless.
1973 Rathkamp et al. (3080) reported that MSS from an 85-mm U.S. blend nonfiltered cigarette contained NAT at less than 20 ng/cig.
1974 Hoffmann et al. (1761) confirmed the report by Klus and Kuhn (2136) of the presence of NNN in cigarette MSS. They suggested
that nicotine and nornicotine were NNN precursors with nicotine actually being the more important precursor because of its
preponderance in tobacco. Their results differed, however, from those of Klus and Kuhn on the level of NNN in MSS from a
commercial blended cigarette; Hoffmann et al. (1761) reported that the MSS from a nonfiltered U.S. blended cigarette contained
137 ng of NNN.
1974 Hecht et al. (1576) reported the level of NNN in tobacco paralleled the nitrate level. They also suggested the TSNA levels in
tobacco may be controllable by appropriate selection of the curing process. Flue-cured tobaccos usually show the lowest NNN
level vs. the levels in tobaccos cured by other methods, e.g., air-curing.
1974 Hoffmann et al. (1733) reported that various types of commercial tobacco contained substantial levels of NNN at levels ranging
from 2 to 90 mg/g (2 to 90 ppm). Two commercial cigarette samples showed NNN levels of 2.2 and 6.6 mg/g. They noted:
This is to our knowledge the highest concentration of a positively identified NNA yet reported in an environmental source.
NNAs in meat, fish, beverages, and related materials rarely exceed 0.1 ppm.
1976- Hecht et al. (1563, 1565) suggested that nicotine was the precursor of NNK and 4-(N-methylnitrosamino)-4-(3-pyridinyl)-1-
1977 butanal in tobacco via opening of the pyrrolidine ring of nicotine.
1977 The Royal College of Physicians (3364) noted:
N’-Nitrosonornicotine has been identified in both tobacco smoke and unburnt tobacco, the concentration in the latter being
2,000 to 9,000 parts per billion – concentrations much higher than those of other nitroso compounds found in meat, fish, or
beverages. Its presence may be of great biological importance and could explain the correlation between tobacco chewing
and the development of cancer of the mouth.
1979 For tobaccos, Hoffmann et al. (1679) reported levels of 0.2 to 45 ppm of NNN and 0.1 to 35 ppm of NNK. For cigarettes, they
reported MSS levels of 0.2 to 3.7 μg/cig for NNN and 0.12 to 0.44 μg/cig for NNK.

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 N-Nitrosamines 701

Table XV-4 (Continued)

A Brief Chronology of the Research on Tobacco-Specific N-Nitrosamines
Year Investigation

1979 After reviewing earlier data that indicated NNN was moderately carcinogenic in the Syrian golden hamster, Hoffmann et al.
(15A28) concluded:
Since NNN is present in ppm levels in tobacco and in microgram amounts in the smoke of a cigarette, it may contribute to
the carcinogenicity of tobacco smoke.
1979 The U.S. Surgeon General (4005) reported the identification of NNN and NAT in MSS. MSS levels listed for NNN were those
reported by Hoffmann et al. (1679) (0.2 to 3.7 μg/cig. No quantitative data were listed for NAT.
1980 Hecht et al. (15A18) reported high rates of benign and malignant tumors in two groups of F344 rats treated with TSNAs. One
group of rats was treated with NNN; the other group was treated with NNK. For each group, the TSNA (3.4 mmol total dosage)
was administered in 60 subdoses over a period of 20 weeks.
1981 Adams et al. (23) reported the results of their study on the transfer of 4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone
(NNK) from tobacco to MSS and its formation from tobacco components during the tobacco smoking process.
1981 McCoy et al. (15A36) studied the influence of ethanol in the diet on the tumorigenicity of NNN administered to Syrian golden
hamsters at two dose levels. In the group of test animals whose caloric intake was equal to that of the control group, no
accelerating effect of ethanol on NNN tumorigenicity was observed.
1981 Hoffmann et al. (1710) reported that, in a study involving subcutaneous injections into Syrian golden hamsters, the tumor
production data indicated NNK was a more potent carcinogen than NNN. The authors stressed the importance of this finding
because of the relatively high exposure (approximately 1 µg/cig for an 85-mm filtered cigarette) of smokers to NNK (see also
Table 9) which they described:
As a carcinogen more potent than the strongly carcinogenic N’-nitrosonornicotine… Exposure to NNK in tobacco and
tobacco smoke should certainly be minimized.
1981 In the U.S. Surgeon General’s 1981 report (4009), the relative tumorigenicities of NNN, NNK, and (NAT were discussed:
NNN is a moderately active carcinogen in mice, rats, and Syrian golden hamsters, whereas NNK is a strong carcinogen to
the respiratory tract of all three species; NAT has so far not been bioassayed.
After it was noted that conclusive epidemiologic data were not available to define the precise effect of NNN in humans, the
following statement was cited from a 1978 IARC report:
NNN should be regarded for practical purposes as if it were carcinogenic to humans.
1982 Brunnemann et al. (471) described the environmental occurrence of NNAs derived from foods and other consumer items,
including tobacco products. They also discussed the possibility of the in vivo formation of NNAs in blood serum, gastric
secretions, and urine.
1982 The IARC (1867) concluded that there was sufficient laboratory evidence to categorize NNN as carcinogenic in laboratory animals.
1982 In the 3rd Annual Report on Carcinogens by the National Technical Information Service (2686), the National Toxicology Program
officials noted:
Cigarette smokers, tobacco chewers, cancer researchers, and organic chemists are at greatest risk of exposure to
N-nitrosonornicotine… Smokers and persons breathing tobacco smoke may inhale a significant amount of
N-nitrosonornicotine. The amount of this substance in commercial U.S. tobacco products varies from 1.9 to 88.5 ppm; this
is one of the highest values of an experimental nitroso compound reported in the literature.
1982 In the U.S. Surgeon General’s 1982 report (4011), it was stated:
At this time, there is no experimental evidence on the formation of TSN (tobacco-specific nitrosamines) in the lung upon
inhalation of tobacco smoke. However, a smoker of one or two packs of cigarettes daily retains…1 to 4 milligrams of
nornicotine…thus, in vivo formation of tobacco-specific NNAs is a real possibility.
The report also concluded that NNK is “…by far the most potent carcinogens of the TSNAs.” In this 1982 report, NNK was
included in a list of “toxic and tumorigenic agents of cigarette smoke.” It was noted that the level of NAT in MSS of U.S.
cigarettes ranged from 0.15 to 4.6 ng/cig. It was also pointed out that no carcinogenicity bioassay data were currently available
for NAT in 1982.
1982 In their review on MSS and SSS composition and SSS:MSS ratios, Klus and Kuhn (2142) summarized the published data
[Hoffmann et al. (1679)] on MSS and SSS yields of several tobacco-specific NNAs (NNN, NNK, NAT).
1983 Using radiolabeled compounds, Adams et al. (29) conducted a detailed study on the formation and transfer of NNK: It was
reported that 6.9-11.0% of the tobacco component transferred to MSS; this amount represented 26-37% of the NNK in MSS, the
remainder (63-74%) was considered to be formed from nicotine during the smoking process. However, conflicting data were later
presented by Fischer et al. (1193, 1199) who reported that NNN and NNK in cigarette MSS arose only by transfer from the
tobacco rod and were not formed pyrogenetically during the smoking process.

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 702 The Chemical Components of Tobacco and Tobacco Smoke

Table XV-4 (Continued)

A Brief Chronology of the Research on Tobacco-Specific N-Nitrosamines
Year Investigation

1983 Hecht et al. (15A16) reported the induction of lung tumors in Syrian golden hamsters treated with a single dose of 1 milligram of
4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone (NNK).
1983 Castonguay et al. (15A08) reported:
As a result of tobacco smoking, NNN [N’-nitrosonornicotine] and NNK [4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-
butanone] are among the most ubiquitous procarcinogens detected in the human environment.
In their carcinogenicity study, Castonguay et al. found that a total dose of 0.1 mmol of NNK induced 3.76 lung tumor/mouse, or
a total of 86.5 lung tumors. This value was 29 times higher than that found in the similarly treated NNN group. The number of
lung carcinomas in the NNK group was 41 times higher than that in the NNN group.
1983 Brunnemann et al. (499) studied the influence of stem (and their nitrate content) on the volatile and tobacco-specific NNAs in MSS
and SSS. They reported that the MSS yields of “tar”, nicotine, carbon monoxide, and carbon dioxide were not greatly influenced by
filler nitrate content. This should be contrasted with previous reports from the same laboratory – at a time when nitrate addition or
high-nitrate tobacco use was touted as beneficial – on the reduction in smoke yields of “tar”, nicotine, PAHs, phenols, and carbon
monoxide as a result of nitrate addition [Wynder and Hoffmann (4332), Hoffmann and Wynder (1797, 1798)]. The SSS yield of
NDMA was extremely high (>1000 ng/cig). SSS yields of NDMA and NNN were dependent on filler nitrate content.
1983- Hecht et al. (15A17, 15A22) and Hecht and Lin (15A21) demonstrated the genotoxicity (Ames test with Salmonella
1984 typhimurium) of NNK and NNN [Hecht et al. (15A17)].
1984 As noted previously, since the early 1980s, Hoffmann and his colleagues at the American Health Foundation have presented or
published numerous reviews, many repetitious in content, of their views on NNAs. In particular, they have emphasized the TSNAs,
their levels in tobacco, in MSS and SSSs, and in ETS, their tumorigenicity in laboratory animals, and their supposed involvement in
tumor induction in tobacco users, e.g., Hecht et al. (15A17), Hoffmann et al. (1688, 1730, 1731, 1746, 1770, 1772, 15A26, 15A27),
Djordjevic et al. (1014), Hecht and Hoffmann (1571, 1571a, 15A20), Hoffmann and Hecht (1727); Brunnemann and Hoffmann
(15A03).
1984 Although their data showed that an increase in the nitrate content of cigarette tobacco reduced the MSS levels of FTC “tar”, nicotine,
carbon monoxide, catechol, and B[a]P, Adams et al. (28) emphasized that significantly higher yields of volatile NNAs and TSNAs were
found in the MSS of an 85-mm nonfiltered cigarettes whose nitrate contents were increased by sodium nitrate addition. Despite
reductions in MSS levels of “tar”, nicotine, B[a]P, and catechol, Adams et al. considered that the “carcinogenic potential” of the whole
MSS from the enhanced-nitrate cigarettes was increased primarily due to elevated yields of nitrogen oxides (NOx), volatile NNAs, and
TSNAs. They stressed the importance of the NOx as a precursor in the endogenous formation of NNAs during tobacco smoke inhalation.
However, they ignored the fact that 1) only traces of nitrogen dioxide NO2 exist in cigarette MSS, 2) over 95% of its NOx content is nitric
oxide, NO, and 3) other components in tobacco smoke reduce the nitric oxide-to-nitrogen dioxide conversion (NO→NO2) [Cooper (815),
Cooper and Hege (816)]. On the basis of their findings. Adams et al. concluded:
The findings of this study support the recommendation that the nitrate content of tobacco products should be reduced.
1984 Hoffmann et al. (1769) reported the following results from the MSS and SSS analyses of U.S. commercial cigarettes:
Level Found, ng/cig
TSNA MSS SSS
NNN 120-1000 150-1700
NNK 80-770 170-410
NAT 140-1000 150-270

In this study, subcutaneous injection of NNN (three levels: 9.0, 3.0, and 1.0 mmol/kg, thrice weekly for 20 weeks) into F344 rats
showed a dose response with respect to nasal tumors (60% and 100% at the higher two levels) and carcinoma of the nasal cavity.
Lung adenomas were observed at all three dose levels. In a parallel experiment with NNK, relatively high carcinogenicity in the
rats was observed. They wrote:
Perhaps the most important finding was that even the lowest dose of NNK induced a high percentage of lung tumors in males
(85%) and a significant yield of lung tumors in females (30%). These lung tumors included squamous cell carcinomas.
In an NAT experiment, similar to those for NNN and NNK, NAT was not carcinogenic at any of the three dose levels.
1986 IARC (1870) concluded that the TSNAs are the most abundant suspected carcinogens in tobacco smoke. It considered NNN and
NNK to be proven carcinogens for laboratory animals. It considered the evidence limited for defining the carcinogenicity of
NAB in laboratory animals and inadequate to label NAT as a carcinogen for laboratory animals.
1987 Adams et al. (31) presented data on the levels of TSNAs in MSSs and SSSs from different types of cigarette. TSNAs comprised
NNN, NNK, NAB, and NAT. For the latter three, the per cigarette SSS levels substantially exceeded the MSS levels.

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 N-Nitrosamines 703

Table XV-4 (Continued)

A Brief Chronology of the Research on Tobacco-Specific N-Nitrosamines
Year Investigation

1987 Brunnemann et al. (469) identified a new TSNA 4-(N-methyl-nitrosamino)-4-(3-pyridinyl)-1-butanol (iso-NNAL) in snuff and
cigarette tobaccos. It was not detected in either cigarette MSS or SSS. In a study involving iso-NNAL, NNN, and NNK, LAVOIE
et al. (15A34) determined the tumorigenicity of the three in mice.
1987 Klus et al. (15A32) measured several ETS-related TSNAs in indoor air of an 83-m3 office under various smoking conditions.
NNN varied from 0.7 to 6 pg/L, NNK varied from 0.2 to 10.7 pg/L. They found no correlation with the carbon monoxide levels.
1988 Tricker et al. (3945) reported that nicotine was not N-nitrosated to NNN under simulated gastric conditions. However,
nornicotine, anabasine, and anatabine were N-nitrosated to NNN, NAB, and NAT, respectively, under such conditions. They also
reported that NNK decomposed slightly under these conditions.
1989 Hecht and Hoffmann (15A19) considered both NNN and NNK as powerful carcinogens because they induced benign and
malignant tumors of the lung, nasal cavity, esophagus, pancreas and/or liver in mice, rats, and hamsters.
1989- Caldwell and Conner (573) reported:
1990
The methodology previously reported [by others] leads to significant overestimation of NNA concentrations in cigarette smoke.
The overestimations were true for both volatile NNAs and TSNAs in MSS and SSS for the Kentucky Reference Cigarette K1R4F
used in their study: MSS data indicate the levels found were 380% high for NPYR and 83%, 38%, 27%, and 19% for NAB, NAT,
NNK, and NNN, respectively. Thus, it is highly probable that the levels of NNAs in smoke tabulated in articles such as those by
Hoffmann and Hecht (1727) and frequently cited by the EPA and the Surgeon General are incorrect.
1990 Hoffmann and Hecht (1727) reviewed the evidence supporting the roles of various classes of tobacco smoke components in
cancer induction by tobacco smoke. They concluded that PAHs and NNK are the major carcinogens involved in lung cancer
induction by cigarette smoke. In their 1990 publication, they stated:
These exposure estimates [for benzo[a]pyrene] and the determinations of the tumorigenic potential of [polycyclic aromatic
hydrocarbons] in bioassays strongly suggest that [polycyclic aromatic hydrocarbons] play a significant role in the
induction of respiratory tract cancer in smokers…
Human exposure to [4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone (NNK)] is consistent with its potential role as
a causative agent for lung cancer…
These calculations [relating smoker exposure to 4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone (NNK) to dose
level needed to induce respiratory tract tumors in hamsters], which ignore the probable endogenous formation of [4-(N-
methylnitrosamino)-1-(3-pyridinyl)-1-butanone (NNK)…], point to a significant risk for the smoker and strongly support
the role of [4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone (NNK)] as an important etiological factor in lung cancer.
However, they also noted:
The organospecificity of [4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone (NNK)] for the lung is consistent with its
role in tobacco smoke-induced respiratory carcinogenesis. The lung is the main target organ for [4-(N-methylnitrosamino)-
1-(3-pyridinyl)-1-butanone (NNK)] administered [per os] or [subcutaneously] to rats and hamsters… Lung tumorsa have
also been induced in mice after topical applications of high doses of [4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone
(NNK)]… It has not been tested by inhalation.
a The tumor type was the adenoma, not the squamous cell carcinoma supposedly associated with cigarette smoking in smokers.

1990 In their list of 43 “tumorigenic agents in tobacco and tobacco smoke,” a list cited frequently in reports issued by various
governmental agencies (EPA, USPHS), Hoffmann and Hecht (1727) listed three TSNAs: NNN, NNK, and NAB, the same three
listed previously in 1986 by Hoffmann and Wynder (1808) and Iarc (1870) and subsequently by Hoffmann and his colleagues
(1740, 1741, 1743, 1744, 1773)
1991 In the introduction to their publication on lung and pancreatic cancer, Hecht and Hoffmann (1571a) reiterated their previous
conclusion on the role of PAHs and NNK in cancer causation in tobacco smokers:
Polynuclear aromatic hydrocarbons and NNK [4-(N-methyl-nitrosamino)-1-(3-pyridinyl)-1-butanone] are the major
carcinogens involved in lung cancer induction by cigarette smoke and that NNK [4-(N-methylnitrosamino)-1-(3-
pyridinyl)-1-butanone] is a likely candidate for induction of pancreatic cancer in smokers.
1992 Mimicking intragastric conditions, Caldwell et al. (575, 576) studied nicotine N-nitrosation and found it to be extremely slow.
They concluded:
It is unlikely that nicotine itself contributes to exposure to nitroso compounds [N’-nitrosonornicotine (NNN), 4-(N-
methylnitrosamino)-4-(3-pyridinyl)-1-butanal, and 4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone (NNK)] due to
chemically mediated intragastric nitrosation.

(Continued )

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 704 The Chemical Components of Tobacco and Tobacco Smoke

Table XV-4 (Continued)

A Brief Chronology of the Research on Tobacco-Specific N-Nitrosamines
Year Investigation

Caldwell et al. confirmed, in part, the 1988 findings of Tricker et al. (3945) who had previously studied the potential endogenous
formation of TSNAs under conditions simulating normal human gastric conditions.
1991- Brunnemann et al. (459, 460) sampled indoor air in bars, restaurants and trains; the levels found for NNN ranged from 0 to 23
1992 pg/L; for NNK, 1 to 29 pg/L; for NAT), 0 to 9 pg/L.
1992 In 1992 Chung et al. (793a) demonstrated that components, e.g., phenethyl isothiocyanate, indole-3-carbinol, in green tea and
cruciferous vegetables inhibited lung tumorigenesis induced by NNK.
1993 Carmella et al. (15A05) identified 4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanol (NNAL) and its glucuronide in the urine
of cigarette smokers, thus providing the first evidence for metabolites of TSNAs in human urine. No NNK was detected. Results
with smokers’ urine were consistent with those found previously with monkeys’ urine.
1993 Hoffmann et al. (1773) again cited the list of 43 tumorigens in tobacco and smoke from Hoffmann and Hecht (1727). Despite the
fact that in 1991, Hecht and Hoffmann (1571a) concluded that “polynuclear aromatic hydrocarbons and NNK [4-(N-methyl-
nitrosamino)-1-(3-pyridinyl)-1-butanone] are the major carcinogens involved in lung cancer induction by cigarette smoke and
that NNK is a likely candidate for induction of pancreatic cancer in smokers”, they listed NNK, NNN, and NNAL in this
publication only as “likely causative agents for tobacco-related cancers.”
1993 Castonguay (15A07) described the inhibition in A/J mice of NNK-induced lung tumorigenesis by ellagic acid, a polyphenolic
dilactone.

tobacco users. Figure XV-3 is a plot of the chronology from
1983 through 2004 of TSNA-related references listed in our
Reference section. It is obvious from the graphical depiction
that the decade from the late 1980s to the late 1990s was a
highly productive period for such studies. It is also obvious
from the references in bold print that the American Health
Foundation was a major contributor to our knowledge on
TSNAs.
XV.D N-Nitrosamino Acids
The results of several epidemiological studies suggested an
association between the use of chewing tobacco or snuff and
oral cancer. These products differ from smoking products
(cigarettes, cigars, pipe tobaccos) in that they are not sub-
jected to the high temperatures encountered in the smok-
ing process. Thus, smokeless products contain little, if
any, of the combustion products alleged to be significant

15A56 Reference numbers listed in bold print represent

15A20 conference presentations and/or journal publications
15A19 15A06 15A03 by Hoffmann and his American Health Foundation
3954 3181 4405 colleagues.
3948 2995 3944 aReferences listed as 15A22, etc. may be found in the
3374 1770 3182 Bibliography at the end of the text and are listed as
15A22a 3373 1688 2994 additional references to Chapter 15.
15A16 15A44 2917b 1198 2235 15A45
15A08 15A34 2674 1197 1771 4128
Ref. 3179 15A04 1676 1193 1750 4077
No. 2728 15A43 656 1196 1191 1571a 3953 3943b
1724 15A27 469 1195 1036 1200 2168 3342 3816
1559 15A17 379 3947 1194 1014 1199 1777 15A05 2916 3176a 4129
1558 3184 2852 324 3945 1192 995 1013 1005 3177 2915 2917 3343
1003 2990 1746 70 3184 1012 720 486 739a 2996 2637 1305 2700
667 2441 1725 15A23 67 3180 1002 573 484 549 2992 4161 2561 1304 2638
650 2437 728 15A21 65 2436 573 484 464 542 1702 2997 2051 951 2618
99 1696 595 2559b 64 1571 547 483 459 501 1573a 2993 1988 557 2588
98 1694 468 657 63 572 543 326 325 487 1562a 1775 2943a 1016 505 2362
29 660 26 99 62 508 466 205 202 463 554 502 2169 1011 279 2052
22 25 24 36 33 19 204 201 76 460 313 59 1001 670 50 507

1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993– 1995– 1997– 1999– 2001– 2003–
1994 1996 1998 2000 2002 2004
Year

Figure XV-3  References pertinent to tobacco-specific N-nitrosamines, 1983 to 2004.

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 N-Nitrosamines 705
tumorigens, for example, the PAHs and their N-containing
analogs, in tobacco smoke. As a result, snuff and chewing
tobacco NNAs became suspect because they were the only
components known to be laboratory animal tumorigens.
Preformed NNAs in these tobacco products and NNAs
endogenously formed in the product users were considered
by many to be the causal factor for oral cancer in snuff
dippers [Hoffmann and Adams (1677), Brunnemann et al.
(507a, 510, 15A04), Hoffmann et al. (1684, 1697, 1707, 1713,
1722), Hecht et al. (15A23), Adams et al. (33), Prokopczyk
et al. (15A44), Carmella et al. (15A06), Tsuda and Kurashima
(15A56), Djordjevic et al. (1008)] and in tobacco chewers
[Brunnemann et al. (468, 498), Wenke et al. (15A58),
Hoffmann et al. (1730, 1731), IARC (1869), Prokopczyk et al.
(2995), Tsuda and Kurashima (15A56)].
In studies to elucidate the possible tumorigens in chewing
tobacco and snuff, the only known components tumorigenic
in laboratory animals identified were various NNAs, particu-
larly the TSNAs NNN and NNK plus a group of N-nitrosamino
acids, including NPRO. Whereas discussions and investiga-
tions on volatile NNAs [Druckrey and Preussmann (1057),
Serfontein and Hurter (3595–3599)] and several TSNAs
NNN, NAB [Boyland et al. (422, 423)] have appeared in the
literature for over four decades, reports on identifications of
N-nitrosamino acids are much more recent.
Ohshima et al. (2852) identified several N-nitrosamino
acids, 3-(methylnitrosamino)propanoic acid [also known as N-
methyl-N-nitroso-β-alanine (NMPA)], 4-(methylnitrosamino)
butanoic acid (NMBA), and 1-nitroso-2-piperidinecarboxylic
acid (also known as N-nitrosopipecolic acid), in various types
of tobacco (cigarette, chewing, pipe, cigar, and snuff tobaccos).
Decarboxylation of these N-nitrosamino acids would yield
NEMA, N-nitrosomethylpropylamine, and NPIP. IARC
(1986) did note the 1985 Ohshima et al. findings on these
N-nitrosamino acids in tobacco.
Following their identification of several N-nitrosamino
acids in snuff, Djordjevic et al. (992) investigated these
acids in 1R1 and 1R4F reference tobaccos from the
University of Kentucky. In addition to detecting 4-(N-
methylnitrosamino)-4-(3-pyridinyl)-1-butanol (iso-NNAL),
4-(N-methylnitrosamino)-4-(3-pyridinyl)-1-butanal, and the
common TSNAs, the following N-nitrosamino acids were
identified: 4-(N-methylnitrosamino)-4-(3-pyridinyl)butanoic
acid (iso-NNAC), 4-(methylnitrosamino)butanoic acid
(NMBA), 3-(methylnitrosamino)propanoic acid (N-methyl-
N-nitroso-β-alanine; NMPA), 2-(methylnitrosamino)acetic
acid (N-methyl-N-nitrosoglycine, N-nitrosarcosine (NSAR),
1-nitroso-2-piperidinecarboxylic acid, and NPRO. Djordjevic
et al. considered these NNA compounds important in cancer
causation, particularly in snuff and chewing tobacco users.
Djordjevic et al. (992) confirmed the findings of Ohshima
et al. (2852) on the presence of N-nitrosamino acids in tobacco.
In addition to the N-nitrosamino acids identified by Ohshima
et al., Djordjevic et al. identified 4-(N-methylnitrosamino)-4-
(3-pyridinyl)-1-butanoic acid (iso-NNAC). The highest con-
centrations of these N-nitrosamino acids were found in snuffs
and black tobacco. They also identified 3-(methylnitrosamino)
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78836_C015.indd 705
propanoic acid (NMPA) in tobacco and MSS and estimated
its transfer from tobacco to MSS to be 0.85%.
In studies with N-nitrosamino acid-spiked cigarettes,
Brunnemann et al. (466) reported that added NMPA did
not completely decarboxylate. Some was esterified to the
methyl ester. Some of the intact acid, its methyl ester, and
its decarboxylation product, NEMA, appeared in the MSS.
Similar to NMBA, some NMBA transferred intact from the
tobacco to the MSS, some formed the methyl ester, which
appeared in the MSS, and some decarboxylated to yield
N-nitrosomethylpropylamine, which also appeared in the
MSS. NPRO primarily decarboxylated to NPYR. NSAR pri-
marily decarboxylated to NDMA.
Djordjevic et al. (1012) identified 4-(N-methylnitrosa-
mino)-4-(3-pyridinyl)-1-butanoic acid (iso-NNAC) in
tobacco and in MSS. This acid was found only in the MSS
from cigarettes containing tobacco spiked (2 mg/cigarette)
with cotinine. From the results of in vitro nitrosation studies
with radiolabeled cotinine and nicotine, Djordjevic et al. (995)
proposed that the formation of 4-(N-methylnitrosamino)-
4-(3-pyridinyl)-1-butanoic acid (iso-NNAC) in tobacco
proceeds via cotinine and its hydrolysis product 4-methyl-4-
(3-pyridinyl)-1-butanoic acid rather than via nicotine.
Brunnemann et al. (464) presented a more detailed expo-
sition of their 1989 findings on the fate in “spiked” ciga-
rettes of several N-nitrosamino acids [2-(methylnitrosamino)
acetic acid (NSAR), 3-(methylnitrosamino)propanoic acid
(NMPA), 4-(methylnitrosamino)butanoic acid (NMBA), and
N-nitrosoproline (NPRO)]. These acids are delivered intact to
MSS, undergo esterification to the methyl ester and are deliv-
ered as such to MSS, and/or decarboxylate and are delivered
to MSS as the NNAs NDMA, NEMA, NMPA, and NPYR,
respectively.
Djordjevic et al. (1013) described in greater detail their
identification of 4-(N-methylnitrosamino)-4-(3-pyridinyl)-
1-butanoic acid (iso-NNAC) in tobacco and in MSS. They
reported that iso-NNAC was found only in the smoke
from cigarettes containing cotinine-spiked tobacco (2 mg/
cigarette) [see Djordjevic et al. (1012)]. Djordjevic et al.
(1005, 1008) identified three new N-nitrosamino acids in
snuff tobacco: 2-(methyl-nitrosamino)-3-phenylpropanoic
acid, 2,5-di(methylnitrosamino)pentanoic acid, and 2,6-
di(methylnitrosamino)hexanoic acid. They discussed not
only the identification of the three new N-nitrosamino
acids but also the carcinogenic potential of these and other
N-nitrosamino acids, particularly in the context of tobacco
chewing or snuff dipping.
Djordjevic et al. (993) reported that the levels of
N-nitrosamino acids in snuff tobaccos were often 150 times
those found in cigarette tobaccos (usually about 1 ppm).
Examination of the results of the studies on N-nitrosamino
acids in tobacco smoke reveals the importance of amino acids
(and their precursors, the tobacco proteins) in N-nitrosamino
acid formation before and during the smoking process.
Figure XV-4 illustrates some of the relationships among the
amino acids, N-nitrosamino acids, their methyl esters, and
N-nitrosamines.
11/13/08 7:15:03 PM
 706 The Chemical Components of Tobacco and Tobacco Smoke

H2N-(CH2)n-COOH H3C-N(NO)-(CH2)n-COOCH3 COOH COOH

XVIII XXII
NH2 N N COOCH3
NO
H3C-NH-(CH2)n-COOH H3C-N(NO)-(CH2)n-COOH XXVI XXVII XXX
NO
XIX XX

HOOC-CH(NH2)-(CH2)n–1-COOH H3C-N(NO)-(CH2)n-H N COOH N COOH N

XXIII XXI H
XXVIII NO XXIX NO XXXI
H2N-(CH2)n-CH(NH2)-COOH R-(CH2)n-CH(R)-COOH
COOH COOH
where R = H3C-N(NO)-
XXIV
XXV
n = 3 (-NH3) n = 4 (-NH3) NH N N
NO NO
XXVIII XXXII XXXII XXXIII XXXIV

Figure XV-4  Relationships among amino acids, N-nitrosamino acids, their esters, and N-nitrosamines.

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 N-Nitrosamines 707
XV.E Tobacco-Specific N-Nitrosamines:
An Exception among the Major
MSS Toxicants
Since the mid-1950s various MSS toxicants, either as an indi-
vidual component or a class of components, have had their
moment of publicity but one by one their importance gradu-
ally faded. Chronologically, the first toxicants to become
infamous were the tumorigenic PAHs, with B[a]P at the pin-
nacle because of its potent tumorigenicity to mouse skin and
its per cigarette MSS yield. The chronology of the rise to
notoriety of the various individual and/or class of toxicants
has been previously depicted [see Figure  1 in Rodgman
et al. (3307)] but not shown is when the prominence of most
of them declined.
In the mouse skin-painting bioassay, neither B[a]P nor the
total tumorigenic PAHs accounted for the observed specific
tumorigenicity (4354). The B[a]P content of CSC accounted
for less than 2.5% and the total tumorigenic PAH content of
CSC accounted for less than 3.5% of the CSC specific tum-
origenicity [1056, 4312, see p. 626 in (4332)]. Inclusion of
tumorigenic aza-arenes reported by Van Duuren et al. (4027)
did not improve the situation. Hoffmann and Wynder (1798)
reported that doubling or tripling the level of seventeen tum-
origenic PAHs in CSC significantly increased the percent
tumor-bearing animals (% TBA), whereas others reported
that a 10-fold (3311) or 30-fold (2320) increase in the B[a]P
level in CSC produced no change in the % TBA. In the early
1960s, the promoting effect of MSS phenols on tumorigenic
PAHs was advanced to explain the tumorigenic response
observed in CSC-painted mice. Inclusion of this effect in
the assessment accounted for about 5% of the % TBA. In
addition, reports of no change in the tumorigenicity of CSC
when significant amounts (75% to 90%) of the phenols were
removed from MSS (and the CSC) by selective filtration [see
p. 626 in (55), 4344] and the inhibition of the specific tum-
origenicity of B[a]P by phenol (149) diminished the alleged
importance of the promoting effect of phenols.
To offset the decrease in importance of the PAHs, aza-
arenes, and phenols, ciliastatic components in MSS then
became the in-vogue toxicants. It was asserted, based on stud-
ies with clam cilia and mammalian ciliated tissue, that certain
MSS toxicants impair lung ciliary activity, thus preventing
removal of tumorigen-containing smoke particles from the
lung. MSS components proposed as significant ciliastats
included formaldehyde, acetaldehyde, acrolein, HCN, formic
and acetic acids, and phenol. However, after the reported find-
ings of Dalhamn et al. in 1968, the ciliary assertion faded
because of the demonstration that less than a third of the cili-
astats reach the lung cilia in human smokers (892, 893).
In the mid-1960s, several other MSS toxicants had their
brief moment of infamy, for example, 210Po, NO2, CO, Ni. In
their comparison of lung cancer incidence in uranium miners
exposed to 210Po vs. cigarette smokers exposed to MSS 210Po,
Harley et al. (75) questioned the significance of 210Po in
tobacco-induced lung cancer. Concern over NO2 diminished
with the demonstration that over 95% of the NOx in MSS was
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78836_C015.indd 707
NO, not NO2, and the conversion of NO to NO2 was impeded
by other MSS components (94).
In the early 1960s, the formation of NNAs during tobacco
smoking was suggested (423) as well as the possible presence
of NNN and NAB in MSS (423, 3313). Between 1964 and the
early 1970s, several volatile NNAs were identified in MSS.
It was also reported that 60% to 85% of the volatile NNAs,
like the phenols, are selectively filtered from MSS (514, 1236,
1761, 2635). The identification of several TSNAs, including
NNN and NAB, then followed.
Why have TSNAs maintained their status as important
MSS toxicants while the importance of other individual and/
or classes of toxicants has faded?
Alternate exposures are possible with toxicant classes
other than the TSNAs, including NNAs, but the TSNAs, as
defined, are “tobacco-specific.” In other words, no alternate
exposure exists for TSNAs. In the detailed 1984 outline of
chemical carcinogenesis edited by Searle (3568), the only
class of MSS tumorigens discussed in 22 chapters compris-
ing nearly 1400 pages was the NNAs [see pp. 839–844 in
Preusmann and Eisenbrand (2990)]. Most of the data cited
[see Tables VII to IX, pp. 841, 843, 844 in (2990)], are those
from publications by Hoffmann and his colleagues (514,
1677, 1680, 1685).
Since the early 1960s, a “less hazardous” cigarette has
been defined on the basis of three criteria: (1) the per ciga-
rette delivery of a specific toxicant has been lowered, (2) the
ratio of the specific toxicant to MSS “tar” has been lowered,
and (3) the specific tumorigenicity of the MSS “tar” as mea-
sured in the mouse skin-painting bioassay has been lowered.
From bioassay results of more than 330 NNAs plus knowl-
edge of fewer than sixty specific NNAs in MSS, it is obvi-
ous that the MSS NNAs cannot meet criterion (3). Over 330
N-nitroso compounds variously administered to forty different
species have been reported as tumorigenic. No laboratory
species is resistant to NNAs. In their summary of the results
from 323 N-nitroso compounds bioassayed from 1956 to
1984, Preussmann and Stewart (2991) reported that 87% of
the N-nitroso compounds are tumorigenic. Over 70% of the
N-nitroso compounds studied were NNAs; the remainder
were N-nitrosamides.
Administration of most NNAs to laboratory animals via
skin painting seldom results in carcinoma induction at the
application site. Generally, tumors develop at site(s) remote
from the painting site and various organs may be involved.
This major difference between PAH and NNA tumorige-
nicity led to defining NNAs as organ-specific tumorigens.
Failure to produce tumors with NNAs at the painting site
subsequently led to studies of NNAs administered by alter-
nate routes (injection [subcutaneous, intravenous, intraperito-
neal], per os, intratracheal instillation, etc.). Administration
of NNAs by inhalation was studied infrequently.
Skin-painting studies with six NNAs (N-nitrosobutyl-
methylamine, NDEA, NDELA, iso-NNAL, NNK, NNN)
present in tobacco and/or tobacco smoke were reported by
Brune and Henning (15A02), F. Hoffmann and Graffi (15A30),
Herrold (15A24), Herrold and Dunham (15A25), IARC (1870),
11/13/08 7:15:07 PM
 708 The Chemical Components of Tobacco and Tobacco Smoke
Hoffmann et al. (1786a), and LaVoie et al. (15A34). Tumors
developed elsewhere in the test animals but none at the paint-
ing site. In a painting study by Deutsch-Wenzel et al. (956a),
NNN induced a few skin tumors, but no dose-response rela-
tionship was observed over a 12.5- to 200-µg range. In the
same study, the tumorigenic potency to skin of N-nitroso-
N-methylurea was estimated to be about 4% of that of B[a]
P. In painting studies with N-nitroso-N-alkylureas, tumors did
develop at the skin-painting site, but to date, no N-nitroso-N-
alkylurea has been identified in tobacco or MSS.
XV.F Direct Transfer of TSNAs from
Tobacco vs. Their Formation
during the Smoking Process
Nicotine, nornicotine, anabasine, and anatabine are precur-
sors of TSNAs in tobacco and tobacco smoke (29, 1564). Both
nicotine and nornicotine are considered to be NNN precur-
sors. Since NNAs (both volatile and tobacco-specific) occur
in tobacco, part of the NNAs in cigarette MSS was reported
to be due to direct transfer of NNAs from tobacco to MSS, the
remainder due to formation and transport during the smoking
process (201). For NNK, the transfer from tobacco to MSS
ranges from 6.9% to 11.0% of the amount in the tobacco; this
represents about 30% of the NNK in MSS. Similarly, about
40% of the NNN in MSS is transferred from the tobacco.
Hoffmann et al. maintain that the remainder of NNN and
NNK in MSS is formed during the smoking process (1558,
1734). Both the levels of volatile NNAs and TSNAs in MSS
are proportional to the nitrate content of the tobacco filler
(3985). However, the premise of the pyrogenesis of NNN and
NNK has been challenged by Fischer et al. (1193, 1199), who
reported that these compounds occur in cigarette MSS only
by transfer from the tobacco rod. Castonguay (15A07) stated
that NNK is transferred from tobacco to smoke during the
smoking process. In agreement with Fischer et al., Renaud
et al. (15A46) concluded that direct tobacco-to-smoke transfer
was the dominant factor explaining the presence of TSNAs
in MSS. From their study of the contribution of 13C-nicotine
Table XV-5
N-Nitrosamines in Tobacco and/or Tobacco Smoke
N-Nitrosamines
1-Nitroso-2-azetidinecarboxylic acid
4-(N-Methylnitrosamino)-1-(3-pyridinyl)butanone oxide
1-Nitroso-4-hydroxyproline
1-Nitroso-3-piperidinecarboxylic acid
1-Nitroso-4-piperidinecarboxylic acid
3-Nitroso-4-thiazolidinecarboxylic acid
a Bioassay results reported by Castonguay et al. (15A08)
b Bioassay results in laboratory animals are summarized in Preussmann and Stewart (2991); yes = tumor induction, no = nega-
tive response. Number in [] represents catalog number in Preussmann and Stewart (2991).
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78836_C015.indd 708
to 13C-NNN and 13C-NNK levels in MSS CSC, Moldoveanu
et al. concluded that NNN and NNK are generated during
the smoking process (2599), thus contradicting the views of
Fischer et al. (1193, 1199), Castonguay (15A07), and Renaud
et al. (15A46). Moreover, the pyrogenesis situation was fur-
ther clouded by data on the effect of tobacco nitrate on the
MSS TSNA yields (1552). Analysis of MSS TSNAs indicated
that NNN and NAT yields increased when nitrate was added
to the tobacco but the NNK yield did not.
XV.G Infrequently Studied Tobacco
and/or Smoke Secondary Amines
and Their N-Nitrosamines
During extensive investigations of the composition of
tobacco smoke in general and cigarette MSS in particular,
much effort was expended in the early 1960s to define the
nature of N-nitrosation during curing and the smoking pro-
cess. As more and more N-nitrosamines (NNAs) were identi-
fied in tobacco and/or tobacco smoke, they were categorized
as follows: volatile NNAs, nonvolatile NNAs, TSNAs, and
N-nitrosamino acids. Within these four categories, only
about sixty NNAs have been identified to date as tobacco
and/or tobacco smoke components. Except for an excursion
into the identification of N-nitrosamino acids, identification
of NNAs in MSS almost ceased when NNK and to some
extent NNN became the toxicants of choice. This situa-
tion raises the question, If a detailed study similar to those
conducted on the PAHs and aza-arenes were conducted,
how many additional NNAs could be identified in tobacco
and/or tobacco smoke?
Table XV-5 lists several NNAs reported as tobacco com-
ponents that are seldom discussed. To date, none of them has
been identified in tobacco smoke.
While Table XV-6 is not necessarily complete, it suf-
fices for the following discussion. In Table XV-6 are
listed twenty-two dialkylamines, identified in tobacco
and/or smoke as the amine or the NNA. For four NNAs
(N-nitrosoisobutylmethylamine, N-nitrosoethylpropylamine,
Identified in Smoke (S)
and/or Tobacco (T)
CAS No. S T Activity
55556-98-4 — +
76014-82-9 — + yesa
2443-30-3 — +
65445-62-7 — +
6238-69-3 — + no [173]b
88381-44-6 — +
11/13/08 7:15:08 PM
 N-Nitrosamines 709

Table XV-6
Aliphatic Secondary Amines and Volatile N-Nitrosamines in Tobacco and Tobacco Smoke
R R=H R = NO
| Identified in Smoke (S) Identified in Smoke (S)
R1-N-R2 or Tobacco (T) or Tobacco (T) Biological
R1 = R2 = CAS No. S T CAS No. S T Activity

CH3- CH3- 124-40-3 + + 62-75-9a + + yes [1]b

CH3- CH3CH2- 624-78-2 + + 10595-95-6a + + yes [52]b
CH3- CH3(CH2)2- 627-35-0 + + 924-46-9 + + yes [66]b
CH3- (CH3)2CH- 4747-21-1 + + + —
CH3- CH3(CH2)3- 110-68-9 + + 7068-83-9a + — yes [71]b
CH3- (CH3)2CHCH2- — — 2504-18-9 + —
CH3- (CH3)(C2H5)CH- + — — —
CH3- (CH3)2CH(CH2)2- + — — —
CH3- CH2=C(CH3)- 22023-64-9 + — — —
CH2CH3- CH2CH3- 109-89-7 + + 55-18-5 a + + yes [7]b
CH2CH3- CH3(CH2)2- 20193-20-8 — — 25413-61-0 + +
CH2CH3- (CH3)2CHCH2- — — 71607-99-3 + +
CH2CH3- CH3(CH2)3- 13360-63-9 — — + — yes [122]b
CH3(CH2)2- CH3(CH2)2- 142-84-7 + + 621-64-7 a + + yes [21] b
CH3(CH2)2- (CH3)2CH- 21968-17-2 + + — —
CH3(CH2)2- (CH3)(C2H5)CH- + — — —
(CH3)2CH- (CH3)2CH- 108-18-9 + — 601-77-4 + — yes [34]b
(CH3)2CH- CH3(CH2)3- 39099-23-5 + — — —
CH3(CH2)3- CH3(CH2)3- 111-92-2 — + 924-16-3 a + + yes [36]b
CH3(CH2)3- (CH3)2CHCH2- 20810-06-4 + — + —
(CH3)(C2H5)CH- (CH3)(C2H5)CH- 626-23-3 — + — — yes [45]b
(CH3)3C- (CH3)2CH- + — — —
a Compound listed as a toxicant in one or more lists published since 1986 (1217, 1727, 1740, 1741, 1743, 1744, 1773, 1808, 1870, 2825).
b Bioassay results in laboratory animals are summarized in Preussmann and Stewart (2991); yes = tumor induction,
no = negative response. Number in [] is catalog number in Preussmann and Stewart (2991).

N-nitrosoethylisobutylamine, N-nitroso-n-butylethylamine), the
corresponding amines have not been identified in tobacco smoke.
It is highly probable that the four amines are present as MSS
components. Alternatively, NNAs corresponding to the other
ten dialkylamines identified in tobacco and/or tobacco smoke
have not yet been identified in smoke, for example, no NNA cor-
responding to sec-butylmethylamine, isopentylmethylamine,
or isopropylidenemethylamine identified as MSS components
has been identified in MSS. Synthetically, the corresponding
NNAs are as easily prepared as N-nitrosodimethylamine or
N-nitrosodiethylamine so their pyrogenesis during the smoking
process should not be hindered. Thus, it is highly probable that
the ten NNAs are present in tobacco smoke.
Many other secondary amines have been identified
in tobacco smoke but for most of them no corresponding
NNA has been identified in smoke. These include a series
of N-substituted anilines, all amenable to N-nitrosation
{XXXV}. Others include the alkyl derivatives of pyrrolidine
{XXXVI}, piperazine {XXXVII}, and piperidine {XXXVIII}.
The amines pyrrolidine {XXXVI}, piperazine {XXXVII},
and 1,2,3,6-tetrahydropyridine {XXXIX} have been iden-
tified in cigarette MSS but not piperazine {XXXVII} (see
structures in Table XV-7). For each piperazine, mono- and
di-N-nitroso derivatives are possible. Morpholine {XL} and
an alkyl derivative have also been identified in tobacco. For
completeness, azetidine {XLI} is included in Table XV-7. In
many instances, the NNAs listed in Table XV-7 are readily
synthesized and have been tested for tumorigenicity in labo-
ratory animals [see Preussmann and Stewart (2991)].
Table XV-7 lists forty-six secondary amines, most of
which have been identified as components of tobacco and/or
its smoke. In only a few cases have the corresponding NNAs
been identified as tobacco and/or smoke components. It is
highly probable that the NNAs corresponding to the remaining
secondary amines may also be tobacco smoke components.
Among the numerous classes of smoke components are
several other types of secondary amines, for example, the
pyrroles, indoles, carbazoles, and imidazoles. However,
their highly aromatic nature and the acidity of the imino
hydrogen probably preclude any significant N-nitrosation
either in the tobacco or during the smoking process. Despite
the fact that a dozen or so theoretically N-nitrosatable sub-
stituted pyrroles; nearly fifty alkyl derivatives of indole
{XLII}; carbazole {XLIII} and several of its alkyl deriva-
tives, benzocarbazoles, and dibenzocarbazoles; and several
alkyl derivatives of imidazole and benzimidazole {XLIV}

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 710 The Chemical Components of Tobacco and Tobacco Smoke

have been identified in tobacco smoke, no NNA correspond-
ing to any of them has been identified to date in tobacco
smoke (Figure XV-5).
It is obvious that the number of NNAs in tobacco and/or
tobacco smoke might be substantially greater than the sixty
or so NNAs now known to be present. Since the per cigarette
yields of the yet unidentified NNAs may be at the picogram
or femtogram levels, their contribution to MSS toxicological
properties may not be particularly meaningful or important.
However, they may be just as important from a biological

Table XV-7
Aromatic and Cyclic Secondary Amines and N-Nitrosamines in Tobacco and Tobacco Smoke

© 2009 by Taylor & Francis Group, LLC

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 N-Nitrosamines 711

Table XV-7 (Continued)

Aromatic and Cyclic Secondary Amines and N-Nitrosamines in Tobacco and Tobacco Smoke

point of view as those MSS components repeatedly listed as
toxicants for which no or questionable quantitative data are
available, for example, the much discussed dibenzo[def,p]
chrysene (dibenzo[a,l]pyrene) (1557, 1727, 1740, 1741, 1743).
To put the NNAs in perspective and to determine how
many more are actually present in MSS, what may be needed
is an extensive study corresponding to the excellent studies
on PAHs (3756–3758) and aza-arenes (3750) conducted and
reported by U.S. Department of Agriculture (USDA) person-
nel in the late 1970s and early 1980s.
It is also interesting to note that 4-(methylnitrosamino)-1-
(3-pyridyl)-1-butanol (NNAL), the major metabolite of NNK
(1557), is usually not listed as a cigarette MSS toxicant even
though NNAL has been reported to be both tumorigenic to
several rodent species (15A08) and mutagenic in the Ames
Salmonella typhimurium test.

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 712 The Chemical Components of Tobacco and Tobacco Smoke
7 H
N N
6
2 6
5 9
3 5
4
XLII
Figure XV-5  Indole {XLII}, carbazole {XLIII}, and 1H-benzimidazole {XLIV}.
XV.H Flue-Curing and Tobacco-
Specific N-Nitrosamines
As described by Williams (4247) there is general agreement
among tobacco scientists that TSNAs are not present in either
freshly harvested, that is, green flue-cured and burley tobac-
cos. As the tobaccos are cured either by air curing in the
case of burley or in heated barns for flue-cured varieties, the
amounts of TSNAs rise to their final levels. In the case of
air curing, the process has changed little over the past fifty
years. However, for flue curing, the process changed drasti-
cally in the United States during the 1960s and 1970s due to
the introduction of energy-efficient bulk-curing barns heated
by exhaust gases of liquid propane gas or similar burners.
It is at this point that a breakdown must have occurred
between tobacco agriculturists and chemists. The emission
of NO2 during the combustion of liquid propane or natural
gas is well known. In fact, the North Carolina Department
of Environment and Natural Resources (NCDENR) has elec-
tronic spreadsheets available for download from its Web site
that North Carolina industries may use in estimating their
NO2 emissions during natural gas or liquid propane combus-
tion. In retrospect, any competent chemist would predict the
potential nitrosation of tobacco alkaloids during flue curing
in the presence of combustion exhaust gases. However, with-
out the knowledge of TSNA formation during direct heating
of green tobaccos, the agricultural community adopted the
new energy-efficient technique. It appears that prior to this
“technological advance,” the formation of TSNAs during flue
curing by traditional methods was not a problem.
Earlier, at least two research groups discovered the prob-
lem with direct-heating flue curing of tobacco. Peele et al.
(2917) demonstrated that modification of the curing process
for flue-cured tobacco permitted significant control of its
TSNA levels. The curing process was altered from one involv-
ing direct-fired burners to one involving a heat exchange sys-
tem. During approximately the same period, Williams (258)
applied for and was granted a U.S. patent on essentially the
same modification of the flue-curing barns to achieve the
same significant reduction in TSNAs. An example of the
TSNA reductions in flue-cured tobacco and its smoke was
shown by Rodgman and Green [see Figure 3, p. 522 in (3300)].
The tobacco data were from Williams (4247), the smoke data
from Doolittle et al. (1051).
© 2009 by Taylor & Francis Group, LLC
78836_C015.indd 712
8 1
7 2
3 2
N
N 4 H
H
XLIII XLIV
During the past few years, advances have been made to
reduce NNAs, specifically TSNAs, in tobacco and tobacco
smoke. The agronomic community with the help of the
tobacco industry has made significant headway in discon-
tinuing direct heating for flue curing as a means to reduce
TSNAs in tobacco and tobacco smoke. This advancement
is desirable from a product stewardship perspective and has
little if any effect on tobacco quality. Biological response
data on individual TSNAs indicate that TSNAs play a minor
role in MSS carcinogenesis [see Tables 1 and 5 in Rodgman
and Green (3300)]. Comparisons of the biological effects
(Neutral Red cytotoxicity, mutagenicity in the Ames test
with several Salmonella typhimurium strains) of mainstream
CSCs from flue-cured tobacco cigarettes with normal and
reduced levels of TSNAs, indicated no significant difference
between the biological activity of the two CSCs [Doolittle
et al. (1051)]. Although the Doolittle et al. data appear to
support the hypothesis on a whole-smoke basis that main-
stream TSNAs are of relatively minor toxicological impor-
tance, the sensitivity of the Ames assay is not sufficient to
differentiate between the cigarettes tested. For example,
consider the following points published by Doolittle et al.
(1051):
• The minimum amount of NNK needed for a muta-
genic response in the Ames assay is 200 µg.
• The maximum amount of CSC that can be tested
is 250 µg.
• In 250 µg of CSC there is 1.33 and 0.13 ng of NNK
from direct-fired and heat-exchanged flue-cured
tobacco, respectively.
• The amount of NNK in the CSC from either flue-
cured tobacco smoke is too low for a response.
Every practical effort should be made to reduce the
amounts of alleged human carcinogens from tobacco prod-
ucts. However, whether the reduction or elimination of
TSNAs from MSS will result in a “less hazardous” cigarette
is unknown.
Table XV-8 lists the sixty-seven N-nitrosamines identified
to date in tobacco and/or tobacco smoke. Of these fifty-three
N-nitrosamines have been identified in smoke, fifty-one in
tobacco, and thirty-seven in both.
11/13/08 7:15:17 PM
 N-Nitrosamines 713

Table XV-8
N-Nitrosamines in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke
Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

(Continued )

© 2009 by Taylor & Francis Group, LLC

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 714 The Chemical Components of Tobacco and Tobacco Smoke

Table XV-8 (Continued)

N-Nitrosamines in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C015.indd 714 11/13/08 7:15:26 PM

 N-Nitrosamines 715

Table XV-8 (Continued)

N-Nitrosamines in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 716 The Chemical Components of Tobacco and Tobacco Smoke

Table XV-8 (Continued)

N-Nitrosamines in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C015.indd 716 11/13/08 7:15:29 PM

 N-Nitrosamines 717

Table XV-8 (Continued)

N-Nitrosamines in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C015.indd 717 11/13/08 7:15:39 PM

 718 The Chemical Components of Tobacco and Tobacco Smoke

Table XV-8 (Continued)

N-Nitrosamines in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C015.indd 718 11/13/08 7:15:44 PM

 N-Nitrosamines 719

Table XV-8 (Continued)

N-Nitrosamines in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

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 720 The Chemical Components of Tobacco and Tobacco Smoke

Table XV-8 (Continued)

N-Nitrosamines in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C015.indd 720 11/13/08 7:15:48 PM

 16 Nitroalkanes, Nitroarenes,
and Nitrophenols
In his 1954 catalog of tobacco smoke components, Kosak
(2170) listed no organic nitro-containing component. In
1959, Johnstone and Plimmer (1971), in their compilation
of tobacco and tobacco smoke components, also listed no
organic nitro-containing component.
In their 1964 review (4319) and 1967 book (4332) on
tobacco smoke carcinogenicity, Wynder and Hoffmann did
not mention a nitroalkane or a nitroarene. In his 1968 review,
Stedman (3797) listed no organic nitro-containing compo-
nent identified in tobacco and tobacco smoke composition.
His list of the agricultural chemicals used in tobacco agron-
omy [see Table XVI in (3797] also contained no nitro-con-
taining compound.
In their review of the N-containing components in tobacco
and smoke, Schmeltz and Hoffmann listed thirty nitro com-
ponents [see Table X in (3491)] separated into six nitroalkanes
identified by Hoffmann and Rathkamp (1755) and Rathkamp
et al. (3086) in the late 1960s, eight monocyclic nitroarenes
identified by Hoffmann and Rathkamp in 1970 (1758), and
sixteen nitrophenols, including one nitronaphthol, reported
by Klus and Kuhn in 1975 (2137).
In their 1980 catalog (1884), Ishiguro and Sugawara also
listed thirty nitro components in tobacco smoke. All the nitro
components they listed were those tabulated in the 1977 arti-
cle by Schmeltz and Hoffmann (3491).
With the limiting analytical technology available in 1982,
Lee et al. (2329) at the American Health Foundation reported
that they were unable to measure significant quantities of
4-nitro-1,2-benzenediol (4-nitrocatechol) in cigarette MSS.
El-Bayoumy et al. in a conference presentation (1122) and a
journal publication (1124) reported that 1-nitronaphthalene,
1-nitropyrene, and 6-nitrochrysene, if present in cigarette
smoke, were at yields lower than their analytical capability.
In its 1986 monograph on tobacco smoking, the Inter-
national Agency for Research on Cancer (IARC) discussed
many of the details of N-nitrosamines and tobacco-specific
N-nitrosamines in tobacco smoke. Despite the reports prior
to 1985 on the identification in tobacco smoke of many nitro
components (1755, 1758, 2137, 3086), IARC listed only one
nitro compound, 2-nitropropane, as a biologically active
smoke component [see Table 19, pp. 86–87 in (1870)]. In its
listing of the evaluation of tobacco smoke components for
© 2009 by Taylor & Francis Group, LLC
78836_C016.indd 721
carcinogenicity, IARC defined the evidence in 1986 of the
carcinogenicity in animals and humans of 2-nitropropane as
sufficient [see Appendix 2, p. 393 in (1870)]. Hoffmann and
Wynder (1808) included 2-nitropropane in their list of major
toxic and tumorigenic agents in nonfiltered cigarette MSS.
Although not dealing with cigarette smoke in this particular
1987 study, Grimmer et al. (1406a) identified 1-nitropyrene
in diesel exhaust.
Of the many nitro components in tobacco smoke, only
nitrobenzene, nitromethane, and 2-nitropropane were dis-
cussed repeatedly since 1986. In reports dealing primarily
with commercial cigarettes, these three nitroalkanes were
listed periodically in various publications as toxic smoke
components, biologically active smoke components, tum-
origenic smoke components, or carcinogenic smoke compo-
nents: nitrobenzene (1741, 1743, 1744), nitromethane (1743,
1744), 2-nitropropane (1217, 1727, 1740, 1741, 1743, 1744,
1773, 1808, 2825). 2-Nitropropane was also described as a
known carcinogen in the MSS from all-flue-cured or all-bur-
ley cigarettes (1716).
In 2003, Cheng et al. (692, 693) reported the identification
in CSC of five nitro-polycyclic aromatic hydrocarbons. They
included 1-and 4-nitropyrene, 1,6- and 1,8-dinitropyrene,
and 6-nitrochrysene. In 2004, Cheely et al. (683) described
an analytical procedure that enabled the identification of
1-nitronaphthalene, 1-nitropyrene, and 6-nitrochrysene in
cigarette MSS.
Although 2-nitropropane was much discussed as a tum-
origen or carcinogen in cigarette smoke and its categoriza-
tion by IARC as having yielded sufficient evidence to rate
it as both an animal and a human carcinogen, it seldom was
designated as a “Hoffmann analyte.” While it did not use
the term “Hoffmann analyte” in its report, the Department
of Health (Canada) proposed that analytical data on the per
cigarette yields of over forty components in tobacco smoke
should be a requirement to indicate the hazardous nature of
cigarette smoke (16A01). No nitroalkane was included in its
list. Neither nitrobenzene nor nitromethane appeared in any
“Hoffmann analyte” list.
Table XVI-1 lists the nitroalkanes, nitroarenes, and nitro-
phenols identified in tobacco, tobacco smoke, and tobacco
substitute smoke.
721
11/13/08 5:34:31 PM
 722 The Chemical Components of Tobacco and Tobacco Smoke

Table XVI-1
Nitroalkanes, Nitroarenes, and Nitrophenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke
Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

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 Nitroalkanes, Nitroarenes, and Nitrophenols 723

Table XVI-1 (Continued)

Nitroalkanes, Nitroarenes, and Nitrophenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 724 The Chemical Components of Tobacco and Tobacco Smoke

Table XVI-1 (Continued)

Nitroalkanes, Nitroarenes, and Nitrophenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Nitroalkanes, Nitroarenes, and Nitrophenols 725

Table XVI-1 (Continued)

Nitroalkanes, Nitroarenes, and Nitrophenols in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 17 Nitrogen Heterocyclic Components
XVII.A Monocyclic Four-
AND Five-Membered N-Containing
Ring Compounds
XVII.A.1 Background
Tobacco (Nicotiana tabacum) is a unique agricultural crop
used to prepare a variety of commercial products (ciga-
rettes, pipe tobacco, cigars, chewing tobacco, snuff, etc.).
Consumers enjoy tobacco by placing it into their mouth or
nasal cavity (in the case of oral and snuff products) or by
lighting the tobacco article (cigarette, cigarillo, cigar, etc.)
and inhaling the tobacco smoke produced. As a result, the
chemical composition of both the leaf and the tobacco smoke
are important to consumers (for its flavor and appeal) and
to scientists attempting to understand the chemical organo-
leptic, pharmacological, and toxicological properties of this
extremely complex consumer product.
Tobacco is a natural product that contains numerous
classes of chemical compounds. As a living entity, tobacco
contains all of the complex biological machinery necessary
to sustain life. Chemical constituents in the tobacco leaf are
influenced by numerous factors as the tobacco plant develops
from seed to cured leaf. These factors include genetic poten-
tial, environmental conditions, cultural practices, and curing
methods. Interactions among the factors also influence the
chemical composition of the cured leaf. The genetic makeup
of the plant provides the potential to produce or not to pro-
duce certain compounds, the realization of these potentials
depend on environmental variations that the plant endures
during growth and processing conditions employed to manu-
facture the finished tobacco product (677a).
Although the chemical composition of the tobacco leaf is
important, tobacco smoke also contains an extensive variety
of chemical compounds. The presence and relative concen-
trations of these tobacco smoke components depend on (1)
the composition of the tobacco leaf, (2) tobacco additives, (3)
manufacturing processes, (4) the physical form and materials
used to construct the different smoking articles, and (5) the
smoking procedure.
An elemental analysis for carbon, hydrogen, and nitrogen in
foods and tobacco indicates that there is only about 5% nitro-
gen in dry tobacco (2439). The percent carbon, hydrogen, and
oxygen (by difference) of dry tobacco leaf are about 43, 6,
and 43%, respectively (2798), with the remainder being trace
levels of metals and nonmetals. The majority of the nitrogen
in tobacco leaf resides in the proteins, alkaloids, nitrates, and
amino acids. The N-containing compounds in tobacco leaf
have often been associated with the quality of the leaf. This
is especially true with burley tobacco (3973). Nitrogenous
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78836_C017.indd 727
compounds in tobacco and smoke have an enormous range
of taste and odor quality and intensity. Many are odorless
and tasteless (proteins, nitrates), some have extremely pleas-
ant tastes and odors, for example, some pyrazines (2439) and
imidazoles, while others are very strong, pungent, and offen-
sive, for example, some pyridines (1803).
In this section, we present information on four- and
five-membered N-containing ring compounds identified in
tobacco, tobacco smoke, and tobacco substitute smoke. The
classes of compounds include azetidines, pyrrolidines, 2- and
3-pyrrolines, pyrroles, pyrazoles, imidazolidines, imidazo-
lines, imidazoles, and 1,2,4-triazoles (Figure XVII.A-1).
XVII.A.2 Four-Membered N-Containing Rings
Few four-membered N-containing ring compounds have been
identified in tobacco or tobacco smoke. These compounds
are classified as azetidines. Nicotianamine, first isolated from
tobacco by Noma et al. in 1971 (2796a), has also been identi-
fied in numerous other plant species (3528a). Nicotianamine is
a derivative of 2-azetidinecarboxylic acid, an amino acid iden-
tified in numerous plant species, including Nicotiana tabacum
(2330b). The precursor for the biosynthesis of azetidine in
tobacco and azetidine-2-carboxylic acid, in particular, is con-
sidered to be methionine (2330b). The bacterial plant pathogen
tabtoxin (L-threonine, N-[2-amino-4-(3-hydroxy-2-oxo-3-
azetidinyl)-1-oxobutyl]-) was isolated from wildfire tobacco (a
wild species of Nicotiana tabacum) in 1971 (3819a).
The scant information on azetidine compounds can be
found in several review articles on the chemistry of com-
pounds identified in tobacco and tobacco smoke. In their
1977 review, Schmeltz and Hoffmann (3491) reported the
presence of 2-azetidinecarboxylic acid and nicotianamine in
tobacco. Hecht et al. (1580) reported the identification of aze-
tidine in both tobacco and smoke in 1977. Brunnemann and
Hoffmann (486) reported the presence of the nitrosamine,
1-nitroso-2-azetidinecarboxylic acid in tobacco in 1991.
Table XVII.A-1 lists the four-membered N-containing
ring compounds identified in tobacco, tobacco smoke, and
tobacco substitute smoke. Only five compounds are known to
exist in tobacco and tobacco smoke that contain an azetidine
ring. All five have been identified in tobacco. Azetidine has
been identified in tobacco and tobacco smoke.
XVII.A.3 Five-Membered N-Containing Rings
Tobacco and smoke chemists have shown an intense interest
in the chemistry and biochemistry of this diverse class of
compounds. Numerous studies on the presence of nitrogenous
compounds in tobacco and tobacco smoke have appeared
727
11/24/08 12:27:27 PM
 728 The Chemical Components of Tobacco and Tobacco Smoke

R R
H H
NH N N N N
5 2 5 2

4 3 4 3 R R
Azetidine Pyrrolidine 2-Pyrroline 3-Pyrrolines Pyrroles

R R
H H
N N H
N N N
N 2 5 2 N
5
R 3
4 NH 4 N N R N
3
Pyrazoles Imidazolidine 2-Imidazoline Imidazoles 1,2,4-Triazole

Figure XVII.A-1  Representative structures of the 4- and 5-membered N-containing ring compounds in tobacco, tobacco smoke, and
tobacco substitute smoke.

over the past forty-five years and various aspects of the origin
of these compounds in tobacco and their presence in tobacco
smoke by direct transfer, pyrosynthesis, and combustion
processes have been examined. Books, reviews, and articles
by Wynder and Hoffmann (4332), Stedman (3797), Neurath
(2724), Tso (3972, 3973), Chaplin (677a), Leffingwell (2337),
Schmeltz and Hoffmann (3491), Hecht et al. (1580), Leete
(2330c), Bush and Saunders (557a), Green (1351), Newell
et al. (2769), Ishiguru and Sugawara (1884), Heckman and
Best (1587), Gorrod and Wahren (1334d), Davis and Nielsen
(910a), and Gorrod and Jacob (1334c) contain synopses of
much of the information we know today on N-containing
ring compounds in tobacco and tobacco smoke.
During the 1970s and 1980s, an exceptional amount
of research on tobacco and smoke component isolation
and identification was conducted and published. This was
largely due to many scientific advancements that occurred
in chromatographic methods during this period. The results
of several excellent studies on tobacco leaf composition by
Lloyd et al. (2389), Dickerson et al. (965), Roberts and Rohde
(3219), Takahara et al. (3858), Demole et al. (937–939, 941,
943, 943a), Fujimori et al. (1247, 1249, 1250), Chuman et al.
(731–739), Schumacher (3550), and Schumacher and Vestal
(3561) are included here for reference. The Swedish Tobacco
Company published nearly one hundred articles on the com-
position of tobacco, primarily Oriental tobacco. The many
Swedish Tobacco Company investigators included Aasen,
Almqvist, Behr, Enzell, Hlubucek, Kimland, Nishida, and
Wahlberg, all of whom co-authored many tobacco com-
position articles (1–13, 52, 53, 84, 91–94, 227, 229–236,
1149–1157a, 1205a, 1660–1662, 2092–2095, 3315, 4083–
4102). Excellent detailed summaries of their identification

Table XVII.A-1
4-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 728 11/24/08 12:27:28 PM

 Nitrogen Heterocyclic Components 729
of hundreds of tobacco components and the generation of
them from various terpenoid structures were presented and
published in the late 1970s and early 1980s by Enzell (1149,
1150), Enzell and Wahlberg (1156), and Wahlberg and Enzell
(4089, 4090).
The basic five-membered N-containing ring compounds
found in tobacco; whether they contain one or more nitro-
gens, arise from several metabolic and catabolic pathways.
Additionally, many N-containing ring compounds are formed
via nonenzymatic browning reactions.
Amino acids and proteins are produced in living species
and are essential compounds of tobacco plants. One of the
most important metabolic pathways in plants is the Krebs
tricarboxylic acid cycle (2337, 3973). The Krebs cycle con-
trols the metabolic carbon-nitrogen balance in living plants
by converting carbon dioxide via photosynthesis to such
intermediates as oxaloacetic, a-ketoglutaric, and pyruvic
acids. Concurrently, inorganic nitrogen as nitrates is assimi-
lated through the plant roots and is subsequently reduced to
ammonia by hydrogen originating from reactions occurring
in the Krebs cycle. Ammonia then reacts with oxaloacetic,
a-ketoglutaric, and pyruvic acids to form aspartic and glu-
tamic acids and alanine, which provide the nitrogen for fur-
ther synthesis of other amino acids (1351). These amino acids
are then used as the nitrogen pool from which many of the
other nitrogenous compounds of the tobacco plant are formed.
For example, the pyrrolidine ring can be formed from argin-
ine or ornithine via a series of metabolic reactions involving
arginine decarboxylase or ornithine decarboxylase to form
putrescine (1,4-diaminobutane) which is then converted to
4-methylaminobutanal via putrescine N-methyltransferase,
S-adenosine-methionine, and methylputrescine oxidase.
Via cyclization and demethylation, pyrrolidine is produced
(3973). Numerous other metabolic reactions occur that pro-
duce five-membered N-containing ring compounds such as
the pyrrolines, pyrroles, pyrazolines, pyrazoles, imidazoli-
dines, imidazolines, and imidazoles.
From the time of harvest through curing and aging, many
changes take place in the concentrations of tobacco leaf
amino acids and proteins (3972). According to Gaines and
Miles (1270a), one of the extremely important aims of this
process is to accomplish a degradation of tobacco proteins.
This degradation produces numerous types of short-chained
amino acid oligomers, free amino acids, and many function-
alized N-containing compounds, such as alcohols, aldehydes,
acids, aldehydes and esters. Among these catabolic break-
down products are the simple four-, five-, and six-membered
N-containing ring compounds and a variety of alkaloids
and alkaloid-type compounds that are oxidized, reduced, or
otherwise functionalized.
The origins of the five-membered N-containing ring com-
pounds in leaf are also attributed at least partially to nonen-
zymatic browning or Maillard reactions between sugars and
amino acids (965). Many compounds formed by nonenzy-
matic browning reactions have desirable flavor and aroma
characteristics that taken together form the characteristic
bouquet and taste associated with tobacco (2337).
© 2009 by Taylor & Francis Group, LLC
78836_C017.indd 729
A wide variety of five-membered N-containing ring com-
pounds have been isolated and identified in tobacco smoke.
Two general mechanisms are involved: direct transfer of
tobacco components to tobacco smoke and the generation of
smoke components by combustion and pyrolysis of tobacco.
In 1977 it was estimated that the direct transfer of compo-
nents from leaf to smoke accounted for about one-third of the
smoke constituents identified in tobacco smoke at that time
(1351). This process is relatively simple and many of its fac-
tors are understood. This process has been discussed in some
length by Wakeham (4103). The second mechanism involves
the pyrolysis, combustion, and subsequent pyrogenesis of
smoke components. This process is complex and involves the
tobacco, the means and materials used in constructing the
smoking article, and the actual smoking process (puff volume,
duration, puff interval, etc.). The relationships between vari-
ous leaf constituents and their pyrolysis products are the
ones most difficult to trace yet they are the most necessary to
understand (1351).
In contrast to the number of leaf components that generally
transfer directly to smoke (~33%), only about 16% of the 313
tobacco and tobacco smoke compounds that contain a five-
membered N-containing ring were found in both tobacco and
tobacco smoke. A considerable portion of the smoke yields
from these compounds was no doubt due to transfer of the
compounds directly from tobacco, although some of the yield
of these compounds is produced by pyrolysis, combustion,
and pyrogenesis of a variety of compounds in tobacco.
As mentioned previously the largest contributors of
organic leaf nitrogen are the leaf proteins, alkaloids, and
amino acids. A majority of the protein in the tobacco con-
sists of the enzymes associated with photosynthesis. The
single most abundant protein in tobacco is called Fraction
I and is designated functionally as ribulose-l,5-diphosphate
carboxylase. Our knowledge of the genomic makeup of
tobacco has advanced tremendously in the last twenty years.
Once the Tobacco Genome Initiative is completed, over 90%
of the genetic map of tobacco will be known (429b, 429c).
Numerous databases of genes, enzymes, and reactions occur-
ring in Nicotiana species are already available.
The identities of the free amino acids of cured leaf are
well known (1351). Of the forty-four amino acids reported
in leaf, a majority have also been found in tobacco smoke.
Proline and asparagine are the major amino acids in flue-
cured tobacco, whereas asparagine and aspartic acid are the
major amino acids in burley tobacco. These plus glutamine
and histidine are the principal amino acid precursors of the
five-membered N-containing ring compounds in tobacco.
High-temperature pyrolysis studies of protein and amino
acids have been described in a series of papers by Smith
et al. (3724, 3727a, 3728a, 3729), Patterson et al. (2902–2905),
Higman et al. (1647), Schmeltz (3477–3479), Sugimura et al.
(3829), and Yamamoto et al. (4365a). Under these pyrolytic
conditions, pyrodegradation and pyrosynthesis were extensive.
In general, pyrolysis gave complex mixtures that were qualita-
tively similar regardless of the specific amino acid being pyro-
lyzed. Compounds identified included aromatic hydrocarbons
11/24/08 12:27:28 PM
 730 The Chemical Components of Tobacco and Tobacco Smoke

such as benzene and naphthalene, their N-containing analogs

such as pyridine and quinoline, pyrrole, aromatic nitriles such Table XVII.A-2
as benzonitrile and 1-naphthonitrile, aniline, and phenols. Studies on the Pyrolysis of Amino Acids
As suggested by Patterson et al. (2904), this similarity of
Amino Acid CAS. No. References
results indicates that the amino acids and proteins undergo
degradation into common intermediates of two-, three-, and Amino acids Kato et al. (2048, 2049), Kosuge
four-carbon types which subsequently recombine to form et al. (2178a), Masuda et al.
more thermally stable aromatic systems. To be discussed in (2486), Nebert et al. (2688a)
a subsequent chapter is the pyrogenesis of the potent muta- Alanine 107-95-9 Matsumoto et al. (2491b)
Arginine 74-79-3 Matsumoto et al. (2491b)
gens 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) and
Asparagine 7006-34-0 Matsumoto et al. (2491b)
3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) from
Cysteine 52-90-4 Matsumoto et al. (2491b)
tryptophan (3829) and 2-aminodipyrido[1,2-a:3’,2’-d]imida- Cystine 24645-67-8 Matsumoto et al. (2491b)
zole (Glu-P-2) and 2-amino-6-methyldipyrido[1,2-a:3’,2’-d] Glutamic acid 6899-05-4 Matsumoto et al. (2491b), Ohgaki
imidazole (Glu-P-1) from glutamic acid (3828a, 4365a), all et al. (2849b), Sugimura (3828a),
four of which were subsequently identified in tobacco smoke Takeda et al. (3863a), Takayama
(3828c). Table XVII.A-2 catalogs many of the pyrolysis stud- et al. (3862b), Yamamoto et al.
ies conducted on amino acids. (4365a)
Pyrolysis and smoke studies of amino acids indicate that Glutamine 56-85-9 Matsumoto et al. (2491b)
they are potential precursors of several nitrogen heterocyclic Histidine 71-00-1 Matsumoto et al. (2491b),
ring systems found in tobacco smoke. Proline has been shown Smith et al. (3722a)
Histidine, 3-methyl- Smith et al. (3722a)
to be efficiently converted to pyrrole upon pyrolysis (3219,
Lysine 56-87-1 Matsumoto et al. (2491b),
3724) and in addition has been proposed as a possible precur-
Wakabayashi et al. (4102a)
sor of pyrocoll (2593, 4336). g-Amino acids and dicarboxy- Methionine 63-68-3 Matsumoto et al. (2491b)
lic amino acids are capable, under pyrolytic conditions, of Ornithine 70-26-8 Matsumoto et al. (2491b)
forming 2-pyrrolidones (1967, 3079) and by a similar mecha- Ornithine, N5- 372-75-8 Matsumoto et al. (2491b)
nism, D-amino acids can form 2-piperidones (1967, 3079). A (aminocarbonyl)-
side effect of the pyrolysis of amino acids is the formation of {citrulline}
hydrogen cyanide. Phenylalanine 63-91-2 Matsumoto et al. (2491b),
Johnson and Kang (1967) studied the hydrogen cyanide Sugimura et al. (3829)
yields from pyrolysis of compounds containing ring nitrogen Serine 6898-95-9 Kato et al. (2048), Matsumoto
et al. (2491b)
and found that these heterocycles, particularly those with five-
Threonine 72-19-5 Matsumoto et al. (2491b)
membered rings, produced the highest yields of hydrogen
Tryptophan 73-22-3 Hosaka et al. (1835a), Matsukura
cyanide. These results are in accord with those of Smith et et al. (2491a), Matsumoto et al.
al. (3724) in which proline was found to give high yields of (2491b), Negishi and Hayatsu
hydrogen cyanide. The pathway seems to be through pyrrole (2689a), Sugimura et al. (3829),
which is formed in excellent yield (67%) on pyrolysis of pro- Takayama et al. (3862d),
line. Patterson et al. (2908) had previously found that pyrrole Yamazoe et al. (4370a),
on pyrolysis at 850°C is converted in 49% yield to hydrogen Yoshida and Matsumoto (4390)
cyanide. This may not be the only pathway for the formation Tyrosine 60-18-4 Matsumoto et al. (2491b)
of hydrogen cyanide from proline because Johnson and Kang Valine 7004-03-7 Matsumoto et al. (2491b)
(1967) found that proline can generate hydrogen cyanide
more readily than pyrrole.
Protein and free amino acids found in tobacco leaf contrib-
ute significantly through pyrodegradation and pyrosynthesis
to the formation of many nitrogenous compounds found in In freshly harvested leaf, both reducing sugars and amino
tobacco smoke. The nonvolatility of these compounds either acids are present, and these are known to react to form non-
as free acids, proteins, or members of tobacco pigment, for volatile sugar-amino acid compounds, known as Amadori
example, porphyrins, make them particularly liable to pyro- compounds (1671b). A number of these Amadori com-
lytic destruction because they, unlike nicotine and the other pounds have been isolated from flue-cured tobacco leaf by
plant alkaloids, are not readily volatilized and swept away as Cousins (841a), Tomita et al. (3923), Yamamoto et al. (4362),
the more intense heat of the cigarette coal approaches (3724). and Wahl (4081a). Noguchi et al. (2794a) have shown how
There are also interactions that occur among amino acids, the free amino acid concentration of leaf decreases during
proteins, and carbohydrates during plant growth and during aging and the Amadori compound levels initially increase
smoke formation. These interactions form complex mixtures and then slowly decrease. These changes, especially the
of leaf constituents and complex mixtures resulting from the decrease in Amadori compounds, indicate the possible prog-
pyrodegradation and pyrosynthesis of reaction products of ress of Maillard-type reactions during natural aging of leaf
amino acids, proteins, and carbohydrates. tobaccos.

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 Nitrogen Heterocyclic Components 731
Dickerson et al. (965) found evidence for progress of the
Maillard reaction in their studies on aged flue-cured leaf
where a number of formylpyrroles were isolated. Dickerson
et al. (965) followed the formation of several formylpyrroles
from a specific Amadori compound. The Amadori compound
was converted via the Maillard reaction to a 3-deoxyosulose
which further reacted with either an amino acid or an amine
to form the isolated formylpyrroles. In addition to the form-
ylpyrroles, a number of pyrazines and furans, characteristic
of nonenzymatic browning reactions, were also isolated from
flue-cured tobacco. Thus, there is evidence for the Maillard
reaction occurring even before smoking.
Sometimes in sugar-amine browning systems where pyra-
zines are isolated, there is also found another class of nitro-
gen heterocyclic compounds, the imidazoles (1835b, 1947a).
These compounds have been reported in tobacco smoke by
Schumacher and co-workers (3553). In contrast to the pyra-
zines, only a few imidazoles have been isolated from non-
enzymatic browning reactions of foods. This might be due
to the unusually high boiling points and polarity of these
compounds. Grimmett (1410b) has reviewed the formation of
imidazoles from the interaction of carbohydrates and amine
sources, and many of the same compounds found to be pyra-
zines precursors can also form imidazoles. Simple sugars,
starches, and cellulose — all known tobacco leaf constituents
— are reported to react with amines, including ammonia, to
form imidazoles (1351).
Many of the reactions producing imidazoles in tobacco
and tobacco smoke involve the interaction of carbohydrates
with ammonia, which has several precursors in tobacco.
Amino acids and proteins can contribute to the formation of
smoke amines and the formation of ammonia. Johnson et al.
(1964) conclusively demonstrated through experiments with
15N-glycine that it is an ammonia source. In addition to amino
acids, nitrates have been shown to be efficiently converted
during the smoking of a cigarette to ammonia (1964). This
ammonia from nitrates was shown to participate in the for-
mation of many nitrogenous compounds in smoke. Thus, leaf
nitrates as well as amino acids and proteins are considered
the major sources of ammonia in tobacco smoke.
As to the mode by which certain leaf constituents may
form imidazoles, it is commonly recognized that a-dicarbo-
nyl compounds may react with aldehydes in the presence of
ammonia to form nitrogen heterocyclic compounds such as
imidazoles. The required a-dicarbonyl compounds and alde-
hydes are well-known pyrolysis products of carbohydrates
either through thermal (1170a) or Maillard-type (1671a) deg-
radations, and many of these compounds have been isolated
from tobacco smoke (3797). It is possible that a-aminoketones,
such as those proposed as intermediates in the formation of
pyrazines, may also be involved with the formation of imi-
dazoles because reactions producing imidazoles from these
compounds have been reported (1410b). Although the forma-
tion of imidazoles through carbohydrate and amino acid or
protein interaction is especially appealing due to the analo-
gies which can be made with pyrazines, a second origin is
also possible. Tobacco leaf contains an appreciable amount
© 2009 by Taylor & Francis Group, LLC
78836_C017.indd 731
of the amino acid histidine, either in its free form or as part
of tobacco protein. Pyrodegradation of this compound in a
manner similar to that of tryptophan (2047) could also be a
source of some imidazoles in tobacco smoke.
The contribution of the five-membered N-containing ring
compounds in tobacco and tobacco smoke to smoke flavor
is not as well known. The flavor evaluations of some tobac-
co-derived imidazoles have been described by Schumacher
et al. (3553a). The flavors of these compounds are an exam-
ple of how relatively nonvolatile, flavorless compounds in
tobacco leaf can be transformed during the smoking process
into a part of the characteristic aroma of tobacco smoke.
Leffingwell et al. (2341) and Roberts (3215) in their review
of natural tobacco flavor reported that several acetylpyrroles
provided a nutty, woody, and sweet taste to tobacco smoke
but that formylpyrroles often added harshness to the tobacco
smoke aroma. Imidazoles have been reported to provide a
sweet chocolate or nutty character to tobacco smoke at low
levels but can be bitter at high levels (3215).
The principal precursor for the biosynthesis of ring struc-
tures of pyrrolidine, pyrroline, and pyrrole is glutamine
(2056b, 2659a, 2848a). Pyrrole structures can also be pro-
duced in plants from arginine or ornithine (2056b). The bio-
synthetic pathway for the production of the imidazole ring
structure involves the biosynthesis of histidine through a
series of ten enzymatic reactions (57a). The first intermedi-
ate of the pathway (phosphoribosyl pyrophosphate) is also
the starting point for purine and pyrimidine biosynthesis.
The amino acid glutamine provides much of the backbone
for imidazole, which is an intermediate in histidine biosyn-
thesis (429d). From imidazole glycerol phosphate five addi-
tional enzymatic steps are needed for the plant to produce
histidine. The imidazoline and imidazolidines rings can
be produced by enzymatic hydrogenation of the imidazole
ring. The imidazolidine ring is also believed to be produced
biosynthetically when glutamate condenses with carbamyl
phosphate to form hydantoin or imidazolidine-2,4-dione.
The hydantoin can be enzymatically reduced to imidazo-
lidines (225a). Additionally, hydantoin can be produced in
plants by hydrogenation of allantoin (2,5-dioxo-4-imida-
zolidinylurea), a cyclic amide naturally occurring in many
plants (4068a). Pyrazolidine, pyrazoline, and pyrazoles are
produced in plants from 1,3-diaminopropane via pyrazoles
synthase (C3) (437a).
The five-membered N-containing ring compounds with
three nitrogens are the 1,2,3-triazoles and the 1,2,4-triazoles.
Triazoles are not produced in plants naturally but are found
as structural components of many pesticides and herbicides.
Seven herbicides containing a five-membered N-containing
ring have been identified in tobacco as residues. The pesti-
cides containing a 1,2,4-triazole ring include three fungicides
(Triadimefon®, Penconazole®, and Triadimenol®), one her-
bicide (Sulfentrazone®), and one insecticide (Triazophos®).
Two 1,2,3-triazoles (as benzotriazoles) have been identified
in tobacco and tobacco smoke to date, Azinphos-Methyl-
Oxon® and Azinphos-Methyl®. Both of these pesticides
are insecticides. Azinphos-Methyl-Oxon® has also been
11/24/08 12:27:28 PM
 732 The Chemical Components of Tobacco and Tobacco Smoke

(a position) through four methine bridges (=CH-) to form a

Table XVII.A-3 large flat ring structure (see Figure XVII.A-2). A porphyrin
Distribution of 5-Membered N-Containing Ring in which no metal is inserted in its cavity is called a free
Compounds between Tobacco and Tobacco Smoke base.
Many organic analogs that contain a porphryin ring
Number of Identified 5-Membered N-Containing
Ring Compounds in Tobacco and Tobacco Smoke
are biological pigments and are closely related molecules
responsible for many of the vivid colors in living organisms.
Smoke and They often occur combined with metal ions and various
Component Total Smoke Tobacco Tobacco substituents as coordination complexes. Chlorophylls are
Pyrroles 116 88 50 22
magnesium complexes of porphyrin derivatives (also called
Pyrrolidines 79 64 36 21 phorbines). In plants, these pigments are responsible for pho-
Pyrrolines 28 23 7 2 tosynthesis and play important roles as respiratory pigments,
Pyrazoles 16 13 3 0 electron transport carriers, and oxidative enzymes. Several
Imidazoles 62 57 8 3 chlorophylls have been identified in tobacco, the most com-
Imidazolidines 10 8 3 1 mon being chlorophyll a and chlorophyll b. Chlorophyll a
Imidazolines 3 1 2 0 is a waxy blue-black microcrystalline green-plant pigment,
Triazoles 7 2 8 3 C55H72MgN4O5, with a characteristic blue-green alcohol
Totals 321 256 117 52 solution. Chlorophyll b is a similar green-plant pigment,
C55H70MgN4O6, having a brilliant green alcohol solution.
Several other chlorophyll derivatives have also been isolated
from tobacco (3770a).
identified as a degradation product of Azinphos-Methyl®. The biosynthesis of porphyrin involves glycine and suc-
All of these triazoles were reported as tobacco pesticide resi- cinyl-CoA (from the citric acid cycle) to form d-aminolevu-
dues (928a, 2913a, 3663, 2650a). The remaining fungicide in linic acid (dALA). Two dALA molecules are combined into
this series of five-membered N-containing ring compounds porphobilinogen (PBG), which contains the pyrrole ring.
with three nitrogens is Iprodione®. Iprodione® is an imida- Four PBGs are then combined through deamination into
zolidinecarboxamide and has been reported as a fungicide hydroxymethylbilane (HMB), which is hydrolyzed to form
residue on tobacco (3585, 3633, 3661a). the circular tetrapyrrole, uroporphyrinogen III. This mol-
Table XVII.A-3 lists the distribution of five-membered ecule undergoes a number of further modifications. The bio-
N-containing ring compounds identified in tobacco, tobacco synthesis is complicated and requires anywhere from seven
smoke, and tobacco substitute smoke. to thirty enzymatic reactions involving a variety of catalytic
Table XVII.A-4 lists 321 compounds, of which 116 are pyr- activities, including decarboxylation, methylation, metal ion
roles, seventy-nine are pyrrolidines, and twenty-eight are pyr- chelation, and porphyrin ring oxidation. Intermediates are
rolines. There are sixteen pyrazoles listed in Table XVII.A-4. used in different species to form particular substances, but,
Sixty-two imidazoles, ten imidazolidines, and three imida- in plants and tobacco in particular, the main end-product is
zolines have been identified in tobacco and tobacco smoke. protoporphyrin IX, which is combined with magnesium to
Five compounds with a 1,2,4-triazole ring have been identi- form chlorophyll (3770a).
fied in tobacco. Two compounds with a 1,2,3-triazole ring (as Table XVII.A-5 lists the compounds in tobacco, tobacco
benzotriazoles) have been identified in tobacco and tobacco smoke, and tobacco substitute smoke with multiple five-
smoke. The compounds in Table XVII.A-4 exhibit a great membered N-containing rings. While fourteen porphyrin-
deal of functionality. Although each contains a five-mem- containing compounds have been identified in tobacco, only
bered N-containing ring, some are alcohols, ketones, sugar- porphyrin itself has been identified in tobacco smoke (1899,
amines, acids, esters, and imides. Of the 321 compounds 3491).
listed in Table XVII.A-4, 256 are found in tobacco smoke,
117 are found in tobacco, and 52 are present in both tobacco
and tobacco smoke.

XVII.A.4 Compounds in Tobacco, Tobacco

NH N
Smoke, and Tobacco Substitute
Smoke With Multiple Five-Membered
N-Containing Rings
N HN
Porphyrins are a class of biologically important heterocy-
clic compounds with a characteristic chemical structure that
includes four pyrrole groups (five-membered organic rings
each containing a nitrogen atom) linked on opposite sides Figure XVII.A-2  Porphyrin.

© 2009 by Taylor & Francis Group, LLC

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 Nitrogen Heterocyclic Components 733

Table XVII.A-4
5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke
Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

(Continued)

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 733 11/24/08 12:27:31 PM

 734 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.A-4 (Continued)

5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 734 11/24/08 12:27:32 PM

 Nitrogen Heterocyclic Components 735

Table XVII.A-4 (Continued)

5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 735 11/24/08 12:27:33 PM

 736 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.A-4 (Continued)

5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 736 11/24/08 12:27:34 PM

 Nitrogen Heterocyclic Components 737

Table XVII.A-4 (Continued)

5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 737 11/24/08 12:27:35 PM

 738 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.A-4 (Continued)

5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 738 11/24/08 12:27:36 PM

 Nitrogen Heterocyclic Components 739

Table XVII.A-4 (Continued)

5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 739 11/24/08 12:27:37 PM

 740 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.A-4 (Continued)

5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 740 11/24/08 12:27:38 PM

 Nitrogen Heterocyclic Components 741

Table XVII.A-4 (Continued)

5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 741 11/24/08 12:27:39 PM

 742 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.A-4 (Continued)

5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 742 11/24/08 12:27:42 PM

 Nitrogen Heterocyclic Components 743

Table XVII.A-4 (Continued)

5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 743 11/24/08 12:27:42 PM

 744 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.A-4 (Continued)

5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 744 11/24/08 12:27:43 PM

 Nitrogen Heterocyclic Components 745

Table XVII.A-4 (Continued)

5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 745 11/24/08 12:27:44 PM

 746 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.A-4 (Continued)

5-Membered N-Containing Ring Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

Table XVII.A-5
Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with Multiple 5-Membered
N-Containing Rings

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 746 11/24/08 12:27:46 PM

 Nitrogen Heterocyclic Components 747

Table XVII.A-5 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with Multiple 5-Membered
N-Containing Rings

XVII.B Monocyclic Six-Membered
N-Containing Ring Compounds
XVII.B.1 Introduction
Over the years several detailed composition studies on the
volatile components in flue-cured [Lloyd et al. (2389) and
Dickerson et al. (965)], burley [Roberts and Rohde (3219),
Demole et al. (937, 938, 940–942), and Fujimori et al. (1249–
1252, 1256)], Maryland [Schumacher (3550)], and Oriental
tobaccos [Kimland et al. (2092–2095), Almqvist et al. (52),
Aasen et al. (5, 11b), Hlubucek et al. (1660, 1660a, 1661, 1662),
Schumacher (3561), Fukuzumi et al. (1257, 1258), and Chuman
et al. (731–739)] have been published (2337, 3797). Similarly,
the composition of tobacco smoke (3797) has advanced tre-
mendously over the years (1373), notably by the works of
Schumacher et al. (3553), Heckman and Best (1587), Grob
(1412–1427), Bartle et al. (199, 200), Neurath (2719–2753),
Elmenhorst (1129–1140), Newell et al. (2769), Hoffmann and
colleagues (480, 486, 735, 1580), the tobacco research person-
nel at the U.S. Department of Agriculture, Atlanta, Georgia,
and many others [see additional listing in (2337)].
Tobacco chemists have shown considerable interest in the
chemistry and biochemistry of the diverse set of N-containing
compounds in tobacco and tobacco smoke. Numerous stud-
ies on the presence of nitrogenous compounds in tobacco
and tobacco smoke have been published. These studies have
reported on various aspects of the origins of nitrogenous

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 748 The Chemical Components of Tobacco and Tobacco Smoke
compounds in tobacco, their synthesis, pyrolysis, and trans-
fer to smoke. Several books and reviews [Tso (3972–3974b),
Neurath (2724), Stedman (3797), Wynder and Hoffmann
(4332), Schmeltz and Hoffmann (3491), Leffingwell (2337),
Hecht et al. (1580)] have been written on N-containing com-
pounds in tobacco and tobacco smoke.
The levels of chemical compounds in tobacco are affected
by genetics, environmental conditions, and agronomic prac-
tices. Considering the six-membered N-containing ring
compounds and especially the alkaloid-type components
(five- and six-membered and multiple six-membered nitrogen
heterocycles) of tobacco, this is especially true. There have
been numerous reviews on factors affecting plant growth
and nicotine/alkaloid accumulation in tobacco [Bush and
Saunders (557a), Chaplin and Miner (677a), Bush and Crowe
(17B04), Leete (2331a, 2331–2334), Bush (555a), Strunz and
Findley (17B56), Bush et al. (17B05)].
Section XVII.B provides information on compounds in tobacco
and tobacco smoke that contain a six-membered N-containing
ring (piperidines, tetrahydropyridines, pyridines, piperazines,
dihydropyrazines, pyrazines, pyrimidines, pyridazines, and tri-
azines), compounds with a five-membered (pyrrolidine, pyrrole,
imidazole) plus a six-membered N-containing ring (pyridine), and
compounds containing two or more six-membered N-containing
rings (piperidines, pyridines). The formation of these compounds
in tobacco from biosynthetic pathways and from nonenzymatic
processes will be presented, as well as means of their generation
and delivery to tobacco smoke.
XVII.B.2 Biosynthesis of Six-Membered
N-Containing Ring Compounds
and the Five- and Six-Membered
and Multiple Six-Membered Nitrogen
Heterocycles of Tobacco
The next few paragraphs will discuss the biosynthesis of the six-
membered N-containing ring compounds and especially the
alkaloid-type components (five- and six-membered and multi-
ple six-membered nitrogen heterocycles) of tobacco. Following
the biosynthesis section, information will be provided on the
formation of some of the six-membered N-containing ring
compounds that occur during tobacco aging and processing.
Finally, a discussion of how these six-membered N-containing
ring compounds and especially the alkaloid-type components
arise in tobacco smoke will be presented.
Over sixty species of Nicotiana exist that produce nico-
tine alkaloids (nicotine, nornicotine, anatabine, anabasine).
Nicotine is the predominant alkaloid in over 50% of the
Nicotiana species. Nornicotine is the major alkaloid in about
30% to 40% of Nicotiana species. Anabasine and anatabine
are not usually the principal alkaloids in Nicotiana (17B05).
Tobaccos that accumulate and have high levels of alkaloids
tend to also have accumulations of minor alkaloids, for
example, cotinine, myosmine, nicotyrine, 2,3′-bipyridine,
and numerous derivatives of the major alkaloids, for example,
alkyl, acyl, and nitroso derivatives of nicotine and the other
© 2009 by Taylor & Francis Group, LLC
78836_C017.indd 748
major alkaloids. The starting materials for the biosynthesis
of the alkaloids are all present in tobacco. The precursors
for pyridine, pyrrolidine, piperidine, and the most abundant
nicotine alkaloids (nicotine, anabasine, anatabine, cotinine,
myosmine) are well known and have been reviewed by Bush
et al. (17B05). Although great advances in our understanding
of alkaloid biosynthetic processes have occurred over the last
fifty years, the metabolic and degradative processes occur-
ring in Nicotiana species are still being researched. The
biosynthesis of some of the six-membered N-containing ring
compounds (pyrazines, pyridazines, and triazoles) is still not
completely understood. As mentioned above, the biosynthe-
sis of pyridine, pyrrolidine, and piperidine will be presented.
The subsequent biosynthesis of the major alkaloids will
then follow. It should be noted that although biosynthesis is
the most important means of producing the six-membered
N-containing ring compounds and the alkaloids found in
tobacco, other processes for their production in leaf are also
operative. Several tobacco processing operations such as
aging, fermentation, thermal treatments of tobacco prior to
use in products, tobacco expansion, blending operations, and
additive applications can vary (both increase or decrease) the
concentration of various six-membered N-containing ring
compounds and alkaloids.
Pyridine and the pyridine ring of nicotine, nornicotine,
anabasine, and anatabine are formed from nicotinic acid. Yang
et al. (17B62) reported that quinolinic acid was the precursor to
nicotinic acid via quinolinic acid phosphoribosyl-transferase.
Glyceraldehyde-3-phosphate (from glycerol) and aspartic
acid via a series of enzymes are converted to quinolinic acid.
Jackanioz and Byerrum (17B17) showed that 14C-labeled
aspartate and malate incorporated into the C-2 and C-3 posi-
tions of the pyridine ring when these amino acids were fed to
tobacco plants. The total biosynthetic pathway and intermedi-
ates involved have not yet been completely elucidated.
The most accepted biosynthetic pathways for piperidine
is lysine via D‘-piperidine (3973, 17B05). Piperidine can also
be formed through decarboxylation and dehydrogenation of
nicotinic acid (17B37).
The pyrrolidine ring and particularly the N-methylpyrrolidine
ring of nicotine is biosynthesized through putrescine (1,4-
butanediamine), N-methylputrescine, and 4-methylamino-
butanal to the N-methyl-D‘-pyrrolinium salt (17B41). Dewey
et al. (17B11) and Leete (17B29) fed 14C-ornithine to tobacco
and found incorporation of activity in the C-2′ and C-5′
carbons of the N-methylpyrrolidine ring. Arginine via
arginine decarboxylase forms agmatine that is converted to
putrescine as a second source of this intermediate for the pro-
duction of the pyrrolidine ring. Again, some of the interme-
diates and enzymes involved in the biosynthetic production
of pyrrolidine are still not completely known (2334, 17B02,
17B63, 17B64).
Dawson et al. (17B07, 17B08) showed that nicotinic acid
formed the pyridine ring in nicotine. Yang et al. (17B62)
showed that the pyrrolidine ring of nicotine was attached at
the C-3 position of the pyridine ring of nicotine. Dawson et al.
(17B07) in another publication showed that the hydrogen at
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 Nitrogen Heterocyclic Components 749

the C-6 position of nicotinic acid was lost during nicotine
formation. Dawson and Osdene (17B09) and Leete (2330c)
showed that nicotine formation proceeds through the reduc-
tion of nicotinic acid to 3,6-dihydronicotinic acid. Friesen
and Leete (1241a) proposed that dihydronicotinic acid forms
a zwitterion by proton transfer that readily decarboxylates
to yield 1,2-dihydropyridine. 1,2-Dihydropyridine in turn
reacts with N-methyl-D‘-pyrrolinium salt to yield 3,6-dihy-
dronicotine. The 3,6-dihydronicotine is oxidized with the
loss of the hydrogen originally present at the C-6 position
of nicotinic acid and retention of the hydrogen added in the
reduction step to 3,6-dihydronicotinic acid. This pathway
adequately explains the majority of the intermediates formed
during nicotine biosynthesis and the fact that all nicotine in
tobacco plants is (-)-2‘S-nicotine (Figure XVII.B-1).
Although nicotine is formed and is present in large quan-
tities in tobacco, it is important to understand that the vast
majority of all nicotine in tobacco is present in the form of
organic salts. Very little nicotine exists in the free base form
due to the acidic nature of tobacco. The exact identities of the
nicotine salts that exist in tobacco are not known but there
have been several reports by Perfetti (2918a, 2924, 2926,
3156), Seeman et al. (17B48), and Dixon et al. (989) who have
speculated on the various salt forms of nicotine.
Both of the six-membered N-containing rings of anat-
abine (pyridine and piperidine) can be formed from the two
methylene carbons and nitrogen of aspartate and two car-
bons from a glycerol derivative via nicotinic acid (2330c,
17B32, 17B33, 17B37). Nicotinic acid is reduced to 3,6-di-
hydronicotinic acid and decarboxylated to 1,2-dihydropyri-
dine and 2,5-dihydropyridine. 1,2-Dihydropyridine reacts
with 2,5-dihydropyridine via an electrophilic attack to form
3,6-dihydroanatabine which aromatizes to (-)-2‘S-anatabine
(17B36).
Although one might expect that anatabine and anabasine
could be interconverted enzymatically in the plant, as these
compounds differ by only two hydrogens, this does not
appear to be true. The pyridine ring of anabasine has been
shown to originate from nicotinic acid via decarboxylation
(17B54). The precursor for the piperidine ring is lysine via
D‘-piperidine with the nitrogen derived from the e-nitrogen of
lysine (17B35). This was shown to occur via 14C-lysine feed-
ing studies by Leete (17B30, 17B34). 14C was incorporated
into the C-2‘ position of the piperidine ring of anabasine.
Nornicotine is formed from nicotine during the growth
period of the tobacco plant and during senescence (17B06).
Enzymatic demethylation of nicotine yields nearly equal
quantities of the (+) and (-) isomers of nornicotine (17B05).

H
COOH
H
H
2H COOH
-CO2 N
N N
H
H H
Nicotinic acid 3,6-Dihydronicotinic acid 1,2-Dihydropyridine
N-methyl-
pyrrolium ion

N H

H N
CH3 -2H H
N H
CH3
N
(-)-2'S-Nicotine
H
-CH3 -CH3 3,6-Dihydronicotine

N
N
H
H H
N H
N
(-)-Nornicotine
(+)-Nornicotine
-2H -2H

COOH
N

N N
Myosmine Nicotinic acid

Figure XVII.B-1  Proposed biosynthetic pathways for production of several pyridine alkaloids (17B05).

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 750 The Chemical Components of Tobacco and Tobacco Smoke
Myosmine can be formed from nornicotine by enzymatic
dehydrogenation (2332, 17B24).
Cotinine and 2,3‘-bipyridyl and their derivatives represent
the major oxidized alkaloids in tobacco. Cotinine is synthe-
sized from nicotine via enzymatic oxidation or autooxidation
(1157, 17B03). 2,3‘-Bipyridyl is formed by oxidation of anat-
abine. Frankenburg et al. (1221a, 1222-1224) were the first to
identify 2,3‘-bipyridyl as a fermentation product along with
3-acylpyridine. Other oxidized alkaloids identified in green
and cured tobacco are nicotyrine, nicotinic acid, nicotin-
amide, and nicotine-N-oxides. Enzell et al. (1149a) found that
these oxidation products of tobacco alkaloids tend to increase
in yield during curing and storage of tobacco.
Pyrimidines play a central role in cellular regulation and
metabolism. They are substrates for DNA and RNA biosyn-
thesis, regulators of biosynthesis of some amino acids, and
cofactors in the biosynthesis of phospholipids, glycolipids,
sugars, and polysaccharides (17B45). Pyrimidine biosynthe-
sis is very complicated and involves formic acid, glutamate,
and aspartate as starting materials in a series of enzymatic
reactions to eventually form orotic acid. Orotic acid, or uracil-
6-carboxylic acid, is an intermediate in the metabolism of
pyrimidine nucleotides. The naturally occurring derivatives
of pyrimidine are components of the nucleic acids cytosine,
thymidine, and uracil. Free pyrimidine and functionalized
pyrimidine compounds in tobacco are believed to be formed
from the catabolism of various nucleosides (17B21).
Although pyrazines, for example, pyrazine-2-carboxylate
and pyrazine 2,3-dicarboxylate, are formed biosynthetically,
the vast majority of the varied pyrazine derivatives in tobacco
are formed during curing via nonenzymatic reactions.
Pyrazines can arise in tobaccos by a number of chemical
pathways ranging from the heating or aging of proteins and
amino acids to the interaction of amino acids and/or ammo-
nia with sugars or carbonyl constituents. No single pathway is
involved in the formation of pyrazine. The formation of pyra-
zine compounds is complex and depends on a variety of fac-
tors and chemical mechanisms (2339b). Adachi et al. (17B01)
postulated that tetramethylpyrazine is derived enzymatically
from two moles of acetoin (acetylmethylcarbinol) and two
moles of ammonia. This finding was supported by the find-
ings of Demain et al. (17B10) that a block in the isoleucine-
valine pathway leads to the accumulation and excretion of
a large amount of tetramethylpyrazine. Shu (17B51) treated
acetoin with amino acids to determine whether ammonia is
released, leading to the formation of tetramethylpyrazine.
His results showed that all reactions between amino acids
and acetoin generate not only alkylated pyrazines, for exam-
ple, tetramethylpyrazine, but also the corresponding Strecker
aldehydes.
Pyridazines and triazines are not usually biosynthesized
in plants. The exception is azathymine (6-methyl-1,2,4-triaz-
ine-3,5(2H,4H)-dione) which has been identified in modified
bases from DNA of tobacco mosaic virus (3973). The major-
ity of the identified pyridazines and triazines in tobacco are
believed to originate from residues of agronomic chemicals.
The pyridazine structure is found in herbicides containing
© 2009 by Taylor & Francis Group, LLC
78836_C017.indd 750
maleic hydrazide. The triazine structure is found in the tobacco
herbicide Metribuzin® and the fungicide Anilizine®.
A variety of alkyl-, acyl-, and hydroxyacyl-substituted
alkaloids exists in tobacco. These have been identified and
studied by a number of research groups [Bolt (389), Warfield
et al. (4133), Matsushima et al. (17B39), Severson et al.
(17B49), Zador and Jones (17B65)]. The mechanisms pro-
posed for the biosynthesis of these alkaloids are oxidation
or formylation. For example, N‘-formylnornicotine [2-(3-
pyridinyl)-1-pyrrolidinecarboxaldehyde] can be formed by
formylation of nornicotine or by oxidation of the N-methyl
group of nicotine (2330c, 17B03). Additionally, Burton et al.
(17B03) have proposed that many acylated alkaloids are
formed via acylation of secondary amine alkaloids (994).
The concentrations of these alkylated and acylated alkaloids
are small in comparison to the total alkaloid concentration
in tobacco. Their occurrence is mainly influenced by plant
genetics and agricultural practices (17B05). It is believed that
their accumulation in leaf may be significant to flavor percep-
tion (17B05).
A number of tobacco N-nitrosamines are listed in this
chapter. Chapter 15 is devoted to N-nitrosamines, but a few
comments must be included here. Interest in tobacco-specific
N-nitrosamines (TSNAs) has been a result of reports that some
of them have induced malignant tumors in mice, rats, and ham-
sters [Boyland et al. (421a, 422, 423), Hecht et al. (1557–1559,
1563–1571a, 1574–1585)]. The TSNAs of greatest interest are
N‘-nitrosonornicotine (NNN), N‘-nitrosoanatabine (NAT),
N‘-nitrosoanabasine (NAB), and 4-(methylnitrosamino)-1-
(3-pyridyl)-1-butanone (NNK). The formation of TSNAs can
be biosynthetic (via mechanisms within the plant itself), pro-
duced by bacteria on the surface of the plant, and by organic
reactions of flue gas during curing practices [Peele et al.
(2917), see also Figure 5 in Rodgman and Green (3300)].
XVII.B.3 Other Means for the Formation of
the Six-Membered N-Containing Ring
Compounds Found in Tobacco
Nitrogenous compounds in tobacco account for approxi-
mately 12% to 25% of the dry weight of freshly harvested
tobacco leaves (841a, 2337), (2% to 6% expressed as nitro-
gen). As previously mentioned, the large variation in types
and yields of nitrogenous compounds in tobacco is due to the
great number of Nicotiana species, the variety of different
agricultural practices, and soil types worldwide for the culti-
vation of different tobaccos. The major organic nitrogen con-
stituents of tobacco leaf are nicotine and related alkaloids,
proteins, and amino acids (2337). The alkaloids as discussed
above are biosynthesized along with a portion of most of
the six-membered N-containing ring compounds found in
tobacco. But there are also other ways that these compounds
can be produced.
The varied methods of curing and aging tobacco cause
only a small decrease in the total nitrogen content, but sig-
nificant changes occur as a result of organic transforma-
tions from one type of nitrogenous compound to another, for
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 Nitrogen Heterocyclic Components 751

example, the enzymatic hydrolysis of leaf protein produces Examples of how processing tobacco affects the produc-
free amino acids (1493). After curing, dynamic changes tion of flavorful pyrazine was provided by Mays et al. (17B40)
continue to occur during aging of tobacco leaf. Weybrew et and Green et al. (1369) of R.J. Reynolds Tobacco (RJRT)
al. (4226) and Tomita et al. (3923) recognized in 1965 that Company. Ammonia/carbon dioxide expansion was conducted
chemical reactions of amino acids in tobacco play an impor- on flue-cured, burley, and processed tobacco sheet. Test and
tant role in the formation of tobacco flavor. Employing model control cigarettes were fabricated. The tobacco aroma of the
systems, reactions of amino compounds with sugars or car- ammonia/carbon dioxide-processed tobaccos increased in all
bonyl compounds were shown to produce flavor compounds cases after processing vs. the control materials. Comparison
present in tobacco (2047, 2048, 2337, 3649). of the per cigarette MSS yields of eight pyrazines indicated
During aging, tobacco undergoes a natural “sweating” their yields in the MSS from ammonia/carbon dioxide-ex-
process several times. This “sweating” is a mild natural fer- panded tobacco were significantly greater than those in the
mentation that produces some heating of the tobacco. This control tobacco MSS [see Tables 3, 4, and 5 in (3261)].
fermentation releases reducing sugars, amino acids, pheno- Additionally, browning reactions can occur during the
lics, and flavonoids through nonenzymatic browning reac- smoking process (2337). Some of the reaction products
tions to produce the flavor characteristic of aged tobacco. occurring during the smoking process involve six-membered
Much of the flavor that is produced is due to Maillard and N-containing ring compounds that can significantly contrib-
Strecker reactions of amino acids with reducing sugars (or ute to tobacco smoke flavor and aroma, for example, some
other carbonyls). The role of nonenzymatic browning reac- pyrazine and pyridine derivatives (2339b).
tions of amino acids and sugars is generally accepted as
being one of the most important processes in which natural XVII.B.4 Six-Membered N-Containing Ring
flavors are produced (2337). Compounds in Tobacco and Tobacco
There are at least three other ways (other than through
Smoke
biosynthesis) that the six-membered N-containing ring com-
pounds can be formed in tobacco leaf (2337). Knowledge of tobacco smoke composition grew rapidly each
year by the application of new analytical methods. Prior to
• Oxidative transformations 1959, only sixteen nitrogen compounds had been reported in
• Ambient temperature nonenzymatic transformations tobacco and tobacco smoke. In 1959, Johnstone and Plimmer
• Heat-induced nonenzymatic transformations (1971) summarized the identification of about fifty nitrogen
compounds. Ten years later, Neurath (2724) reported on
It must be remembered that compounds formed by enzy- the presence in tobacco and tobacco smoke of 181 nitrogen
matic processes can react subsequently in a nonenzymatic compounds, among which were two piperidines, twenty-four
transformation. Additionally, by examining the chemical pyridines, ten pyridines, and eleven alkaloids. In this report,
transformations involved in the production of compounds we have cataloged thirty-seven piperidines, 312 pyridines,
via nonenzymatic browning reactions, several routes can be seventy-eight pyrazines, and over 160 alkaloids.
involved in the production of the same compounds from dif- Table XVII.B-1 details the distribution of six-membered
ferent precursors (2337). N-containing ring compounds in tobacco and tobacco smoke.
A type of Maillard reaction that occurs naturally in
tobacco which requires the presence of active a-dicarbonyl
components is the Strecker degradation of a-amino acids to Table XVII.B-1
aldehydes and ketones of one less carbon atom. Schonberg Distribution of 6-Membered N-Containing Ring
and Moubacher (17B46, 17B47) studied the mechanism of Compounds between Tobacco and Tobacco Smoke
the Strecker degradation involving pyruvaldehyde and a- Number of Identified 6-Membered N-Containing
alanine leading to the formation of 2,5-dimethylpyrazine Ring Compounds in Tobacco and Tobacco Smoke
and 2,5-dimethyl-3-ethylpyrazine. The fact that differ- Smoke and
ent amino acids can produce the same flavor compounds Component Total Smoke Tobacco Tobacco
has been shown by a number of workers in studies on the
relative formation of pyrazines under controlled reaction Piperidines 37 31 11 5
conditions between amino acids and glucose (2048, 2337). Tetrahydropyridines 5 2 4 1
Dihydropyridines 6 4 2 0
Similar studies have shown that thermal decompositions of
Pyridines 341 295 116 70
various amino acids and other aminohydroxy compounds
Piperazines 10 10 0 0
such as glucosylamine can directly form pyrazine mixtures Dihydropyridazines 3 1 3 1
(17B60). Because of the complexity of the chemical interac- Pyrazines 100 83 62 45
tions and transformations involved, the types and ratios of Pyrimidines 33 14 20 1
active flavor products, for example, pyrazines, formed by 1,2,4-Triazines 2 0 2 0
nonenzymatic browning are dependent on the reaction con- 1,3,5-Triazines 1 0 1 0
ditions that may occur during aging or during the smoking Totals 538 440 221 123
process itself.

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 752 The Chemical Components of Tobacco and Tobacco Smoke
H 4
N N
R
N N
Piperidine Tetrahydro Dihydro-
pyridine pyridines
N N
N N
N N
Pyrazidine
Pyrazine Pyrimidine
Figure XVII.B-2  Structures of the 6-membered N-containing compounds found in tobacco and tobacco smoke.
Of the 538 identified compounds, about 82% (or 440 com-
pounds) are found in tobacco smoke and about 41% (or 221
compounds) are found in tobacco. Eighteen percent (98 com-
pounds) are found only in tobacco and 59% (317 compounds)
are found only in tobacco smoke. Of the 538 compounds,
23% (123 compounds) are found in both tobacco and smoke.
Figure XVII.B-2 illustrates the general structures for the
ten types of six-membered N-containing ring compounds
found in tobacco and tobacco smoke. The four major com-
pound classes are the piperidines, pyridines, pyrazines, and
the pyrimidines. A brief discussion of general information on
each of these four classes of six-membered N-containing ring
compounds follows.
XVII.B.4.1 Piperidine and the Tetra-
and Dihydropyridines
Piperidine and D3-piperidine were first identified by Neurath
et al. in 1965 (2749) and 1966 (2734), respectively [see
Table 3 in Neurath (2724)]. The piperidines in tobacco and
tobacco smoke are found as substituted ketones, acids, and
alkyl derivatives. None of the forty-eight nonaromatic six-
membered N-heterocycles found in tobacco and tobacco
smoke has been shown to provide positive contributions to
the flavor of tobacco smoke, although piperidine is on the
GRAS list as a food flavor (3215).
Pyrolysis and smoke studies of amino acids indicate that
they are potential precursors of several nitrogen heterocyclic
ring systems found in tobacco smoke (1351). For example,
indole can be formed from tryptophan, proline has been
shown to be efficiently converted to pyrrole upon pyrolysis
(3219, 3726), and g-amino acids can be pyrolyzed to form
2-pyrrolidones (1967, 3079). By a similar mechanism,
g-amino acids form 2-piperidones (1967, 3079).
XVII.B.4.2 Pyridines
A great variety of pyridines (currently 341) has been identi-
fied in tobacco and tobacco smoke. As a class, there are more
pyridines in smoke than any other heterocycle. Vohl and
Eulenberg (4064) were the first to isolate and identify pyri-
dine in tobacco smoke in 1871. Since that time a wide vari-
ety of substituted (methyl- [picolines], dimethyl- [lutidines],
© 2009 by Taylor & Francis Group, LLC
78836_C017.indd 752
H
5 3
6 2
N N
H
Pyridine Piperazine
N
R N N
N NH* R
N
1,2,4-Triazines 1,3,5-Triazines
ethyl-, allyl-, butyl-, vinyl-, cyano-, formyl-, alkylamino-)
pyridines have been identified. Most of the substituted groups
in these pyridines occur at the three-position, although there
are some substituted pyridines with functionalities at the
two- and four-positions (2724).
The presence of pyridine compounds in smoke is natu-
rally associated with the tobacco alkaloids. The formation
of substituted pyridines that occur during the pyrolysis of
nicotine has long been known [Woodward et al. (4275a),
Kaburaki et al. (2006), Jarboe and Rosene (1923a), Schmeltz
et al. (3499)]. Pyridine, 3-methyl- and/or 4-methylpyridine,
3-vinylpyridine, and 3-cyanopyridine have all been identi-
fied as major pyrolysis products of nicotine. Minor pyridine
pyrolysis products included 2-methylpyridine, dimethylpyri-
dines, 3-ethylpyridine, and 2- and/or 4-cyanopyridine. All
have been identified in tobacco smoke. While the formation
of pyridines from nicotine might be expected to involve sim-
ple rupture of the pyridine-pyrrolidine bond, a more complex
pathway is taking place. When either nicotine-N-methyl-
14C or nicotine-2‘-14C was pyrolyzed, several alkylated 14C-
labeled pyridines were among the products. This indicated
that fragments of the pyrrolidine ring can recombine and aro-
matize to give pyridines (1580).
The pyrolytic formation of pyridines has been observed
in studies on a number of nitrogenous substances. Pyrolysis
of tobacco pigment and of tobacco leaf gave a spectrum of
pyridines similar to those observed in smoke [Schmeltz et al.
(3499), Schlotzhauer and Schmeltz (3463)]. Pyridines were
observed in the pyrolysis of proline [Higman et al. (1647)]
and pyridine was a product of pyrolysis of poly-L-proline
[Johnson et al. (1968)]. Pyrolysis of nicotinamide at 1050°C
gave pyridines and 3-cyanopyridine, among other products
[Bruzel and Schmeltz (515)]. Pyridines were also observed
in pyrolysates of pyrrole, maleic hydrazide, and N,N-
dimethyldodecylamine [Patterson et al. (2907, 2908)]. In
view of the above mentioned results on pyrolysis of nicotine-
14C and previous mechanistic studies [Hurd et al. (1851)], it
is not surprising that pyridines should arise on pyrolysis of
such diverse N-containing compounds. Studies on cigarettes
enriched in nicotine or nornicotine indicated that nornicotine
was an important precursor for pyridines [Glock and Wright
(1316), Hecht et al. (1580)].
11/24/08 12:27:48 PM
 Nitrogen Heterocyclic Components 753
Pyridines can be formed by mechanisms other than pyroly-
sis. The reaction of aldehydes with amino acids has been shown
to generate pyridines (50). When a glycine-propanal mixture
was heated to 180°C, 3,5-dimethyl-2-ethylpyridine, 3,5-di-
methyl-4-ethylpyridine, and 3,5-dimethylpyridine formed.
Glycine-propanal mixtures, also heated to 180°C, gave 2,5-
dimethylpyridine and 3,4-dimethylpyridine. This is an exam-
ple of a nonpyrolytic method of forming pyridines. As small-
chain aldehydes required for this reaction are abundant in
smoke, this is a feasible route to pyridines.
Pyridines contribute to the characteristic tobacco flavor
of smoke. Fujimori (1248) identified twenty-six pyridines
as components of tobacco aroma. Leffingwell et al. have
tabulated the flavor and aroma characteristics of many pyri-
dines (2341). Pyridines as a class of compounds enhance
tobacco flavor, add burley flavor, or can add flue-cured fla-
vor. Pyridines are responsible for that characteristic note in
smoke that identifies the smoke as that from tobacco (1587a).
Hoffmann and Wynder (1803) have made the comment that
pyridines are responsible for the off-taste and irritancy of the
smoke from large cigars and that pyridines reduce the inhal-
ability of cigar smoke.
Roberts commented that two particular pyridine com-
pounds were noteworthy, 2-acetylpyridine [1-(2-pyridinyl)-
ethanone] and 2-methyl-5-isopropylpyridine [2-methyl-5-(1-
methylethyl)-pyridine] (3215). The former adds some sweet,
roasted, and musty notes and the latter adds body and burley
character to the tobacco blend. Additionally some pyridines
may react with other smoke compounds synergistically. For
example, it is believed that some pyridines reduce the sweet
burnt-sugar taste of cyclopentenones and furanones (3215).
XVII.B.4.3 Pyrazines
Pyrazines constitute a very small percentage by weight
of smoke condensate (5 to 50 mg/cigarette), but pyrazines
as a class of tobacco and tobacco smoke compounds are
very important because of their positive flavoring proper-
ties. Pyrazine, methylpyrazine, and 2,6-dimethylpyrazine
were first recognized in tobacco smoke in 1965 by Testa
and Testa (3888). To date, one hundred pyrazines have been
identified in tobacco and tobacco smoke. Over 50% of the
identified pyrazines are found in both tobacco and tobacco
smoke.
In the 1968 review by Stedman (3797), he listed only
three pyrazines as components of tobacco smoke: pyra-
zine, 2-methylpyrazine, and 2,6-dimethylpyrazine. In that
same year, Neurath and Dünger (2732) identified eight addi-
tional pyrazines, including 2-methyl-5-(2’-furyl)pyrazine.
Leffingwell in 1976 (3237) mentioned six new pyrazines,
including three acetyl-substituted pyrazines. Green (1351),
in 1977, disclosed another eight novel pyrazines, including
2-methyl-5-phenylpyrazine, 3-methylpyrazinol, and pyrrolo
[1,2-a]pyrazine. Heckman and Best (1587) have also identi-
fied a number of pyrazines, including five cyclopentapyra-
zines. There is a great diversity of pyrazines that have been
identified in tobacco smoke.
© 2009 by Taylor & Francis Group, LLC
78836_C017.indd 753
Pyrazines have also been isolated from tobacco (938).
Their presence in leaf arises from biosynthesis and from
browning reaction chemistry that can occur during curing and
tobacco processing. At present, sixty-two pyrazines have been
identified in tobacco. Bright et al. (431) have demonstrated
that the necessary precursors for the formation of pyrazines
are present in tobacco leaf. In their experiments, the levels
of dimethylpyrazine in untreated tobaccos were measured
and then the same tobaccos were heated at 120°C for four
hours and the levels measured again. In each case, the level of
dimethylpyrazine was found to be very low in the untreated
tobacco and appreciably increased following the roasting.
Their results also showed a decrease in amino acid levels dur-
ing the heat treatment of the tobaccos, indicating the possible
involvement of amino acids in the formation of the pyrazines.
Some pyrazines have been isolated from flue-cured (965) and
burley tobaccos (937). The presence of pyrazines in tobaccos
may be due to reactions of leaf precursors at the temperature
used in curing of these tobacco types (1351).
Amadori compounds are b-ketoamino acids that are struc-
turally similar to b-hydroxyamino acids. Amadori compounds
can yield pyrazines. Leffingwell (2337) and Green (1351)
have both mentioned the presence of Amadori compounds
in leaf, as has Tomita (3923), who stated that Amadori com-
pounds account for as much as 2% of the dry weight of flue-
cured leaf. Thermal treatment of Amadori compounds does, in
fact, give pyrazines as decomposition products [Shigematsu
et al. (17B50)]. The formation of 2,5-bis-(tetrahydroxybutyl)
pyrazine (fructosazine) from the reaction of fructose or glu-
cose with alcoholic ammonia and from self-condensation of
glucosamine or isoglucosamine has been known for a long
time (17B57); in fact, the earliest reports date back to the
beginning of the twentieth century. Deoxyfructosazine and
its 2,6-isomer have been isolated from mixtures obtained by
reaction of glucose and fructose with ammonia under weakly
acidic conditions (1153, 1156, 17B13). The fructosazine and
deoxyfructosazine isomers can be obtained synthetically by
use of such sugar-ammonia reactions. The yields and isomer
ratios are somewhat contingent on the choice of sugar (glu-
cose or fructose) and the mole ratio of sugar to ammonium
formate (1153). For example, xylose and aqueous ammo-
nium formate yielded 2,5-bis (D-threo-trihydroxypropyl)
pyrazine (xylulosazine) and the related 2,5- and 2,6-deoxyx-
ylulosazines (1248). Several deoxyfructosazine isomers have
been isolated from tobacco (1352). The tobacco-derived
deoxyfructosazines were shown to improve the aroma and
taste of tobacco (1351). Lynm (2420, 2421, 2423, 2424) at
RJRT conducted several studies on the presence, formation,
and analysis of deoxyfructosazines in tobacco and tobacco
products.
Two mechanisms have been suggested for pyrazine forma-
tion during smoking; pyrolytic decomposition of leaf con-
stituents and nonenzymatic sugar-amine reactions. Kato et al.
(2048) showed that direct pyrolysis of serine yielded pyrazine,
methylpyrazine, ethylpyrazine, 2-ethyl-6-methylpyrazine, 2,6-
diethylpyrazine, and 2,6-diethyl-6-methylpyrazine. Pyrolysis
of threonine gave 2,5-dimethylpyrazine, trimethylpyrazine,
11/24/08 12:27:48 PM
 754 The Chemical Components of Tobacco and Tobacco Smoke
and 2,5-dimethyl-3-ethylpyrazine. Sugars condense with
amino acids to form sugar-amino acid adducts which then
undergo Amadori rearrangement to give Amadori compounds.
Although pyrolysis of selected leaf constituents gen-
erates pyrazines, the diversity and abundance of pyra-
zines in smoke cannot be adequately accounted for by this
mechanism alone. Maga and Sizer (2439) and Enomoto et
al. (17B12) have reviewed the occurrence of pyrazines in
roasted foods and proposed pathways for pyrazine forma-
tion. Their summaries present a large array of pyrazines
found in the flavor fractions of a number of roasted foods.
It is striking that nearly all pyrazines commonly found in
tobacco smoke have been identified in at least one roasted
food. For example, 2,3-dimethylpyrazine has been found in
peanuts, barley, coffee, baked potatoes, mushrooms, lamb
fat, and tobacco smoke (1587a).
Of particular interest in relating leaf to smoke composition
are the studies of Koehler and co-workers (17B26, 17B27) on
the formation of pyrazine compounds in sugar-amino acid
systems. Using model systems, Koehler and Odell (17B27)
showed that pyrazines are formed when sugars and amino
acids are heated between 100 and 150°C. Glucose reacts with
either an amino acid or ammonia to form a glycosylamine.
The amino acid complex then undergoes a Strecker-type deg-
radation to yield an eneaminol which can also be formed by
the loss of water from glucosylamine. The eneaminol then
isomerizes and undergoes reverse aldol condensation to form
1-aminoacetone which is known to self-condense to yield
pyrazines (116). As shown by Schonberg and Moubacher
(17B46), during the condensation of the aminoacetone fur-
ther reaction with aldehydes can take place. Similar pathways
can be postulated for the generation of 1-aminoacetaldehyde,
1-aminopropionaldehyde, and 1-amino-2-butanone from
sugar-amine reactions. Hypothetical reaction of these amin-
ocarbonyl compounds either individually or in pairs can
account for most of the alkylpyrazines reported in smoke
(1351). Additionally, Koehler and Odell (17B27) showed that
a number of smaller compounds, acetaldehyde, glycerol,
glyoxal, 2,3-butanedione, and acetol also yielded pyrazines
when heated with nitrogen sources. Koehler et al. (17B26)
had previously shown, using radiotracer techniques, that the
sugar moiety served as the principal source of carbon atoms
and that the amine furnished only nitrogen to the pyrazine
molecule. These data imply that sugar decomposes to small
intermediary carbonyl compounds which in turn react with
the nitrogen source, for example, amine or amino acid, to
form pyrazines.
Other possible mechanisms for the formation of pyrazines
during smoking are possible. For instance, leaf carbohydrates
could be degraded either through pyrolysis or Maillard reactions
to form a-dicarbonyl compounds, which could, in turn, react
with amino acids to undergo a Strecker degradation forming
© 2009 by Taylor & Francis Group, LLC
78836_C017.indd 754
the a-aminocarbonyl compounds [1671a, 2439, Velisek et al.
(17B59)] which can condense to form pyrazines (1351).
Pyrazines are the most important N-heterocycles in char-
acterizing the aroma and flavor of tobacco and tobacco smoke
(2341, 3215, 3491, 3553). The alkylpyrazines, for example,
provide the cocoa and nutty-type notes associated with
tobacco smoke. 2-Acetylpyrazine [1-pyrazinylethanone], iso-
lated and identified in burley tobacco by Roberts (3202, 3204)
in 1963, contributes a nutty, popcorn-type flavor unique to
tobacco smoke. Pyrazines, in general, contribute the “brown
notes” associated with tobacco smoke taste (3215). It is obvi-
ous that cigarette MSS flavor and aroma may be enhanced by
addition of appropriate pyrazine compounds to the tobacco
blend, for example, among the 460 pure compounds listed by
Doull et al. (1053) as possible cigarette tobacco ingredients
used by U.S. cigarette manufacturers are twenty-three (5%)
pyrazine derivatives. In 1977, RJRT conducted an immense
study on Philip Morris’s Merit cigarette that advertised the
use of a “flavor package.” One of the interesting results of
that study was that the MSS from Merit contained numerous
alkylpyrazines, particularly higher levels of tetramethylpyra-
zine, and several trimethylpyrazines compared to other com-
mercial cigarettes brands of similar FTC “tar.” Much of the
Merit research conducted at RJRT was summarized by Lloyd
(2385a).
XVII.B.4.4 Pyrimidines
There are thirty-three pyrimidine derivatives identified in
tobacco and tobacco smoke. The vast majority of these com-
pounds (67%) have been identified in tobacco. Only fourteen
are known to exist in tobacco smoke. As previously men-
tioned, the naturally occurring derivatives of pyrimidine are
components of nucleic acids: cytosine, thymidine, and uracil.
Free pyrimidine and functionalized pyrimidine compounds
in tobacco are believed to be formed from the catabolism
of various nucleosides (17B21). Several of the pyrimidine-
containing compounds in tobacco are agronomic chemical
residues while other compounds identified in tobacco smoke
are formed from those agronomic residues.
Pyrimidine derivatives do not generally have positive fla-
vor notes and are considered neutral to poor. Some pyrimidine-
derived flavors (although not found in tobacco or tobacco smoke)
have meaty notes. There are also some pyrimidine flavorants
that do possess good flavor potential for tobacco products, for
example, 2-methyl-5,7-dihydrothieno[3,4-d]pyrimidine. This
compound contains a bicyclic ring structure and has been iden-
tified in tobacco. 2-Methyl-5,7-dihydrothieno[3,4-d]pyrimidine
is said to have a fresh roasted, sweet nut flavor with a pop-
corn character (17B22). It is a compound listed by Doull et al.
as an ingredient in flavor formulations used by one or more
members of the U.S. tobacco industry (1053).
11/24/08 12:27:48 PM
 Nitrogen Heterocyclic Components 755

Table XVII.B-2
Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring
Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 755 11/24/08 12:27:49 PM

 756 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-2 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 756 11/24/08 12:27:50 PM

 Nitrogen Heterocyclic Components 757

Table XVII.B-2 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 757 11/24/08 12:27:51 PM

 758 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-2 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 758 11/24/08 12:27:52 PM

 Nitrogen Heterocyclic Components 759

Table XVII.B-2 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 759 11/24/08 12:27:53 PM

 760 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-2 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 760 11/24/08 12:27:54 PM

 Nitrogen Heterocyclic Components 761

Table XVII.B-2 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 761 11/24/08 12:27:55 PM

 762 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-2 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 762 11/24/08 12:27:56 PM

 Nitrogen Heterocyclic Components 763

Table XVII.B-2 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 763 11/24/08 12:27:57 PM

 764 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-2 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 764 11/24/08 12:27:58 PM

 Nitrogen Heterocyclic Components 765

Table XVII.B-2 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 765 11/24/08 12:27:59 PM

 766 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-2 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 766 11/24/08 12:28:02 PM

 Nitrogen Heterocyclic Components 767

Table XVII.B-2 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 767 11/24/08 12:28:02 PM

 768 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-2 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 768 11/24/08 12:28:03 PM

 Nitrogen Heterocyclic Components 769

Table XVII.B-2 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 769 11/24/08 12:28:04 PM

 770 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-2 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 770 11/24/08 12:28:05 PM

 Nitrogen Heterocyclic Components 771

Table XVII.B-2 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 771 11/24/08 12:28:08 PM

 772 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-2 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 772 11/24/08 12:28:08 PM

 Nitrogen Heterocyclic Components 773

Table XVII.B-2 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 773 11/24/08 12:28:09 PM

 774 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-2 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 774 11/24/08 12:28:10 PM

 Nitrogen Heterocyclic Components 775

Table XVII.B-2 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 775 11/24/08 12:28:11 PM

 776 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-2 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 776 11/24/08 12:28:12 PM

 Nitrogen Heterocyclic Components 777

Table XVII.B-2 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 777 11/24/08 12:28:13 PM

 778 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-2 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 778 11/24/08 12:28:16 PM

 Nitrogen Heterocyclic Components 779

Table XVII.B-2 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-Membered N-Containing Ring

XVII.B.5 Compounds in Tobacco and Tobacco
Smoke Containing a Five-Membered
and a Six-Membered N-Containing Ring
The origin of all the work that has been done on the iso-
lation and identification of the tobacco and tobacco smoke
began with this relatively small group of compounds. The
initial tobacco and tobacco smoke compound that was of so
much interest was nicotine. Literally thousands of scientific
articles, reviews, and books have been published on various
aspects of nicotine, for example, pharmacological and meta-
bolic properties, chemical and structural properties, occur-
rence, biogenesis, and pyrolysis. The scope of all the work
on nicotine alkaloids is so broad that a comprehensive review
is beyond the scope of this chapter. The several hundred
references listed in Table XVII.B-4 testify to the enormous

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78836_C017.indd 779 11/24/08 12:28:17 PM

 780 The Chemical Components of Tobacco and Tobacco Smoke
amount of research that has been conducted on the nicotine
alkaloids. Instead, a brief history of the initial work on the
isolation and identification of nicotine follows.
XVII.B.5.1 Nicotine and Tobacco Alkaloids with a
Six-Membered N-Containing Ring and a
Second Five-Membered N-Containing Ring
Nicotine is the unique component of tobacco. The history
associated with the discovery of nicotine and use of the “oil”
derived from tobacco dates to about 1571 (17B16). This “oil”
prepared by the French chemist Gohory undoubtedly contained
some level of nicotine and was used as a remedy for diseases of
the skin. In 1660, another French chemist, Lefevre, described
means to steam distill tobacco to obtain oil that had medicinal
uses (3477). In 1807, Cerioli discovered what he called the “olio
essenziale” of tobacco (17B15). In 1809, Vauquelin apparently
made the same discovery. Both researchers described the oil
as a volatile and colorless substance. Vauquelin recognized the
basic nature of the material but failed to recognize its alkaloi-
dal properties. He attributed the basicity of the material to the
presence of ammonia (410).
In 1822, Hermbstädt confirmed Vauquelin’s results of the
presence of the oil described in sixteen different species of
what is now known as Nicotiana (17B15). It was not until
1828 that Posselt and Reimann (2981) succeeded in isolat-
ing a pure sample of the oil and recognized it as an alka-
loid. They characterized it as a water-clear liquid, boiling at
246°C under atmospheric pressure, and miscible with water,
alcohol, and ether. They named the pure compound nicotine
after Jean Nicot who introduced tobacco into the French
court in about 1560 (17B42). In 1826, Unverdorben isolated
a water-soluble base from a dry distillate of tobacco (282).
The base contained nicotine. Melsens (2528), in 1843, suc-
ceeded in isolating nicotine from the smoke of pipe tobacco
and assigned the empirical formula, C12H14N2 (2724). In
1893, Pinner (17B44) reported on the final clarification of the
constitution of nicotine, determined via degradation stud-
ies. Pinner’s structural formula for nicotine was confirmed
by the classical synthesis of nicotine by Pictet and Rotschy
(17B43) in 1895. For many years, nicotine was believed to
be the only alkaloid in tobacco (17B18). It was not until 1928
that Ehrenstein reported the identification of nornicotine in
tobacco [see Markwood (17B38)]. Anabasine was isolated in
tobacco by Smith (17B53) in 1935. Späth and Kesztler (17B55)
isolated anatabine in tobacco in 1934 [Markwood (17B38)].
Gautier and LeBon in 1892 were the first chemists to clearly
recognize that additional alkaloids accompanied nicotine
in tobacco smoke. These additional alkaloids were the sec-
ondary alkaloids and decomposition products of alkaloids.
Unfortunately, Gautier and LeBon did not report further on
their observations (2223, 2224). Wenusch and Schöller (4210,
4211) in the early 1930s worked diligently to separate the sec-
ondary alkaloids in tobacco smoke. Though they were not
wholly successful they did discover and determine the for-
mula for myosmine in cigar smoke in 1936 with the collabo-
ration of Späth (2224). By 1936, Wenusch and Schöller (4213)
© 2009 by Taylor & Francis Group, LLC
78836_C017.indd 780
had distinguished a large number of tobacco smoke bases in
cigar and cigarette smoke by their behavior during steam dis-
tillation and extraction. Several of the alkaloid-related com-
ponents (a-, b-, and g-socratine, obelin, lohitam, anodmin,
lathraein, poikiline, and gudham) first reported by Wenusch
and Schöller (4210, 4211) were subsequently demonstrated to
be mixtures or mislabeled components of previously known
alkaloids. Until the study by Kuffner, Schick, and Bühn in
1959, there was much confusion concerning the correct iden-
tity of the secondary alkaloids of tobacco smoke. Kuffner et
al. (2224) demonstrated that obelin was a salt of ammonia,
a- and b-socratine were mixtures of nicotyrine and 2,3’-
bipyridine, and g-socratine was l-nornicotine. Poikiline was
characterized as 4-amino-1-(3-pyridyl)-butanone. Many of
these characterization corrections are described in Johnstone
and Plimmer (1971) and Borgerding et al. (410).
To date, ninety-five alkaloids with both a five-membered
and a six-membered N-containing ring have been identified
in tobacco and tobacco smoke [see Table XVII.B-4]. In all
cases, the six-membered ring is pyridine; the attached five-
membered ring may be a pyrrolidine, pyrroline, pyrrole, or
an imidazole ring. The vast majority of these tobacco alka-
loids contain a pyrrolidine ring that is substituted at the
three-position of the pyridine ring. Table XVII.B-3 shows the
distribution of the ninety-five tobacco alkaloids that occur in
tobacco, tobacco smoke, and in both. Table XVII.B-4 lists
the compounds containing a five-membered N-containing
ring plus a six-membered N-containing ring that have been
identified in tobacco and/or tobacco smoke.
Sixty-two nicotine alkaloids have been identified in tobacco.
Fifty-four have been identified in tobacco smoke and twenty-
one of the ninety-five nicotine alkaloids are found in both
tobacco and tobacco smoke. The vast majority of the nicotine
alkaloids (fifty-four of sixty-two) contain a pyrrolidine ring
connected to a pyridine ring. The most common functional-
ities associated with the pyrrolidine-containing nicotine alka-
loids are alkyl, nitroso, carboxyl, amino, and acyl groups.
Table XVII.B-3
Distribution of Components with a 6-Membered
N-Containing Ring and a Second 5-Membered
N-Containing Ring between Tobacco and Tobacco
Smoke
Number of Identified Compounds in Tobacco and
Tobacco Smoke with a 6- and a 5-Membered Ring
Smoke and
Component Total Smoke Tobacco Tobacco
Pyridine Ring with a 2nd N-Containing Ring (Type)
Pyrrolidine 72 34 54 16
(nicotinoids)
Pyrroline 2 1 2 1
Pyrrole 19 18 5 4
Imidazole 2 1 1 0
Totals 95 54 62 21
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 Nitrogen Heterocyclic Components 781

Table XVII.B-4
Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-and a 5-Membered
N-Containing Ring
Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

(Continued )

© 2009 by Taylor & Francis Group, LLC

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 782 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-4 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-and a 5-Membered
N-Containing Ring

© 2009 by Taylor & Francis Group, LLC

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 Nitrogen Heterocyclic Components 783

Table XVII.B-4 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-and a 5-Membered
N-Containing Ring

(Continued )

© 2009 by Taylor & Francis Group, LLC

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 784 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-4 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-and a 5-Membered
N-Containing Ring

© 2009 by Taylor & Francis Group, LLC

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 Nitrogen Heterocyclic Components 785

Table XVII.B-4 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-and a 5-Membered
N-Containing Ring

(Continued )

© 2009 by Taylor & Francis Group, LLC

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 786 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-4 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-and a 5-Membered
N-Containing Ring

© 2009 by Taylor & Francis Group, LLC

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 Nitrogen Heterocyclic Components 787

Table XVII.B-4 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-and a 5-Membered
N-Containing Ring

(Continued )

© 2009 by Taylor & Francis Group, LLC

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 788 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-4 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-and a 5-Membered
N-Containing Ring

© 2009 by Taylor & Francis Group, LLC

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 Nitrogen Heterocyclic Components 789

Table XVII.B-4 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with a 6-and a 5-Membered
N-Containing Ring

The structures of some of the most common tobacco alka-
loids found in smoke are shown in Figure XVII.B-3. The trans-
fer rate for nicotine is generally about 10% to 12% but a number
of factors, including the cut width of the tobacco, the shape of
the cigarette, the moisture content of the tobacco, and various
tobacco additives can significantly affect nicotine delivery to
mainstream smoke [Kuhn and Klus (2231), Hecht et al. (1580)].
Many of the alkaloids of tobacco smoke consist of components
originally in the tobacco, which transfer unchanged, and vari-
ous pyrolysis products of the nicotine alkaloids.
Nicotine is a major precursor of a large number of volatile
bases in tobacco smoke. On heating nicotine at temperatures
greater than 400°C, various patterns of fragmentation occur
N N
N H
CH3 N N
N
Nicotine Nornicotine 2',3'-Dehydronicotine
O N
N
N CH3 N N
Cotinine Myosmine Nicotyrine
Figure XVII.B-3  Common tobacco alkaloids found in tobacco
and tobacco smoke.
depending on the gaseous atmosphere and other experimental
conditions. Myosmine (4275a) and 3-cyanopyridine [Woodward
et al. (17B61)] are two of many pyrolysis products of nicotine at
500 to 730°C. The yields and type of pyrolysis products depend
on the substrate used to hold the alkaloid, the particular alka-
loid tested, for example, nicotine or nornicotine, the tempera-
ture ramping regime, the final temperature attained, the holding
time at maximum temperature, and reactor type employed for
the pyrolysis experiment. The major identified pyrolytic prod-
ucts of nicotine at temperatures 400 and 900°C (in a nitrogen
or helium atmosphere) include all of the compounds shown in
Figure XVII.B-3. In addition to these compounds, ammonia,
methylamine, and a number of smaller fragments are formed
from heterolytic cleavage of nicotine. Nicotine is not fragmented
significantly at temperatures below 600°C in reactors without
packing. At reactor temperatures of 600°C (with samples in an
inert atmosphere) about two-thirds of the nicotine is split mainly
CH3
into myosmine (1’,2’-dehydronornicotine) and 3-vinylpyridine.
At 700°C, nicotine is completely decomposed, with the major
products being 3-vinylpyridine, 3-methylpyridine, and pyridine.
At 800 and 900°C, extensive cleavage and recombination of frag-
N
ments occur to yield such products as quinoline, naphthalene,
H and benzonitrile. From examination of the pyrolysis products
produced, dehydrogenation, demethylation, and scission of the
pyrrolidine ring are initial steps in the pyrolysis of nicotine. In a
Cl-C2 fragmentation of this ring, dehydrogenation of the result-
ing N-methylaminoalkyl chain would give metanicotine which,

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 790 The Chemical Components of Tobacco and Tobacco Smoke
on further elimination, produces the observed 3-(1,3-butadienyl)
pyridine and subsequently 3-vinylpyridine by appropriate cleav-
age. Fragmentation of the pyrrolidine ring in the 2,3- or 1,5 posi-
tions might ultimately give 3-cyanopyridine after dealkylation of
the side chain (3797).
The mechanism of thermal degradation of nornicotine is
generally similar to nicotine although differences in thermo-
stability exist (175, 17B25). Nornicotine is less stable than nic-
otine and the pyrrolidine ring fragments at temperatures below
400°C. At 400°C (in an inert atmosphere) myosmine and
3-methylpyridine are major pyrolytic products, but at 500°C
only a small amount of myosmine is formed. Since myosmine
is relatively stable (44% unchanged) on pyrolysis at 500°C, this
compound may not be an intermediate of nornicotine pyroly-
sis at higher temperatures (175). An alternative explanation is
that myosmine formed from nornicotine may react with other
pyrolytic products which are not produced when myosmine is
pyrolyzed alone. Although the available evidence is sparse, it
appears that the pyrolytic mechanism of myosmine is differ-
ent from that of nicotine and nornicotine (175). At 500°C (in
an inert atmosphere) myosmine gives lower yields of 3-meth-
ylpyridine and 3-ethylpyridine and higher yields of 3-cyano-
pyridine than nornicotine. This pattern may indicate that a
C3-C4 split is favored in the five-membered ring; scission of
this bond might be preferred over a C2-C3 fragmentation adja-
cent to the relatively stable C=N bond (3797).
Studies with cigarettes treated with 14C-nicotine have
been valuable in determining the delivery of nicotine and its
pyrolysis products to MSS and sidestream smoke (SSS). These
experiments were reviewed in 1975 by Jenkins et al. (1933a).
In a typical study with nicotine-2’-14C, the total 14C-activity in
mainstream total particulate matter (TPM) was 15.4% of the
original activity in the tobacco burned, while the contribution
of the alkaloids to mainstream TPM was 14.9% (1836). Thus,
96.8% of the 14C- activity of the mainstream TPM was due to
transfer of alkaloids and 3.2% was due to products formed from
nicotine during smoking; mainstream gas phase (4.1%) con-
tained only pyrolysis products. In the sidestream TPM, 41.1% of
the original 14C was detected, that is, 10% of this material was
decomposition products. Sidestream gas phase (16.3%) exclu-
sively comprised pyrolysis products. Most of the remaining 14C-
activity (20.2%) was found in the butt. Thus, approximately 30%
of nicotine in a cigarette is converted to products that appear in
the SSS and MSS. Pyrolysis studies on nicotine, discussed in
the previous section, indicate that pyridines would comprise a
significant portion of the particulate-phase products. However,
nicotine can undergo other transformations during smoking,
including reactions with nitrogen oxides (1580). These are dis-
cussed in the chapter on nitrosamines (see Chapter 15).
Several studies have been conducted on the fate of nico-
tine during smoking. Jenkins and Comes (17B20) and Perfetti
(2920–2922, 2924) have examined the fate of exogenous vs.
endogenous transfer of nicotine during smoking. These authors
concluded that the transfer into smoke of exogenous nicotine
(regardless of its form [free base or salt, d- or l- conforma-
tion]) was similar to that of endogenous material, in contrast to
observations with tobacco sterols. Thus, use of 14C-nicotine in
© 2009 by Taylor & Francis Group, LLC
78836_C017.indd 790
tracer studies on cigarette smoke is justified. A comparison of
the fate of 14C-nicotine in a pyrolysis study vs. its fate during
the smoking of a cigarette resolved a long-standing disagree-
ment between those investigators who maintained that the fate
of a compound on pyrolysis at a temperature similar to that in a
burning cigarette was the same as the fate of that compound in a
smoked cigarette and those who maintained that the fates would
definitely be different. Schmeltz et al. (3512), with 14C-nicotine
in a study on pyrolysis vs. cigarette smoking, reported that the
fates were quite different. On the basis of their findings, they
stated: “These results suggest to us that pyrolysis experiments
may be of limited value for establishing the fate of nicotine and
possibly other tobacco components in a burning cigarette.”
The transfer rate of nornicotine during smoking is signifi-
cantly lower than that of nicotine, with typical values ranging
from 5% to 8% [Glock and Wright (1316), Haag and Larson
(17B14)]. When high nornicotine tobaccos were smoked, sig-
nificant increases in the levels of myosmine were observed
compared to conventional burley cigarettes. Similar results were
obtained when cigarettes were enriched with nornicotine (1316).
Thus, nornicotine is not only an efficient precursor for pyridines,
but also for myosmine as previously mentioned. This is thought
to contribute to the unfavorable taste of smoke from nornicotine-
rich (so-called “Cherry-red”) tobacco. The ease of formation of
myosmine from nornicotine is likely to be an important factor in
its relatively low transfer rate.
The nicotine alkaloids contribute substantially to the unique
flavor of tobacco smoke, mainly due to their rather large con-
centration in tobacco and their rather substantial transfer to
tobacco smoke. The nicotine alkaloids as a class are not con-
sidered positive flavorants as they contribute a harsh, irritating
flavor to the smoke. Nicotine and its contribution to smoking
satisfaction is a subject unto itself that is fraught with numer-
ous social and scientific controversies and will not be discussed
here. It is well known that tobacco products that contain no or
very low levels of nicotine (for numerous reasons) have never
found consumer acceptance or commercial success.
XVII.B.5.2 Compounds in Tobacco and Tobacco
Smoke with Two or More Six-
Membered N-Containing Rings
In tobacco and tobacco smoke, the seventy-six identified com-
pounds with two or more six-membered N-containing rings
(Table XVII.B-5) include 2,2‘-bipiperidine, several bipyridines,
anatabine-type compounds, anabasine-type compounds, ana-
talline, and nicotelline-type compounds. They are distributed
as follows:
1. A total of thirty-nine bipyridines, the majority of
which are derivatives of 2,3’-bipyridine, plus several
2,2’-, 2,4’-, 3,3’-, and 4,4’-bipyridine derivatives.
2. Anatabine and anabasine derivatives, which num-
ber sixteen and fifteen, respectively.
3. Three compounds with two pyridine rings and a
piperidine ring [anatalline (2,4-di(3-pyridinyl)pip-
eridine] and anabasamine [5-(2-piperidinyl)-2,3’-
bipyridine] plus its methyl derivative].
11/24/08 12:28:28 PM
 Nitrogen Heterocyclic Components 791

(3491). All of the alkaloids in Figure XVII.B-4, including bipi-

Table XVII.B-5 peridine, the bipyridines, anatabine, anabasine, anatalline, and
Distribution of Components with Two or More nicotelline, can be biosynthesized from lysine and nicotinic
6-Membered N-Containing Rings between Tobacco acid in Nicotiana species to some extent depending on the spe-
and Tobacco Smoke cies (429b, see KEGG, Alkaloid biosynthesis II — Reference
Number of Identified Compounds in Tobacco pathway, EC-Number 1.1.1.206, Pathway 00960, see http://
and Tobacco Smoke with Two 6-Membered www.genome.jp/kegg/pathway/map/map00960.html).
N-Containing Rings Nicotelline (3,2’:4’,3’’-terpyridine) is another minor alka-
loid of tobacco initially isolated from tobacco by Kuffner
Smoke and
Component Total Smoke Tobacco Tobacco
and Kaiser (17B28). It was originally believed be formed by
the condensation of two molecules of nicotinoylacetic acid
Compounds with two or more 6-membered N-containing rings (17B31), although this compound could also result from the
(Type) degradation of nicotine. However, feeding experiments of
Piperidine + piperidine 1 0 1 0 [2’-14C]-nicotine or ethyl [carbonyl-14C]-nicotinoyl acetate to
Pyridine + piperidine 15 11 8 4 tobacco (17B58) failed to yield labeled nicotelline. Currently,
(anabasine-type) nicotelline and anatalline [2,4-di(3-pyridinyl)-piperidine]
Pyridine + pyridine 39 38 8 7 are considered to be formed by the trimerization of dihydro-
(bipyridines) pyridines from nicotinic acid (17B23). A similar reaction is
Pyridine + di- or 16 12 9 5
proposed for the formation of the terpyridines. These alka-
tetrahydro-pyridine
loids are possibly artifacts produced by nonenzymatic reac-
(anatabine-type)
tions which could occur during the harvesting and curing of
2 Pyridines + piperidine 3 1 3 1
3 Pyridines 2 2 2 2
tobacco. The lack of optical activity in the isolated anatalline
Totals 76 64 31 19
supports this hypothesis (17B31).
Various bipyridines are also formed during tobacco fermen-
tation [Frankenburg and Gottscho (1223)]. As much as 3% of
4. Two compounds with three pyridines, the so-called
the nicotine originally present in cigar tobacco was converted
terpyridines, one of which is nicotelline (3,2’:4’,3’’-
to 2,3’-bipyidine and other oxidative compounds (3973).
terpyridine).
One study by Dubinin and Chelintsev (1075a) reported on
5. One bipiperidine compound has been identi-
the pyrolytic products of anabasine heated at 580 to 650°C
fied in both tobacco and tobacco smoke (2,2‘-
in a charcoal-filled reactor. Exclusive of gases, the major
bipiperidine).
products were reported to be pyridine, 2-methylpyridine,
Of the seventy-six compounds in this class, sixty-four have 2-ethylpyridine, 5-methylisoquinoline, and 2,3’-bipyridine.
been identified in tobacco smoke, thirty-one have been identi- The preponderance of the 2-alkylpyridines might indicate
fied in tobacco, and nineteen in tobacco and tobacco smoke. preferential cleavage of the pyridine ring, which would be
Figure XVII.B-4 illustrates the structures of some of the unexpected; evaluation of these findings is difficult since the
common tobacco alkaloids found in tobacco and tobacco use of charcoal in the reactor may have produced a catalytic
smoke with two or more six-membered N-containing rings. effect and altered the pyrolytic reactions markedly (3797).
Although nicotine is the principal alkaloid in commercial In terms of the flavor potential of this class of compounds,
tobaccos (Nicotiana tabacum and Nicotiana rustica), norni- very little is known. A minor tobacco alkaloid, 2,3’-bipyri-
cotine is the main alkaloid in most other species of Nicotiana. dine, has been reported (17B19) to exhibit a sensitizing effect
Anabasine is the third most abundant tobacco alkaloid. on tobacco flavor and to suppress astringency (3215, 17B52).
Anabasine is found in the stem of the Nicotiana glauca plant. Table XVII.B-6 lists the compounds containing two or
Anatabine has been reported as a minor alkaloid in the roots more six-membered N-containing rings identified in tobacco
of these plants, although it is present also in the leaf and stem and tobacco smoke.
4
H H 5 3 N
N N 6 4'
N 5' H N
2' 6' N CH3
N
2,2'-Bipiperidine 2,3'-Bipyridine 2,2'-Bipyridine N-Methylanabasine

HN
N N N
N N
H H N
N N N

Anatabine Anabasine Nicotelline Anatalline

Figure XVII.B-4  Common tobacco alkaloids found in tobacco and tobacco smoke with two or more 6-membered N-containing rings.

© 2009 by Taylor & Francis Group, LLC

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 792 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-6
Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with Two or More 6-Membered
N-Containing Rings

© 2009 by Taylor & Francis Group, LLC

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 Nitrogen Heterocyclic Components 793

Table XVII.B-6 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with Two or More 6-Membered
N-Containing Rings

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 793 11/24/08 12:28:31 PM

 794 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-6 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with Two or More 6-Membered
N-Containing Rings

© 2009 by Taylor & Francis Group, LLC

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 Nitrogen Heterocyclic Components 795

Table XVII.B-6 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with Two or More 6-Membered
N-Containing Rings

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 795 11/24/08 12:28:32 PM

 796 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.B-6 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with Two or More 6-Membered
N-Containing Rings

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 796 11/24/08 12:28:33 PM

 Nitrogen Heterocyclic Components 797

Table XVII.B-6 (Continued)

Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke with Two or More 6-Membered
N-Containing Rings

Detailed examination of the lists presented in this chap- It is obvious from the tabulation that the six-membered
ter on monocyclic nitrogen heterocycles indicates 709 com- N-containing ring compounds with one or more nitro-
pounds have been identified to date in tobacco and tobacco gens represent nearly 75% of the compounds identified
smoke. The data are summarized in Table XVII.B-7. to date.

Table XVII.B-7
Tobacco and Tobacco Smoke Compounds with 6-Membered Rings, with a 5- and a 6-Membered Ring, or with Two
or More 6-Membered N-Containing Rings
Ring Type No. of Compds. No. of Compds.
6-Membered Ring Pyridine Ring with a (No. of Compounds with Two or (No. of
with One or More No. of Compds. (No. of 2nd N-Containing Agronomic More 6-Membered Agronomic
Nitrogens Agronomic Chemicals) Ring (Type) Chemicals) N-Containing Rings (Type) Chemicals)

Piperidines 37 Pyrrolidine 72 (2)g Piperidine + piperidine 1

(nicotinoids)
Tetrahydropyridines 5 Pyrroline 2 Pyridine + piperidine 15
(anabasine-type)
Dihydropyridines 6 Pyrrole 19 Pyridine + pyridine 39
(bipyridines)
Pyridines 341 (4)a Imidazole 2 (1)h Pyridine + di- or tetrahydro- 16
pyridine (anatabine-type)
Piperazines 10 2 Pyridines + piperidine 3
Dihydropyridazine 3 (3)b 3 Pyridines 2
Pyrazines 100 (1)c
Pyrimidines 33 (4)d
1,2,4-Triazines 2 (1)e
1,3,5-Triazines 1 (1)f
Totals 538 95 76
a Chlorpyrofos® (insecticide), Chlorpyriphos® (insecticide), Nitrapyrin® (bacteriocide), Picloram® (herbicide)
b Maleic hydrazide and salts (herbicide)
c Thionazine® (insecticide)
d Primicarb® (insecticide), Pirimiphos-methyl® (insecticide), Dimetherimol® (fungicide), Diazinon®, (insecticide)
e Metribuzin® (herbicide)
f Anilazine® (fungicide)
g Black Leaf 40® (insecticide)
h Admire® (insecticide)

© 2009 by Taylor & Francis Group, LLC

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 798 The Chemical Components of Tobacco and Tobacco Smoke
XVII.C Lactams
Kosak (2170) listed no lactam identified in tobacco smoke prior
to 1954. In 1959, Johnstone and Plimmer (1971) listed cotinine
as an alkaloid in tobacco and smoke. They did not categorize it
or any other tobacco or smoke component as a lactam.
In its 1963 monograph on tobacco and smoke components,
Philip Morris (2939) listed cotinine as a tobacco and smoke
component. Ishiguro and Sugawara (1884), in their 1980
monograph on tobacco smoke components, listed a total of
seventy-two amides, imides, and lactams; a total of sixteen
lactams was listed [see Table I-15 in (1884)]. The reference for
all of the sixteen lactams listed was Schumacher et al. (3553).
The International Agency for Research on Cancer (IARC)
Working Group met in 1985 to assess the carcinogenic risk
from tobacco smoking. Its monograph summarizing the IARC
findings was published in 1986. In it, the IARC stated that there
was a large spectrum of amides, imides, and lactams in tobacco
smoke (including some fifty aliphatic amides) [see p.109 in
(1870)]. The IARC view on these three compound classes was
based on the 1977 review by Schmeltz and Hoffmann (3491)
and publications in 1977 and 1981 by Schumacher et al. (3553)
and Heckman and Best (1587), respectively.
Of the thirty-five lactams reported in tobacco smoke by
Schumacher et al. (3553) at the 1975 Tobacco Chemists’
Research Conference (TCRC) and published in 1977, twenty-
one were new to the tobacco smoke literature. As noted in
Chapter 13 and Chapter 14, used in this study was a recently
developed analytical technology that permitted fractionation
and identification of the water-soluble components of ciga-
rette smoke condensate (CSC). Similarly in their 1978 TCRC
presentation and 1981 publication, Heckman and Best (1587)
reported the identification of two additional new lactams in
tobacco smoke, 3-ethyl-5-methylene-3-pyrrolid-2-one and
N-methyl-5-(1-methylethylidene)-3-pyrrolid-2-one. They
also confirmed the presence in tobacco smoke of many of
the lactams previously reported (3553). In his earlier study of
the mainstream smoke from an all-burley tobacco cigarette,
Heckman (1986) identified eight lactams.
Lactams frequently reported in both tobacco and its smoke
but seldom classified as lactams are 1-methyl-5-(3-pyridinyl)-
2-pyrrolidinone (cotinine) and several of its derivatives such
as norcotinine. Ishiguro and Sugawara (1884) listed them as
alkaloids [see Table I-12 in (1884)] not lactams.
Examination of the structures of several of the CSC
components indicates that the decision regarding their cate-
gorization is somewhat difficult. In Figure XVII.C-IA, repre-
sentative structures for an imide and a lactam are presented.
To which of these categories—imide or lactam—should the
smoke component 1,7-dihydro-6H-purine-2,6-dione (xan-
thene) {I} be assigned? Its structure {I} is depicted in Figure
XVII.C-IB. In Structure {II} in Figure XVII.C-1B, its imide
configuration is accentuated. Structure {III} illustrates that
two lactam configurations exist in the xanthene molecule. This
same situation is present with the other purine-derived smoke
components. Although there may be some disagreement on
the preciseness of our selection, for the sake of completeness
© 2009 by Taylor & Francis Group, LLC
78836_C017.indd 798
O N O N O
H H
Imide Lactam
configuration configuration
Figure XVII.C-1A  The imide and lactam configurations.
O
N N O O
N
N
H
NH N NH N NH
N H H
H N N
O H
O
H
O
I II III
6H-Purine-2,6-dione, 1,7-dihydro-(xanthine)
(CAS No. 69-89-6)
Figure XVII.C-1B  The imide {II} and lactam {III} configura-
tions in 1,7-dihydro-6H-purine-2,6-dione (xanthine) {I}.
such components are listed in each chapter in its major cata-
log table. As a result, the total number of components in each
of the major catalog tables may be slightly inflated.
Table XVII.C-1 lists a total of 118 lactams identified in
tobacco and/or tobacco smoke. Of the 118, thirty-five were
identified in tobacco, ninety-seven were identified in tobacco
smoke, and fourteen were identified in both tobacco and
tobacco smoke.
XVII.D Oxazoles and Oxazines
Several oxazoles and oxazines have been identified in
tobacco and tobacco smoke. Oxazoles are generally known
as 1,3-azoles or five-membered-ring aromatic heterocyclic
compounds with an oxygen and a nitrogen separated by one
carbon. Oxazole is the parent compound. Isoxazoles are in
this same family of compounds and are generally known as
1,2-azoles. These five-membered-ring aromatic heterocyclic
compounds contain adjacent oxygen and nitrogen atoms.
Oxazole is an analog of imidazole where the nitrogen atom
in position 1 is replaced by oxygen. Isoxazole is an analog of
pyrazole, that is, the nitrogen atom at position 1 is replaced
by oxygen [Gilchrist (17D01)]. Oxazolidine and isoxazolidine
are the reduced forms of oxazole and isoxazole, respectively.
Several oxazolidine and isoxazolidine derivatives, for exam-
ple, oxazolidinediones and isoxazolidinones, have also been
identified in tobacco and tobacco smoke. One other com-
ponent identified in tobacco is related to the oxazoles and
isoxazole. It is an oxadiazole derivative, N-(4-bromophenyl)-
5-(1-naphthalenylmethyl)-1,3,4-oxadiazol-2-amine.
Benzoxazole is a heterocyclic aromatic organic compound
with a fused benzene-oxazole ring structure. Benzoxazole
(1-oxa-3-azaindene) and several alkylated benzoxazoles have
been identified in tobacco smoke. Benzoxazoles found in
11/24/08 12:28:35 PM
 Nitrogen Heterocyclic Components 799

Table XVII.C-1
Lactams in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 799 11/24/08 12:28:36 PM

 800 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.C-1 (Continued)

Lactams in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 800 11/24/08 12:28:37 PM

 Nitrogen Heterocyclic Components 801

Table XVII.C-1 (Continued)

Lactams in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 801 11/24/08 12:28:38 PM

 802 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.C-1 (Continued)

Lactams in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 802 11/24/08 12:28:39 PM

 Nitrogen Heterocyclic Components 803

Table XVII.C-1 (Continued)

Lactams in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 803 11/24/08 12:28:40 PM

 804 The Chemical Components of Tobacco and Tobacco Smoke
Table XVII.C-1 (Continued)
Lactams in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke
tobacco smoke are believed to arise by the mutual condensa-
tion of the oxazole and benzene rings during the combustion/
pyrolysis of tobacco (1884). The only substituted benzox-
azole known in tobacco is residue from the organophosphate
insecticide Phosalone®.
Oxazines are six-membered-ring analogs of piperazine
where the nitrogen atom in position 4 is replaced by an
oxygen atom. The oxazines in tobacco and tobacco smoke
are morpholine and several morpholine derivatives. The
most discussed morpholine recently is N-nitrosomorpholine
(NMOR). This volatile N-nitrosamine (NMOR) has been
identified in both tobacco and tobacco smoke. Morpholine
is an organic heterocycle that features both amine and ether
functional groups. Morpholine is also called tetrahydro-1,4-
oxazine. Figure XVII.D-1 illustrates the parent structures of
the oxazoles and oxazines identified in tobacco and tobacco
smoke.
Numerous reviews have been written on the compounds
identified in tobacco and tobacco smoke over the last five
© 2009 by Taylor & Francis Group, LLC
78836_C017.indd 804
decades (1884, 1900, 1971, 2170, 2270, 2939, 3224, 3797). Few
have listed the oxazole- and oxazine-related compounds iden-
tified in tobacco and tobacco smoke. Latimer (2270) in 1955
listed 231 compounds identified from tobacco and tobacco
smoke. In his review, he listed tetrahydro-2-methyl-6-(3-
pyridyl)-1,2-oxazine, a tobacco alkaloid, as the first oxazine
identified in tobacco smoke. Roberts et al. in 1975 (3224)
listed 2783 compounds identified in tobacco and tobacco
smoke. In their report, five oxazole-related compounds identi-
fied in tobacco smoke were listed (2,4-dimethylbenzoxazole,
2-methylbenzoxazole, oxazolidinedione, 5-ethyl-N-methyl-
2,4-oxazolidinedione, and 5-methyl-2,4-oxazolidinedione).
Roberts et al. did not report any oxazole- or oxazine-related
compounds found in tobacco. In 1980, Ishiguro and Sugawara
(1884) listed 1889 identified tobacco smoke components in
their monograph, only six oxazole-related compounds were
listed (dimethyloxazole, 5-methyl-2,4-oxazolidinedione,
2,4-oxazolidinedione, 3,4,5-trimethylisoxazole, 2-methyl-
benzoxazole, and 2,5-dimethylbenzoxazole). The citations
11/24/08 12:28:41 PM
 Nitrogen Heterocyclic Components 805
O O
N NH
Oxazole Oxazolidine
4 3
N N
5 2
O O
1
1,3,4-Oxadiazole
Figure XVII.D-1  Parent structures of the oxazoles and oxazines identified in tobacco and tobacco smoke.
by Ishiguro and Sugawara for all but the dimethyloxazole
were to the Schumacher et al. (3553) and Newell et al. (2769)
reports on tobacco smoke composition. Roberts in 1988
(3215) tabulated 5868 identified compounds in tobacco and
tobacco smoke. By functional groups, 3044 compounds
had been identified in tobacco, 3996 had been identified in
smoke, and 1172 were identified in both tobacco and tobacco
smoke. A large portion of the oxazole- and oxazine-related
compounds in tobacco and tobacco smoke was originally
identified by employees at the Research and Development
Department of R.J. Reynolds Tobacco Company (RJRT) who
were highly proficient in the isolation and identification of
compounds in tobacco and tobacco smoke. From 1955 until
1988, they reported on nineteen (of the forty-four) oxazole-
and oxazine-related compounds in smoke and six (of the
fourteen) oxazole- and oxazine-related compounds in burley,
Maryland, flue-cured, Oriental, and Perique tobaccos (965,
1075, 1360, 1364, 1375a, 1586, 1587, 1590, 2270, 2337, 2339a
2761, 2762, 2765, 2766, 2767, 2769, 2775, 2777, 3547, 3549,
3550, 3553, 3557). Demole (4570a) at Firmenich (Geneva,
Switzerland), under contract to RJRT, identified twenty-five
additional oxazoles in cigarette smoke condensate.
Oxazole- and oxazine-related compounds do not appear
to be endogenous in green tobacco but are found in tobaccos
that undergo heat treatments during curing and tobacco
processing (965, 1590, 2337, 2339c, 2359). Additionally, it
is known that in certain biomolecules, oxazoles can result
from the cyclization and oxidation of serine or threonine
nonribosomal peptides (17D02). Whether similar reactions
occur in tobacco is not known. The Maillard or nonenzy-
matic browning reaction has generated much interest over the
past seventy years [Nagodawithana (17D07)]. The Maillard
reaction mainly involves the reaction of free amino groups
of amino acids and reducing sugars (17D07). The principal
chemistry of this reaction was reviewed by Hodge in 1953
(17D03). The aromas in most thermally processed foods,
such as bread, cereal products, roasted peanuts, and roasted
coffee, are generated during Maillard reactions [Maga
(17D05, 17D06)]. Numerous heterocyclic compounds aris-
ing from the Maillard reaction have been identified in food
© 2009 by Taylor & Francis Group, LLC
78836_C017.indd 805
H
O N N
N O
O
Isoxazole Isoxazolidine Benzoxazole
H
N
Morpholine
and model systems. These heterocycles include furans, thi-
azoles, thiophenes, oxazoles, pyrroles, pyridines, and pyra-
zines (17D07). Several mechanisms have been proposed for
the formation of oxazole- and oxazine-related compounds in
food flavors, including the Strecker degradation (17D04). For
example, hydroxyacid amides can react with acetone to pro-
duce oxazoles. Similar reaction products from the Maillard
reaction and Strecker degradation are known in tobacco (965,
1590, 2337, 2339c, 2359).
Maga (17D06) has reviewed the occurrence of oxazoles
and oxazolines in a variety of processed food systems. Most
of them possess green, sweet, and nutty aroma qualities and
have been identified in coffee, soy sauce, wheat, and cooked
beef and some of them have very low odor thresholds. In 1976,
Leffingwell discussed how certain flavorants (reaction products)
can be produced in tobacco and tobacco smoke (2337).
Because of the complexity of the chemical interactions and
transformations involved, the types and ratios of active flavor
products formed by nonenzymatic browning are dependent
on the reaction conditions that may occur during aging or
during the smoking process itself.
One of the flavorants discussed by Leffingwell (2337)
that was identified in tobacco by Lloyd et al. (2389) was
3,4-dihydro-3-oxo-4-(phenylmethyl)-1H-pyrrolo[2,1-c][1,4]
oxazine-6-carboxaldehyde. This particular tobacco flavor has
a hot peppery characteristic (2337). Leffingwell and Alford
(2339a) and Li et al. (2359) identified 2,4,5-trimethyloxazole
in Perique and burley tobacco, respectively, and reported it
has a boiled beef, nutty, sweet, and green flavor. The appli-
cation of oxazole-and oxazine-related flavor compounds to
tobacco is not normally undertaken because the flavor and
aroma characteristics of these compounds are rather weak.
No oxazole- or oxazine-related compound was included in
the list by Doull et al. (1053) of individual flavor compounds
used by one or more of the U.S. cigarette manufacturers or
individual flavor compounds used outside the United States
[see Tables 1 and 7A in (3266)].
Agrochemical residues containing an oxazole-related func-
tionality that have been found on tobacco include Clomazone®,
a broad spectrum herbicide, Phosalone®, an organophosphate
11/24/08 12:28:41 PM
 806 The Chemical Components of Tobacco and Tobacco Smoke
Table XVII.D-1
The Distribution of Oxazole- and Oxazine-Related Compounds Identified in
Tobacco and Tobacco Smoke
Oxazole-Related Total No.
Compounds Compounds Tobacco
Benzoxazole 9 1
Isoxazole 4 3
Oxazole 30 1 29
Oxazolidine 4 1
Morpholine 9 8
Total 56 14
commonly used as an insecticide, and Vinclozolin®, a common
fungicide. Dimethomorph® or Acrobat® is a common fungi-
cide used on tobacco that contains morpholine functionality.
Analytical measurements for the determination and
quantification of oxazole- and oxazine-related compounds
in tobacco and tobacco smoke include gas chromatogra-
phy (GC) with packed or capillary columns, high perfor-
mance liquid chromatography (HPLC) usually with reverse
phase (RP) columns, and mass spectrometry (MS) methods
(GC-MS and LC-MS).
Table XVII.D-1 lists the distribution of oxazole- and
oxazine-related compounds identified in tobacco and tobacco
smoke. A total of fifty-six compounds have been identified:
nine are benzoxazole derivatives, four are isoxazole deriva-
tives, thirty are oxazole derivatives, four are oxazolidine
derivatives, and nine are morpholine derivatives. Fourteen
of the compounds are found in tobacco, forty-four are found
in tobacco smoke, and two are found in both tobacco and
tobacco smoke. Table XVII.D-2 lists the fifty-six oxazole-
and oxazine-related compounds identified in tobacco and
tobacco smoke.
XVII.E Aza-Arenes
An aza-arene is defined as a fused ring compound with two
or more fused rings and consisting only of carbon, hydrogen,
and nitrogen. Alkyl-substituted derivatives are also included
in the aza-arene category. Overall, many of the aza-arenes are
structurally comparable to the polycyclic aromatic hydrocarbons
(PAHs) but include at least one nitrogen in the ring. In his
early 1954 compilation of reported tobacco smoke compo-
nents, Kosak (2170) listed no fused-ring polycyclic nitrogen
compounds in tobacco smoke, the class of compounds sub-
sequently termed the aza-arenes. Five years later, the only
fused-ring N-heterocyclic compound listed by Johnstone and
Plimmer (1971) as a tobacco smoke component was the bicy-
clic compound quinoline. Except for the replacement of a –CH=
linkage with a nitrogen (–N=) at the 1-position, quinoline is
structurally similar to the PAH naphthalene (Figure XVII.E-1).
However, the reference cited by Johnstone and Plimmer
was the 1929 study by Gabelya and Kipriyanov (1263), who
described the identification of quinoline in a “destructive
© 2009 by Taylor & Francis Group, LLC
78836_C017.indd 806
Agrochemical
Smoke Both Product
8 0 1
1 0 1
0 0
3 0 1
3 2 1
44 2 4
distillate” of tobacco, not in a sample of tobacco smoke pre-
pared by a tobacco smoking procedure. A similar identifica-
tion of benzo[a]pyrene (B[a]P) in the destructive distillate of
tobacco by Roffo (3323, 3325) was criticized by Wynder and
Hoffmann (4319, 4332), who asserted that a tobacco destruc-
tive distillate was not tobacco smoke.
In 1960, Van Duuren et al. (4027), in an extension of their
studies on the tumorigenic PAHs in mainstream cigarette
smoke condensate (CSC), described their findings on tumori-
genic N-heterocyclic compounds in the CSC. They reported the
identification of dibenz[a,h]acridine {I}, dibenz[a,j]acridine
{II}, and 7H-dibenzo[c,g]carbazole {III} (Figure XVII.E-2)
in CSC at per cigarette levels of 0.1 ng, 2.7 ng, and 0.7 ng,
respectively. These levels were substantially less than that of
the reported per cigarette yield of B[a]P in the late 1950s or
early 1960s. Similar to the situation noted above that quino-
line is a nitrogen analog of naphthalene, dibenz[a,h]acridine
{I} is a nitrogen analog of dibenz[a,h]anthracene (DB[a,h]
A) {IV}. These two compounds are dimensionally similar.
Over five decades ago, these three N-heterocyclics had been
reported as tumorigenic to mouse skin [see the summary
by Hartwell (1544)]. Two of these compounds, dibenz[a,h]
acridine and dibenz[a,j]acridine, were also reported by Van
Duuren et al. to be present in the pyrolysates (750°C, nitro-
gen atmosphere) from both nicotine and pyridine.
Contradictory findings have been reported on the pres-
ence or absence of these three N-heterocyclic compounds,
for example, Wynder and Hoffmann (4319, 4332) reported
that members of their research group, Candeli et al. (587),
were able to confirm the presence of dibenz[a,j]acridine but
not dibenz[a,h]acridine in mainstream CSC. The per ciga-
rette yield of dibenz[a,j]acridine reported by Candeli et al.
was significantly greater than that reported by Van Duuren
et al. (4027), 10.0 ng/cigarette vs. 2.7 ng/cigarette. Other than
brief mentions by Wynder and Hoffmann (4319, 4332) of the
results obtained by Candeli et al. (587) on dibenz[a,j]acridine
in CSC, the experimental procedures involved in its identifi-
cation do not appear to have been published in the usual way
in a peer-reviewed journal. At a mainstream smoke (MSS)
yield for dibenz[a,j]acridine of 2.7 ng/cigarette or 10.0 ng/
cigarette, as reported by Van Duuren et al. and Candeli et al.,
respectively, it is difficult to understand why no confirmation
11/24/08 12:28:42 PM
 Nitrogen Heterocyclic Components 807

Table XVII.D-2
Oxazoles- and Oxazine-Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 807 11/24/08 12:28:42 PM

 808 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.D-2 (Continued)

Oxazoles- and Oxazine-Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 808 11/24/08 12:28:43 PM

 Nitrogen Heterocyclic Components 809

Table XVII.D-2 (Continued)

Oxazoles- and Oxazine-Related Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C017.indd 809 11/24/08 12:28:44 PM

 810 The Chemical Components of Tobacco and Tobacco Smoke
N pyrolysates. They wrote:
Quinoline Naphthalene
Figure XVII.E-1  Quinoline and naphthalene.
of the presence of this aza-arene had been reported by highly
competent investigators from the early 1960s through the
mid-1990s! Similarly, no confirmations of the presence of
dibenz[a,h]acridine or 7H-dibenzo[c,g]carbazole have been
presented to date. Studies on these and other aza-arenes in
cigarette MSS or nicotine pyrolysates are described briefly
in the following paragraphs. The question remains: Was the
preliminary isolation procedure (vacuum distillation of the
smoke condensate at 100°C, 0.5 mm pressure) used by Van
Duuren et al. (4027) responsible for the formation of the
dibenzacridines and the dibenzocarbazole?
In 1970, Kaburaki et al. (2006) reported the results of their
detailed study of the pyrolysis of nicotine at various tempera-
tures in air and in an inert atmosphere (nitrogen). They did
not report the identification of the two tumorigenic benzacri-
dines reported previously by Van Duuren et al. (4027) as
identified components in their nicotine pyrolysates.
From their study of the pyrolysis of several nitrogenous
components of tobacco, including nicotine, Schmeltz et al.
(3499) reported:
We could not detect benzo(a)pyrene in nicotine pyrolyzates,
nor could we confirm the presence of the physiologically
active dibenzacridines and dibenzcarbazole [sic] reported in
tobacco smoke and in nicotine and pyridine pyrolyzates by
Van Duuren [4027].
In their review of the pyrogenesis of tobacco smoke com-
ponents, Chortyk and Schlotzhauer (722) emphasized these
reported findings, that is, the failures of several groups
N (4027) were not identified in this study by Schmeltz et al.
N (3512). They noted:
I II
N the smoke. To this group of minor smoke constituents hav-
H ing nicotine as a precursor belong the dibenzacridines [Van
III IV
Figure XVII.E-2  Some polycyclic components of tobacco smoke.
© 2009 by Taylor & Francis Group, LLC
78836_C017.indd 810
of investigators to confirm the presence of the two diben-
zacridines and the 7H-dibenzo[c,g]carbazole in nicotine
Since nicotine is the most abundant and best known tobacco
alkaloid, its pyrolysis has been thoroughly studied [Woodward
et al. (4275a), Jarboe and Rosene (1923a)]. More recent work
[Kaburaki et al. (2006)] on the pyrolysis of nicotine and
various alkyl-pyridines has resulted in a proposed mecha-
nism for the thermal degradation of nicotine … Schmeltz
[Schmeltz et al. (3499)] also studied nicotine and identified a
number of previously unreported compounds in the nicotine
pyrolysates … These included pyrrole, acenaphthene, indole,
skatole, and anthracene and/or phenanthrene. However, the
presence of dibenzacridines and dibenzcarbazole, previously
reported in nicotine and pyridine pyrolysates, could not be
confirmed [Van Duuren et al. (4027)].
Schmeltz and Hoffmann (3491), in their review of the
N-containing components of tobacco and tobacco smoke,
discussed the generation of various pyridines from nicotine
during both the actual smoking process and pyrolysis. They
did report the identification by Van Duuren et al. (4027) of
the two dibenzacridines in cigarette smoke and nicotine
pyrolysate. They did not, however, comment on the reports
issued between 1960 and 1977 on the inability of several
other groups of investigators [Candeli et al. (587), Kaburaki
et al. (2006), Schmeltz et al. (3499)] to confirm the 1960 find-
ings of Van Duuren et al. (4027).
In 1979, Schmeltz et al. (3512) reported their results from
an elaborate study on the fate of radiolabeled nicotine dur-
ing pyrolysis and during the actual smoking of a radiolabeled
nicotine-treated cigarette. Their major findings included:
(1) Under combustion-tube pyrolysis conditions, nicotine in
either silica gel matrix (pyrolysis temperatures at 600°C,
750°C, or 900°C) or tobacco matrix (pyrolysis temperature
at 600°C) underwent extensive degradation to a mixture of
pyridines, quinolines, arylnitriles, and aromatic hydrocar-
bons. (2) In a burning cigarette during actual smoking, a sub-
stantial portion of the nicotine (about 41%) remains intact,
12.5% is oxidized to carbon dioxide, as much as 11% is
degraded to volatile alkylpyridines, and negligible amounts
are converted to neutral or acidic components of the particu-
late phase. (3) Dibenz[a,h]acridine and dibenz[a,j]acridine
reported nearly two decades earlier by Van Duuren et al.
In ongoing studiesa we are now identifying those compounds
that are formed from nicotine only as minor compounds
(<0.1%) which nevertheless can contribute to the toxicity of
Duuren et al. (4027)] …
aNo report of the confirmation of the presence of the dibenzacri-
dines (or the dibenzocarbazole) as a result of these ongoing studies
has been found to date.
11/24/08 12:28:45 PM
 Nitrogen Heterocyclic Components 811

(4) From the experimental results, the authors concluded:
“Pyrolysis experiments may be of limited value for estab-
lishing the fate of nicotine and possibly other tobacco com-
ponents in a burning cigarette.” (5) The pyrolysis system
used in this study [see Higman et al. (1648)] was designed,
according to Higman et al., to be the optimum simulation of
the smoking process. Obviously, nicotine did not behave in
this pyrolysis system as it did in the burning cigarette during
actual smoking.
Close examination of the text and the conclusions
expressed in the 1979 Schmeltz et al. publication on the
fate of nicotine during pyrolysis and during actual smok-
ing reveals that at least two of the authors (Hoffmann and
Schmeltz) have definitely changed their opinion with regard
to their long-held view on the supposed equivalence of com-
pound behavior during pyrolysis and actual smoking; for
example, Wynder and Hoffmann (4332) earlier wrote in sup-
port of this equivalence:
Most pyrolysis studies with tobacco, tobacco extracts,
extract fractions, individual components, and tobacco addi-
tives are performed in a nitrogen atmosphere. This proce-
dure has often been criticized on the grounds that many of
the toxic constituents formed during smoking of tobacco
products occur as a result of combustion in air rather than
in a nitrogen atmosphere. This criticism, however, cannot
be maintained in view of studies by Newsome and Keith
[2780] which demonstrated that a reducing rather than an
oxidizing atmosphere exists at the cone region of a burning
cigarette.
With regard to the production of dibenzacridines and the
dibenzocarbazole from nicotine during pyrolysis and the
smoking process, Table XVII.E-1 summarizes the current
state of knowledge.
For example, authors of numerous articles in the 1980s
[Hoffmann and Wynder (1808)], in the 1990s [Hoffmann
and Hecht (1727), Hoffmann et al. (1773), OSHA (2825),
Hoffmann and Hoffmann (1740, 1741)], and in the 2000s
[Hoffmann and Hoffmann (1743), Hoffmann et al. (1744),
and Fowles and Bates (1217)] on the toxicants in tobacco
and tobacco smoke repeatedly listed dibenz[a,h]acridine,
dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole as tum-
origenic or adversely biologically active MSS components
despite the following: (1) The presence of these three aza-
arenes in MSS had not been confirmed in several investiga-
tions conducted between 1963 and 1990 (3260). (2) Between
1990 and 2000, additional studies failed to confirm their
presence in MSS (2021, 3414). (3) Several summaries of the
attempts to confirm the findings of Van Duuren et al. have
been published (172, 3260, 3265). In 2002, Rustemeier et al.
(3370) did report the presence of dibenz[a,j]acridine in the

Table XVII.E-1
Dibenz[a,h]acridine {I}, Dibenz[a,j]acridine {II}, and 7H-Dibenzo[c,g]carbazole {III}
in Nicotine Pyrolysates (Pyr) and Mainstream Cigarette Smoke Condensate (CSC)
Dibenz[a,h]acridine Dibenz[a,j]acridine 7H-Dibenzo[c,g]carbazole

Investigators Pyr CSC Pyr CSC Pyr CSC

Van Duuren et al. (4027) yes yes Yes yes no yes

Candeli et al. (587); Wynder NE no NE yes NE NE
and Hoffmann (4319, 4332)
Kaburaki et al. (2006) no NE No NE NE NE
Schmeltz et al. (3499) no NE No NE no NE
Schmeltz et al. (3512) no no No no no no
Snook (3733) NE no NE no NE no
Snook et al. (3750) NE no NE no NE no
Grimmer et al. (1409) NE no NE no NE no
Kamata et al. (2021) NE no NE no NE NE
Sasaki and Moldoveanu (3414) NE no NE no NE NE
Rustemeier et al. (3370) NE no NE yes NE NE

yes = Compound identified.

no = Compound not found or identified.
NE = Substrate not examined for compound in question.
Examination of these results indicates that Van Duuren et al. (4027) reported the identification of the three
N-heterocyclic compounds {I, II, and III} in MSS CSC and two of them {I and II} in a nicotine pyrolysate; whereas,
Candeli et al. (587) failed to identify I but did identify {II} in MSS CSC. The 1963 Candeli et al. findings on {II} in
MSS CSC were not confirmed in 1979 by investigators (3512) from the same laboratory: Hoffmann participated in
both the 1963 and 1979 studies. Two studies (3499, 3512) confirmed the 1960 report by Van Duuren et al. that
7H-dibenzo[c,g]carbazole {III} was not present in a nicotine pyrolysate.

© 2009 by Taylor & Francis Group, LLC

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 812 The Chemical Components of Tobacco and Tobacco Smoke
MSSs from several ingredient-treated cigarettes. All yields
were reported as less than 2.72 ng/cigarette. It might have
been appropriate, in view of the numerous failures to confirm
the presence of dibenz[a,j]acridine in cigarette smoke, for
Rustemeier et al. to have provided more meaningful infor-
mation on its presence.
Other tumorigens in cigarette MSS, including several
whose presence was and is suspect, have been listed since
the early 1960s.
In 1960, Mold et al. (2592) reported the isolation and
identification of the tricyclic N-heterocyclic 5H,10H-
dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll) {V}
(Figure XVII.E-3) from CSC and demonstrated its rela-
tionship to its precursor in tobacco, the amino acid pro-
line. Obviously, pyrocoll is not an aza-arene but an amide.
Rodgman and Cook (3279) reported the identification of
indole, carbazole, and several alkylated indoles and car-
bazoles in CSC and confirmed the presence of 5H,10H-
dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll) {V}
described previously by Mold et al. (2592). Rodgman and
Cook also assessed previously reported biological studies on
indole, 3-methylindole (skatole), and carbazole: None was
reported to be tumorigenic in laboratory animals [Hartwell
(1544), Shubik and Hartwell (3664)].
Poindexter and Carpenter (2972) identified 9H-pyrido[3,
4-b]indole (norharman) {VI} and 1-methyl-9H-pyrido[3,
4-b]indole (harman) {VII} (Figure XVII.E-3) isolated from
CSC. They reported the yield of the total harmans in burley
and flue-cured smokes to be between 15 and 20 mg/g of tobacco
smoked, values 40 to 50 times that of the total harmans in the
unsmoked tobaccos. Since the weight of tobacco in cigarettes
sold at that time approximated 1 g, the delivery of these two
compounds was about 15 to 20 mg/cigarette. They concluded
from experiments with radiolabeled tryptophan that the har-
mans (found to be radiolabeled in the smoke) were generated
pyrogenetically from a reaction between aldehydes (form-
aldehyde for norharman, acetaldehyde for harman) and the
tryptophan in tobacco. Schmeltz et al. (3505) reported 5H,10H-
dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll) {V},
9H-pyrido[3,4-b]indole (norharman) {VI}, and 1-methyl-9-
H-pyrido[3,4-b]indole (harman) {VII} in tobacco smoke.
Testa and Testa (3886, 3887) also confirmed the presence of
5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyro-
coll) in CSC.
O numerous lists of tobacco smoke tumorigens published in
N amines had not been included in their numerous lists pub-
N N
N N N lished between 1986 and 1997 (1727, 1773, 1806) nor in simi-
H H
CH3
O number in tobacco smoke is low, we decided to discuss them
V VI VII
Figure XVII.E-3  Some amino acid-derived N-heterocyclics iden-
tified in tobacco smoke.
© 2009 by Taylor & Francis Group, LLC
78836_C017.indd 812
In 1964, the Advisory Committee to the U.S. Surgeon
General (3999) briefly discussed only four fused-ring
N-heterocyclic compounds in tobacco smoke: quinoline plus
the two dibenzacridines (dibenz[a,h]acridine, dibenz[a,j]
acridine) and the dibenzocarbazole (7H-dibenzo[c,g]carba-
zole) reported by Van Duuren et al. (4027).
In his 1968 review of tobacco and tobacco smoke compo-
sition, Stedman (3797) discussed the identification of tum-
origenic N-heterocyclic compounds [dibenz[a,h]acridine,
dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole] reported
by Van Duuren et al. (4027), as well as the identification of the
following N-heterocyclic compounds: 5H,10H-dipyrrolo[1,2-
a:1’,2’-d]pyrazine-5,10-dione (pyrocoll), 9H-pyrido[3,4-b]
indole (norharman), 1-methyl-9H-pyrido[3,4-b]indole (har-
man), and 9H-pyrido[2,3-b]indole.
In his early 1970s outline of recent research on tobacco
and tobacco smoke composition, Wakeham (4103) noted the
reported presence of 9H-pyrido[3,4-b]indole (norharman)
and 1-methyl-9H-pyrido[3,4-b]indole (harman) in cigarette
smoke and discussed their possible formation by reaction of
tryptophan and an aldehyde. As noted by Rodgman (3253a),
the structure of the aldehyde reacting with tryptophan ulti-
mately dictates the structure of alkylated norharmans found
in CSC (see Table XVII.E-2).
In addition to 5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,
10-dione (pyrocoll), Izard et al. (1899) reported the identifi-
cation of its homolog methyl-5H,10H-dipyrrolo[1,2-a:1’,2’-d]
pyrazine-5,10-dione (methylpyrocoll) in CSC.
During a presentation at the 1975 TCRC and in a 1977
publication on their study of the water-soluble portion of
CSC, Schumacher et al. (3553) reported the identifications
of 1-methyl-9H-pyrido[3,4-b]indole (harman), 5H,10H-
dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll), octa-
hydro-5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione
(octahydropyrocoll), and 2-ethyl-9H-pyrido[2,3-b]indole.
The results of research in Japan in the late 1970s brought
attention not to any aza-arenes themselves but to a group of
their amine derivatives, many of which showed inordinately
high mutagenicity in the Ames test with several strains of
Salmonella typhimurium. The source originally studied
was cooked foodstuffs and pyrolysis products from sev-
eral amino acids, which resulted in their being described
as “cooked food” mutagens. Later, they became known as
the N-heterocyclic amines. When the N-heterocyclic amines
were shown to be tumorigenic in addition to being highly
mutagenic and subsequently identified in tobacco smoke,
they were included by Hoffmann and his colleagues in their
1997 and later (1740, 1741, 1743, 1744). The N-heterocyclic
lar lists by IARC (1870) and OSHA (2825). Even though their
in a separate section that follows this one on aza-arenes.
In the 1979 Surgeon General’s report (4005), the aza-arenes
dibenz[a,h]acridine, dibenz[a,j]acridine, 7H-dibenzo[c,g]
carbazole, quinoline, and alkylated quinolines in CSC were
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 Nitrogen Heterocyclic Components 813

Table XVII.E-2
Chronology of Selected Aza-Arenes: Dibenz[a,h]acridine, Dibenz[a,j]acridine, 7H-Dibenzo[c,g]carbazole, Quinoline
Year Event

1929 Gabelya and Kipriyanov (1263) reported the identification of quinoline in a destructive distillate from tobacco. Destructive distillation
of tobacco is not considered to be equivalent to the tobacco smoking process [see comments by Wynder and Hoffmann (4319, 4332)].
1935 Barry et al. (194) (members of the Kennaway group in the United Kingdom) compared the tumorigenicity of dibenz[a,h]
anthracene (DB[a,h]A) with that of heterocyclic compounds in which one or both of the meso-carbons were replaced by nitrogen.
The aza-arene dibenz[a,h]acridine was found to be less tumorigenic (mouse skin) than its PAH counterpart DB[a,h]A. They also
reported that the tumorigenicity of dibenz[a,j]acridine was less than that of dibenz[c,h]acridine.
1937 In the first reported investigation of the tumorigenicity of 7H-dibenzo[c,g]carbazole, Boyland and Brues (421a) reported that mice
skin painted with it developed carcinomas at the painting site.
1937 Bachmann et al. (137a) reported that dibenz[a,j]acridine injected subcutaneously induced sarcomas in mice, i.e., dibenz[a,j]
acridine was sarcogenic. Its sarcogenicity was relatively weak compared to that noted for similarly injected PAHs.
1940 Badger et al. (140) reported that oral administration to 10 mice of 5 mg/week/mouse of dibenz[a,h]acridine resulted in one mouse
with an epithelioma and papilloma of the forestomach; another mouse showed stomach papillomas. Duration of the experiment
was 627 days. Similar administration of dibenz[a,j]acridine (10 mice, 5 mg/week/mouse) gave no tumors in 572 days. In their
introduction, the authors stated:
There is now little doubt that cigarette smoking is the major factor concerned with the ever-increasing incidence of
bronchogenic carcinoma in men. Both cigarette-tobacco tars and particulates from air pollution contain various carcinogenic
polynuclear compounds.
1940 In their study of the response of the lungs of strain Aa mice to various compounds, Andervont and Shimkin (79) demonstrated that 20
of 20 strain A mice given a single injection of 0.5 mg of dibenz[a,h]acridine in 0.1 ml of tricaprylin developed multiple adenomas in
14 weeks but no sarcomas at the injection site. All 14 mice administered a single injection of 1 mg of dibenz[a,h]acridine in 0.3 ml of
sesame oil developed multiple adenomas in 40 weeks but no sarcomas at injection site. Andervont and Shimkin also compared the
response of the lungs of strain A mice to a single intravenous injection of 0.25 mg of each of nine compounds dispersed in 0.25 ml of
water. Among the nine compounds were DB[a,h]A, B[a]P, benz[a]anthracene (B[a]A], dibenz[a,h]acridine, and 7H-dibenzo[c,g]
carbazole. A calculated “carcinogenic index” [% tumor bearing animals x mean number of adenomas in animals showing a positive
response for each of these compounds at 8, 14, and 20 weeks] gave the following sequence:
DB[a,h]A > 7H-dibenzo[c,g]carbazole > B[a]P > dibenz[a,h]acridine > B[a]A
a The strain A mouse was developed for lung tumor research in laboratory animals. Without treatment of any kind, 70 to 90% of strain A
mice develop adenomas, a type of lung tumor, between 12 and 18 months of age [Shimkin (3652)].

1946 Dubinin and Chelintsev (1075a) reported quinoline, isoquinoline, and several substituted pyridines in a pyrolysate of anabasine, a
tobacco alkaloid structurally related to nicotine.
1951 Hartwell (1544) listed several studies in which dibenz[a,j]acridine and 7H-dibenzo[c,g]carbazole were reported to be tumorigenic
in skin-painting (epitheliomas) and subcutaneous-injection (sarcomas) experiments.
1954 At the International Cancer Congress, São Paolo, a new short-term test was reported by Smith (3722a). By this test, the
“tumorigenicity” of a test compound could be estimated in less than a week vs. the 18 to 20 months required in skin-painting
studies. The extent and rapidity of the disappearance of the sebaceous glands after 4 daily applications of the test compound
(PAHs, aza-arenes, etc.) were considered to be related to the tumorigenicity of the test compound. Because of the absence of the
ultimate end point – a tumor, this test did not receive the endorsement originally anticipated.
1954 Kosak (2170) did not list quinoline as a tobacco smoke component, perhaps because it was reported as a component of a
destructive distillate of tobacco rather than a component of tobacco smoke. However, he did list B[a]P as a questionable tobacco
smoke component even though it too was identified in a destructive distillate of tobacco by Roffo (3323, 3325).
1956 Lacassagne et al. (2247a) reported the tumorigenicity of dibenz[a,h]acridine and dibenz[a,j]acridine to the skin and subcutaneous
tissue of mice. The tumorigenicity of 76 other unsubstituted and substituted benzacridines was also cataloged. The authors noted:

All [angular benzacridines] have a characteristic odor which is reminiscent of cigar smoke.

Since 1967, two unsubstituted angular benzacridines (benz[a]acridine, benz[c]acridine) and over a dozen of their alkyl substituted
derivatives have been identified in tobacco smoke (1409, 2021, 2120, 2132, 2596a, 3300, 3337, 3339, 3499, 3750, 3752).
1957 In the first supplement to Hartwell’s 1951 compilation of compounds tested for tumorigenicity, Shubik and Hartwell (3664)
summarized the results of additional published studies on the tumorigenicity of 7H-dibenzo[c,g]carbazole in mice and rats.

(Continued)

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 814 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.E-2 (Continued)

Chronology of Selected Aza-Arenes: Dibenz[a,h]acridine, Dibenz[a,j]acridine, 7H-Dibenzo[c,g]carbazole, Quinoline
Year Event

1959 Johnstone and Plimmer (1971) listed quinoline as a tobacco smoke component, but the reference cited was the report of Gabelya
and Kipriyanov (1263) who identified quinoline in a destructive distillate of tobacco.
1960 Van Duuren et al. (4027) vacuum distilled a solution of the basic portion of 250 grams of cigarette “tar” at 100°C/0.5 mm
pressure. The residue (10 g) was successively chromatographed on alumina and several Whatman’s papers. Bands corresponding
to the aza-arenes dibenz[a,h]acridine and dibenz[a,j]acridine were rechromatographed until their ultraviolet absorption and
fluorescence spectra were identical with those of authentic samples. Chromatography of the neutral fraction of the CSC gave an
isolate whose properties were identical with an authentic sample of 7H-dibenzo[c,g]carbazole. No 7H-dibenzo[c,g]carbazole was
detected. The estimated amounts of dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole isolated from the “tar”
were 0. 1, 2.7, and 0.7 ng/cig, respectively. They estimated the levels of B[a]P and DB[a,h]A in the same CSC to be 5.0 and 0.5
ng/ciga, respectively. Van Duuren et al. noted:
It is clear that the heterocyclics here described make a significant contribution to the reported carcinogenicity of tobacco tars.
a It is interesting to note the deliveries recorded by Van Duuren et al. for B[a]P (5 ng/cig) and DB[a,h]A (0.5 ng/cig) and

compare them to values subsequently listed by Hoffmann and Hecht (1727) and Hoffmann and Hoffmann (1740) who
listed a range for B[a]P of 20–40 ng/cig and a single value for DB[a,h]A of 4 ng/cig! Why did these authors not acknowledge
the values reported by Van Duuren et al.?
1960 Van Duuren et al. (4027) also investigated the possibility that pyridine and nicotine were precursors of these nitrogen heterocyclics.
Pyrolysis of pyridine or nicotine (750 °C, nitrogen atmosphere) yielded pyrolysates in which dibenz[a,h]acridine and dibenz[a,j]
acridine were identified by the same procedures used with CSC. As in the CSC case, dibenz[a,j]acridine was more plentiful than
dibenz[a,h]acridine in the pyridine and nicotine pyrolysates. No 7H-dibenzo[c,g]carbazole was found in either pyrolysate.
1960 Van Duuren et al., citing unpublished data by Nelson et al. (2689d) on mouse skin-painting with the basic fraction of CSC, noted
that the skin-painting experiments gave negative results and attributed this finding to the fact that:
The basic fraction used in those experiments would not have been sufficient to yield skin tumors even if the benzacridines
had been as potent for the skin as benzo[a]pyrene, which is not the case. They also noted that Wynder and Wright (4354)
reported weak tumorigenicity with more concentrated fractions from the basic fraction.
1961/ Balasubrahmanyam and Quin (175) identified quinoline, isoquinoline, and various substituted pyridines in the pyrolysates from
1962 the tobacco alkaloids nornicotine and myosmine.
1962 Van Duuren (4022a) described methods for the separation and identification of 7H-dibenzo[c,g]carbazole in cigarette MSS.
1962 Rodgman and Cook (3279) reported the isolation in crystalline form and the identification of a series of homologous indoles
(indole, skatole, etc.) as well as several carbazoles from cigarette MSS.
1963 Candeli et al. (587) investigated the aza-arenes in CSC with the method described by Van Duuren et al. in 1960. It was noted:
With some modifications, this method …by Candeli et al…enabled us to isolate from 100 cigarettes 1.0 mg [dibenz[a,j]
acridine]. The presence of [dibenz[a,h]acridine] could not be confirmed.
1963 Wynder and Hoffmann (4317) described the results of mouse skin-painting tests with dibenz[a,j]acridine applied in 0.5 and 0.1%
acetone solutions three times weekly to the backs of 20 Swiss female mice. After 12 to 14 months, tumors were induced in 16
(80%) and 15 (75%) mice, respectively, with 60% of the animals in each test developing carcinomas. Wynder and Hoffmann
(4332) offered the following explanation for the difference between these extremely high results and the much lower one reported
by LacassagnE et al. (2247a):
This relatively high tumor response in mouse skin (compared to the findings of Lacassagne et al. (2247a)) might be partially
explained by the high purity of the compounds, due mainly to the absence of the ‘Morgan’s base’ a dihydrodibenz[a,j]acridine.
Only by repeated column chromatography on alumina can a [dibenz[a,j]acridine] be isolated that is free of the dihydro product
(absence of N-H band in infrared absorption spectrum).
In another study reported by Wynder and Hoffmann (4317), mouse skin was initiated with a single application of 300 mg of
7,12-dimethylbenz[a]anthracene and then painted with a 0.5% solution of dibenz[a,j]acridine, three times weekly. The same tumor
response was observed as with dibenz[a,j]acridine alone except that the tumors appeared 2 to 3 months earlier. The investigators
interpreted this finding as indicating:
There is no significant tumor-promoting activity of [dibenz[a,j]acridine], despite its strong hyperplastic effect.”

1964 The report of the 1964 Advisory Committee to the U.S. Surgeon General (3999) identified dibenz[a,h]acridine, dibenz[a,j]
acridine, and 7H-dibenzo[c,g]carbazole as carcinogenic polycyclic compounds isolated from cigarette smoke, classified them as
weakly carcinogenic, and listed their amounts in cigarette MSS as 0.1, 2.7, and 0.7 ng/cig. The report also listed quinoline as a
tobacco smoke component.

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 Nitrogen Heterocyclic Components 815

Table XVII.E-2 (Continued)

Chronology of Selected Aza-Arenes: Dibenz[a,h]acridine, Dibenz[a,j]acridine, 7H-Dibenzo[c,g]carbazole, Quinoline
Year Event

1964 In addition to discussing the dibenzacridines and dibenzocarbazole in tobacco smoke and the two dibenzacridines in a nicotine
pyrolysate reported by Van Duuren et al. (4027), Wynder and Hoffmann (4319) discussed the identification by Jarboe and Rosene
(1923a) of quinoline in a nicotine pyrolysate produced at 600–900°C in an inert atmosphere.
1964 Kuhn (2228) reviewed the pyrogenesis of aza-arenes from tobacco and nicotine. The dibenzacridines were tabulated with reference
to the 1960 paper of Van Duuren et al. (4027). He listed quinoline as a pyrolysis product of nicotine and nornicotine but not as a
tobacco smoke component.
1964 Testa and Testa (3886) report quinoline as a tobacco smoke component. Its presence was subsequently confirmed by Grob and
Völlmin (1427) and Kaburaki et al. (1992a).
1965 Sawicki et al. (3419a) identified dibenz[a,h]acridine and dibenz[a,j]acridine in polluted air in the amounts of 80 and 40 ng/1000
m3 of air, respectively.
1968 Stedman (3767) wrote:
The presence of the dibenzacridines and 7H-dibenzo[c,g]carbazole in cigarette smoke…is of special interest since these
compounds are carcinogenic and may contribute to the weak tumorigenic activity of the basic fraction in laboratory
animals [Wynder and Wright (4354); Wynder and Hoffmann (4319)].
NOTE: Stedman apparently missed the point that 7H-dibenzo[c,g]carbazole, because of its structure, was not present in
the basic fraction but was found in the neutral fraction of CSC [see Van Duuren et al. (4027)].
1969 Rothwell and Whitehead (3339) improved the method of isolation of 7H-dibenzo[c,g]carbazole from complex mixtures such as
CSC by formation of complexes of the aza-arenes and PAHs with purines.
1970 In a study of the composition of nicotine pyrolysates (400°, 500°, 550°, 600°, 650°, 700°, 800°C; nitrogen and air atmospheres),
Kaburaki et al. (2006) were unable to confirm the presence of the aza-arenes (dibenz[a,h]acridine, dibenz[a,j]acridine) reported by
Van Duuren et al. in 1960 for nicotine pyrolysis (750°C, nitrogen atmosphere). Because there is sufficient overlap between the
pyrolysis conditions used by Kaburaki et al. and by Van Duuren et al., the profound difference in composition results (presence vs.
absence of the aza-arenes in question) cannot be explained by minor differences in pyrolysis conditions.
In addition, the tumorigenicity of 7H-dibenzo[c,g]carbazole was compared with that of B[a]P:
Weekly administration of 3 mg of 7H-dibenzo[c,g]carbazole for 15 weeks resulted in 13% more animals dying with
respiratory tract cancer than died with same dose level of B[a]P. With lower total dose levels (15 mg) of B[a]P only, 30%
of the animals developed respiratory tract tumors vs. 89% of the animals treated with the same dose of 7H-dibenzo[c,g]
carbazole. The tumors in the 7H-dibenzo[c,g]carbazole group appeared earlier than those in the B[a]P-treated group.
1972 Schmeltz et al. (3499) studied the pyrolysis (800-860 °C, nitrogen atmosphere) of nitrogen-containing materials (tobacco, tobacco
pigment, nicotine) and reported:
We could not detect benzo(a)pyrene in nicotine pyrolyzates, nor could we confirm the presence of the physiologically active
dibenzacridines and dibenzcarbazole reported in tobacco smoke and in nicotine and pyridine pyrolyzates by Van Duuren…
Here again, the slight difference in the temperature (750°C vs. 800–860°C) of the inert atmosphere (nitrogen) pyrolysis cannot
explain the profound difference in the compositional findings (presence vs. absence of the aza-arenes in question).
1973 The IARC Working Group reported that skin painting with dibenz[a,h]acridine induced skin tumors in mice (1864a).
Subcutaneous injection into mice produced sarcoma at the injection site plus an increased incidence of pulmonary adenomas. In
1973, dibenz[a,h]acridine had not been tested by other administration routes or in other species. The IARC noted that no human
data were available, but it did note:
Coal tar and other materials which are known to be carcinogenic to man may contain [dibenz[a,h]acridine].
The IARC concluded that dibenz[a,j]acridine induced skin tumors in mice following topical application. At the highest dose tested
by subcutaneous injection, it induced sarcomas at the injection site and an increased incidence of pulmonary adenomas. Negative
results were obtained by the oral route in the mouse, but the test was considered inadequate because of the small number of
animals tested. Dibenz[a,j]acridine had not been tested in other species at that time. No human data were available, but the IARC
considered that some materials known to be carcinogenic to man may contain dibenz[a,j]acridine.
1973 The IARC Working Group considered 7H-dibenzo[c,g]carbazole to be:
Carcinogenic in the mouse, rat, hamster, and possibly in the dog. It has both a local and a systemic carcinogenic effect.
Following oral administration in the mouse, forestomach tumors and hepatomas occurred; intratracheal administration to
hamsters produced tumors of the respiratory tract. In comparison with benzo[a]pyrene, [7H-dibenzo[c,g]carbazole]
appears to be a stronger respiratory tract carcinogen for the hamster.

(Continued)

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 816 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.E-2 (Continued)

Chronology of Selected Aza-Arenes: Dibenz[a,h]acridine, Dibenz[a,j]acridine, 7H-Dibenzo[c,g]carbazole, Quinoline
Year Event

Though 7H-dibenzo[c,g]carbazole had been reported as a component of CSC, no case reports or epidemiological data concerning
human exposure were available.
1976 In his review on polycyclic tumorigens, Dipple (983) labeled dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]
carbazole as “carcinogenic heterocyclic compounds” with “slight” activity. However, in a later review in 1984, Dipple et al. (984)
revised the assessment of 7H-dibenzo[c,g]carbazole, listing it as a highly potent tumorigen.
1976 Wynder and Hoffmann (4347) listed dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole as:
Tumorigenic agents identified in the particulate phase of tobacco smoke, each possessing low biological activity and only
traces detected in the smoke of 100 cigarettes. Dibenz[a,j]acridine was detected in amounts of 1.0 microgram per 100
cigarettes [10 ng/cig].
They categorized dibenz[a,j]acridine and dibenz[a,h]acridine as “known animal carcinogens,” but noted that these aza-heterocyclic
compounds are “minor carcinogens” in tobacco smoke.
1976 Hoffmann et al. (1780) reported that the basic fraction of CSC which contains dibenz[a,h]acridine and dibenz[a,j]acridine was not
tumorigenic to mouse skin, cf. Wynder and Wright (1957), Wynder and Hoffmann (4319, 4332).
1977 Schmeltz and Hoffmann (3491), in their review of N-containing compounds in tobacco and tobacco smoke discussed the benzacridines:
Nicotine has…been shown to produce on pyrolysis the animal carcinogens, dibenz[a,h]acridine…and dibenz[a,j]acridine…both
of which are present in tobacco smoke…Acridans have been reported in smoke… Subsequent dehydrogenation of the acridans
could lead to acridines. The only examples of the latter reported in smoke are two benzacridines [dibenz[a,h]acridine, dibenz[a,j]
acridine]; these have been shown to form during pyrolysis from nicotine… A dibenzocarbazole [7H-dibenzo[c,g]carbazole]…has
also been reported in tobacco smoke… The last three fused ring compounds cited are tumorigenic in the experimental animal.
Schmeltz and Hoffmann listed quinoline as both a tobacco and a tobacco smoke component as well as an “animal carcinogen (rat
liver).”
1979 In a brief section of the chapter on cigarette smoke composition, the aza-arenes (including dibenz[a,h]acridine, dibenz[a,j]acridine,
and 7H-dibenzo[c,g]carbazole), their tumorigenicity, and their mutagenicity were discussed in the 1979 Surgeon General’s report
(4005). The report noted:
Mutagens thus far identified in cigarette smoke are: Quinoline (MS 1.7 mg/cigarette; SS 18 mg/cigarette), all seven isomeric
methylquinolines MS (0.7 mg/cigarette; SS 8 mg/cigarette)… Quinoline induces hepatomas when fed in high doses to rats…
1979 Rinkus and Legator (3157) reported dibenz[a,h]acridine and dibenz[a,j]acridine to be mutagenic substances in the Ames
Salmonella typhimurium test.
1979 Schmeltz et al. (3512) studied the fate of radiolabeled nicotine during pyrolysis and during actual smoking in a burning cigarette
spiked with radiolabeled nicotine. The radiolabeled nicotine was pyrolyzed (nitrogen atmosphere) from a silica gel matrix at several
temperatures (600°C, 750°C, and 900°C) and from a tobacco matrix at 600 °C. None of three aza-arenes – dibenz[a,h]acridine,
dibenz[a,j]acridine, 7H-dibenzo[c,g]carbazole – identified by Van Duuren et al. (4027) in CSC was found in the smoke study by
Schmeltz et al. Neither of the two dibenzacridines reported by Van Duuren et al. in a nicotine pyrolysate was found in the several
nicotine pyrolysates generated by Schmeltz et al. (3512).
The differences concerning the presence or absence of these aza-arenes in several such studies involving CSCs and/or nicotine
pyrolysates were summarized by Rodgman (3255, 3257).
1982 In the 1982 Surgeon General’s report (4010), the aza-arenes dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]
carbazole were described as “tumor-initiating agents in the particulate phase of tobacco smoke” and their MSS levels as 0.1, 3 to
10, and 0.7 ng/cig, respectively. It was noted, from data provided by Hoffmann et al. (1781, 1782), that dibenz[a,j]acridine
possessed much higher tumorigenic activity than dibenz[a,h]acridine and 7H-dibenzo[c,g]carbazole, cf. Dipple et al. (983).
1982 Adams et al. (35) reported the identification and quantitation of quinoline (0.2 to 1.3 mg/cig), isoquinoline (0.1 to 0.9 mg/cig), and
the seven isomeric methylquinolines (0.5 to 2.5 mg/cig) in the MSS of several commercial cigarettes. They noted:
Quinoline is the most abundant aza-arene in [mainstream] cigarette smoke.
1984 In their review of polycyclic aromatic tumorigens, Dipple et al. (983) classified dibenz[a,h]acridine and dibenz[a,j]acridine as
possessing only Slight tumorigenicity. They classified 7H-dibenzo[c,g]carbazole as possessing High tumorigenicity (same
category as 1,2-dihydrobenz[j]aceanthrylene (cholanthrene), 3-methyl-1,2-dihydrobenz[j]aceanthrylene (3-methylcholanthrene),
7,12-dimethylbenz[a]anthracene, and B[a]P).

1984 In their review of tumorigenic aromatic amines in which fused ring polycyclic amines are discussed, Garner et al. (1275a) neither
mention nor list quinoline as a tumorigenic compound

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 Nitrogen Heterocyclic Components 817

Table XVII.E-2 (Continued)

Chronology of Selected Aza-Arenes: Dibenz[a,h]acridine, Dibenz[a,j]acridine, 7H-Dibenzo[c,g]carbazole, Quinoline
Year Event

1985/86 The IARC (1870) in its 1986 report on its 1985 deliberations found sufficient evidence to classify dibenz[a,h]acridine, dibenz[a,j]
acridine, and 7H-dibenzo[c,g]carbazole as carcinogenic in laboratory animals. The IARC noted that “nicotine is a specific
precursor for the two acridines”, totaling ignoring contradictory evidence from several groups of investigators who were unable to
confirm the presence of these dibenzacridines in nicotine pyrolysates. The IARC listed quinoline as a smoke component but did
not include it in its tabulation of compounds vs. “the degree of evidence [for carcinogenicity] in animals (and humans). ”
1986 Hoffmann and Wynder (1808) published a list of components classified as toxicants and/or tumorigens in tobacco and smoke.
Much of the information in their report on quinoline, dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole had
been provided to the IARC for inclusion in its 1986 article (1870).
1990 Hoffmann and Hecht (1727), in their compilation of 43 “tumorigenic components of tobacco and tobacco smoke”, listed
dibenz[a,h]acridine, dibenz[a,j]acridine, 7H-dibenzo[c,g]carbazole, and quinoline as tumorigenic aza-arenes in CSC. This list was
subsequently used by the EPA (1990) in its attempt to have environmental tobacco smoke classified as a Group A (human)
carcinogen. Hoffmann and Hecht paid little attention to the discrepancies between the 1960 report of Van Duuren et al. on the
presence of these aza-arenes in CSC and nicotine pyrolysates and later reports from other investigators who failed to confirm the
Van Duuren findings on these compounds either in CSC or nicotine pyrolysates [see Table XVII.E-1)].
In their tabulation, Hoffmann and Hecht listed quinoline with no comment as to its carcinogenicity as reported in the “IARC
evaluation of evidence of carcinogenicity in laboratory animals [and] in humans.” In their text, they noted:
Quinoline, a liver carcinogen in rats…and in newborn mice…, is present in cigarette smoke at a concentration of 1-2 mg/
cigarette [Dong et al. (1042)].
1991 In a memorandum to the EPA, Rodgman (3255) summarized the inconsistencies between the 1960 findings reported by Van
Duuren et al. on dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole in nicotine pyrolysates and/or mainstream
CSC vs. the findings in the comparable 1963 study of Candeli et al. [reported by Wynder and Hoffmann (4319, 4332)], the 1970
study of Kaburaki et al. (2006), the 1972 and 1979 studies of Schmeltz et al .(3499, 3512), and the 1986 and 1987 reports by
Grimmer et al. (1409). The expanded summary is shown in Table XVII.E-1. Summaries of the studies of benzacridines in cigarette
smoke by Kamata et al. (2021) and Sasaki and Moldoveanu (3414) were added.
A possible explanation of the differences in the results concerning the presence or absence of these three aza-arenes in mainstream
CSC may be the differences between cigarettes fabricated in 1960 and those fabricated more recently after the 1970s. The pre-1960
cigarettes were substantially higher in nicotine. However, there does not appear to be a logical explanation for the difference in the
results (presence vs. absence) of these three compounds in nicotine pyrolysates prepared in 1960, 1963, 1970, 1972, and 1979.
Post-1960 advances in analytical technology should have improved the ability to isolate/identify low levels of these three aza-arenes.
1994 Osha (2825), in its goals for clean air legislation, presented its own list of 43 tobacco smoke components tumorigenic in animals
or man. Its list differed slightly from that of Hoffmann and Hecht (1727). OSHA included the three aza-arenes reported by Van
Duuren et al. (4027) but omitted quinoline.
1994 In a response to the OSHA (2825) publication, Rodgman (3257) presented the information in Table XVII.E-1 as reasons why the
benzacridines and the benzocarbazole should be removed from the list. Valid scientific reasons for deleting other listed
components were also presented.
1997 Hoffmann and Hoffmann (1740) revised the 1990 Hoffmann-Hecht list of “43 tumorigenic components” of tobacco smoke (1727),
expanding the list to 60 components by deleting chrysene and crotonaldehyde in agreement with the OSHA (2825) list and by adding
19 other components, including the 8 N-heterocyclic amines known as the “cooked food” mutagens. Still retained in the Hoffmann-
Hoffmann 1997 list were the aza-arenes quinoline, dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole.
1998 In a letter to the Editors of Beiträge Tabakforschung zur International, Hoffmann and Hoffmann (1741) submitted a list of
biologically active components of cigarette MSS, including the four aza-arenes quinoline, dibenz[a,h]acridine, dibenz[a,j]acridine,
and 7H-dibenzo[c,g]carbazole.
2000 Fowles and Bates (1217) included dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole in their list of tobacco
and tobacco smoke toxicants.
2001 Hoffmann and Hoffmann (1743) in their list of tobacco and tobacco smoke toxicants again included dibenz[a,h]acridine, dibenz[a,j]
acridine, and 7H-dibenzo[c,g]carbazole despite the numerous reports of research that failed to confirm the 1960 Van Duuren et al.
reported finding.
Hoffmann et al. (1744) again included dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]carbazole in their list of
tobacco and tobacco smoke toxicants.
2003 Rodgman (3265) assessed the various published reports in which numerous tobacco and tobacco smoke components were
classified as toxicants (1217, 1727, 1740, 1741, 1743, 1744, 1773, 1808, 2825). The numerous deficiencies and errors in the
reports were cataloged.

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 818 The Chemical Components of Tobacco and Tobacco Smoke
discussed but not the presence or biological properties of any
of the “cooked food” mutagens identified in tobacco smoke.
In the 1982 report of the Surgeon General [see Table 10, p. 214
in (4010)], 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-
9H-pyrido[3,4-b]indole (harman) were classified as “toxic
and tumorigenic agents of cigarette smoke” in amounts of 3.2
to 8.1 mg/cigarette and 1.1 to 3.1 mg/cigarette, respectively,
in mainstream CSC. None of the other highly mutagenic
N-heterocyclic amine mutagens present in tobacco smoke
was discussed.
Table XVII.E-2 lists, with appropriate citations, the chro-
nology of the studies pertinent to the aza-arenes and other
polycyclic nitrogen compounds in tobacco smoke. A similar
chronology of studies pertinent to the N-heterocyclic amines,
the “cooked food” mutagens, is presented in a subsequent
section.
XVII.E.1 Alternate Exposures to Aza-Arenes
In the several lists of tumorigenic components in tobacco
and/or tobacco smoke, three N-heterocyclic compounds
(dibenz[a,h]acridine, dibenz[a,j]acridine 7H-dibenzo[c,g]car-
bazole) appear on the list of forty-three by Hoffmann and
Hecht (1727) and OSHA (2825) and the list of sixty by
Hoffmann and Hoffmann (1740). Quinoline was on several
lists but was omitted from the OSHA list (Table XVII.E-3).
Table XVII.E-4 lists the many tobacco smoke components
similar in structure to those listed in Table XVII.E-3.
Even though, as indicated in Table XVII.E-1 and the
text accompanying it, the presence of the three pentacyclic
N-heterocyclic compounds in tobacco smoke is equivocal,
the alternate exposure to them and similar components is dis-
cussed below.
In their 1956 review of angular benzacridines and diben-
zacridines and their tumorigenicity, Lacassagne et al. (2247a)
Table XVII.E-3
Summary of Lists of Tumorigenic Aza-Arenes in Tobacco Smoke
Component Ho & Hea OSHAb
Quinoline × …
Dibenz[a,h]acridine × ×
Dibenz[a,j]acridine × ×
7H-Dibenzo[c,g] × ×
carbazole
a Ho & He = Hoffmann and Hecht (1727)
b OSHA = OSHA (2825)
c Ho & Ho = Hoffmann and Hoffmann (1740)
d See IARC (1870)
© 2009 by Taylor & Francis Group, LLC
78836_C017.indd 818
made the following interesting observation, pertinent to the
alleged “carcinogenicity” of benzene, frequently used as a
solvent in tumorigenicity studies in the 1930s, 1940s, and
1950s: “These molecules [the angular benzacridines] are
very soluble in benzene and acetone (two solvents currently
used for the investigations of carcinogenic activity).”
In addition to the exposure to acridines and benzacridines
in tobacco smoke, other exposures to various acridines and
benzacridines have been cataloged in the scientific literature.
Many of the sources (Table XVII.E-5) comprise environ-
mental pollutants.
Unlike the PAHs and the N-nitrosamines, nontobacco
smoke exposure to the acridines/benzacridines does not
include foods. However, exposures other than tobacco smoke
to polycyclic nitrogen compounds include exposures to the
N-heterocyclic amines, the so-called “cooked food” muta-
gens, in a variety of foods.
Table XVII.E-6 lists, with appropriate citations, the aza-
arenes reported in tobacco and tobacco smoke.
Table XVII.E-7 summarizes the variation in the struc-
tures of the aza-arene compounds identified in tobacco and/
or tobacco smoke. Of particular interest with regard to the
294 aza-arenes cataloged in Table XVII.E-6 is that only
twenty-three of the 294 have been identified as tobacco
components. Of the twenty-three, just fifteen have been
identified in both tobacco and smoke. The number of aza-
arenes identified in smoke is 286. Those isolated from or
identified in tobacco in greater than trace amounts include
1H-indole, 2,3-dihydro-1H-indole, 9H-pyrido[3,4-b]indole
(norharman), 1-methyl-9H-pyrido[3,4-b]indole (harman),
1H-purine, and quinoline.
Because of their classification as significant tumorigens
in tobacco smoke (1740, 1741, 1743, 1744) and their inordi-
nately high mutagenicity in the Ames test with Salmonella
typhimurium (2327c, 3828c), the amino derivatives of several
IARC Evaluationd of Evidence
re Tumorigenicity in
MS Level Laboratory
Ho & Hoc Wt/cigc Animals Humans
× 1–2 mg … …
× 0.1 ng sufficient …
× 3–10 ng sufficient …
× 0.7 ng sufficient …
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 Nitrogen Heterocyclic Components 819

Table XVII.E-4
Tobacco Smoke Components Related to Aza-Arenes in Tumorigen Listsa
Quinolines [35]b Acridines [28]b Carbazoles [20]b

Quinoline Acridine 9H-Carbazole

Quinoline, 5-amino-
Quinoline, butyl-
Quinoline, dihydro-
Quinoline, dihydroethyl-
(3 isomers)
Quinoline, dihydromethyl-
(3 isomers)
Quinoline, dimethyl-(5 isomers)
Quinoline, ethyl-(2 isomers)
Quinoline, methyl-(6 isomers)
Quinoline, (1-methylethyl)-
Acridine, 9,10-dihydro-
Acridine, 9,10-dihydro-
(4 homologs)
Acridine, ethyl-
Acridine, methyl-
Acridine, propyl-
Benz[a]acridine
Benz[a]acridine, dimethyl-
9H-Carbazole, 2-amino-
9H-Carbazole, dimethyl-
(4 isomers)
9H-Carbazole, 9-ethyl-
9H-Carbazole, methyl-
(5 isomers)
9H-Carbazole, tetramethyl-
9H-Carbazole, trimethyl-
11H-Benzo[a]carbazole

Quinoline, methyltetrahydro- Benz[c]acridine 5H-Benzo[b]carbazole

(2 isomers)
Quinoline, propyl- Benz[c]acridine, dimethyl-
(5 isomers)
Quinoline, tetrahydro-(2 isomers) Benz[c]acridine, methyl- 7H-Benzo[c]carbazole
(5 isomers)
Quinoline, tetramethyl- Benz[c]acridine, trimethyl-
(2 isomers)
Quinoline, trimethyl- 1H-Dibenzo[a,c]carbazole
Dibenz[a,h]acridine
Quinolinecarbonitrile (2 isomers) 13H-Dibenzo[a,i]carbazole
Dibenz[a,i]acridine
8-Quinolinol 7H-Dibenzo[c,g]carbazole
8-Quinolinol, 7-methyl- Dibenz[a,j]acridine
Dibenz[c,h]acridine
a Omitted from the list are the N-heterocyclic amines discussed in a subsequent chapter.
b Number in square bracket = number of reported components

aza-arenes are discussed in detail in Section XVII.F devoted

to the N-heterocylic amines identified in tobacco smoke.
However, in addition to the N-heterocylic amines, several aza-
arene-related fused N-containing ring compounds with two or
more ring nitrogens plus various functional groups have been
identified in tobacco and/or tobacco smoke. Classic examples
Table XVII.E-5 of such compounds in tobacco include adenosine, 5’-adenylic
Aza-Arene Sources Other than Tobacco Smoke acid, and many purines. Table XVII.E-8 lists many such compo-
Acridine/Benzacridine Source Reference nents identified in tobacco and/or tobacco smoke. Examination
of the structures of the various derivatives indicates the inclu-
Automobile exhaust 3419b, 4247a sion of a variety of functional groups, for example, amino,
Coal-fired residential furnace emission 1407b carboxylic acid, carboxamide, hydroxyl, and various carbohy-
Coal distillate 1334c, 2210a
drates. It should be noted that Table XVII.E-8 does not include
Coal tar 2261a, 2534a
the nine N-heterocyclic amines because they are described and
Crude oil 1407a, 3519c
High boiling petroleum distillate 2519a
discussed in detail in Section XVII.F. In contrast to the aza-
Industrial stack effluent 3419a arenes which occur predominately in tobacco smoke, fifty-five
Urban suspended particulate matter 35, 636a, 1040a, 3419c of the seventy-six components with functional groups listed in
Cigarette smoke condensate 1884, 3491 Table XVII.E-8 were identified in tobacco and only twenty-
four were identified in tobacco smoke.

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 820 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.E-6
Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke
Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

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 Nitrogen Heterocyclic Components 821

Table XVII.E-6 (Continued)

Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 822 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.E-6 (Continued)

Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Nitrogen Heterocyclic Components 823

Table XVII.E-6 (Continued)

Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 824 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.E-6 (Continued)

Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Nitrogen Heterocyclic Components 825

Table XVII.E-6 (Continued)

Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 826 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.E-6 (Continued)

Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Nitrogen Heterocyclic Components 827

Table XVII.E-6 (Continued)

Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 828 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.E-6 (Continued)

Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Nitrogen Heterocyclic Components 829

Table XVII.E-6 (Continued)

Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 830 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.E-6 (Continued)

Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Nitrogen Heterocyclic Components 831

Table XVII.E-6 (Continued)

Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 832 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.E-6 (Continued)

Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Nitrogen Heterocyclic Components 833

Table XVII.E-6 (Continued)

Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 834 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.E-7
Structures of Aza-Arenes in Tobacco and Tobacco Smoke
Identified in Smoke Present in Tobacco

No. of Nitrogens No. of Nitrogens

Ring Type 1 2 3 Total 1 2 4 Total

Bicyclic 107 63 3 173 14 4 1 19

Tricyclic 43 28 0 71 2 2 0 4
Tetracyclic 30 0 0 30 0 0 0 0
Pentacyclic 10 0 0 10 0 0 0 0
Hexacyclic 0 1 0 1 0 0 0 0
Total 190 92 3 285 16 6 1 23

XVII.F N-Heterocyclic Amines 9H-pyrido[3,4-b]indole (harman) {II} and 9H-pyrido[3,4-b]

Although not originally classified at the time as “cooked
food” mutagens, several amino acid-derived N-heterocyclic
compounds were identified in cigarette smoke condensate
(CSC) in the early 1960s: 5H,10H-Dipyrrolo[1,2-a:1’,2’-d]
pyrazine-5,10-dione (pyrocoll) {I} by Mold et al. (2592) and
9H-pyrido[3,4-b]indole (norharman) {II} and 1-methyl-9-
H-pyrido[3,4-b ]indole (harman) {III} by Poindexter and
Carpenter (2972) (Figure XVII.F-1).
Proline is the precursor in tobacco of 5H,10H-dipyrrolo[1,2-
a:1’,2’-d]pyrazine-5,10-dione (pyrocoll) {I} in tobacco smoke.
Tryptophan is the major precursor in tobacco of 1-methyl-
indole (norharman) {III} as well as indole and its alkylated
homologs in tobacco smoke.
In the late 1970s, Japanese investigators, in their detailed
studies of components of various “cooked foods,” isolated
and identified the first of a series of N-heterocyclic amines
as pyrolysis products of several amino acids. Sugimura
et al. (3829) reported the isolation and identification of
3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (designated
as Trp-P-1) {IV} and 3-amino-1-methyl-5H-pyrido[4,3-b]
indole (Trp-P-2) {V} (Figure XVII.F-2) from tryptophan
pyrolysates.

N
N N
N N N
H H
CH3
O
I II III
5H,10H-Dipyrrolo[1,2-a:1',2'- 9H-Pyrido[3,4-b] 1-Methyl-9H-pyrido[3,4-b]indole
d]pyrazine-5,10-dione indole (harman)
(pyrocoll) (norharman)

Figure XVII.F-1  Pyrocoll, norharman, and harman.

R1 NH2 R1 NH2
N
N N
N
NH2 N R1
NH2 N N N
N R1 H
H N R2
R2
IV R1 = R2 = CH3 VI R1 = CH3 VIII R1 = H X R1 = CH3 R2 = H
V R1 = CH3 R2 = H VII R1 = H IX R1 = CH3 XI R1 = R2 = CH3

Figure XVII.F-2  N-Heterocyclic amines, the “cooked food” mutagens.

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 Nitrogen Heterocyclic Components 835

Table XVII.E-8
Derivatives of Fused N-Containing-Ring Compounds with Two or More Nitrogens in the Rings

(Continued )

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 836 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.E-8 (Continued)

Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Nitrogen Heterocyclic Components 837

Table XVII.E-8 (Continued)

Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 838 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.E-8 (Continued)

Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Nitrogen Heterocyclic Components 839

Table XVII.E-8 (Continued)

Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 840 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.E-8 (Continued)

Aza-Arenes and Other Polycyclic Nitrogen Compounds in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

Yamamoto et al. (4365a) reported the isolation and iden-
tification of the mutagenic N-heterocyclic amines 2-amino-
6-methyldipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1) {VI} and
2-aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2) {VII} from
glutamic acid pyrolysates. Yoshida and Matsumoto (4388)
and Matsumoto et al. (2492) reported the identification of
2-amino-9H-pyrido[2,3-b]indole (AaC) {VIII} and 2-ami-
no-3-methyl-9H-pyrido[2,3-b]indole (MeAaC) {XIII-IX} in
CSC (Figure XVII.F-2).
A unique feature of several of compounds {IV–VII} was
their inordinately high mutagenicity in the Ames system
(Salmonella typhimurium). Mutagenic activities on a rever-
tant per microgram basis as determined in the Ames test
with Salmonella typhimurium strains TA 98 and TA 100 for
several of these compounds are shown in Table XVII.F-1
[Sugimura (3828c), Lee et al. (2327c)]. To put in perspective
the extremely high values for the mutagenic activities listed in
Table XVII.F-1, it should be noted that the mutagenic activity

Table XVII.F-1
Mutagenic Activities of N-Heterocyclic Amines Towards Salmonella typhimuriuma
Mutagenic Activity, Revertant/μg
Identified in
Compound Abbreviation Tobacco Smoke TA 98b TA 100b TA 98c TA 100c

Dipyrido[1,2-a:3’,2’-d] Glu-P-1 yes 49000 3200 73000 4000

imidazole, 2-amino-6-methyl-
Dipyrido[1,2-a:3’,2’-d] Glu-P-2 yes 1900 1200 600 400
imidazole, 2-amino-
5H-Pyrido[4,3-b]indole, Trp-P-1 yes 39000 1700 20000 500
3-amino-1,4-dimethyl-
5H-Pyrido[4,3-b]indole, Trp-P-2 yes 104200 1800 103000 2000
3-amino-1-methyl-
9H-Pyrido[2,3-b]indole, AaC yes 300 20 — —
2-amino-
9H-Pyrido[2,3-b]indole, MeAaC yes 200 120 — —
2-amino-3-methyl-
Imidazo[4,5-f]quinoline, IQ yes 433000 7000 222000 11000
2-amino-3-methyl-
Imidazo[4,5-f]quinoline,2- MeIQ yes 661000 30000 1327000 70000
amino-3,4-dimethyl-
9H-Pyrido[3,4-b]indole norharman yes — — — —
9H-Pyrido[3,4-b]indole, harman yes — — — —
1-methyl-
Cigarette smoke condensate CSC — — — 2 1
Benzo[a]pyrene B[a]P yes — — 200 —
a Tests with Salmonella typhimurium involved use of S-9 mix.
b Ames test data with Salmonella typhimurium reported by Sugimura (3828c).
c Ames test data with Salmonella typhimurium reported by Lee et al. (2327c).

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 Nitrogen Heterocyclic Components 841
of benzo[a]pyrene (B[a]P) (strain TA 98) when tested under the
same conditions is about 200 revertant/mg of B[a]P. In separate
studies, Levitt et al. (2355a) and Nagao et al. (2667b) demon-
strated the mutagenicity of the previously identified tobacco
smoke components 9H-pyrido[3,4-b]indole (norharman) {II}
and 1-methyl-9H-pyrido[3,4-b]indole (harman) {III}.
Heckman and Best (1587) reported the identification of
nearly 270 previously unidentified and confirmation of over
150 previously identified N-containing components in CSC.
These included several components structurally similar to some
of the N-heterocyclic amines 9H-pyrido[2,3-b]indole, 2-methyl-
9H-pyrido[2,3-b]indole, 2-(2-methylpropyl)-9H-pyrido[2,3-b]
indole, 2-pentyl-9H-pyrido[2,3-b]indole, 1-butyl-9H-pyrido
[3,4-b]indole, 1-propenyl-9H-pyrido[3,4-b]indole, and a par-
tially characterized norharman.
In addition to their mutagenicity in the Ames test (Salmonella
typhimurium), several of the mutagenic N-heterocyclic
amines were subsequently reported to be tumorigenic, par-
ticularly in feeding experiments, to several laboratory animal
species. The tumorigenicity in mice of 3-amino-1,4-dim-
ethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-
5H-pyrido[4,3-b]indole (Trp-P-2) was reported by Matsukura
et al. (2491a) and in rats by Hosaka et al. (1835a). Takayama et
al. (3862d) demonstrated the tumorigenicity in rats of 3-amino-
1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1
-methyl-5H-pyrido[4,3-b]indole (Trp-P-2).
Ohgaki et al. (2849b) described the tumorigenicity in mice
and Takayama et al. (3862b) described the tumorigenicity in rats
of 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1)
and 2-aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2). 2-Ami-
no-3-methylimidazo[4,5-f]quinoline (IQ) {X} was reported to
be tumorigenic in rats by Takayama et al. (3862c) and Tanaka
et al. (3865c) and in mice by Ohgaki et al. (2849, 2849a).
Ohgaki et al. (2849, 2849a) also reported the tumorigenicity
in mice of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and
COOH
H2N
NH2
COOH
HOOC NH2
COOH
XII
HOOC
HOOC NH2
COOH
HOOC NH2
Figure XVII.F-3  Theoretical conversion of glutamic acid {XII} to aminobutanoic acids {XIII, XIV} and aminopyridines {XV–XVII}.
© 2009 by Taylor & Francis Group, LLC
78836_C017.indd 841
2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), both
compounds being components in broiled fish, fried beef, and
beef extract. As indicated in Table XVII.F-1, both 2-amino-3
-methylimidazo[4,5-f]quinoline (IQ) (4367, 4368) and 2-ami-
no-3,4-dimethyl-imidazo[4,5-f]quinoline (MeIQ) (2039) have
been reported in tobacco smoke.
Rodgman (3253a) discussed the theoretical relationships
(Figures XVII.F-3 and XVII.F-4) among glutamic acid {XII},
its possible degradation products 4-aminobutanoic {XIII}
and 2-aminobutanoic acid {XIV}, 2-amino-3-methylpyridine
{XV} and 2-amino-6-methylpyridine {XVI}, 2-aminopyridine
{XVII} and the possible reactions between these substituted
aminopyridines to form 2-amino-6-methyldipyrido[1,2-
a:3’,2’-d]imidazole (Glu-P-1) {VI}, 2-aminodipyrido[1,2-
a:3’,2’-d]imidazole (Glu-P-2) {VII}, and two similar products,
2-amino-9-methyldipyrido[1,2-a:3’,2’-d]imidazole {XVII}
and 2-amino-3,6-dimethyldipyrido[1,2-a:3’,2’-d]imidazole
{XIX}, not yet identified in tobacco smoke or cooked foods.
The aminobutanoic acids {XIII and XIV} and the aminopyri-
dines {XV-XVII} noted in Figures XVII.F-3 and XVII.F-4
have been reported as tobacco smoke components.
Rodgman also discussed the already identified and other
possible theoretical relationships (Figure XVII.F-5) between
tryptophan {XX} and 9H-pyrido[3,4-b]indole (norharman)
{II its methyl homolog 1-methyl-9H-pyrido[3,4-b]indole
(harman) {III} and other substituted norharmans {VI, R =
C2H5, CH3CH=CH, and n-C4H9}, the tryptophan pyroly-
sis products 3-amino-1,4-dimethyl-5H-pyrido-[4,3-b]indole
(Trp-P-1) {IV} and 3-amino-1-methyl-5H-pyrido[4,3-b]
indole (Trp-P-2) {V}; the alkyl- and dialkyl-indoles; indole-
3-acetonitrile ; the 2-amino-9H-pyrido[2,3-b]indoles [AaC
{VIII} and MeAaC {IX}] plus other pyrido[2,3-a]indoles
{R = H, CH3, C2H5, (CH3)2CHCH2, or n-C5H11} (see Table
XVII.F-6). All of the compounds noted in (Figure XVII.F-4)
have been reported as tobacco smoke components.
COOH
COOH + NH2
XIII XIV
N
NH2
CH3 XV
N
CH3
NH2
N XVII
NH2
XVI
11/24/08 12:29:16 PM
 842 The Chemical Components of Tobacco and Tobacco Smoke

NH2
N
N NH2
N
N
+
N
NH2
CH3
CH3
XV XVII VI

NH2
N
N NH2
N
N
+
N
NH2
XVII XVII VII

CH3
CH3 NH2
N
N NH2
N
N
+
N
NH2
XVI XVII XVIII

NH2
N
N NH2
N
N
+ CH3
N
NH2 CH3
CH3
CH3
XV XV XIX

Figure XVII.F-4  Theoretical routes for conversion of glutamic acid-derived aminopyridines to possible tobacco smoke components.

In the 1979 report of the U.S. Surgeon General (4005),
the aza-arenes dibenz[a,h]acridine, dibenz[a,j]acridine, 7H-
dibenzo[c,g]carbazole, quinoline, and alkylated quinolines
in CSC were discussed but not the presence or biological
properties of the N-heterocyclic amines identified in tobacco
smoke. However, in the 1982 report of the Surgeon General
(4010), 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9-
H-pyrido[3,4-b]indole (harman) were classified as “toxic and
tumorigenic agents of cigarette smoke” in amounts of 3.2 to
8.1 mg/cigarette and 1.1 to 3.1 mg/cigarette, respectively, in
mainstream CSC. None of the N-heterocyclic amines present
in tobacco smoke was discussed.
Snook and Chortyk (3739, 3740) reported the cigarette
mainstream smoke (MSS) yield of 9H-pyrido[3,4-b]indole
(norharman) to be 1.2 to 13.4 mg/cigarette; that for 1-methyl-
9H-pyrido[3,4-b]indole (harman) to be 0.3 to 3.8 mg/ciga-
rette. They found a linear relationship between the yield of
MSS “tar” and the yields of 9H-pyrido[3,4-b ]indole (norhar-
man) and 1-methyl-9H-pyrido[3,4-b]indole (harman). In con-
trast to the 1962 findings of Poindexter and Carpenter (2972),
Snook and Chortyk reported yields of these two compounds
were not influenced by the tobacco type.
In his review of the studies of the mutagenicity of CSC,
DeMarini (933) discussed the significance of the findings
of Yoshida and Matsumoto (4388) and Matsumoto et al.
(2492) on the mutagenicity of 2-amino-9H-pyrido[2,3-b]
indole (AaC) (80 ng/cigarette) and 2-amino-3-methyl-9H-
pyrido[2,3-b]indole (MeAaC) (7 ng/cigarette).
None of the authors contributing to the American Chemical
Society’s 1984 monograph [Searle (3568)] on chemical car-
cinogens mentioned the N-heterocyclic amines as mutagens
and/or tumorigens.
Yamashita et al. (4367, 4368) identified and quantitated
the following N-heterocyclic amines in mainstream CSC: 2-
amino-3-methylimidazo[4,5-f]quinoline (IQ) (0.3 ng/ciga-
rette), 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1)
(0.3 ng/cigarette), 3-amino-1-methyl-5H-pyrido[4,3-b]indole
(Trp-P-2) (0.2 ng/cigarette), 2-amino-9H-pyrido[2,3-b]indole
(AaC) (16.9 ng/cigarette), and 2-amino-3-methyl-9H-pyrido
[2,3-b]indole (MeAaC) (1.6 ng/cigarette).

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 Nitrogen Heterocyclic Components 843

R
R COOH

NH2 NH2 NH2

N
N N N
H H H
VIII R = H IX R = CH3 XX R2
R-CHO
COOH CN

R NH
N N N
N H
H H
R

R1

NH
N R2
N H
H
R

NH
N
H
R

Figure XVII.F-5  Possible tryptophan-derived compounds in tobacco smoke.

In his 1986 review of the isolation and identification of the
N-heterocyclic amines, the high mutagenicity in the Ames
test (Salmonella typhimurium) of several of them, their tum-
origenicity in laboratory animals, and their various sources,
including CSC, Sugimura (3828c) wrote the following about
their importance as human carcinogens:
Taking various factors into consideration, it is probably
impractical and not realistic to make risk estimations from
the carcinogenicity data on rodents given a single carcino-
gen. However, for a simple extrapolation of animal data for
risk estimation, TD50 values, which are the doses needed to
develop cancers in 50% of animals fed on carcinogens [IQ,
Trp-P-1, Trp-P-2, Glu-P-1, Glu-P-2, AaC, and MeAaC] for
their life time, have been calculated based on mouse experi-
ments … If we assume the average TD50 value of heterocyclic
amines should be about 8 mg/kg/day, we can roughly estimate
the risk of these carcinogenic heterocyclic amines for human
beings. The intake of heterocyclic amines was calculated
from available data on their quantities in foods. Apparently
the human intake is about 0.0002% times the TD50 obtained
from animal data. This means that heterocyclic amines may
not be so serious for human cancer development.
Sugimura added:
On the other hand, it is also true that human beings are
being exposed to many heterocyclic amines and many other
carcinogens with tumor promoters and/or suppressing factors
for carcinogenesis. At this moment, it is honest to state that
no solid information on the estimation of risk of heterocyclic
amines has been obtained in any direction, either positive or
negative.
As in the case of the carcinogens whose activity can be
substantially reduced by anticarcinogens [see review by
Rodgman (3255)], Lee et al. (2327c) reported that main-
stream CSC significantly inhibited the mutagenicity of
several of these N-heterocyclic amines when tested in the
Ames assay with Salmonella typhimurium, strain TA 98
in the presence of the S-9 mix. The N-heterocyclic amines
tested included 2-amino-3-methylimidazo[4,5-f]quinoline
(IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ),
2-amino-6-methyl-dipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1),
2-aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2), 3-amino-
1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), and 3-amino-
1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2). The mutagenic
activities of these mutagens were suppressed as much as 80%
by addition of 50 to 100 mg of CSC per plate. Enzymatic
studies indicate that CSC is a potent inhibitor of cytochrome
P-450 dependent monooxygenase. Therefore, it appears that
CSC exerts its antimutagenicity by inhibiting the P-450 sys-
tem. Lee et al. (2327c) also reported that fractionation of CSC
yields fractions that show low mutagenicity themselves but
are significantly antimutagenic.
Although many of the N-heterocyclic amines are indeed
present in cigarette MSS, it should be remembered that the

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 844 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.F-2
Summary of Lists of Tumorigenic N-Heterocyclic Amines in Tobacco Smoke
Mainstream Smoke Yield (ng/cig) Reported by

2001
1986–1994 1997 1998 Hoffmann &
IARC (1870), Hoffmann & Wynder Hoffmann & Hoffmann & Hoffmann (1743) 2001 1997–2001
(1806), Hoffmann & Hecht (1727), Hoffmann Hoffmann Hoffmann et al. Fowles & Bates Smith et al.
Component Hoffmann et al. (1773), OSHA (2825) (1740) (1741)a (1744) (1217) (3711–3713)

AaC a NL b 25–260 25–260 25–260 NL b ND c–258

MeAaC NL 2–37 2–37 NL NL 1.6–37
Glu-P-1 NL 0.37–0.89 0.37–0.89 0.37–0.89 NL ND–0.89
Glu-P-2 NL 0.25–0.88 0.25–0.88 0.25–0.88 NL 0.25–0.88
PhIP NL 11–23 11–23 11–23 NL ND–22.9
IQ NL 0.26 0.3 0.3 NL 0.26–0.49
MeIQ NL NL NL NL NL 0.28–0.75
Trp-P-1 NL 0.29–0.48 0.3–0.5 0.3–0.5 NL 0.19–0.3
Trp-P-2 NL 0.82–1.1 0.8–1.1 0.8–1.1 NL ND–0.2
a AaC = 2-amino-9H-pyrido[2,3-b]indole; MeAaC = 2-amino-3-methyl-9H-pyrido[2,3-b]indole; Glu-P-1 = 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]
imidazole; Glu-P-2 = 2-aminodipyrido[1,2-a:3’,2’-d]imidazole; PhIP = 2-amino-1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridine; IQ = 2-amino-3-methyl-
3H-imidazo[4,5-f]quinoline; MeIQ = 2-amino-3,4-dimethyl-3H-imidazo[4,5-f]quinoline; Trp-P-1 = 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole; Trp-P-2 =
3-amino-1-methyl-5H-pyrido[4,3-b]indole.
b NL = not listed.

c ND = not detected

major part of the research on this class of compounds was
initiated and extended because of their presence in a great
number of cooked foodstuffs consumed by a great number
of people. When the N-heterocyclic amines were shown to
be tumorigenic in addition to being highly mutagenic and
subsequently identified in tobacco smoke, they were included
by Hoffmann and his colleagues in their numerous lists of
tobacco smoke tumorigens published in 1997 and later (1740,
1741, 1743, 1744). The N-heterocyclic amines had not been
included in their numerous lists published between 1986 and
1997 (1727, 1773, 1806) nor in similar lists published by IARC
(1870) and OSHA (2825). Table XVII.F-2 summarizes some
details of these N-heterocyclic amines in tobacco smoke.
Because of their concerns about the mutagenicity of
numerous commonly consumed heated foods, many of the
studies of the isolation, identification, and estimation of
N-heterocyclic amines in heated foodstuffs or heated food
components, particularly amine-containing components
such as amino acids, proteins, and peptides, were conducted
by Japanese investigators. This becomes obvious from exam-
ination of the authors and coauthors of the references listed
in Table XVII.F-3.
With the reporting of the Ames mutagenicity test with
Salmonella typhimurium in the mid-1970s and the dem-
onstration of its utility, the number of studies on potential
mutagenic systems and the mutagenicity-tumorigenicity rela-
tionship virtually exploded. By highly competent application
of up-to-date isolation and characterization techniques plus
utilization of the Ames test, Sugimura and his staff at the
Japanese National Cancer Research Institute contributed
significantly to our knowledge of the structures, properties,
and precursors in foods of the N-heterocyclic amines. While
the methodologies differed, the 1977 isolation and identifi-
cation of the N-heterocyclic amines (Trp-P-1, Trp-P-2) from
a tryptophan pyrolysate paralleled the historic 1932 isola-
tion and identification of polycyclic aromatic hydrocarbons
(PAHs) [B[a]P, benzo[e]pyrene (B[e]P), benz[a]anthracene
(B[a]A), perylene] from coal tar. In the 1930s, the Kennaway
group in the United Kingdom used ultraviolet spectropho-
tometry [Hieger (1631)] to monitor coal tar PAHs during their
concentration and purification by repeated precipitations and
recrystallizations of PAH-picric acid complexes [Cook et al.
(796a, 797)]. In the mid-1970s, Sugimura et al. (3829a) in
Japan used the Ames test (Salmonella typhimurium, TA 98
strain/S-9) to monitor tryptophan pyrolysate mutagens (Trp-
P-1, Trp-P-2) during their concentration and purification
by sequential chromatography on silicic acid, alumina, and
CM-Sephadex® columns.
References to several early studies on the identification
of biologically active compounds in heated foodstuffs are
included in Table XVII.F-3, for example, the 1956 study by
Kuratsune (2237) of PAHs such as B[a]P in roasted coffee
and the similar mid-1960s studies of PAHs in broiled meat
[Lijinsky and Shubik (2364a, 2364b)]. PAHs such as B[a]
P were identified in both studies. The major concern of the
early investigators was the possible presence of tumorigenic
PAHs, particularly B[a]P, in the heated foodstuff. Of course,
it was subsequently demonstrated that B[a]P, in addition to
its tumorigenicity to mouse skin, is also mutagenic in the
Ames test. However, its specific mutagenicity is insignificant

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 Nitrogen Heterocyclic Components 845

Table XVII.F-3
N-Heterocyclic Amines: Mutagenicity of Beverages, Heated Foods, and Heated Food Components
Food or Food
Component References

Foods, heated (grilled,
broiled, etc.)
  Beef, extract
  Beef, broiled, fried,
and/or charred
  Cuttlefish, broiled
  Eggs, fish, meat
  Flour, rice
  Soybeans
  Fish, broiled, charred
  Herring, broiled
  Mackerel, broiled
  Pike, broiled
  Sardine, broiled
  Sardine, broiled
Protein pyrolysates
  Albumin
  Soybean globulin
  Calf thymus
  Egg white
  Serum albumin
  Casein, collagen,
  Gluten, histone,
  Insulin, lysozyme,
  Ovalbumin, zein,
  Tobacco protein
  Polypeptides
  Carnosine
  Glycyl glycine a
  Glycyl glutamic acid
  Glycyl proline
  Glycyl tryptophan
  Leucyl glycyl
   phenylalanine
  Tryptophanyl alanine
  Tryptophanyl glycine
  Tryptophanyl
   tryptophan
  Tryptophanyl tyrosine
Amino acid pyrolysates
  Phenylalanine
  Lysine
  Tryptophan
  Glutamic acid
  Histidine
  Histidine, 3-methyl-
Felton and Knize (1177d), Matsumoto et al. (2492), Nagao et al. (2667a), Sugimura (3828c, 3828e, 3828f), Sugimura et al.
(3829), Sugimura and Nagao (3929b), Tanaka et al. (3865b)
Commoner et al. (790a), Hargraves and Pariza (1501a), Hayatsu et al. (1555b), Ohgaki et al. (2849a), Takayama et al. (3862c),
Turesky et al. (3988b)
Commoner et al. (790a), Felton et al. (1177d), Hayatsu et al. (1555a, 1555b), Jägerstad et al. (1916b), Kasai et al. (2037d),
Lijinsky and Shubik (2364a, 2364b) a, Nagao et al. (2667c), Ohgaki et al. (2849a), Takayama et al. (3862c), Yasuda et al. (4382a)
Ohgaki et al. (2849a), Yamaguchi et al. (4361a)

 Sugimura and Nagao (3828b)

Kasai et al. (2037c, 2037d), Nagao et al. (2667c),
Yamaizumi et al. (4361b), Yasuda et al. (4382a)

 Nagao et al. (2667f)


Ohgaki et al. (2849a), Takayama et al. (3862c)
Matsumoto (2491c), Nagao et al. (2667f), Nebert et al. (2688a), Yoshida and Matsumoto (4387b), Yoshida et al. (4390)
Yasuda et al. (4382a)
Ohgaki et al. (2849b),Yoshida et al. (4389a)

 Nagao et al. (2667b)



 Matsumoto et al. (2491c)


Johnson et al. (1968)





 Matsumoto et al. (2491c)






Kato et al. (2048, 2049), Kosuge et al. (2178a), Masuda et al. (2486), Nebert et al. (2688a)
Sugimura et al. (3829)
Wakabayashi et al. (4102a)
Hosaka et al. (1835a), Matsukura et al. (2491a), Negishi and Hayatsu (2689a), Sugimura et al. (3829), Takayama et al. (3862d),
Yamazoe et al. (4370a), Yoshida and Matsumoto (4390)
Ohgaki et al. (2849b), Sugimura (3828a), Takeda et al. (3863a), Takayama et al. (3862b), Yamamoto et al. (4365a)
Smith et al. (3722a)

(Continued)

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 846 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.F-3 (C0ntinued)

N-Heterocyclic Amines: Mutagenicity of Beverages, Heated Foods, and Heated Food Components
Food or Food
Component References

  Alanineb, arginine, 
  Asparagine, citrulline, 
  Cysteine, cystine, 
  Glutamic acid, 
  Glutamine, histidine,  Matsumoto et al. (2491b)
  Lysine, methionine, 
  Ornithine, 
  Phenylalanine, serine, 
  Threonine, tryptophan, 
  Tyrosine, valine 
Beverages
  Coffee, roasted Aeschbacher and Würzner (38a), Kuratsune (2237) c, Nagao et al. (2667d, 2667e), Sugimura (3828d)
  Coffee, instant Aeschbacher and Würzner (38a), Fujita et al. (1256a), Kosugi et al. (2178b)
  Tea Nagao et al. (2667e), Sugimura (3838d)
  Brandy Sugimura (3828d)
  Sake Takase and Murakami (3862a)
Cigarette smoke DeMarini (930-933), Matsumoto et al. (2492), Sugimura (3828d), Yoshida and Matsumoto (4388)
condensate
a No mutagens detected in glycyl glycine pyrolysate.
b The pyrolysates from the various amino acids studied showed mutagenicities (Ames test) in the following sequence (revertant/mg of pyrolysate), the amino
acid (tryptophan) yielding the highest mutagenic pyrolysate listed first: Tryptophan, serine, glutamic acid, ornithine, lysine, arginine, citrulline, threonine,
alanine, cystine, glutamine, methionine, cysteine, tyrosine, phenylalanine, histidine, asparagine, valine.
c This was a polycyclic aromatic hydrocarbon (PAH) study, with emphasis on the generation of B[a]P.

compared to that of several of the N-heterocyclic amines (see early 1930s and the identification of B[a]P in coal tar by Cook
Table XVII.F-1). The presence of PAHs in numerous foods et al. (796a, 797), exposures to N-nitrosamines tumorigenic
was discussed previously. in laboratory animal bioassays have been studied [Magee and
From their studies of heated foods or food pyrolysates Barnes (2441a)] since the mid-1950s. In contrast, exposures
(thirty different foods, including rice, flour, soy beans, fish, to N-heterocyclic amines tumorigenic in laboratory animal
meat, eggs), Sugimura (3828b) reported: bioassays have only been studied for about thirty years (since
the mid-1970s and the availability of the Ames test).
• Mutagenicity was proportional to the protein Sugimura (3828b) reported comparisons of the mutagen-
content. icities (Ames test) of various beverages (coffee, brandy, tea)
• Mutagenicity was proportional to the levels of spe- and CSC. The data are summarized in Table XVII.F-4.
cific amino acids (tryptophan, glutamic acid, etc.)
in the constituent protein.
• Mutagenicity was dependent on water content and
heating temperature, for example, for foods with Table XVII.F-4
low water content, the mutagens appear at 300°C; Mutagenicity of Common Beverages vs. Cigarette
for those with high water content, the mutagens Smoke Condensate
appear at 400°C.
Exposure
Agent Level ST Straina S-9 Mix Revertants
Estimates of daily exposures to PAHs and N-nitrosamines
in foods, beverages, and other factors have been made Cigarette one, inhaled TA 98 yes 4000
by numerous investigators. Estimates of exposures to Coffee 200 ml TA 100 no 180000
N-heterocyclic amines are limited. Part of the reason is the Teab 200 ml TA 100 no mutagenic
difference in time span since the particular class of com- Brandy 50 ml TA 100 no 10500
pounds was found to be tumorigenic and/or mutagenic: a ST = Salmonella typhimurium
Exposures to PAHs tumorigenic in laboratory animal bioas- b Japanese green tea
says have been studied for more than seven decades (since the

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 Nitrogen Heterocyclic Components 847

In another comparison of mutagenicities toward

Table XVII.F-5 Salmonella typhimurium TA 98, Nagao et al. (2667c) calcu-
Benzo[a]pyrene Equivalency of Extracts of Charred Fish lated the B[a]P equivalency of extracts of charred fish and
and Meat meat. Their data, with additions [charred food weight in
ounces, cigarette equivalents based on B[a]P], are shown in
Sample B[a]P Equivalency, Cigarette Equivalency
Table XVII.F-5.
Analyte wt., g ng Based on B[a]Pa
Table XVII.F-6 lists identified tobacco smoke compo-
Sardine 100 (3.5)b 35800 2983 nents actually or possibly derived from the amino acids
Mackerel 60 (2.1) 68200 5683 glutamic acid, tryptophan, or proline. In the mid-1980s,
Beefsteak 190 (6.7) 85500 7125 Rodgman (3253a) discussed both the known relationships as
a Calculation based on assumption of MSS yield of 12 ng/cig of B[a]P. well as several theoretically possible relationships between
b Number in parentheses is weight in ounces. the three amino acids and many of the compounds listed in
Table XVII.F-6. It also lists, with appropriate citations, the
amino acid-derived compounds reported in tobacco smoke
As noted previously, Sugimura (3828c) reported in his and citations to the studies demonstrating their mutagenic-
1986 review his estimate of the exposure of humans to ity and tumorigenicity. Additional references to the tobacco
N-heterocyclic amines with the limited data at his disposal. smoke components may be found in the section on the aza-
From his estimate, Sugimura concluded that at that time arenes (Section XVII.E) and Chapter 4 on the three amino
N-heterocyclic amines might not be serious in human can- acids (Section IV.B).
cer development and no solid information on the estimation Table XVII.F-7 summarizes the chronology of the studies per-
of risk of N-heterocyclic amines had been obtained in any tinent to the N-heterocyclic amines in tobacco smoke and in com-
direction, either positive or negative. monly consumed cooked foodstuffs. Included in Table XVII.F-7

Table XVII.F-6
Components Related to N-Heterocyclic Amines in Tobacco Smoke: Identification and Biological Properties
References to

Compound Identification in Smoke Mutagenicitya Tumorigenicityb

Glutamic acid-derived:
Glutamic acid
Butanoic acid, 2-amino-
Butanoic acid, 4-amino-
2-Pyridinamine
2-Pyridinamine, 3-methyl-
2-Pyridinamine, 6-methyl-
Dipyrido[1,2-a:3’,2’-d]
imidazole, 2-amino-
{Glu-P-2}
Dipyrido[1,2-a:3’,2’-d]
imidazole, 2-amino-6-methyl-
{Glu-P-1}
Buyske et al. (526), Izawa et al. (1910),
Izawa and Taki (1914)
Hecht et al. (1580)
Izawa et al. (910),
Izawa and Taki (1914)
Heckman and Best (1587), Saint-Jalm
and Morée-Testa (3386)
Lippiello et al. (2378a)
Lippiello et al. (2378a), Sanders et al.
(3410)
Clapp (751), Clapp et al. (755, 756), Yamamoto et al. (4365a), Sugimura Ohgaki et al. (2849a, 2849b), Takayama
Massey (2484a) (3828c), Lee et al. (2327c) et al. (3862c), Sugimura (3828c)
Clapp (751), Clapp et al. (755, 756), Yamamoto et al. (4365a), Sugimura Ohgaki et al. (2849a, 2849b), Takayama
Massey (2484a) (3828c), Lee et al. (2327c) et al. (3862c), Sugimura (3828c)

Tryptophan-derived:
Tryptophan
9H-Pyrido[3,4-b]indole Poindexter and Carpenter (2972) Levitt et al. (2355a), Nagao et al. USPHS (4010)
{norharman} (2667g)
9H-Pyrido[3,4-b]indole, Heckman and Best (1587)
1-butyl-
9H-Pyrido[3,4-b]indole, Schumacher et al. (3553)
1-ethyl-

(Continued)

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 848 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.F-6 (Continued)

Components Related to N-Heterocyclic Amines in Tobacco Smoke: Identification and Biological Properties
References to

Compound Identification in Smoke Mutagenicitya Tumorigenicityb

9H-Pyrido[3,4-b]indole,
1-methyl- {harman}
9H-Pyrido[3,4-b]indole, 1-methyl-
1,2,3,4-tetrahydro-
9H-Pyrido[3,4-b]indole, 1-propenyl-
5H-Pyrido[4,3-b]indole, 3-amino-
1,4-dimethyl-
{Trp-P-1}
5H-Pyrido[4,3-b]indole, 3-amino-1-
methyl- {Trp-P-2}
1H-Pyrido[2,3-b]indole
9H-Pyrido[2,3-b]indole, 2-ethyl-
9H-Pyrido[2,3-b]indole, 2-methyl-
9H-Pyrido[2,3-b]indole, 2-(2-
methylpropyl)-
9H-Pyrido[2,3-b]indole, 2-pentyl-
9H-Pyrido[2,3-b]indole, 2-amino-
{AaC}
9H-Pyrido[2,3-b]indole, 2-amino-3-
methyl- {MeAaC}
Poindexter and Carpenter (2972)
Heckman and Best (1587)
Yamashita et al. (4367, 4368)
Yamashita et al. (4367,4368)
Heckman and Best (1587)
Schumacher et al. (3553)
Heckman and Best (1587)
Heckman and Best (1587)
Heckman and Best (1587)
Yoshida and Matsumoto (4388),
Matsumoto et al. (2492), Yamashita
et al. (4367, 4368)
Yoshida and Matsumoto (4388),
Matsumoto et al. (2492), Yamashita
et al. (4367, 4368)
Levitt et al. (2355a), Nagao et al.
(2667g)
Schumacher et al. (3553)
Sugimura et al. (3828c, 3829,
3829a), Lee et al. (2327c)
Sugimura et al. (3829, 3829a),
Sugimura (3828c), Lee et al.
(2327c)
Yoshida and Matsumoto (4388),
Matsumoto et al. (2492), DeMarini
(933), Sugimura (3828c)
Yoshida and Matsumoto (4388),
Matsumoto et al. (2492), DeMarini
(933), Sugimura (3828c)
USPHS (4010)
Matsukura et al. (2491a), Hosaka
et al. (1835a), Takayama et al.
(3862d), Sugimura (3828c)
Matsukura et al. (2491a), Hosaka
et al. (1835a), Takayama et al.
(3862d), Sugimura (3828c)
Ohgaki et al. (2849b), Sugimura
(3828c)
Ohgaki et al. (2849b), Sugimura
(3828c)

Imidazo[4,5-f]quinoline, 2-amino-3,4-
dimethyl- {MeIQ}
Imidazo[4,5-f]quinoline, 2-amino-3-
methyl- {IQ}
Indole, 2,3-dimethyl-
Indole-3-acetonitrile
Proline-derived:
Proline
5H,10H-Dipyrrolo[1,2-a:1’,2’-d]
pyrazine-5,10-dione {pyrocoll}
5H,10H-Dipyrrolo[1,2-a:1’,2’-d]
pyrazine-5,10-dione, methyl-
{methylpyrocoll}
5H,10H-Dipyrrolo[1,2-a:1’,2’-d]
pyrazine-5,10-dione, 1,2a,3,5a,8,10a-
hexahydro-
5H,10H-Dipyrrolo[1,2-a:1’,2’-d]
pyrazine-5,10-dione,
1,2a,3,5a,8,10a-hexahydro-3-methyl-
5H,10H-Dipyrrolo[1,2-a: 1’,2’-d]
pyrazine-5,10-dione, octahydro-
a Mutagenic (Salmonella typhimurium).
b Tumorigenic to mammalian skin.
Bao et al. (179a), Levasseur et al. Ohgaki et al. (2849), Lee et al. Ohgaki et al. (2849)
(2354a), Massey (2484a), Rodgman (2327c)
(3255, 3257, 3265), Rodgman and
Green (3300), Smith et al. (3714)
Yamashita et al. (4367, 4368) Yoshita et al. (4389a), Ohgaki et al. Ohgaki et al. (2849a),
(2849a), Lee et al. (2327c) Takayama et al. (3862b,
3862c), Tanaka et al. (3865c).
Rodgman and Cook (3279), Izard et al.
(1898), Schmeltz et al. (3506)
Izard et al. (1898)
Izawa et al.(1910), Izawa and Taki
(1914)
Mold et al. (2592), Rodgman and Cook
(3279), Schmeltz et al. (3505), Testa
and Testa (3886)
Izard et al. (1898)
Schumacher et al. (3553)
Schumacher et al. (3553)
Schumacher et al. (3553)

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 Nitrogen Heterocyclic Components 849

Table XVII.F-7
Chronology of N-Heterocyclic Amine Studies
Year Event

1959 The only fused ring N-heterocyclic compound listed by Johnstone and Plimmer (1971) as a component of tobacco smoke
was the bicyclic compound quinoline.
1960 Mold et al. (2592) reported the isolation and identification of the tricyclic N-heterocyclic 5H,10H-dipyrrolo[1,2-a:1’,2’-d]
pyrazine-5,10-dione (pyrocoll) from CSC and its relationship to its precursor in tobacco, the amino acid proline.
1961/1962 Poindexter and Carpenter (2972) reported the isolation and identification of 9H-pyrido[3,4-b]indole (norharman) and
1-methyl-9H-pyrido[3,4-b]indole (harman) from CSC. They reported that the yield of the total harmans in burley and
flue-cured MSSs was between 15 and 20 mg/gram of tobacco smoked, values which were 40 to 50 times that of the harmans
in the unsmoked tobacco. Since the weight of tobacco in cigarettes sold at that time approximated 1 gram, the yield of these
two compounds was about 15-20 mg/cig. Poindexter and Carpenter concluded from experiments with radiolabeled
tryptophan that the harmans (found to be radiolabeled in the smoke) were generated pyrogenetically from a reaction between
aldehydes (formaldehyde for norharman, acetaldehyde for harman) and the tryptophan in tobacco.
1962 Rodgman and Cook (3279) confirmed the presence in CSC of 5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione
(pyrocoll) and also reported the identification of indole, carbazole, and several alkylated indoles and carbazoles. Rodgman
and Cook (3279) also reviewed the previously reported biological studies on indole, 3-methylindole (skatole), and carbazole:
None of the three was reported to be tumorigenic.
1964 Schmeltz et al. (3505) reported 5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll), 9H-pyrido[3,4-b]indole
(norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman) as tobacco smoke components. Testa and Testa (3886) also
identified 5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll) as components of CSC.
1964 The Advisory Committee to the U.S. Surgeon General (3999) briefly discussed only four fused-ring N-heterocyclic
compounds in tobacco smoke, quinoline and the two dibenzacridines (dibenz[a,h]acridine, dibenz[a,j]acridine) and the
dibenzocarbazole (7H-dibenzo[c,g]carbazole) reported by Van Duuren et al. (4027).
1968 In his review of tobacco smoke composition, Stedman (3797) discussed the identification of tumorigenic N-heterocyclic
compounds (dibenz[a,h]acridine, dibenz[a,j]acridine, 7H-dibenzo[c,g]carbazole) reported by Van Duuren et al. (4027) as
well as the following N-heterocyclic compounds: 5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll) reported
by Mold et al. (2592) and 9H-pyrido[3,4-b]indole (norharman), 1-methyl-9H-pyrido[3,4-b]indole (harman), and
9H-pyrido[2,3-b]indole reported by Poindexter and Carpenter (2972).
1971/1972 Wakeham (4103) noted the reported presence of 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9H-pyrido[3,4-b]indole
(harman) in cigarette smoke and discussed their formation from a reaction product of tryptophan and an aldehyde. As noted
by Rodgman (3253a), the structure of the aldehyde reacting with tryptophan ultimately dictates the structure of alkylated
norharmans found (see Table XVII.F-6) in CSC.
1974 In addition to 5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll), Izard et al. (1899) reported the identification
of methyl-5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (methylpyrocoll) in CSC.
1974/1975/ In a 1974 in-house report, a 1975 TCRC presentation, and a 1977 publication on their study of the water-soluble portion of
1977 CSC, Schumacher et al. (3553) reported the identifications of 1-methyl-9H-pyrido[3,4-b]indole (harman), 5H,10H-
dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll), octahydro-5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione
(octahydropyrocoll), and 2-ethyl-9H-pyrido[2,3-b]indole.
1977 Sugimura et al. (3829a) reported the isolation and identification of the N-heterocyclic amines 3-amino-1,4-dimethyl-5H-
pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) from tryptophan pyrolysates.
1977 In separate studies, Levitt et al. (2355a) and Nagao et al. (2667b) demonstrated the mutagenicity of 9H-pyrido[3,4-b]indole
(norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman) in the Ames test.
1978 Yamamoto et al. (4365a) reported the isolation and identification of 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole
(Glu-P-1) and 2-aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2) from glutamic acid pyrolysates.
1978/1981 Heckman and Best (1587) reported the identification of nearly 270 previously unidentified and over 150 previously identified
N-containing components in CSC. These included several components structurally similar to the N-heterocyclic amines:
9H-pyrido[2,3-b]indole, 2-methyl-9H-pyrido[2,3-b]indole, 2-(2-methylpropyl)-9H-pyrido[2,3-b]indole, 2-pentyl-9H-pyrido[2,3-b]
indole, 1-butyl-9H-pyrido[3,4-b]indole, 9H-1-propenyl-pyrido[3,4-b]indole, and a partially characterized norharman isomer.
1979 In the 1979 Surgeon General’s report (4005), the aza-arenes dibenz[a,h]acridine, dibenz[a,j]acridine, 7H-dibenzo[c,g]
carbazole, quinoline, and alkylated quinolines in CSC were discussed but not the presence or properties of the
N-heterocyclic amines identified in tobacco smoke.
1980/1981 Yoshida and Matsumoto (4388) and Matsumoto et al. (2492) reported the identification of 2-amino-9H-pyrido[2,3-b]indole
(AaC) and 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAaC) in CSC.
1981 Matsukura et al. (2491a) demonstrated the tumorigenicity in mice of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole
(Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2).
Hosaka et al. (1835a) demonstrated the tumorigenicity in rats of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole
(Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2).
(Continued)

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 850 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.F-7 (Continued)

Chronology of N-Heterocyclic Amine Studies
Year Event

1982 In the 1982 report of the Surgeon General (4010), 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9H-pyrido[3,4-b]indole
(harman) were classified as “toxic and tumorigenic agents of cigarette smoke” in amounts of 3.2 to 8.1 mg/cig and 1.1 to 3.1
mg/cig, respectively, in cigarette MSS. None of the other N-heterocyclic amines present in tobacco smoke was discussed.
1982/1984 Snook and Chortyk (3739) reported the MSS yield of 9H-pyrido[3,4-b]indole (norharman) to be 1.2 to 13.4 mg/cig; that for
1-methyl-9H-pyrido[3,4-b]indole (harman) to be 0.3 to 3.8 mg/cig. They found a linear relationship between the yield of
cigarette MSS “tar” and the yields of 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman).
In contrast to the 1962 findings of Poindexter and Carpenter, Snook and Chortyk reported that the MSS yields of these two
compounds were not influenced by the tobacco type.
1983 Demarini (933) reviewed the studies on the mutagenicity of CSC. He discussed the studies of Yoshida and Matsumoto
(4388) and Matsumoto et al. (2492) on the mutagens 2-amino-9H-pyrido[2,3-b]indole (AaC) (80 ng/cig) and 2-amino-3-
methyl-9H-pyrido[2,3-b]indole (MeAaC) (7 ng/cig).
1984 None of the authors contributing to the 2nd edition of the American Chemical Society’s monograph, edited by Searle
(3568), on chemical carcinogens mentioned the tumorigenic and mutagenic N-heterocyclic amines reported in cigarette
smoke and/or numerous cooked foods. In fact, the only class of tumorigens in cigarette MSS discussed in the 1400-page
treatise was the N-nitrosamines. No tumorigenic PAH was mentioned as a component of cigarette MSS.
1984 Ohgaki et al. (2849) demonstrated the tumorigenicity in mice and Takayama et al. (3862b) demonstrated the tumorigenicity in rats
of 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1) and 2-aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2).
Takayama et al. (3862c) demonstrated the tumorigenicity in rats of the tobacco smoke component 2-amino-3-
methylimidazo[4,5-f]quinoline (IQ).
1984/1985 Ohgaki et al. (2849a, 2849b) demonstrated the tumorigenicity in mice of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)
and 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), found in broiled fish, fried beef, beef extract, and CSC.
1985 Takayama et al. (3862d) demonstrated the tumorigenicity in rats of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole
(Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2).
Tanaka et al. (3865b) demonstrated the tumorigenicity of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ).
1985 In an in-house presentation, Rodgman (3253a) discussed the already identified and other possible theoretical relationships
between tryptophan and the substituted norharmans, the tryptophan pyrolysis products 3-amino-1,4-dimethyl-5H-
pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), the 2-amino-9H-pyrido[2,3-b]
indoles (AaC and MeAaC), indole-3-acetonitrile, and the alkyl- and dialkylindoles.
He also discussed the theoretical relationships among glutamic acid, its possible degradation products 2- and
4-aminobutanoic acid, 2-aminopyridine, 2-amino-3- and 6-methylpyridine, and the possible reactions between these
substituted aminopyridines to form 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1), 2-aminodipyrido[1,2-
a:3’,2’-d]imidazole (Glu-P-2), and two similar products not yet identified.
1985/1986 In its 1985 review, published in 1986, of the various problems from exposure to numerous components in tobacco smoke,
the IARC (1870) did not designate the N-heterocyclic amines as a problem. IARC did list several tryptophan-derived
tobacco smoke isolates including 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman). The
per cigarette MSS yields of these two components were listed as 9.5 to 14.1 and 2.5 to 5.8 mg/cig, respectively. No mention
was made of the N-heterocyclic amines in CSC or the degree of evidence for their carcinogenicity in animals and humans.
The identification of several N-heterocyclic amines was reported in 1985 and 1986 by Yamashita et al. (4367, 4368).
1985/1986 Yamashita et al. (4367,4368) identified and quantitated the per cigarette yields of the following N-heterocyclic amines in CSC:
2-amino-3-methylimidazo[4,5-f]quinoline (IQ) 0.3 ng/cig
3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) 0.3 ng/cig
3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) 0.2 ng/cig
2-amino-9H-pyrido[2,3-b]indole (AaC) 16.9 ng/cig
2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAaC) 1.6 ng/cig
1986 Hoffmann and Wynder (1808) in their list of tobacco and tobacco smoke tumorigens did not list any N-heterocyclic amine.
1986 Sugimura (3828c) reviewed the isolation and identification of the N-heterocyclic amines, their high mutagenicity in the Ames test
(Salmonella typhimurium) of several of them, their tumorigenicity, and their various sources – including CSC for many. However,
Sugimura did write the following about the importance of the “cooked food” mutagens as human carcinogens:
Taking various factors into consideration, it is probably impractical and not realistic to make risk estimations from the
carcinogenicity data on rodents given a single carcinogen. However, for a simple extrapolation of animal data for risk
estimation, TD50 values, which are the doses needed to develop cancers in 50% of animals fed on carcinogens [IQ, Trp-
P-1, Trp-P-2, Glu-P-1, Glu-P-2, AaC, and MeAaC] for their life time, have been calculated based on mouse experiments…
If we assume the average TD50 value of heterocyclic amines should be about 8mg/kg/day, we can roughly estimate the risk
of these carcinogenic heterocyclic amines for human beings. The intake of heterocyclic amines was calculated from
available data on their quantities in foods. Apparently the human intake is about 0.0002% times the TD50 obtained from
animal data. This means that heterocyclic amines may not be so serious for human cancer development.

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 Nitrogen Heterocyclic Components 851

Table XVII.F-7 (Continued)

Chronology of N-Heterocyclic Amine Studies
Year Event

Sugimura added:
On the other hand, it is also true that human beings are being exposed to many heterocyclic amines and many other
carcinogens with tumor promoters and/or suppressing factors for carcinogenesis. At this moment, it is honest to state
that no solid information on the estimation of risk of heterocyclic amines has been obtained in any direction, either
positive or negative.
1990 Felton and Knize (1177d) reviewed the results of numerous studies on the mutagenicity and tumorigenicity of the
N-heterocyclic amines.
1990 Manabe et al. (2448) identified the N-heterocyclic amine 1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridin-2-amine (PhIP) in CSC.
1991 By their addition to tobacco, Clapp (751) reported the contribution of various individual amino acids (asparagine, aspartic
acid, arginine, glutamine, glutamic acid, histidine, proline, lysine, tryptophan, phenylalanine, creatine, creatinine) to the
Ames test mutagenicity of cigarette MSS.
1993 Lee et al. (2327c) reported that the CSC from cigarette MSS significantly inhibited the mutagenicity of several N-heterocyclic
amines as measured in the Ames assay with Salmonella typhimurium, strain TA 98 in presence of the S-9 mix. The
N-heterocyclic amines tested included:
2-amino-3-methylimidazo[4,5-f]quinoline (IQ),
2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ),
2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1),
2-aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2),
3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1),
3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2).
The mutagenic activities of these mutagens were suppressed as much as 80% by addition of 50 to 100 mg of CSC per plate.
1993 In their list of toxicants and tumorigens in tobacco and MSS, Hoffmann et al. (1773) did not include any N-heterocyclic amines.
1994 In its list of toxicants and tumorigens in MSS, OSHA (2825) did not include any N-heterocyclic amines.
1997 Hoffmann and Hoffmann (1740) issued a revised list of tumorigenic components in tobacco and tobacco smoke. Their
revision of the Hoffmann-Hecht (1727) list included, in addition to several vapor-phase components, the following eight
N-heterocyclic amines:
2-amino-3-methylimidazo[4,5-f]quinoline (IQ),
2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ),
2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1),
2-aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2),
3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1),
3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2).
2-amino-9H-pyrido[2,3-b]indole (AaC)
2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAaC)
1998 In a letter to the editors of Beiträge zur Tabakforschung International, Hoffmann and Hoffmann (1741) listed eight
N-heterocyclic amines as biologically active agents in the MSS of non-filtered cigarettes. They also included the three
aza-arenes reported as MSS components by Van Duuren et al. in 1960.
1999/2000 Clapp et al. (755,756) reported that reduction of the level of protein in flue-cured tobaccos by 70% resulted in a reduction of
80% in the mutagenicity of the MSS “tar” (strain TA 98 Salmonella typhimurium) and 50% (strain TA 100). Reduction of
the protein level in burley tobacco by 50% resulted in reductions in mutagenicity of its MSS “tar” of 81% and 54%, with
strain TA 98 and TA 100, respectively.
2001 Hoffmann and Hoffmann (1743) and Hoffmann et al. (1744) listed eight N-heterocyclic amines as biologically active agents
in the MSS of non-filtered cigarettes. In both publications, the three aza-arenes reported as MSS components by Van Duuren
et al. in 1960 were listed.
2002/2003 In a presentation and publication, Rodgman and Green (3300) discussed the deficiencies of many of the lists of toxicants in
cigarette MSS.
2003 Rodgman (3265) outlined the major problems with the lists published by Hoffmann and colleagues (1740, 1741, 1743, 1744)
and others.
2005 Kinae et al. (2095a) reported that N-heterocyclic amines [2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-
dimethylimidazo[4,5-f]quinoline (MeIQ), 1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridin-2-amine (PhIP)] were produced in
an incubated solution of D-glucose and several amino acids at much lower temperatures and longer time periods than those
encountered in the cooking of various foodstuffs (beef, poultry, fish). Several N-heterocyclic amines not found in CSC were
also generated. The generation of the N-heterocyclic amines, as measured by the Ames test (Salmonella typhimurium
TA 98), increased in proportion to the conditions imposed: 37°C (90 d), 50°C (30 d), 128°C (2 h)

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 852 The Chemical Components of Tobacco and Tobacco Smoke

Table XVII.F-8
N-Heterocyclic Amines in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Nitrogen Heterocyclic Components 853

Table XVII.F-8 (Continued)

N-Heterocyclic Amines in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

are events pertinent to the studies of 5H,10H-dipyrrolo[1,2-
a:1’,2’-d]pyrazine-5,10-dione (pyrocoll), 9H-pyrido[3,4-b]indole
(norharman), and 1-methyl-9H-pyrido[3,4-b]indole (harman).
Although none is an N-heterocyclic amine, their pyrogenesis
from specific amino acids was the background for the subse-
quent studies on N-heterocyclic amines, each of which is derived
from an amino acid.
Table XVII.F-8 lists, with appropriate citations, the
N-heterocyclic amines reported in tobacco and tobacco
smoke. While Table XVII.F-8 lists the citations pertinent to
the nine highly mutagenic N-heterocyclic amines, as noted
previously, citations pertinent to tobacco smoke components
related to them are available in Sections IV.B (amino acids)
and XVII.E (aza-arenes).

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 18 Miscellaneous Components
XVIII.A Sulfur-Containing Components
Sulfur is a well-known constituent of tobacco and is essen-
tial for growth of the plant. In 1990, Tso (3973) reviewed the
chemistry, biology, and physiological aspects of sulfur in
tobacco. It is absorbed by the plant as sulfate, some of which
undergoes reduction during assimilation and becomes incor-
porated into amino acid components of proteins (18A11).
The sulfur content of tobacco varies by tobacco type and
has been reported (3973) to range from 0.4% for flue-cured
varieties to 1.1% for the Maryland tobacco (4246). Sulfur-
containing (S-containing) compounds in or on tobacco can
also come from added flavors and casings such as cocoa, as
a contaminant of the leaf or of flavors and casings, or from
agrochemicals (fertilizers, pesticides, herbicides, insecti-
cides, etc.) applied to the tobacco. Endogenous S-containing
compounds of tobacco include numerous proteins, peptides,
nucleotides, several amino acids (methionine, cysteine, cys-
tine, taurine, homocysteine), and B vitamins (thiamine and
biotin). Sulfur is also available as various inorganic sulfates
or sulfides found in tobacco.
Sulfur is found in many casings and flavors used on
tobacco. Solid flavorants or casing materials used on tobacco,
such as cocoa and licorice, are natural products and just
like tobacco they contain S-containing amino acids and
proteinaceous substances. Some flavor additives used on
tobacco products are S-containing compounds. In 1994, the
tobacco rod of a cigarette produced by any of the then six
major manufacturers could have had any combination of 599
different ingredients (1053), 460 of which were individual
compounds as described by Rodgman (3266). Of the 460,
Rodgman listed 212 identified as untreated tobacco compo-
nents, 245 identified in its smoke, and 168 in both tobacco
and smoke. Those numbers have changed slightly since sev-
eral of the 460 components have recently been identified in
tobaccos by Leffingwell and Alford (2339a) and Peng et al.
(2917a). Within the compounds listed by Doull et al. (1053)
are nine S-containing compounds, for example, methyl sul-
fide, d,l-methionine, 5-methyl-2-thiophenecarboxaldehyde,
3-methylthiopropionaldehyde, and methional.
Tobacco contains residual levels of the S-containing com-
pounds in agrochemicals that are used to treat tobacco, for
example, Benfuracarb®, Oryzalin®, Thiofide®, Malathion®,
Pebulate®, Cyolane®; Thiodicarb®, Trapex®, and Zineb®.
Cigarette mainstream smoke (MSS) contains a wide variety
of S-containing compounds, for example, S-containing amino
acids, residues of herbicides, pesticides, insecticides, and
growth promoters (Malathion®, Captan®, Thiodan®, α- and
β-Endosulfan®, Disulfoton®, Guthion®, and Chlorpyriphos®),
certain organic sulfates and sulfides, and decomposition
© 2009 by Taylor & Francis Group, LLC
78836_C018.indd 855
products of S-containing agrochemicals. MSS components pos-
sess a wide variety of S-containing functionalities (thiol, alkyl-
thio, mercapto, isothiocyanatoalkyl, thiazolyl, phosphinothioyl,
alkyldithio, phosphoramidothio, phosphonodithio, thiacycloal-
kyl, thiadiazinyl, thienyl, thiocarbamato, sulfide, sulfonate, sul-
fonyl, sulfuroxides, and trisulfide). MSS also contains several
polycyclic compounds that contain sulfur (18A14), for example,
benzothiophenes, dibenzothiophenes, and nonbenzeniod aro-
matic heterocycles, for example, benzodioxathiepins.
The sulfur compounds in cigarette MSS reside in both the
volatile and semivolatile fractions of MSS. Some S-containing
compounds are also present in the particulate phase of MSS.
The largest amount of research on S-containing compounds
in MSS has been on those in the vapor phase of MSS. The
low molecular weight S-containing compounds are volatile
and highly odorous at parts per million and parts per billion
concentrations. Their odor characteristics have been reported
by a GC-port sniffing technique [Alford and Houpt (18A01),
Ayya (18A03)].
Because of the odiferous nature of many of the vapor-
phase S-containing compounds in MSS their presence has
often been considered undesirable. However, it must be kept
in mind that smoke is a complex mixture and the contribu-
tion of any single component, depending on its concentration,
can actually add to the overall characteristic of tobacco smoke.
Certain S-containing compounds are excellent tobacco flavors,
such as butyl sulfide (floral), furfuryl mercaptan (coffee), and
allyl disulfide (garlic, nutty) and provide positive smoke taste
characteristics, although their aromas are considered harsh
or garlic (2341). S-containing compounds in tobacco are also
possible precursors to Maillard reaction flavors. S-containing
compounds can participate in Amadori rearrangement and
Strecker degradation (18A03). The unpleasantness of single
odorants should never be a valid reason to ignore or to reduce
their effects in a complex mixture like tobacco smoke.
Ayya (18A03) in 1994 posed the question of whether any
of the S-containing compounds of tobacco smoke might
be important pharmacologically if present in sufficiently
high concentration. There are a number of S-containing
compounds that are pharmacologically active [Rezanka
et al. (18A12)], but none is found in tobacco smoke at con-
centrations that are of any concern. In terms of any of the
S-containing compounds in tobacco or tobacco smoke being
biologically active, the International Agency for Research on
Cancer (IARC) has only tested sulfur dioxide, and various
sulfites, bisulfites, and metabisulfites. In their 1992 mono-
graph (18A05), IARC stated:
There is inadequate evidence for the carcinogenicity in humans
of sulfur dioxide, sulfites, bisulfites and metabisulfites. There
855
11/24/08 12:32:23 PM
 856 The Chemical Components of Tobacco and Tobacco Smoke
is limited evidence for the carcinogenicity in experimental
animals of sulfur dioxide. There is inadequate evidence for the
carcinogenicity in experimental animals of sulfites, bisulfites
and metabisulfites. Overall evaluation: sulfur dioxide, sulfites,
bisulfites and metabisulfites are not classifiable as to their car-
cinogenicity to humans (Group 3).
IARC provides a classification for it overall evaluations
of carcinogenicity to humans (18A04). It classifies individual
compounds and mixtures into five categories based on scien-
tific data on humans and animals. The classification is:
• Group 1: Carcinogenic to humans
• Group 2A: Probably carcinogenic to humans
• Group 2B: Possibly carcinogenic to humans
• Group 3: Not classifiable as to carcinogenicity to
humans
• Group 4: Probably not carcinogenic to humans
There are no known S-containing compounds in tobacco or
tobacco smoke in Group 1, 2A, or 2B. There are only six com-
pounds that are found in Group 3 (Malathion®, ethylenethiourea,
Parathion®, Parathion-methyl®, sulfur dioxide, and ethylene
sulfide). The evidence for the carcinogenicity in humans of all
these compounds was classified as inadequate (18A04).
Periodically during the past five decades, various reviews
and catalogs on the composition of tobacco and tobacco
smoke have been published. Some have listed S-containing
compounds in tobacco and tobacco smoke, while others have
not. In 1936 Bruckner (451) listed 120 known components in
tobacco and tobacco smoke. Of the identified compounds that
Bruckner listed only one contained sulfur (sulfate). In 1954
Kosak (2170) categorized about fifty components in tobacco
smoke whose identities were certain. Under his heading of
Inorganic Components Kosak listed hydrogen sulfide and
thiocyanic acid (?). The question mark indicated that Kosak
did not consider the evidence in the literature to be defini-
tive proof of the identity of the component. Latimer (2270)
in 1955 listed 231 compounds identified from tobacco and
tobacco smoke. Cystine, methionine, thiamine, and sulfur
were present in tobacco and thiocyanic acid, carbonyl sul-
fide, and methyl mercaptan were identified in tobacco smoke.
Johnstone and Plimmer in 1959 (1971) listed 950 compounds
in tobacco and tobacco smoke. In their review, they listed
only two sulfur compounds as identified in tobacco, cystine
and methionine. Obi and Nakano conducted studies on sulfur
in tobacco and tobacco smoke, in 1962 (2822). They deter-
mined that the sulfur content in Japanese tobacco was 0.3%
to 3%, of which 30% to 60% is organic sulfur. In a review of
compounds identified in tobacco and tobacco smoke, Philip
Morris, Inc. in 1963 (2939) listed seventeen S-containing
compounds. Stedman (3797) in 1968 listed 950 identified
compounds in tobacco and tobacco smoke, of these only ten
compounds were S-containing and all were from tobacco
smoke. Izawa (1900) in 1961 reported on 440 identified
tobacco and tobacco smoke components, of these only two
S-containing compounds in tobacco were mentioned (cystine
and methionine). Roberts et al. in 1975 (3224) listed 2783
© 2009 by Taylor & Francis Group, LLC
78836_C018.indd 856
compounds identified in tobacco and tobacco smoke. In their
report, they listed forty-one S-containing compounds iden-
tified in tobacco smoke. There were no S-containing com-
pounds reported in tobacco. In 1980, Ishiguro and Sugawara
(1884) listed 1889 identified tobacco smoke components in
their monograph, forty-six S-containing compounds were
listed. IARC in 1986 (1871) listed only three S-containing
agrochemicals in tobacco. Elmenhorst and Schultz in 1986
(1140) listed thirteen S-containing compounds in their pub-
lication. Roberts in 1988 (3215) tabulated that there were
5868 identified compounds in tobacco and tobacco smoke.
By functional groups, 3044 compounds had been identi-
fied in tobacco, 3996 had been identified in smoke, and 1172
were identified in both tobacco and tobacco smoke. Under
the function group heading Sulfur Compounds, three com-
pounds had been identified in tobacco, thirty-seven were
identified in tobacco smoke, and two compounds were found
in both tobacco and tobacco smoke. In 1994, Ayya (18A03)
summarized the previous work on S-containing compounds
in tobacco smoke. He listed thirty-two sulfur compounds
that had previously been identified in tobacco smoke. In
his report he cited work at Brown and Williams Tobacco
Company on the odor characterization of low molecular
weight S-containing compounds employing a gas chromato-
graph with a sniffing port.
As mentioned previously several reviews on tobacco
and tobacco smoke have not included or have omitted the
S-containing compounds in tobacco and tobacco smoke
These include the reports by Bentley and Berry in 1959 and
1960 (282, 283), Berry (296) in 1963, and the reports by
Sakuma et al. (3394, 3397, 3398) in 1983 and 1984. Bentley
and Berry reported in 1959 that “Sulphur compounds have
been found in smoke [Izawa et al. (1905)] but these have not
been identified.”
Whether there was a lack of analytical instrumentation
and/or methodology for the determination of S-containing
compounds in tobacco and smoke or a lack of concern for
these types of compounds cannot be said. But it is interest-
ing that even by 1994 (18A03) only about forty S-containing
compounds were identified as components of tobacco and
tobacco smoke.
From 1966 through 1974 several notable studies were
conducted on S-containing compounds in tobacco smoke.
In 1966, Philippe (2940) reported on the identification of
thiocyanogen, thiocyanic acid, hydrogen sulfide, carbonyl
sulfide, methylthionitrite, dimethy1 sulfide, carbon disulfide,
and thiophene in MSS. In that same year, ethyl mercaptan
was qualitatively detected by Grob (1419).
Williams and McRae (4246) in 1967 examined the fate of
S-containing compounds in tobacco during cigarette smok-
ing. The nonfiltered cigarettes in their experiments contained
approximately 0.5% sulfur. They determined that 61.4% of
the total sulfur content of the cigarette was found in the ciga-
rette ash and 33.2% was found in the cigarette butt. They
reported that the sulfur content of the whole MSS was 39 µg
per cigarette, which was equivalent to 0.5% of the total sulfur
in the cigarette. In total, they could account for over 95% of
11/24/08 12:32:23 PM
 Miscellaneous Components 857
the total sulfur content measured in the cigarettes used in
their experiments.
Groenen and Van Gemert (1429) in 1971 and Horton
and Guerin (1831) in 1974 reported on the identification of
S-containing compounds in the vapor phase of MSS. Both
investigator groups employed flame photometric detection
(FPD) gas chromatography (GC) for the determination of
sulfur compounds in smoke (1831). Groenen and Van Gemert
identified thirty-seven compounds while Horton and Guerin
identified twenty-eight S-containing compounds. Typical
cigarette yields reported by Horton and Guerin were approxi-
mately 85 µg of H2S, 35 µg of COS, 2 µg of CS2, and 3 µg of
SO2 per cigarette when smoked under standard conditions.
Horton and Guerin reported that the vapor phase of MSS
contained at least twenty-eight sulfur components but that
the quantitative distribution of these components was highly
sensitive to sampling methodologies. Quantitation is an obvi-
ous issue as Williams and McRae (4246) only could account
for 39 µg of sulfur per cigarette in whole MSS.
Generally, sulfur compounds in tobacco samples can
be converted by wet oxidation to sulfate. The sulfate is then
reduced to H2S which is separated by distillation and deter-
mined as methylene blue, by the method of Johnson and Nishita
(18A06). Protein sulfur can also be determined by the oxida-
tion of sulfur to sulfur dioxide and titration with 0.1 N I2 with
starch as an indicator (18A02). These classic methods serve as
determinations of total sulfur in a sample. Similar wet methods
for the analysis of sulfur compounds in tobacco now employ
autoanalyzers and robotics [Mottershead (18A10)]. Total sulfur
in the sample can also be analyzed by X-ray emission spec-
troscopy [Keen et al. (18A07)], atomic absorption spectrometry
[Sah and Miller (18A13)], atomic emission spectroscopy (AES)
and inductively coupled plasma (ICP-AES) [Littlefield et al.
(18A08)] or a variety of other instrumental methods. For exam-
ple, ESR (electron spin resonance) which is equivalent of EPR
(electron paramagnetic resonance) has also been used for the
analysis of the presence of sulfur in tobacco (18A09). Specific
S-containing amino acids in tobacco, for example, methionine,
cysteine, and cystine, are generally analyzed by GC, GC-MS or
liquid chromatographic techniques such as HPLC and LC-MS.
Sulfur in proteins, nucleotides, and peptides are normally ana-
lyzed by digestion of samples into free amino acids and then
determination of the amino acids by GC or LC.
Flame photometric detection (FPD) gas chromatography
(GC) (1429, 1831) and flame ionization detection (FID) GC
(1419) have been used for the determination of S compounds in
tobacco smoke. Although these methods are still used today,
GC-mass spectrometry is normally the preferred method for
the determination and quantification of S-containing compo-
nents in MSS.
Table XVIII.A-1 lists the S-containing components in
tobacco, tobacco smoke, and tobacco substitute smoke. A total
of 260 S-containing components have been identified in tobacco
and tobacco smoke. Of these compounds, 119 were identified
in tobacco smoke, 178 were identified in tobacco, and thirty-
seven were identified in both tobacco and smoke. It is interesting
to note that seventy-nine of the 260 S-containing components
© 2009 by Taylor & Francis Group, LLC
78836_C018.indd 857
in tobacco and/or its smoke are compounds used in tobacco
agronomy.
XVIII.B Halogenated Components
All of the halogens (chlorine [Cl], bromine [Br], fluorine
[F], and iodine [I]) are minor constituents of tobacco and
are essential for growth of the plant. In 1990, Tso (3973)
reviewed the chemistry, biology, and physiological aspects of
each halogen in tobacco. Soil contains low levels of all of the
halogens in the form of salts (halides). Low levels of these
halogenated salts generally promote growth in the plants and
improve quality and yield. At high levels of absorption all
halides can cause toxicity (3979). The various halides are
absorbed by the plant roots and are important in certain oxi-
dative, enzymatic, and plant regulatory processes (3973). The
content of Cl, Br, F, and I in tobacco varies by tobacco type,
soil, and climatic conditions. Typical ranges of Cl, Br, F, and I
reported in tobacco are 0.07% to 3%, 100 to 200 ppm, 4 to 40
ppm, and 0.55 to 1.75 ppm, respectively (3979). Other sources
of halogens in tobacco come from trace amounts of halides in
fertilizers and from agrochemical treatments of tobacco.
Over the last seventy years, several review articles on the
constituents of tobacco and tobacco smoke have been pub-
lished. In 1936 Bruckner (451) discussed the biochemistry
of tobacco. In his book, he briefly mentioned that tobacco
contained chloride. Kosak (2170) in 1954 categorized
about fifty components in tobacco smoke whose identities
were certain. Under his heading of Inorganic Components
KOSAK listed “Chlorides” (?). The question mark indicated
that Kosak did not consider the evidence in the literature to
be definitive proof of the identity of the component. Latimer
(2270) in 1955 listed 231 compounds identified from tobacco
and tobacco smoke. At that time, methyl chloride was the
only halogenated compound identified in tobacco smoke.
Johnstone and Plimmer in 1959 (1971) listed 950 compounds
in tobacco and tobacco smoke. In their review, they listed
only one halogenated compound as identified in tobacco, l,l,-
dichloro-2-2(4,4’-dichlorodipheny1)ethane (TDE or DDD)
and two in tobacco smoke, methyl chloride (specifically) and
certain other unnamed volatile chlorides. Bentley and Berry
in 1959 and 1960 (282, 283), and Berry (296) in 1963 failed
to report any halogenated compounds in tobacco or tobacco
smoke. Izawa (1900) in 1961 reported 440 identified com-
pounds in tobacco and tobacco smoke. In his report he listed
only methyl chloride as being identified in tobacco smoke.
In a review of compounds identified in tobacco and
tobacco smoke, Philip Morris, Inc. in 1963 (2939) listed
seven halogenated compounds: Cl, bromomethane, chlo-
romethane, chloroethane, bromoethane, Endrin®, and TDE.
Stedman (3797) in 1968 listed 950 identified compounds in
tobacco and tobacco smoke, of these only seventeen com-
pounds were halogen-containing. Cl, F, and I were identified
in tobacco, along with tobacco residues of methylene bro-
mide, l,l,l-trichloro-2-(4,4’-dichlorodipheny1)ethane (DDT),
Dieldrin®, Dyrene®, Endrin®, TDE, Telodrin®, Thiodan®,
Toxaphene®, Trichlorfon®, and Diclone®. o-Chloroaniline,
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 858 The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.A-1
Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C018.indd 858 11/24/08 12:32:23 PM

 Miscellaneous Components 859

Table XVIII.A-1 (Continued)

Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C018.indd 859 11/24/08 12:32:24 PM

 860 The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.A-1 (continued)

Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C018.indd 860 11/24/08 12:32:25 PM

 Miscellaneous Components 861

Table XVIII.A-1 (Continued)

Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 862 The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.A-1 (Continued)

Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C018.indd 862 11/24/08 12:32:27 PM

 Miscellaneous Components 863

Table XVIII.A-1 (Continued)

Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C018.indd 863 11/24/08 12:32:27 PM

 864 The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.A-1 (Continued)

Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C018.indd 864 11/24/08 12:32:28 PM

 Miscellaneous Components 865

Table XVIII.A-1 (Continued)

Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C018.indd 865 11/24/08 12:32:31 PM

 866 The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.A-1 (Continued)

Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C018.indd 866 11/24/08 12:32:32 PM

 Miscellaneous Components 867

Table XVIII.A-1 (Continued)

Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C018.indd 867 11/24/08 12:32:33 PM

 868 The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.A-1 (Continued)

Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C018.indd 868 11/24/08 12:32:35 PM

 Miscellaneous Components 869

Table XVIII.A-1 (Continued)

Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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78836_C018.indd 869 11/24/08 12:32:36 PM

 870 The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.A-1 (Continued)

Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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78836_C018.indd 870 11/24/08 12:32:37 PM

 Miscellaneous Components 871

Table XVIII.A-1 (Continued)

Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 872 The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.A-1 (Continued)

Sulfur-Containing Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C018.indd 872 11/24/08 12:32:41 PM

 Miscellaneous Components 873
ethyl chloride, and agrochemical residues from TDE,
Endrin®, chloro-2,2-bis-(4’-chlorophenyl)ethylene (TDEE),
Telodrin®, Thoidan®, and Dyrene® were reported in tobacco
smoke. Roberts et al. in 1975 (3224) listed 2783 components
identified in tobacco and tobacco smoke. In their report, they
listed thirty chloro compounds, two bromo-containing com-
pounds, two fluoro-containing compounds, and one iodo-
containing compound. Thirty-one halogenated compounds
were identified in tobacco smoke and twelve were identified
in tobacco, several were found in both tobacco and tobacco
smoke. In 1980, while noting that the number of confirmed
components exceeded 2500, Ishiguro and Sugawara (1884)
listed 1889 identified tobacco smoke components in their
monograph; seventeen were halogenated. In their review,
Ishiguro and Sugawara stated:
All of the halogenated compounds found in smoke are chlo-
rinated compounds. These probably originate from the chlo-
ride ions [3797] in the tobacco or from residual chlorinated
organic additives. The chlorine atom in methyl chloride
originates [712] mainly from inorganic chlorides.
They listed Cl, Br, I, and F as identified components in
tobacco smoke. In their review, Ishiguro and Sugawara also
examined several agrochemicals and their decomposition
products transferred to smoke. The distribution of the chlori-
nated organic chemicals was examined in detail. It was clear
to them that chlorinated organic agricultural chemicals pro-
duced the chlorinated compounds mentioned in their review
during smoking. They stated:
At present, the use of chlorinated organic insecticides has
been banned in many countries, and their residues in tobacco
have been decreasing every year. Organophosphorus types
and synthetic organic compounds which are less likely to per-
sist have become the mainstay of agricultural chemicals for
tobacco cultivation, displacing the chlorinated organic types.
Unfortunately, their prediction was not totally correct
as a great variety of chlorinated organic agrochemicals are
still being discovered and used today in parts of the world.
However, since 1969 the use of chlorinated pesticides has been
banned in the cultivation of tobacco in the United States. As a
result, l,l,l-trichloro-2-(4,4’-dichlorodipheny1)ethane (DDT)
and TDE in tobacco and in cigarette smoke have decreased
drastically. In the tobacco of a cigarette made in 1965, 13.4
ppm DDT and 20.2 ppm TDE were measured, and in the
tobacco of the leading cigarette brand made in 1993, only
0.02 ppm DDT and 0.013 ppm TDE were detected, a decrease
of more than 98% (999). The small amounts of residual DDT
and TDE in more recently produced cigarettes appear to
originate from imported tobaccos used for blended cigarettes
(1714). It is interesting to note the following: despite the fact
that DDT was banned from agronomic use on tobacco in the
United States in 1969, Chopra and his colleagues between
1969 and 1973 conducted exceptionally detailed studies on
the degradation products generated during the smoking pro-
cess from the p,p’-DDT in p,p’-DDT-treated cigarettes (703,
© 2009 by Taylor & Francis Group, LLC
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707–709, 711–714). Examination of the citations in the cata-
log (Table XVIII.B-3) of chloro compounds identified in the
smoke from DDT-containing tobacco indicates that Chopra
and his colleagues identified ten chloro compounds, includ-
ing transferred DDT.
New types of chlorinated organic agrochemicals are still
being developed. Their popularity and efficiency have not
been displaced by organophosphorus types of agrochemicals
or other synthetic organic compounds. Sakuma et al. (3394,
3397, 3398) in 1983 and 1984 reported on the identification
of numerous compounds in tobacco smoke; no halogenated
compounds were reported. IARC, in 1986 (1871), listed only
four halogen-containing compounds in tobacco and tobacco
smoke in their report on the evaluation of the carcinogenic
risk of chemicals to humans: vinyl chloride and the agri-
cultural chemicals, DDT, Captan®, and Endrin®. Of these
compounds, only vinyl chloride and DDT showed sufficient
evidence of carcinogenicity in experimental animals accord-
ing to the IARC criteria. Most recently in 2005, Eberhardt
(21A19) prepared an extensive review of pesticides used on
tobacco, the transfer rates of pesticides to MSS and side-
stream smoke (SSS), and decomposition products of pes-
ticide residues identified in MSS. In his review, much data
previously presented by Ishiguro and Sugawara (1884) were
presented and updated.
The vast majority of the halogenated compounds presented
in this chapter are covered in other chapters of this book, for
example, Chapters 4, 9, 10, 19, 20, and 21. One particular
group of halogenated compounds only reviewed in this chap-
ter is the dioxins. Dioxins are polychlorinated heterocycles.
The three forms found in tobacco and tobacco smoke are
polychlorodibenzo-p-dioxins, polychlorodibenzofurans, and
polychlorinated biphenyls. Another group of compounds that
is not reviewed elsewhere in the book is the Freon® com-
pounds. Green et al. (1375b) recently reviewed the various
chemicals used in the expansion of tobacco and their effect on
cigarette MSS properties. In their review, Green et al. (1375b)
discussed the use of various Freon® compounds for tobacco
expansion. Rix, in 1989, analyzed expanded tobacco for the
expansion agent Freon® 123 (4859). Additionally, sulfur
hexafluoride and perfluoropropane have been investigated as
alternate tobacco expanding agents (4860, 18B17). As a result,
these classes of compounds will not be discussed further in
this chapter and the reader is directed to the review by Green
et al. (1375b) and references from R.J. Reynolds Tobacco
Company (4859, 4860, 18B05, 18B06 18B08, 18B16, 18B17).
In 2002, Rodgman and Green (3300) reviewed the lit-
erature on tobacco smoke toxicants. In their review, they
discussed the polychlorodibenzo-p-dioxins and polychlo-
rodibenzofurans (PCDDs and PCDFs) identified in tobacco
and tobacco smoke. Rodgman and Green noted that among
the smoke toxicants conspicuous in their absence from all
toxicant lists except that of Fowles and Bates (1217) are the
polychlorodibenzo-p-dioxins (PCDDs) and polychlorodiben-
zofurans (PCDFs). The presence of dioxins in cigarette smoke
was first reported in 1980 by Crummett (854). There are at
least five other publications in which the presence of dioxins
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 874 The Chemical Components of Tobacco and Tobacco Smoke
(PCDDs and PCDFs) in cigarette tobacco or its MSS (3300) is
reported. These include publications by Muto and Takizawa
(2664), Ball et al. (177), Matsueda et al. (2490, 2491), and
Löfroth and Zebühr (2391). The smoke yield data of Muto and
Takizawa (2664) were obtained from a single smoking puff
that entirely consumed the cigarette and is clearly not appro-
priate for comparisons of MSS yields obtained by FTC or
CORESTA methods. The MSS and SSS data of Löfroth and
Zebühr (2391) were obtained from only one Swedish ciga-
rette brand. The PCDD and PCDF data reported by Matsueda
et al. (2491) were for the amount of these compounds con-
tained in the cigarette tobacco, rather than the smoke. The
smoke yield data for the Ball et al. (177) and Matsueda et al.
(2490) experiments were similar. The Ball et al. data were
collected and analyzed by a well-validated method, and the
laboratory where the analyses were performed, that is, ERGO
Forschungsgesellschaft mbH, Hamburg, has been accredited
by the World Health Organization (WHO) for dioxin analy-
sis (177). The analytical data of Ball et al. (177) represent
results from the ten top-selling brands in Germany during the
fourth quarter of 1989. The ERGO scientists chose to present
individual data on each of the tested cigarettes. It should be
noted that the most toxic isomer, 2,3,7,8-tetrachlorodibenzo-
p-dioxin (TCDD), was not detected in any of the samples and
additionally, not every isomer present was quantifiable in each
product tested. The total amount of total PCDDs and PCDFs
was 7.50 and 2.98 pg/cigarette, respectively (see Table  2 of
3300). In 1998, Radovanovic  ´ and Mišic 
´ (18B15) examined the
MSS of Yugoslavian cigarettes for polychlorinated biphenyls
(PCBs). They identified ten PCBs. The level of PCBs identi-
fied ranged from less than 1 ng/g to 78.1 ng/g of smoke con-
densate (18B15). Generally, the levels of PCBs in MSS are
considerably less than the PCDDs and PCDFs (3715).
Dioxins are not typical herbicides used on tobacco. So
where do they come from and why are they so important?
2,4-Dichlorophenoxyacetic acid (2,4-D) was introduced
in 1944 as the first of the phenoxy herbicides, phenoxyacetic
acid derivatives, or hormone weed killers. The phenoxy her-
bicides have complex mechanisms of action resembling those
of auxins (growth hormones). They affect cellular division,
activate phosphate metabolism, and modify nucleic acid
metabolism. These herbicides are highly selective for broad-
leaf weeds and are translocated throughout the plant. 2,4-D
provided most of the impetus in the commercial search for
other organic herbicides in the 1940s. Several compounds
belonged to this group, of which 2,4-D and 2,4,5-trichlo-
rophenoxyacetic acid (2,4,5-T) are the most familiar. Other
important compounds in this group are 4-(2,4-dichloro-
phenoxy)butyric acid (2,4-DB), 2-methyl-4-chlorophenoxy-
acetic acid (MCPA), and 2-(2,4,5-trichlorophenoxy)pro-
pionic acid (Silvex® or Fenoprop®) [Ware and Whitacre
(18B18)].
2,4-D, MCPA, and 2,4,5-T have been used worldwide
for years in very large volume. The latter product, 2,4,5-T,
used mainly to control woody perennials, became the sub-
ject of extended investigation, particularly because of its use
in Vietnam in combination with 2,4-D as Agent Orange.
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Certain samples were found to contain small amounts of a
highly toxic impurity, TCDD (2,3,7,8-tetrachlorodibenzo-p-
dioxin), commonly referred to as tetrachlorodioxin, or dioxin.
Although alterations in manufacturing procedures reduced
the dioxin content to minimal levels, 2,4,5-T registrations
were cancelled and the product voluntarily removed by the
manufacturers in 1985 (18B18).
2,4-D has been and continues to be one of the most use-
ful herbicides ever developed. More than 33 million pounds
manufactured in the United States are used each year in
thirty-five ester and salt forms. In agriculture, it is used on
cereal, grain crops, and sugar cane for the control of broad-
leaf weeds, and on rights-of-way, turf and lawns, and in forest
conservation programs. The manufacturing process for
2,4-D used in the United States does not result in any level of
tetrachlorodioxin contamination. Other members of the phe-
noxys in wide use are 2-(2,4-dichlorophenoxy)propionic acid
(Dichlorprop® or 2,4-DP), 4-(4-chloro-2-methylphenoxy)
butanoic acid (MCPB), and 2-(4-chloro-2-methylphenoxy)
propanoic acid (Mecoprop® or MCPP) (18B18). None of
these compounds [2,4-DB, 2,4-DP, MCPB, MCPA, MCPP,
2-(2,4,5-trichlorophenoxy)propionic acid] has been found in
tobacco or tobacco smoke.
Of the three forms of dioxins found in tobacco and tobacco
smoke, the polychlorodibenzo-p-dioxins (PCDDs, PCDFs,
and PCBs) are a group of chemical compounds that are among
the most toxic and hazardous pollutants in the environment.
The PCDDs, PCDFs, and PCBs compounds, collectively
referred to as dioxins, are impurities associated with certain
end products resulting from the treatment of chlorinated ben-
zenes at elevated temperature and pressure under alkaline con-
ditions. The most notable contaminant of the group is TCDD
(2,3,7,8-tetrachlorodibenzo-p-dioxin) which can be formed
along with other dioxin compounds during the manufacture
of several commercially important products such as the her-
bicide 2,4,5-T, the fungicide pentachlorophenol, and the ger-
micide Hexachlorophene® (18B19). Numerous investigators
have found PCDDs, PCDFs, and PCBs in tobacco as well as
tobacco smoke [1457, Gichner et al. (18B14), Djordjevic et al.
(1000, 1006), Radovanovic ´ and Mišic ´ (18B15)].
Suspicions of the possible long-term health hazards of diox-
ins arose after it was found that 2,4,5-T was teratogenic in the
rat and mouse [Courtney et al. (18B10)]. Shortly thereafter it
was discovered that the 2,4,5-T sample used in this study con-
tained about 30 ppm TCDD (18B10). It was primarily the report
by Courtney et al. (18B10) implicating TCDD as a contami-
nant of 2,4,5-T that led to its further evaluation for teratogenic-
ity [Courtney and Moore (18B11)] and its eventual testing for
mutagenicity. These and other similar reports published during
the late 1960s and early 1970s also stimulated toxicological
studies on other dioxin derivatives as well as studies dealing
with issues such as environmental contamination and move-
ment and analytical detection of these compounds. Numerous
detailed reviews summarizing work in these areas have been
published. The latest and perhaps the most comprehensive
review was prepared by the World Health Organization in
2002 (18B07). Additionally, IARC has prepared a monograph
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 Miscellaneous Components 875
on dioxins (7A03) and Wassom et al. (18B19) reviewed the
genetic toxicology of polychlorodibenzo-p-dioxins.
Dioxins are produced inadvertently as a by-product of
chemical production or during combustion and are wide-
spread pollutants in the environment. They are ubiquitous.
The biggest source of PCDDs, PCDFs, and PCBs is the
large-scale burning of municipal and medical waste. Other
sources include:
• The production of iron and steel;
• Backyard burning of household waste, especially
plastics;
• Fuel burning, including diesel fuel and fuel for
agricultural purposes and home heating;
• Wood burning, especially if the wood has been
chemically treated;
• Electrical power generation; and
• Tobacco smoke.
Dioxins can also be produced from natural processes, such
as forest fires, explosions, and volcanic eruptions. Most diox-
ins are introduced to the environment through the air. The
airborne chemical can attach to small particles that can travel
long distances in the atmosphere. PCDDs, PCDFs, and PCBs
are found in very small amounts in the environment, includ-
ing in the air, water, and soil. As a result they are also present
in some foods. They can also present a health risk at elevated
dosages. As for tobacco smoke, the dosage of dioxins from
cigarettes is extremely low. Exposure estimates suggest that
the smoking of twenty cigarettes per day contributes approxi-
mately 2% to 4% of the total daily exposure to dioxins for a
70 kg adult (177). The major source of exposure to PCDDs,
PCDFs, and PCBS is the diet [Canady et al. (18B07)].
Rodgman and Green (3300) noted in their review of MSS
toxicants that certain dioxins are antitumorigens. Slaga and
DiGiovanni (3685) summarized the studies in which dioxins
were shown to interfere with the enzyme pathways responsible
for tumorigenesis of several of the most potent polycyclic aro-
matic hydrocarbons (PAHs). The dioxins were not listed as MSS
toxicants in previous tabulations of MSS toxicants reviewed
by Rodgman (3255, 3255a, 3257, 3265) and Rodgman and
Green (3300). In fact, only one MSS toxicant list issued since
1990, that of Fowles and Bates (1217), has included the dioxins
even though their presence in MSS was known in 1980 (854).
Dioxins are antitumorigenic to DMB[a]A (7,12-dimethylbenz[a]
anthracene), MC (3-methylcholanthrene, more recently named
1,2-dihydro-3-methylbenz[j]aceanthrylene), B[a]P (benzo[a]pyr-
ene), 7-MB[a]A (7-methylbenz[a]anthracene), 12-MB[a]A (12-
methylbenz[a]anthracene), 5-MeC (5-methylchrysene), and DB
[a,h]A (dibenz[a,h]anthracene) [Berry et al. (18B04), Cohen et al.
(18B09), DiGiovanni et al. (976, 18B12)].
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The IARC classification of carcinogenicity places twenty-five
halogen-containing compounds in tobacco or tobacco smoke in
Groups 1, 2A, 2B, and 3. Table XVIII.B-1 lists the individual
halogen-containing chemicals (agents) and families of chemi-
cals (groups of agents) identified in tobacco and tobacco smoke.
IARC lists 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and
vinyl chloride as Group 1 human carcinogens. Trichloroethylene,
epichlorohydrin [(chloromethyl)oxirane], ethylene dibromide, and
polychlorinated biphenyls (PCBs) are listed by IARC as Group 2A
(probably carcinogenic to humans). Ten halogen-containing com-
pounds are listed in Group 2B (possibly carcinogenic to humans):
Chlordane®, p-chloroaniline, chloroform, chlorophenoxy herbi-
cides, chlorothalonil (2,4,5,6-tetrachloro-1,3-benzenedicarbo-
nitrile), DDT (p,p’-DDT), dichloromethane (methylene chloride),
1,3-dichloropropene, Heptachlor®, and hexachlorobenzene. Nine
halogen-containing compounds are listed in Group 3 (not classifi-
able as to carcinogenicity to humans): chloroethane, m-dichloro-
benzene, o-dichlorobenzene, 1,2-dichloropropane, Hexachloro-
phene®, Methoxychlor®, methyl iodide, polychlorinated diben-
zofurans, and 1,1,1-trichloroethane.
There are numerous analytical methodologies to identify
and quantify halogenated compounds in tobacco and smoke.
The method of analysis will vary among the halogenated
compounds and particularly the pesticide types. Sources
of methods include the FDA Pesticide Analytical Manuals
(PAMs) I and II (18B13), the FDA Index of Residue Analytical
Methods (RAM) (18B13), the methods in the Journal of the
Association of Official Analytical Chemists (18B02, 18B03),
and methods found in journal articles. Generally, the pre-
ferred methods of analysis involve gas chromatography (GC),
liquid chromatography (LC), or GC-mass spectrometry (MS)
techniques. Flame ionization detectors (FID) are normally
used for quantitative analysis of halogen-containing organ-
ics, while electron capture detectors (ECD) are preferred for
quantitative determination of PCDDs, PCDFs, PCBs and
other pesticides [Radovanoviic  ´ and Mišiic ´ (18B15)].
There are 242 identified halogenated compounds in
tobacco and/or tobacco smoke. As seen in Table XVIII.B-2,
the vast majority (192 compounds) contain chlorine only.
Over 85% of all the halogenated compounds found in tobacco
and tobacco smoke are either halogenated agrochemicals,
impurities found in the agrochemicals (PCDDs, PCDFs,
PCBs), or decomposition products from the agrochemicals.
Table XVIII.B-3 lists the 242 halogenated compounds identi-
fied in tobacco and/or tobacco smoke. In a few cases, a halo-
genated component has been identified in tobacco substitute
smoke. Table XVIII.B-3 is divided by halogen type (chloro-,
bromo-, iodo-, and fluoro-compounds) and includes several
halogenated compounds with two or more halogens (mixed
halogenated compounds).
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 876 The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.B-1
Halogenated Components Identified in Tobacco and Tobacco Smoke (18A04)
IARC Group IARC Chemical Name
Classification (Number of Compounds) CAS No. IARC Volume, Date Comment by IARC
Group 1: 2,3,7,8-Tetrachlorodibenzo-para-dioxin 1746-01-6 Vol. 69, 1997 Overall evaluation upgraded from
2A to 1 with supporting evidence
from other relevant data.
Vinyl chloride 75-01-4 Vol. 19, Suppl. 7, Vol. 97,
in preparation
Group 2A: Trichloroethylene 79-01-6 Vol. 63, 1995
Epichlorohydrin 106-89-8 Vol. 11, Suppl. 7, Vol. 71, 1999 Overall evaluation upgraded from
2B to 2A with supporting evidence
from other relevant data.
Ethylene dibromide 106-93-4 Vol. 15, Suppl. 7, Vol. 71, 1999 Overall evaluation upgraded from
2B to 2A with supporting evidence
from other relevant data.
Polychlorinated biphenyls (11) 1336-36-3 Vol. 18, Suppl. 7, 1987
Group 2B: Chlordane 57-74-9 Vol. 79, 2001
p-Chloroaniline 106-47-8 Vol. 57, 1993
Chloroform 67-66-3 Vol. 73, 1999
Chlorophenoxy herbicides (5) Vol. 41, Suppl. 7, 1987
Chlorothalonil 1897-45-6 Vol. 73, 1999
DDT [p,p’-DDT] 50-29-3 Vol. 53, 1991
Dichloromethane [methylene chloride] 75-09-2] Vol. 71, 1999
1,3-Dichloropropene 542-75-6 Vol. 41, Suppl.7, Vol. 71, 1999
Heptachlor 76-44-8 Vol. 79, 2001
Hexachlorobenzene 118-74-1 Vol. 79, 2001
Group 3: Chloroethane 75-00-3 Vol. 52, Vol. 71, 1999
m-Dichlorobenzene 541-73-1 Vol. 73, 1999
o-Dichlorobenzene 95-50-1 Vol. 73, 1999
1,2-Dichloropropane 78-87-5 Vol. 41, Suppl. 7, Vol. 71, 1999
Hexachlorophene 70-30-4 Vol. 20, Suppl. 7, 1987
Methoxychlor 72-43-5 Vol. 20, Suppl. 7, 1987
Methyl iodide 74-88-4 Vol. 41, Suppl. 7, Vol. 71, 1999
Polychlorinated dibenzofurans (18) Vol. 69, 1997
1,1,1-Trichloroethane 71-55-6 Vol. 20, Suppl. 7, Vol. 71, 1999

Agents, groups of agents, mixtures and exposure circumstances (associated with tobacco) evaluated in IARC Monographs Volumes 1-95. This list
contains all agents evaluated as of November-December 2006 that are considered: Carcinogenic to humans (Group 1), probably carcinogenic to
humans (Group 2A), and possibly carcinogenic to humans (Group 2B). For details of the evaluation, the relevant Monograph should be consulted, see
http://monographs.iarc.fr/ENG/Classification/crthgr01.php. Those agents listed have been identified in tobacco or tobacco smoke.

Table XVIII.B-2
The Distribution of Halogenated Components Identified in Tobacco and Tobacco Smoke
Total Tobacco Agrochemical/
Halogen No. Compounds Tobacco Smoke and Smoke Decomposition Product Other
Chloro 192 123 111 42 171 21
Bromo 12 11 6 5 7 5
Iodo 4 3 2 1 2 2
Fluoro 14 13 3 2 9 5
Mixed halogens 20 19 9 8 11 9
Total 242 169 131 58 200 42

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 Miscellaneous Components 877

Table XVIII.B-3
Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 878 The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.B-3 (continued)

Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Miscellaneous Components 879

Table XVIII.B-3 (continued)

Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 880 The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.B-3 (continued)

Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Miscellaneous Components 881

Table XVIII.B-3 (continued)

Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 882 The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.B-3 (continued)

Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Miscellaneous Components 883

Table XVIII.B-3 (continued)

Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 884 The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.B-3 (continued)

Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Miscellaneous Components 885

Table XVIII.B-3 (continued)

Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 886 The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.B-3 (continued)

Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Miscellaneous Components 887

Table XVIII.B-3 (continued)

Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 888 The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.B-3 (continued)

Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Miscellaneous Components 889

Table XVIII.B-3 (continued)

Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 890 The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.B-3 (continued)

Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 Miscellaneous Components 891

Table XVIII.B-3 (continued)

Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

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 892 The Chemical Components of Tobacco and Tobacco Smoke

Table XVIII.B-3 (continued)

Halogenated and Related Components in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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 19 Fixed and Variable Gases
This chapter deals with gases found in tobacco and tobacco
smoke. The gases discussed will be mainly inorganic and not
organic gases. Two types of gases will be discussed, fixed
gases and variable gases.
In the atmosphere, gases, the volume percentages of
which do not change, are called fixed gases. Table XIX-1
gives the volume percentages of these fixed gases. At alti-
tudes below 100 km, nitrogen (N2) makes up about 78% of all
atmospheric gas by volume and oxygen (O2) makes up about
21%. The volume percentages of these fixed gases are con-
stant with increasing altitudes, and the partial pressures of
N2 and O2 are constant fractions of air pressure. Together, N2
and O2 make up 99% of all gases in the atmosphere by vol-
ume. Argon (Ar) at 0.93% makes up the bulk of the remain-
ing 0.97%, with neon (Ne), helium (He), krypton (Kr), and
xenon (Xe) present in trace quantities (19A04). As a result,
the concentrations of fixed gases are the same not only in
the atmosphere but in every material present on the Earth’s
surface where atmospheric gases reside.
Variable gases are gases with volume percentages that
change with time and location. For example, water vapor in
different areas of the world varies with climatic conditions
and geography. Radon is a variable gas as it occurs in only
specific areas of the world. The major variable gases are
water vapor (H2O), carbon dioxide (CO2), carbon monoxide
(CO), ozone (O3), sulfur dioxide (SO2), nitric oxide (NO),
nitrogen dioxide (NO2), low molecular weight hydrocarbons,
and simple aromatic chemicals. Much of the variability in
the concentration of these gases in the atmosphere arises
from the combustion of fossil fuels. Table XIX-2 summa-
rizes the volume percentages of some variable gases in a
clean atmosphere and a polluted atmosphere, such as urban
or industrial areas. Water vapor can vary tremendously and
is dependent primarily on the environment. For example,
water vapor in the atmosphere is always higher in areas
near water and always lower in desert areas. As can be seen,
some of the inorganic and organic gases change apprecia-
bly (CO, SO2, NO, NO2, organic gases) while others change
minimally (CO2, O3), even in polluted atmospheres (19A04).
For example, the concentration of CO2 at point sources such
as smoke stacks can be very elevated. Ozone concentrations
during electrical storms can be elevated to the point that its
characteristic odor is noticeable. As a result they are termed
variable gases.
Again, just as the fixed gases are present in nearly every
material present on the Earth’s surface, variable gases are
also present in all materials that are porous and can be found
on the surfaces of many other materials.
Tobacco contains all of the fixed gases that are present in
the atmosphere. It also contains a variety of variable gases
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78836_C019.indd 893
because it is grown in areas lacking a pristine atmosphere.
Tobacco is often treated with agrochemicals (fertilizers, pes-
ticides, herbicides, etc.). As such, these chemicals can decom-
pose and create residues in or on the tobacco. Additionally, as
tobacco is often cured in atmospheres that contain pollutants
and/or combustion gases, for example, NO, NO2, SO2, SO3,
the concentration of variable gases in the leaf can be elevated.
Nitrogen and oxygen are the most plentiful fixed gases found
in tobacco. Although the other fixed gases Ar, Ne, He, Kr,
and Xe have not been identified in tobacco there is no reason
to believe that they are not present. The variable gases found
in tobacco include ammonia (NH3), bromine (Br2), CO2, CO,
chlorine (Cl2), fluorine (F2), iodine (I2), phosgene (COCl2),
hydrazine (H2N-NH2), hydrogen cyanide (HCN), isocyanic
acid (H-N=C=O), nitrous oxide (N2O), NO, NO2, mixed
nitrogen oxides [N2O + NO + NO2] or NOx, phosphine (PH3),
radon (Rn and 222Rn), and H2O. Biochemically, some of these
variable gases are produced by the plant to regulate growth
processes, for example, NO, NO2, while others are formed,
for example, NH3 via fertilization, or absorbed by the plant
(H2O) and used as energy sources. Some of the variable gases
are found as plant residues from the atmosphere (Rn), while
some are residues from water sources (halogens), agrochemi-
cals (phosgene, hydrazine, HCN, isocyanic acid, phosphine,
etc.) or from other environmental sources, for example, SO2.
The concentration of the fixed and variable gases in
tobacco smoke is not directly related to the concentration
of these gases in tobacco. As tobacco smoke is the result of
combustion and pyrolysis of tobacco, the concentration and
types of fixed and variable gases formed vary considerably.
Over the years, several scientific articles and reviews have
been published that catalog the fixed and variable gases found
in tobacco and tobacco smoke (172, 1140, 1067, 1140, 1971,
2068, 2170, 2799a, 3224, 3797, 4012, 4332, 19A05). One of
the earliest articles that identified certain fixed and variable
gases in tobacco smoke was published by Kosak (2170) in
1954. Kosak listed O2, NH3, CO, CO2, HCN, other “cyanides”
(?), hydrogen sulfide (H2S), thiocyanic acid (?), “chlorides”
(?), “nitrates” (?), and “unsaturated hydrocarbons.” The ques-
tion marks associated with some of the compounds listed by
Kosak indicate that he did not consider the evidence in the
literature to be definitive proof of the identity of the compo-
nent. It is conceivable that the designation “chlorides” (?) and
“nitrates” (?) could have indicated the presence of chlorine,
NO, NO2 and other nitrogen oxides (NOx) in tobacco smoke.
Johnstone and Plimmer (1971) reviewed the constitu-
ents of tobacco and tobacco smoke in 1959 and listed CO,
CO2, carbonyl sulfide (COS), NH3, carbon disulfide (CS2),
cyanogen [(CN)2], hydrogen cyanide (HCN), thiocyanogen
[(SCN)2], NO, and numerous small saturated and unsaturated
893
11/13/08 5:43:18 PM
 894 The Chemical Components of Tobacco and Tobacco Smoke

Jarrell and de la Burde (1924) and Keith and Tesh (2068),

Table XIX-1 who reported in 1965 that the O2 content in whole MSS is
Volume Percentages of Fixed Gases in the Earth’s a function of air entering through the burning cone of the
Atmosphere cigarette, part of which is consumed during combustion, and
diluting air entering through the cigarette paper. The ciga-
Gas Name Chemical Formula Percent rette burning rate, dictated by the cigarette rod packing den-
Molecular nitrogen N2 78.08 sity, the tobacco type employed, and the cigarette paper air
Molecular oxygen O2 20.95 permeability, affected O2 consumption. Nitrogen and argon
Argon Ar 0.93 do not react with tobacco constituents during the burning as
Helium He 0.0015
Neon Ne 0.0005
they are inert gases. Their concentrations were affected by
Krypton Kr 0.0001 the air entering through the burning cone, mainly the dilut-
Xenon Xe 0.000005 ing air. Jarrell and de la Burde (1924) found that the burning
zone of a cigarette represented a reducing atmosphere. The
H2 in the whole smoke was derived nearly exclusively from
hydrocarbons as components of the vapor phase of cigarette the burning of tobacco. During burning, certain tobacco
mainstream smoke (MSS). components split off elementary hydrogen, which for the
Keith and Tesh reported in 1965 on the measurement of most part formed water with available oxygen. The presence
the total MSS issuing from a burning cigarette (2068). By of 8% H2 (by volume) in the gas leaving the burning cone
using a simple puffing mechanism that employed a cold trap was indicative of the existence of a reducing atmosphere in
packed with 5 Å molecular sieve pellets, they were able to the fire cone. The large concentrations of both CO and CO2
quantitatively measure the total vapor mixture from a burn- relative to air indicated that several combustion and pyrolysis
ing cigarette. This quantity, when combined with the sepa- processes were occurring in the burning cigarette. The low
rately trapped particulate material, provided a measure of ratio of CO2 to CO indicated that incomplete combustion of
the total effluent. It was found, contrary to previous thinking, tobacco was occurring. The ratio of CO2 to CO is consid-
that the vapor components of smoke comprised over 95% of ered to be an index (3482) of the combustibility of tobacco.
the weight of material collected from a burning cigarette. Generally, the ratio of CO2 to CO is less than three in nonfil-
By far the greatest proportion of the collected weight of the tered cigarettes.
total MSS vapor phase was contributed by the air entering In 1968, Stedman reviewed the chemical composition of
the cigarette. tobacco and tobacco smoke (3797). The review noted that gas-
Wynder and Hoffmann in 1967 (4332) reviewed the known eous NH3, I2, and H2O were identified constituents of tobacco.
constituents of the particulate and vapor phase of MSS. It also listed CO, CO2, NH3, CS2, COS, Cl2, F2, H2S, HSCN,
Chapter VIII of their book provided historical information and (SCN)2 as compounds present in the vapor phase of MSS.
on our understanding of cigarette combustion processes and In 1968, Elmenhorst and Schultz (1140) reported on the
the composition of the vapor phase of tobacco smoke at that concentrations of various inorganic gaseous components in
time. Wynder and Hoffmann cited the pioneering work of the vapor phase of MSS (Table XIX-3).

Table XIX-2
Volume Percentages of Some Variable Gases (Inorganic and Organic) in the Atmosphere (19A04)
Gas Name Chemical Formula Clean Atmosphere (ppbv) Polluted Atmosphere (ppbv)
Inorganic
Water vapor H2O 3000-4.0 × 107 5.0 × 106-4.0 × 107a
Carbon dioxide CO2 365000 365000
Carbon monoxide CO 40-200 2000-10000
Ozone O3 10-100 10-350
Sulfur dioxide SO2 0.02-1 1-30
Nitric oxide NO 0.005-0.1 0.05-300
Nitrogen dioxide NO2 0.01-0.3 0.2-200
Organic
Methane CH4 1800 1800-2500
Ethane C2H6 0-2.5 1-50
Ethene C2H4 0-1 1-30
Formaldehyde HCHO 0.1-1 1-200
Aromatics C6H5R — 1-30
ª 4.0 × 107- indicates that the volume percentage is negligible, on average.
R = hydrogen or alkyl functionality

© 2009 by Taylor & Francis Group, LLC

78836_C019.indd 894 11/13/08 5:43:20 PM

 Fixed and Variable Gases 895

particulate matter and 67.5 mg was vapor-phase compounds,

Table XIX-3
Fixed Gases in the Vapor Phase of MSS (1140)
Compound Concentration/Cigarette
H2 0.7-1.8 vol %
O2 11-17 vol %
N2 67-78 vol %
Ar 0.8 vol %
H2O 6-9 mg
In 1975, Roberts et al. (3224) reported on R.J. Reynolds
Tobacco Company’s (RJRT) literature study of tobacco and
smoke components. RJRT had been collecting information
from the literature and conducting extensive research on the
identification of chemicals in tobacco and smoke since the
earlier 1950s. As of 1975, RJRT had compiled a listing of
2783 components from tobacco, tobacco smoke, and other
smoking products. Of these compounds 1235 were tobacco
isolates, 2266 were tobacco smoke components, and 356 had
been identified from other smoking products. Approximately
one-half of all the tobacco and smoke components were first
isolated by RJRT research personnel. The lists were divided
into functional group classes, including fixed and variable
gases found in tobacco and smoke. Twenty-five gases had
already been identified in tobacco and smoke by 1975. The
number of fixed and variable gases identified in tobacco and
tobacco smoke has not changed substantially since then.
Ishiguru and Sugawara in 1980 (1884) cataloged the com-
ponents of tobacco smoke. In their review, they listed 1889
components of tobacco smoke [see Table 1 in (1884)]. They
commented that the number could be about 2500 but they
had omitted those components that were only partially iden-
tified. Among the components that they discussed were the
fixed and variable gases in tobacco smoke.
In 1982, Dube and Green (1067) calculated the contribu-
tion of the fixed gases from 500 mg of unfiltered cigarette
MSS. From 500 mg of whole smoke, 22.5 mg was the wet
of which ~10% (or 6.75 mg) was water vapor, ~80% (or 54 mg)
was CO2, and ~10% was organic compounds. The remaining
410 mg of whole smoke contained 310 mg of N2, 65 mg of
O2, 20 mg of CO, an additional 5 mg of CO2, 4 mg of Ar, and
1 mg of H2. Similar analyses were conducted by Keith and
Tesh in 1965 (2068), Norman in 1977 (2799a), and Hoffmann
and Hecht in 1990 [see Table 1 in (1727)]. Table XIX-4 illus-
trates the data on fixed and variable gases in whole tobacco
smoke that was provided by these investigators.
In 1999, Norman (19A05) and Baker (172) reviewed the
literature on cigarette design and materials and smoke chem-
istry, respectively. Their works represent the most recent and
comprehensive reviews on these subjects. Baker discussed the
present fundamental knowledge of cigarette combustion and
smoke formation including how the concentrations of fixed
gases, for example, O2 and H2, fluctuate during cigarette com-
bustion and how variable gases, for example, CO and CO2,
are formed. Norman discussed the complicated field of ciga-
rette design and how each design variable (tobacco type, ciga-
rette shape, weight, and size, cigarette paper properties, filter
designs, etc.) affects cigarette performance and ultimately
cigarette smoke yields (including fixed and variable gases).
XIX.A Analytical Methods
In 1996, Green and Rodgman (1373) summarized all the his-
torical and currently used analytical methods for the identifi-
cation of chemicals isolated from tobacco and tobacco smoke.
Their review is so complete and so well documented that the
reader is directed to read their review article to determine the
analytical method best suited for the analysis of a particular
chemical constituent in tobacco and smoke. All of the past
and current methods for the determination of fixed and vari-
able gases in tobacco and tobacco smoke can be found in
their article and will not be included in this chapter. Only
a few specific examples of analytical methods for the most
important variable gases will be provided (1884).

Table XIX-4
Major Fixed and Variable Gases in Non-Filtered Whole Tobacco Smoke
Keith and Tesh (2068) Dube and Green (1067) Norman (2799a) Hoffmann and Hecht (1727)
Component mg/cig (%) mg/cig (%) % only mg/cig (%)
Nitrogen 295 (67.2) 310 (62a) 58 280-320 (56-64b)
Oxygen 66.8 (13.3) 65 (13) 12 50-70 (11-14)
Carbon dioxide 68.1 (9.8) 59 (11.8) 13.0 45-65 (9-13)
Carbon monoxide 16.2 (3.7) 20 (4.0) 3.5 14-23 (2.8-4.6)
Water 5.8 6.75 (1.4) 1 7-12 (1.4-2.4)
Argon 5.0 (0.8) 4 (0.08) 0.5 (Ar + H2) 5 (1.0)
Hydrogen 0.7 (2.2) 1 (0.2) — 0.5-1.0
Total weight (or %) 457.6 (97) 465.75 (93.2) 88 401.5-496 (81.7-99)
a Percent of total tobacco smoke generated based on 500 mg of whole smoke (1067).
b Number in parentheses represents % of individual compound identified in fixed gases from whole smoke (1727).

© 2009 by Taylor & Francis Group, LLC

78836_C019.indd 895 11/13/08 5:43:21 PM

 896 The Chemical Components of Tobacco and Tobacco Smoke
Although there is no standard International Organization
for Standardization (ISO) or U.S. Federal Trade Commission
(FTC) method for the analysis of fixed gases in cigarette
smoke, fixed gases are normally analyzed by mass spectrom-
etry (MS), gas chromatography (GC), or GC-MS. Generally,
the fixed gases, such as N2, O2, Ar, He, and H2, have been
determined chromatographically with separation based on
molecular size. A molecular sieve packing is normally used
in a stainless steel packed column. Samples are introduced
with either a gas-tight syringe or a sampling valve with a fixed
volume loop. Upon injection, the sample is swept through a
gas chromatograph with carrier gas. After separation in the
column, components are quantified based on the difference
in thermal conductivity between the carrier gas and the com-
ponent. For the analysis of H2 and He, argon is used as the
carrier. Helium is used for all the other gases, such as N2
and O2. Detection limits using a thermal conductivity detec-
tor are typically 0.01% by volume (19A08). Gas samples can
be analyzed by MS via a gas inlet port on the mass spec-
trometer. Methods for the determination of fixed gases in
cigarette smoke have been reported by Routh (19A06) and
Reynolds and Wheeler (3120). There are several methods
for the analysis of the major variable gases from tobacco
smoke, for example, CO, CO2, NO, NO2, HCN, and NH3.
The current standard methods approved by the ISO, FTC,
and Cooperation Centre for Scientific Research Relative to
Tobacco (CORESTA) for the determination of the variable
gases are described by Counts et al. along with analytical
results from a recent worldwide market sample of cigarette
brands (19A02, 19A03).
XIX.A.1 Carbon Dioxide (CO2)
and Carbon Monoxide (CO)
CO2 is a major vapor-phase MSS component exceeded only
by N2. Its concentration is about 10% of the weight of the
whole tobacco smoke (4145), similar to that of O2. The con-
centration of CO is next highest, being about 4% (4145). The
ratio of CO2 to CO is considered to be an index (3482) of the
combustibility of tobacco. The currently approved methods
for the determination of CO are ISO Standard Methods 3308,
3402, 4387, 8454, 10315, and 10362-1. In these methods, CO
is determined by non-dispersion infrared (NDIR) spectros-
copy (19A02).
Historically, GC (474, 2123, 2662, 4145) and NDIR spec-
troscopic analysis (781, 782, 4251, 4252) have generally been
the preferred methods for analysis of CO2 and CO in MSS,
but an electrochemical transducer (ECT) method (447) has
also been used for the analysis of CO, in which the electro-
chemical reaction during oxidation by catalysis is converted
to electrical signals. Sample treatments before GC or NDIR
© 2009 by Taylor & Francis Group, LLC
78836_C019.indd 896
analyses, such as oxidation (474, 4145) of CO to CO2 with
iodine pentoxide, reduction (2123, 2124) of CO to CH4 with
a Ni catalyst, and separation (2634) by lowering the column
temperature to -70°C have also been studied. Gas chromatog-
raphy (2662) with 5 Å molecular sieves as the packing mate-
rials has also been employed. The levels of both CO2 and CO
in smoke increase (4251) as the number of puffs increases.
The amounts of these combustion gases produced in the early
puffs of a cigarette are lower than those analyzed at the end
of a cigarette during smoking (4251, 4252). The relationship
to the length of the cigarette is such that the concentrations
of these components in the vapor phase decrease (3881,
3883) with increasing length, and this can be explained by
the reduction in the amount of tobacco burnt and diffusion
of CO from the wrapper during smoking (19A05). Tobacco
quality is an important factor in terms of the amount of CO
and CO2 produced during cigarette combustion. The amount
of CO produced (474, 3088) is greater for low- to medium-
grade tobaccos, and the amount of CO2 increases (474) as
tobacco quality becomes higher. Experiments with 18O as the
source of atmospheric oxygen indicated that more than 50%
of the oxygen atoms in the CO2 and CO molecules come from
the atmosphere (1884).
XIX.A.2 Nitrogen Oxides (NO, NO2, N2O, NOx)
NOx in tobacco smoke has been quantified by calorimetric
analyses (189, 3441, 3720), such as the Saltzman method
(19A07), and by the chemical emission method (2122), which
has been shown to be a rapid method for quantification
(1884). Most of the NOx present in fresh MSS is NO, only
a small amount of NO2 is present (189, 816, 2803). The con-
centration of NO2 in MSS increases (189, 2803, 3691) with
the age of the smoke, and can reach levels of 200 ppm after
60 seconds (189). NO2 formation is believed to result from
the auto-oxidation of NO. It has also been suggested that
some of the NO2 produced by oxidation is converted (2941,
4058) to methyl nitrite through a reaction with methanol in
the smoke (1884). Predominate precursors of NO are nitrates
(189) and other N-containing compounds in the tobacco. N2O
(2941) and HNO3 (4058) have also been reported as compo-
nents of MSS in addition to the above compounds (1884). The
currently preferred method for the determination of NOx is
chemiluminescence (1930, 19A02).
XIX.A.3 Hydrogen Cyanide (HCN)
HCN in smoke has been analyzed by colorimetry (110, 779,
780, 3088), by the ion selective electrode method (3482), and
by gas chromatography (513). An analysis of HCN in tobacco
smoke by Vickroy and Gaunt (4053) illustrated that HCN can
vary from 144 to 351 µg/cigarette depending on the brand of
11/13/08 5:43:21 PM
 Fixed and Variable Gases 897
cigarettes. The concentration of HCN in MSS increases (110)
with puff number similar to other MSS components. HCN
is present in both the vapor phase and the particulate phase
of MSS (110). Considerable amounts of HCN have also been
found in cigarette butts (110, 779, 780). Today, the preferred
method for the determination of HCN in the vapor and par-
ticulate phase of MSS is colorimetry. HCN is converted to
cyanogen chloride, treated with pyridine, and complexed with
diethyl acetone dicarboxylate (779, 780, 3145). Schmeltz and
Hoffmann (3491) found that tobacco smoke contains cyanogen
and that up to about 5% of the HCN analyzed was produced
by conversion of HCN to cyanogen during analysis (1884).
XIX.A.4 Ammonia (NH3)
The preferred method for the determination of NH3 in MSS is
currently ion exchange chromatography (IEC) (2681a, 19A02).
In this method, NH3 is collected from Cambridge pads and
sulfuric acid traps and then analyzed by IEC (19A02). Previous
methods for the analysis of NH3 in MSS, such as titration and
colorimetry, suffered from interferences (2724, 2787, 19A01.),
principally low-boiling amines. Quantification of NH3 by
means of selective electrodes (3693) has been attempted, but
the results were affected (475) by methylamine. Gas chroma-
tography (129, 475, 2541) has also been employed with good
results, since the effects of the presence of other substances
© 2009 by Taylor & Francis Group, LLC
78836_C019.indd 897
can be substantially reduced. Early methods for the determi-
nation of NH3 involved trapping MSS in an aqueous acidic
solution. The trapped MSS solution was then steam distilled
under alkaline condition to obtain the sample for analysis. It
was discovered that this early method produced extra NH3
(30% to 80%) during the steam distillation procedure (475,
1884). NH3 collected from MSS should be analyzed directly
to achieve accurate quantification (1884). Cigarette blends
with higher levels of nitrogen, such as blends high in burley
tobacco, tend to have higher yields of MSS NH3. The yield of
NH3 in MSS is known to vary with the permeability of the cig-
arette wrappers, when cigarettes were tested with comparable
blends (475). The amount of NH3 produced was greater for
wrappers with higher air permeability. The rate of formation
of NH3 depended strongly on temperature. The yield of NH3
increased with decreasing temperature (1884). Therefore, it
was thought that variations in the burning temperature result-
ing from differences in wrapper quality or its air permeability
determined the amount of NH3 produced (1884).
Table XIX-5 is a catalog of the fixed and variable gases
in tobacco, tobacco smoke, and tobacco substitute smoke.
The catalog contains only thirty-five entries. This number of
entries represents a very small fraction of the total number
of identified components in tobacco and tobacco smoke but
amazingly the weight contributed by fixed and variable gases
represents about 90% of the whole smoke from a cigarette.
11/13/08 5:43:22 PM
 898 The Chemical Components of Tobacco and Tobacco Smoke

Table XIX-5


 






















Fixed and Variable Gases in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke
(,
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Note: The #
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symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.
,,
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© 2009 by Taylor & Francis Group, LLC

78836_C019.indd 898 11/13/08 5:43:24 PM

 Fixed and Variable Gases 899

Table XIX-5 (continued)

Fixed and Variable Gases in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

'$(





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(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C019.indd 899 11/13/08 5:43:25 PM

 900 The Chemical Components of Tobacco and Tobacco Smoke

Table XIX-5 (continued)

Fixed and Variable Gases in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

&#'





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© 2009 by Taylor & Francis Group, LLC

78836_C019.indd 900 11/13/08 5:43:27 PM

 Fixed and Variable Gases 901

Table XIX-5 (continued)

Fixed and Variable Gases in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C019.indd 901 11/13/08 5:43:29 PM

 902 The Chemical Components of Tobacco and Tobacco Smoke

Table XIX-5 (continued)

Fixed and Variable Gases in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(%)





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© 2009 by Taylor & Francis Group, LLC

78836_C019.indd 902 11/13/08 5:43:30 PM

 Fixed and Variable Gases 903

Table XIX-5 (continued)

Fixed and Variable Gases in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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© 2009 by Taylor & Francis Group, LLC

78836_C019.indd 903 11/13/08 5:43:31 PM

 904 The Chemical Components of Tobacco and Tobacco Smoke

Table XIX-5 (continued)

Fixed and Variable Gases in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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© 2009 by Taylor & Francis Group, LLC

78836_C019.indd 904 11/13/08 5:43:31 PM

 Fixed and Variable Gases 905

Table XIX-5 (continued)

Fixed and Variable Gases in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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© 2009 by Taylor & Francis Group, LLC

78836_C019.indd 905 11/13/08 5:43:32 PM

 20 Metallic and Nonmetallic Elements,
Isotopes, Ions, and Salts
XX.A Elements, Isotopes,
and Ions in Plants
Plants require numerous nutrients and compounds to sustain
life. There are at least twenty elements that are used by plants
that are considered essential for growth and reproduction
(20A06, 20A10). For higher plants (such as tobacco) a signifi-
cantly higher number of other elements are needed.
Justus von Liebig (1803–1873) in the mid-nineteenth cen-
tury stated that nutrients are essential for plant life:
We have determined that a number of elements are abso-
lutely essential to plant life. They are essential because a
plant deprived of any one of these elements would cease to
exist (20A58).
Von Liebig (20A58) taught of the absolute need to provide
plants with essential minerals necessary for successful agri-
cultural production. If the soil is not replenished with these
essential elements and associated ions, plant yields decrease
and numerous plant diseases occur. Healthy plants require and
thus contain a great variety of elements, isotopes, and ions.
In general, significant efforts are normally exerted to
maintain a plant’s requirement for nitrogen (N), phosphorus
(P), and potassium (K) through fertilization, while taking
for granted its basic need for carbon (C), hydrogen (H), and
oxygen (O). Knowing the nutrients required to grow plants
is only one aspect of successful crop production. Optimum
plant yield also requires knowing the rate to apply, the
method and time of application, the source of nutrients to
use, and how the elements are influenced by soil and climatic
conditions. The primary nutrients — N, P, and K — are com-
monly found in blended fertilizers, for example, 10-10-10, or
equivalent grades. Primary nutrients are utilized in the largest
amounts by crops and, therefore, are applied at higher rates
than secondary nutrients and micronutrients. The secondary
nutrients; calcium (Ca), magnesium (Mg), and sulfur (S) are
required in smaller amounts than the primary nutrients. The
major source for supplementing the soil with Ca and Mg is
dolomitic lime, although these nutrients are also available
from a variety of fertilizer sources. Sulfur is available in fer-
tilizers in the form of potassium and magnesium sulfate, gyp-
sum (calcium sulfate), and elemental sulfur. Micronutrients;
iron (Fe), manganese (Mn), zinc (Zn), copper (Cu), boron (B),
and molybdenum (Mo) are required in even smaller amounts
than secondary nutrients. They are available in manganese,
zinc and copper sulfates, oxides, oxy-sulfates and chelates, as
well as in boric acid and ammonium molybdate.
Table XX-1 gives the elemental composition of a typical
plant. It is interesting to note that about 96% of the makeup
of a plant is C, H, and O. These elements come from carbon
© 2009 by Taylor & Francis Group, LLC
78836_C020.indd 907
dioxide and water. The carbon dioxide in the atmosphere
contributes the C and O found in plants. It is taken up by
plants through small pores located in the leaves. Water,
on the other hand, is taken up by the roots of plants and is
responsible for contributing only H to the makeup of a plant.
However, the H used to produce water also comes from the
atmosphere. Table XX-1 also shows the classification of the
elements in plants. The elements are classified as structural
elements, primary and secondary nutrients, and micronutri-
ents. Therefore, the atmosphere and sun provide about 96%
of the necessary ingredients for plant growth; and miner-
als provide about 4% of the necessary ingredients for plant
growth (20A10). The elemental composition in Table XX-1
of a typical plant is nearly identical with the elemental com-
position of tobacco, with the exception that tobacco generally
has a slightly higher N level. Elemental analyses for C, H,
and N in tobacco indicate that there is about 5% N in dry
tobacco (2798, 20A06, 20A10). The percent C, H, and O (by
difference) of dry tobacco leaf are about 43%, 6%, and 43%,
respectively (2798, 20A06, 20A10), with the remainder being
trace levels of metals and nonmetals (3973).
XX.A.1 Elements, Isotopes, and Ions in Tobacco
As of 2007, the periodic table contains 117 elements whose
discoveries have been confirmed. Ninety are found natu-
rally on Earth, and the rest are synthetic elements that have
been produced artificially in particle accelerators. Of these
ninety naturally occurring elements, nearly eighty have been
identified in tobacco. Additionally, forty-four isotopes and
twenty-four ions have been identified in tobacco. Tobacco is
undoubtedly one of the plant materials most thoroughly eval-
uated for metal content. It should be noted that the omission
of information about other microelements does not necessar-
ily imply the absence of these elements in tobacco, but rather
a lack of information (3973). The discovery of elements, iso-
topes, and ions in tobacco (and for that matter tobacco smoke)
has only been limited by the discovery and advancement of
new analytical techniques.
Over the years, numerous scientific articles, reviews, and
books have been published that catalog the elements, ions,
and isotopes found in tobacco. One of the earliest articles
on the identification of metals in tobacco was published by
Grandeau in 1862 (20A25) on the identification of rubidium
(Rb) and cesium (Cs) in tobacco. Although it was well known
in the 1860s that numerous metals and nonmetals existed in
tobacco and higher plants (20A58), analytical techniques to
isolate the small levels of metals were not established. A 1934
bibliography by Heffer and Sons (20A26) reviewed literature
907
11/24/08 12:35:13 PM
 908 The Chemical Components of Tobacco and Tobacco Smoke

Table XX-1
Elemental Composition of a Typical Plant (1127b, 20A10)
Percent of Wet Percent of Dry
Element Symbol Weight Weight Descriptor
Oxygen O 81.0 45.0 Essential structural
Carbon C 6.8 44.5 elements available
Hydrogen H 11.5 6.0 from air and water
Nitrogen N 0.2 1.5
Phosphorus P 0.03 0.2 Primary nutrients
Potassium K 0.15 1.0
Calcium Ca 0.05 0.35
Magnesium Mg 0.03 0.20 Secondary nutrients
Sulfur S 0.02 0.15
Chlorine Cl 0.015 0.10
Iron Fe 0.015 0.10
Molybdenum Mo 0.008 0.05 Micronutrients
Zinc Zn 0.003 0.02
Boron B 0.003 0.02
Copper Cu 0.001 0.01
Others 0.175 0.80

citations for 1921 to 1933 on antimony (Sb), bismuth (Bi),
cadmium (Cd), chromium (Cr), cobalt (Co), Cu, lead (Pb),
Mn, mercury (Hg), nickel (Ni), thallium (Tl), tin (Sn), and
Zn. Johnstone and Plimmer (1971) published their review
of chemical constituents of tobacco and tobacco smoke in
1959. In 1966, Tso (20A105) published an excellent his-
torical review of elements identified in tobacco to that date.
Stedman (3797), in his 1968 review, listed aluminum (Al),
arsenic (As), Cu, Cr, Co, iron (Fe), Pb, Mn, Mo, Ni, titanium
(Ti), vanadium (V), and Zn as identified elements in tobacco
and smoke. In 1974, Elliot (1127b) reviewed the nutritional
requirements of tobacco, including metals and metal ions,
and Franzke et al. (1227) published their investigation of the
heavy metals in tobacco. In 1977, Norman (2799a) reviewed
the subject of metals in tobacco at the Tobacco Chemists’
Research Conference (TCRC). The most recent review, in
1996, by Jones and Wilkinson (20A54), concerning historical
agronomic achievements in tobacco science, provided cur-
rent information on elements identified in tobacco. The most
prolific writer on elements, isotopes, and ions in tobacco is
Tso. From his 1966 review of the subject to his 1972 book
on the physiology and biochemistry of tobacco plants (3972)
and his 1990 book (3973) on the production, physiology, and
biochemistry of the tobacco plant, Tso has continuously pro-
vided tobacco scientists with valuable information. His 1990
book (3973) devoted three chapters to metals, isotopes, and
ions in tobacco. In Chapters 17 and 19 (3973), Tso discussed
the presence, physiology, and biochemistry of the following
elements in tobacco plants: Al, As, barium (Ba), beryllium
(Be), bismuth (Bi), B, bromine (Br), Cd, cerium (Ce), cesium
(Cs), chlorine (Cl), Cr, Co, Cu, dysprosium (Dy), erbium (Er),
fluorine (F), gadolinium (Gd), germanium (Ge), gold (Au),
hafnium (Hf), holmium (Ho), indium (In), iodine (I), iridium
(Ir), Fe, lanthanum (La), Pb, lithium (Li), magnesium (Mg),
Mn, Hg, Mo, neodymium (Nd), Ni, N, osmium (Os), palla-
dium (Pd), P, platinum (Pt), polonium (Po), K, praseodym-
ium (Pr), radium (Ra), rhenium (Re), rhodium (Rh), rubidium
(Rb), ruthenium (Ru), samarium (Sm), scandium (Sc), sele-
nium (Se), silicon (Si), silver (Ag), sodium (Na), strontium
(Sr), sulfur (S), tantalum (Ta), tellurium (Te), terbium (Tb),
TI, thorium (Th), thulium (Tm), Sn, Ti, tungsten (W), ura-
nium (U), V, ytterbium (Yb), Zn, and zirconium (Zr). As Tso
stated (3973), “No attempt is made to include all publications
about each element; in fact, some papers were eliminated
intentionally to avoid duplication.”
Tso (3973) estimated that tens of thousands of article have
been written on the production, physiology, and biochemis-
try of the tobacco plant. In Chapter 18 (3973), Tso discussed
radiochemical elements in tobacco and smoke and in Chapter
19 he discussed the physiological disorders in tobacco plants
associated with deficiencies in minerals and micronutrients.
Tobacco plants, like other higher plants, are autotrophs
possessing the capacity to synthesize all of its complex organic
materials provided that carbon dioxide, water, minerals,
and the proper physical environment are available. Their
chemical composition is influenced by environmental factors
such as light, temperature, moisture, soil type, and cultural
practices, as well as inorganic nutrition.
The inorganic requirements of tobacco were consid-
ered in the 1962 book by Sutcliffe (20A101) and in reviews
by Steinberg and Tso (20A98) and others, for example,
McMurtrey (20A66). The essential elements of tobacco may
be grouped into categories depending on their source and
the relative amounts required. C, H, and O are considered
structural elements and are grouped separately because they
are derived from air or water. Obviously, C, H, and O are
found in the vast number of the organic components iden-
tified in tobacco. Evans and Russell (20A20) described the

© 2009 by Taylor & Francis Group, LLC

78836_C020.indd 908 11/24/08 12:35:13 PM

 Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts 909
requirements for these elements that were established when
early investigators determined the basic chemical composi-
tion of tobacco matter and elucidated the essential nature
of the respiratory and photosynthetic processes that occur
in plants. Another group of elements referred to as primary
nutrients include P, K, N, S, Ca, and Mg. These elements also
make up a relatively large portion of the inorganic compo-
nents of tobacco tissues and were established to be essen-
tial by plant physiologists such as Knop, Nobbe, and Sachs
(20A101) prior to 1910. In this period, reagent chemicals were
exceedingly crude and contained many of the essential trace
elements that were being investigated. As a consequence, the
proof of many trace elements in tobacco could not be estab-
lished until chemists learned how to purify the analytical
reagents for testing.
Another group of elements, including B, Cl, Co, Cu, Fe,
Mn, Mo, and Zn, occur in exceedingly small concentrations
in plant materials and are referred to as micronutrient ele-
ments. Fe was shown to be essential by Sachs (20A101) prior
to 1910, but the other trace elements were demonstrated to be
essential only after 1920 (20A20).
During the period 1923 to 1931, Sommer and Lipman
(20A96) established that a variety of plants including tobacco
required Zn and Cu. During the same period, Warrington
(20A111) in England demonstrated that boron was a required
in micronutrient in broad beans. Since then, it has become
clear that these elements are needed for a variety of species,
including tobacco. In 1939, Arnon and Stout (20A05) dem-
onstrated that tomato plants required Mo and since then it
has become apparent that all species need this element for
metabolism (20A20).
The biochemical role of minerals in metabolic processes
of various organisms has been covered in several reviews
by Malstrom and Neilands (20A60), McElroy and Nason
(20A65), Nason and McElroy (20A81), and Nicholas (20A84).
The function of C, H, and O are obvious since they are con-
stituents of fats, carbohydrates, and proteins. N and S are
constituents of amino acids, proteins, coenzymes, and other
compounds. Ca forms a complex with pectic acid and func-
tions as a constituent of the middle lamella of cell walls.
Dixon and Webb (20A13) showed that Ca also plays a role
as a cofactor for certain adenosine triphosphate hydrolyzing
enzymes, for phospholipases, and as a cofactor for the amy-
lases from a variety of plants. Many elements, especially the
cations, play essential roles as cofactors for the enzymes of
various metabolic sequences.
Tso (3973) provided numerous examples in which mineral
deficiency such as Fe or Mo resulted in metabolic lesions that
have been satisfactorily interpreted on the basis of detailed
knowledge of the biochemical role of metals in enzymes of
important metabolic pathways. This biochemical approach to
plant nutrition problems has proved exceedingly valuable to
plant scientists and agricultural producers in terms of identi-
fying diseases and finding solutions to improve crop yields.
Today, an enormous amount of work is being undertaken to
understand the total genome of tobacco (429b, 429c). Detailed
analyses of the metabolic pathways, enzymes involved, and
© 2009 by Taylor & Francis Group, LLC
78836_C020.indd 909
feed-back control and gene repressor mechanisms, including
the metal and nonmetal elements and ions, as essential catalysts
in tobacco, are being thoroughly documented (429b, 429c).
Mineral ions participate in a wide variety of metabolic
processes, electron transport mechanisms, and in nitrate
reduction. By manipulation of the level of inorganic elements
and ions in the nutrient medium, it is possible to influence
the constituents in plants. For over 100 years, tobacco sci-
entists have employed a fundamental research approach in
attempts to understand the complex physiology and biochem-
istry of tobacco involved in the biosynthesis of compounds in
tobacco (3973). Their efforts have greatly improved the eco-
nomics of tobacco production and have led to advancements
in understanding of health issues associated with tobacco and
its various commercial uses (20A20).
Inorganic ions play a very important role in tobacco
metabolism (20A20). There are various sites where inorganic
ions, for example, Ca2+, Mn2+, Mg2+, PO43-, Zn2+, and K1+,
participate in glycolytic reactions. Phosphate participates in a
majority of the reactions as a component of sugar-phosphate
compounds. Phosphate also functions as an important com-
ponent of coenzymes such as uridine diphosphate-glucose,
di- and triphosphopyridine nucleotides, adenosine di- and
triphosphate, etc. Practically every reaction in which phos-
phate is transferred requires Mg as a cofactor, but most of
these enzymes are not highly specific for a divalent cation
activator and will respond to other cations such as Mn (2489).
Another interesting aspect of the glycolytic enzymes is that
Zn is required for alcohol dehydrogenase, lactic acid dehy-
drogenase, aldolase, and triosephosphate dehydrogenase.
The role of Zn as an important inorganic ion, as a bound
component of dehydrogenases and other enzymes, has been
discussed in detail by Vallee (20A110).
K ion is a cofactor for the aldolase reaction. Pyruvic kinase
from all known sources also requires univalent cations, in
addition to a divalent cation. This enzyme needs K, ammo-
nium, or Rb ions as a cofactor. Mg ions serve an important
function in photosynthetic processes in tobacco as it is an
essential constituent of chlorophyll a and chlorophyll b. Some
heavy metal and nonmetal ions are toxic to tobacco and can
serve as metabolic inhibitors. The toxicity of fluoride, for
example, is explained in part on the basis of the formation of
a magnesium-fluorphosphate complex that inhibits the eno-
lase reaction in glycolysis. Other enzymes are inhibited by
substrate analogs, sulfhydryl complexing agents, and metal
chelating agents.
Several cations function as essential cofactors for enzymes
of the citric acid cycle. Magnesium is necessary for the
pyruvic acid oxidase complex and ferrous iron is necessary
for the activity of aconitase from certain sources (20A20).
The isocitric dehydrogenase system which catalyzes a dehy-
drogenation of isocitric acid and also the decarboxylation
of oxalosuccinate to yield α-ketoglutarate requires Mn
for the decarboxylation step (20A03). Mg is a necessary
cofactor for the α-ketoglutarate dehydrogenase complex and
Fe is a cofactor for succinate dehydrogenase (20A19, 20A64,
20A65, 20A80, 20A84). There are numerous cofactors
11/24/08 12:35:13 PM
 910 The Chemical Components of Tobacco and Tobacco Smoke
(Fe2+, -SH compounds, Mn2+, Mg2+, PO43-) and inhibitors
(SCN1-, Br1-, I1-, Cl1-, Na1+, Cu2+, Hg2+, and CN1-) of citric
acid cycle enzymes in tobacco. It is apparent that the vari-
ous enzymes not only require cations but are inhibited by
substrate analogs, substrate competitors, heavy metals, and
sulfhydryl complexing agents (20A20).
Mineral ions play important roles in the electron transport
portion of the terminal respiratory process in tobacco. In this
process, nonheme iron serves an important function in the
electron transfer process. There is also convincing evidence
that Cu ion is important in the process (20A20). Mineral ions
also play an important role in the electron transport processes
of the initial reactions of photosynthesis. In the photosynthetic
processes of tobacco Fe, Cu, Mn, and chloride ions are essen-
tial to the electron transfer processes (20A20).
Metal ions play an important role in nitrate reduction. The
discovery and characterization of the pyridine nucleotide
enzymes involved in nitrate reduction (20A18, 20A65, 20A81,
20A83) made it possible to understand the role of mineral ions
in the nitrate reduction processes. Reduced pyridine nucle-
otides and flavin adenine dinucleotide function as cofactors
in reduction of nitrate, nitrite, hyponitrate, and hydroxylam-
ine. The first step of the reaction involves the reduction of
nitrate to nitrite, and Mo is essential for this reaction. The
reduction of nitrite to hyponitrite and hyponitrite to hydroxy-
lamine requires Cu and Fe ions (20A20).
Many types of tobacco contain radioactive elements such
as 226Ra and 210Po at concentrations ranging from 0.1 to 0.47
pCi/g (1742, 2815, 3982, 3983). Phosphate fertilizers are the
major source of these radioelements (3982, 3983); minor
contributions come from airborne particles carrying 210Pb
and 210Po. These particles are trapped by the trichomes on
the undersides of the tobacco leaves (2467) and were first
reported by Nystrom and Bellin (2815) in 1964.
The 1999 CORESTA monograph on tobacco (910a)
pointed out that trace elements and metal ions can have a pro-
found effect on tobacco quality. Iron, for example, has been
implicated in the speckling effects which develop in “grey
tobacco” deficiency of Virginia tobacco (2338). Al is associ-
ated with development of the black color of cured tobacco,
or so-called “black tobacco” (20A57). Tso (3973) devoted an
entire chapter in his 1990 book to a discussion on the absolute
need for trace elements in tobacco disease prevention (3973,
20A106). Although concentrations of most of these metals are
not very high in tobacco (usually well below percent levels,
typically in the low to middle ppm range) many of these
elements are extremely important to the health of the plant.
Trace levels of metals (Mn, Fe, etc.) in tobacco are impor-
tant as quality factors as they can affect the combustibility
and smolder rate of tobacco. Some of the metals in tobacco
are desirable as quality factors while others are not (Cd, Pb,
Cr) as they have been associated with human health concerns
(20A100). The type and amount of certain inorganic ions are
also important factors in determining the burn and smolder
properties of tobacco. Peterson and Tibbitts (20A86) found
that the concentrations of K1+, Cl1-, SO42+, S2-, Mg2+, and
NO31- in tobacco (in descending order of importance) account
© 2009 by Taylor & Francis Group, LLC
78836_C020.indd 910
for 80% of the variation in leaf combustibility and smolder
(4332).
Tobacco is probably the most frequently examined plant
in the study of microelements. Many microelements are
important for normal tobacco growth and development
(3973). However, the specific roles of some of these elements
are still not well understood. Frequently the presence of cer-
tain microelements is merely a result of the circumstances
of site, season, or species, and therefore may not bear any
physiological or agronomic significance. Tobacco plants are
widely distributed in various locations of the world under dif-
ferent climatic, soil, and culture conditions. Any report of
a certain microelement regarding its level, distribution, and
fertilizer and soil requirements may or may not be applicable
to that particular element under different circumstances. In
1986, Isakander et al. (20A47) determined twenty-eight ele-
ments were in American cigarette tobacco. Today, nearly 150
elements, ions, and isotopes have been identified in tobacco.
XX.A.2 Elements, Isotopes, and Ions
in Tobacco Smoke
In 1954, Kosak (2170) published a list of components reported
to be present in tobacco smoke. His list included “Inorganic
Components.” The inorganic compounds included ammonia,
carbon monoxide, carbon dioxide, hydrogen cyanide, hydro-
gen sulfide, thiocyanic acid (?), oxygen, arsenic (probably
present as As2O3.), “acetates” (?), “chlorides” (?), “cyanides”
(?), and “nitrates” (?). The question marks in Kosak’s publi-
cation indicated that he did not consider the evidence in the
literature to be definitive proof of the identity of the com-
ponent. Since then, a tremendous amount of research has
been conducted and published on metals and ions in tobacco
smoke. During the late 1950s, Cogbill and Hobbs (769) con-
ducted pioneering work on elements found in tobacco smoke.
Two reviews in 1959 by Johnstone and Plimmer (1971) and
Bentley and Berry (282) documented elements found in
tobacco smoke. During the late 1960s and throughout the
1970s, a tremendous amount of research was published by
the Martin Brinkman Co. (2468), Celanese Fiber Marketing
Co. (641), Nadkarni (2666, 20A70), Nadkarni et al. (2667,
20A71–20A79), Morie and Morrisett (2633), Jenkins (20A49),
Franzke et al. (1227), John (2052), Allen and Vickroy (50),
and Perinelli and Carugno (2929) on elements, isotopes,
and ions in tobacco smoke. Concurrently, scientists within
the tobacco industry were conducting research on metals in
tobacco smoke. Much of this work was reviewed by Jenkins
of Philip Morris in 1990 on the uses of nuclear radiation in
tobacco and smoke research (1933).
At present, eighty metal and nonmetal elements, twenty-
four isotopes, and twelve ions have been identified in tobacco
smoke by numerous classical and instrumental analytical tech-
niques. It is an amazing achievement that nearly 90% of the nat-
urally occurring elements have now been identified in tobacco
and tobacco smoke. Although numerous ions in tobacco were
known, research on their identity in tobacco smoke was not
established until the advent of commercial application of ion
11/24/08 12:35:13 PM
 Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts 911
chromatography in the late 1980s. Since then many labora-
tories have gathered extensive experience in the application
of ion chromatography (IC) for the analysis of inorganic and
organic anions, in both tobacco and tobacco smoke (250, 1273,
2931, 3160, 20A16, 20A17, 20A59, 20A85, 20A114).
The presence of radioactivity, both α- and β-particles, in
leaf and tobacco smoke has been reported in many publica-
tions. At earlier periods, the main concern was for β-activity
found in cigars, cigarettes, and tobacco ash (113, 2657, 3367,
20A97). The α-emitting radioactive isotopes were suggested
to be significant because of health concerns to smokers. The
total α-activity in tobacco varies widely in green leaf, cured
leaf tobacco, and tobacco smoke (2466, 3367, 3973). A very
minor amount of 210Po is transferred into the mainstream
smoke (MSS). Twenty-four isotopes have been identified in
tobacco smoke. The discovery of elements, isotopes, and ions
in tobacco smoke has only been limited by the discovery and
advancement of new analytical techniques.
XX.B Methods for the Detection
and Identification of Metals,
Ions, and Isotopes in Tobacco
and Tobacco Smoke
Numerous analytical techniques with a variety of different
methodologies have been employed for the analysis of metals,
nonmetals, isotopes, and ions in tobacco and tobacco smoke
and various other types of organic matter. The subject of the
choice of analytical methodology best suited for the detection
of elements, isotopes, and ions in different matter has been
reviewed by Fassel (20A21), Bock (20A08), Jones and Case
(20A53), Jenkins (1933), Ivanova et al. (20A48), Thompson
et al. (20A103), Sigg et al. (20A94), and Jimoh (20A51). The
analytical methods included classical microanalytical deter-
mination (wet methods), colorimetric determinations, various
atomic absorption spectrophotometric techniques, such as
classical atomic absorption spectroscopy (AAS, with single
or multiple element capability), cold vapor atomic absorp-
tion (CVAA), argon-supported inductively coupled plasmas
(ICP), ICP with atomization-excitation processing, graphite
furnace (GF), atomic absorption spectroscopy (AAS, with or
without Zeeman background correction), GF-AAS with deu-
terium lamp; inductively coupled plasma-atomic emission
spectrometry (ICP-AES), microwave digestion, X-ray emis-
sion, competitive ligand-exchange/stripping voltammetry
(CLE-SV), diffusion gradients through thin films (DGT),
instrumental neutron activation analysis (INAA), ion chro-
matography (IC), and high performance liquid chromatog-
raphy (HPLC). Hyphenated techniques are also becoming
popular, such as inductively coupled plasma-mass spectrom-
etry (ICP-MS) and IC-ICP-MS (20A51). The selection of the
appropriate method depends on several factors, such as the
kind of equipment available, the ease of digestion, the kind
of sample, elements of interest, fume removal, contamination
considerations, matrix effects, and necessary safety precau-
tions (20A08, 20A53, 20A103).
© 2009 by Taylor & Francis Group, LLC
78836_C020.indd 911
The inorganic components of tobacco and tobacco smoke
have been determined by microanalytical techniques, clas-
sical colorimetric determinations, and modern instrumental
methods. For example, Cogbill and Hobbs (769) described
several colorimetric methods for the determination of metals
in tobacco smoke.
X-ray emission spectroscopy has been used in the deter-
mination of metals and metal isotopes in tobacco and tobacco
smoke. (20A62).
Atomic absorption spectroscopy is widely used and is
one of the most established methods for the determination
of metals in tobacco and tobacco smoke. Although quite
reliable, AAS can require separate analyses and recalibra-
tions at varying ranges for each element, with a separate
lamp for each analyte (dependent on the type of AAS equip-
ment). Concurrent determination of multiple metals is pos-
sible, while speciation is often lacking in this method. The
determination of metals in tobacco smoke is often more com-
plicated. One reason for this difficulty is the conversion of
smoke samples to homogeneous solutions so that they can
pass through the aspirator of the instrument. Another is that
for the determination of the ultratrace quantities of metals
in cigarette smoke, a preconcentration step is often required.
Solvent extraction is the method of preconcentration pre-
ferred over most other methods. The choice of solvents that
can provide a high degree of selectivity over a broad pH
range is limited. Alternately, metal complexes that are rel-
atively insensitive to pH changes, for example, ammonium
pyrrolidinecarbodithioate, have been used successfully for a
wide variety of metals (2633) in tobacco and tobacco smoke.
The work of Morie and Morrisett (2633) on the use of AAS
in the determination of metals in tobacco smoke serves as an
excellent example.
Inductively coupled plasma-atomic emission spectroscopy
(ICP-AES) and mass spectrometric (ICP-MS) techniques are
modern, sophisticated, very sensitive, and generally quite
expensive. These methods have been used successfully for the
determination of metals in tobacco and tobacco smoke (20A90,
20A112). The success of these two methods can be affected by
the metal-solvent matrix employed. In many cases presepa-
ration procedures and other special handling techniques are
required. Each method for analysis of metals in tobacco and
tobacco smoke has its own advantages and challenges.
Instrumental neutron activation analysis (INAA) is an
extremely sensitive method for the determination of metals
and metal isotopes. INAA has been used successfully by
Nadkarni et al. (20A73), Jenkins et al. (1934) and Kubota
(2214) to determine numerous inorganic constituents (ele-
ments and several elemental isotopes) in both tobacco and
tobacco smoke (1933). The use of INAA for tobacco and
tobacco smoke analysis has been accepted worldwide (1933).
Tobacco is ideally suited for INAA because of its large abun-
dance and variety of inorganic components. Tobacco is a
readily available, easy-to-handle solid, it produces little gas
during irradiation, and is rapidly assayed by INAA. The lit-
erature on the use of INAA in tobacco is very large because
tobacco is often used as a model in non-tobacco-oriented
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 912 The Chemical Components of Tobacco and Tobacco Smoke
reactor facilities systems for INAA (1933). However, the
applicability of neutron activation analyses (INAA) is lim-
ited by the availability and cost of the necessary equipment.
INAA requires a neutron flux source and gamma-ray count-
ing facilities. The most conventional laboratories are thus
unlikely to pursue this approach. Further, some elements
are normally not determinable by INAA (Pb and Ni), either
because of low sensitivity or strong interferences from other
metals [Perini (20A85)]. Jenkins (1933) noted that despite the
wide-spread use of INAA for tobacco and smoke analysis,
meaningful intercomparison of the INAA results published
in the literature is difficult as there is a lack of descriptive
experimental information on the exact types of the tobac-
cos or tobacco smoke tested. Many laboratories studied only
tobaccos and tobacco smoke native to their own country.
Many laboratories have gathered extensive experience
in the application of ion chromatography (IC) for the anal-
ysis of inorganic and organic anions. Small carboxylate
anions, Groups IA and IIA cations, and heavy metal ions
have been identified in tobacco and tobacco smoke by this
method. Several of these applications have been presented as
tobacco journal (250) and tobacco conference [TCRC (2951),
TSRC(1273)] papers. At the 1999 TSRC, Perini (20A85) pre-
sented a method associated with IC called transition metal IC
(TMIC). TMIC can be used for specific resolution and specia-
tion of transition metal ions in tobacco and related matrices.
Perini showed that TMIC could be used to detect and spe-
ciate at least nineteen transition metal ion.
XX.C The Transference of Elements,
Isotopes, and Ions from
Tobacco to Tobacco Smoke
Nearly all trace metals in tobacco transfer at some small level
into tobacco smoke. The transfer of metals from tobacco into
MSS and sidestream smoke (SSS) has been of interest for a
number of years (2133, 3836–3838, 2530). Transfer of metals
from filters containing metal catalysts has also been of inter-
est as they were thought to be a source of metals entrained
into the MSS (2633). For example, experimental filters with
permanganate salts (20A104) and hopcalite (20A69) have
been reported to remove nitrogen oxides from smoke. The
percent transfer rate of metals in tobacco to tobacco smoke
varies greatly but generally falls within a 0.002% to 7.0%
range (20A91), although percentages as high as 19% have
been reported for Sb (2666).
Numerous researchers have addressed the question of
metal transference employing a variety of different ciga-
rette types, collection devices, and analytical techniques.
Depending on the metal or metals of interest, the method
used, and the cigarette type, the reported results cover a wide
range of values. In some cases the range covers several orders
of magnitude. For one to draw any significant conclusions
from this mass of data would be tenuous. Some of the inad-
equacies associated with diversity of transfer rate reported by
Morgan and Akers (20A68) are:
© 2009 by Taylor & Francis Group, LLC
78836_C020.indd 912
• Tobacco types or blends of tobaccos were often not
identified, and in most cases tobacco filler types
were not processed in a standard fashion.
• Cigarette configurations were often varied and
in many cases the cigarette configuration and
materials used to construct the cigarette were not
mentioned.
• Often only one or two metal species were studied
for a particular tobacco.
• Total particulate matter (TPM) collection proce-
dures were not uniform among studies.
• Analytical methods varied widely and were often
not calibrated against standard materials of known
metal content.
• Large analytical errors were often tolerated to
obtain a numerical value.
Stöber (20A99), in his review of the generation, size distri-
bution, and composition of tobacco smoke aerosols, made the
observation that more than one mechanism for the transport
of metals into MSS is operative. The predominant mecha-
nism is entrainment of small particulate matter. For the more
volatile elements, however, vaporization followed by conden-
sation into the particulate phase appears dominant. The rate
of metal transfer to the smoke is dependent on the volatil-
ity, the temperature profiles in the burning cigarette, and the
filter type. In cigarette smoke, element concentrations vary
among brands and even within the same brand. Numerous
factors influence the metal concentration found in tobacco,
including soil type and pH, the atmosphere, genotype, stalk
position, application of metal-containing fertilizers or agri-
cultural chemicals, for example, herbicides and pesticides
(3973). These same factors affect the concentration of ele-
ments transferred to MSS and SSS. Table XX-2 lists the per-
cent transfer of selected metallic and nonmetallic elements
between tobacco and tobacco MSS.
XX.C.1 Elements in Tobacco Smoke
of Special Interest
Eighty elements, twenty-four isotopes, and twelve ions have
been identified in tobacco smoke. Table XX-2 contains data
on the percent transfer of selected elements into tobacco
smoke. Based on literature data, small portions, at most a
few percent of the metals and nonmetals, transfer from the
tobacco into the smoke. The predominant route of exposure
of humans to metals in cigarette smoke is inhalation. The
smoker will likely inhale both the mainstream vapor and
particulate phase of the smoke, plus some of the smoke that
is generated while the cigarette is smoldering between puffs
(20A50). Nonsmokers may also be exposed to metals in ciga-
rette smoke, through passive inhalation of environmental
tobacco smoke (ETS), but these concentrations are hundreds
of times more dilute (3257).
Among the metals that transfer into the smoke and are
thus inhaled, the International Agency for Research on
Cancer (IARC) (1870) considered As, Be, Cr, Ni, and Cd as
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 Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts 913

Table XX-2
Percent Transfer of Selected Metallic and Nonmetallic Elements between Tobacco
and Tobacco Smoke
Name (per CA
CAS No. Collective Index) Transference to Smoke (%) Reference
7429-90-5 Aluminum 0.009-0.0014 1934
7440-36-0 Antimony 0.003-19 769, 1934,2666, 20A21, 20A67, 20A68
7440-38-2 Arsenic [0.016] a-7.0 769, 1934, 2666, 20A21, 20A68, 20A76
7440-41-7 Beryllium 0-[4.0] 3711, 20A68
7726-95-6 Bromine 0.02-2.41 769, 1933, 1934, 2666, 20A21, 20A67, 20A68
7440-43-9 Cadmium 7-22 2530, 20A68
7440-70-2 Calcium ND b-0.001 769, 1934
7440-45-1 Cerium ND 1934
7440-46-2 Cesium 1.27 2666, 20A21
7782-50-5 Chlorine 1.2-2.2 1933, 1934
7440-47-3 Chromium 0.43-1.74 769, 2666, 1934, 20A21, 20A67, 20A68
7440-48-4 Cobalt 0.5-4.2 769, 1934, 2666, 20A21, 20A67, 20A68
7440-50-8 Copper 0.71-1.7 769, 20A68
7440-57-5 Gold 0.002 2666
7439-89-6 Iron 0.014-1.3 769, 1934, 2666, 20A21, 20A67, 20A68
7439-91-0 Lanthanum ND-11 1934, 2666
7439-92-1 Lead 0.16-6.3 769, 2530, 20A21, 20A67, 20A68
7439-95-4 Magnesium 0.0025 20A67
7439-96-5 Manganese 0.004-0.006 769, 1934, 20A67
7440-02-0 Nickel <0.1-2.4 1934, 2530, 2666, 20A68
7440-09-7 Potassium 0.2-0.51 769, 20A67
7440-17-7 Rubidium 0.18-0.78 1934
7440-19-9 Samarium ND 1934
7440-20-2 Scandium 0.018-2.6 1934, 2666, 20A21
7782-49-2 Selenium 2.5-5.2 2666, 20A21, 20A68
7440-22-4 Silver 0.60-1.08 2666, 20A21
7440-23-5 Sodium 0.25-1.06 769, 1934
7440-66-6 Zinc 0.4-2.7 769, 2530, 2666, 20A21, 20A67, 20A68
a [ ] = Limit of detection
b ND= Not Detected

human carcinogens (1742, 20A28, 20A29) in 1985. In 1989,
the U.S. Department of Health and Human Services (4012)
listed chromium and lead as possible carcinogenic agents in
humans. Additionally, zinc in tobacco smoke has also been
a metal of concern (20A49, 20A50). Today, the list of metals
classified as Group 1 (human carcinogens) has grown to
include As, Be, Cd, Cr6+, Ni, 32P, 239Pu, 240Pu, α- and β-particle
emitting radionuclides (in general), 222Rn, 224Ra, 226Ra, 228Ra,
and 232Th. Additionally, smokeless tobacco (classified as a
Group 1 mixture) and ETS, and tobacco smoke and tobacco
smoking (classified as Group 1 exposure circumstances) have
been classified by IARC as agents considered carcinogenic to
humans (Table XX-3). IARC listed the following agents iden-
tified in tobacco smoke as Group 2A (probably carcinogenic
to humans) or Group 2B (possibly carcinogenic to humans):
Pb, Co, Ni, nitrates, and nitrites.
Nearly all of the metals and isotopes found in tobacco that
transfer to tobacco smoke are a consequence of the use of
metals found naturally in the soil (some radionuclides in the
soil from nuclear reactions and reactors in the area), use of
fertilizer containing metals, or agrochemicals applied to the
tobacco. The radioactive compounds found in highest concen-
tration in cigarette smoke are 210Po and 40K. Other radioac-
tive compounds present include 226Ra, 228Ra, 232Th, and 228Th
(1870). As and As compounds and Cr and some chromium
compounds are causally associated with cancer in humans,
while Ni and Cd and their compounds are probably carci-
nogenic to humans. As levels in tobacco have been elevated
in the past due to the use of arsenical pesticides. Cd levels
may be related to the presence of Cd in phosphate fertilizers
(1870). Today, the so-called Hoffmann analytes include the
following metals, isotopes, and ions: As, Be, Cd, Pb, Cr, Cr6+,
Co, Hg, Ni, 210Po, and Se (3300).
Despite ample scientific evidence to the contrary many in
the scientific community continue to contend that many of
the Hoffmann analytes represent a “clear and present dan-
ger” to smokers. The following excerpts provide information
and comments to the contrary (3300).
XX.C.1.a Arsenic (As)
Over time, substantial decreases have been reported for As
residues on tobacco and dramatic reductions in tobacco smoke.

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 914 The Chemical Components of Tobacco and Tobacco Smoke

Table XX-3
IARC Classification and References to Agents, Groups of Agents, Mixtures and Exposure Circumstances
Evaluated by IARC that are Metals, Metallic Compounds, Radioisotopes, or Tobacco or Tobacco Smoke-
Related Materials
Name CAS No. IARC Reference
Group 1:
Agents and groups of agents:
Arsenic 7440-38-2 20A42, 20A36
Beryllium and beryllium compounds 7440-41-7 20A27, 20A28
Cadmium and cadmium compounds 7440-43-9 20A27, 20A28
Chromium (VI) 1333-82-0 20A32
Gallium arsenide 1303-00-0 20A33
Nickel and nickel compounds 7440-02-0 20A32
Phosphorus-32, as phosphate 14596-37-3 20A41
Plutonium-239 and its decay products (may contain plutonium-240 15117-48-3 and 14119-33-6 20A41
and other isotopes), as aerosols
Radionuclides, α-particle-emitting, internally deposited Numerous isotopes in tobacco smoke 20A41
Radionuclides, β-particle-emitting, internally deposited. Numerous isotopes in tobacco smoke 20A41
Radium-224 and its decay products 13233-32-4 20A41
Radium-226 and its decay products 13982-63-3 20A41
Radium-228 and its decay products 15262-20-1 20A41
Radon-222 and its decay products 10043-92-2 or 14859-67-7 20A37, 20A41
Silica, crystalline (inhaled in the form of quartz or cristobalite from 14808-60-7 20A39
occupational sources)
Thorium-232 and its decay products 7440-29-1 20A41
Mixtures:
Tobacco, smokeless 20A44, 20A36, 20A40
Exposure circumstances:
Involuntary smoking (exposure to secondhand or environmental 20A45
tobacco smoke, ETS)
Tobacco smoking and tobacco smoke 20A45
Group 2A:
Agents and groups of agents:
Indium phosphide 22398-80-7 20A33
Lead compounds, inorganic 7439-92-1 20A35
Nitrate or nitrite (ingested) under conditions that result 14797-55-8 and 14797-65-0 20A34
in endogenous nitrosation
Exposure circumstances:
Cobalt metal with tungsten carbide 20A33
Group 2B:
Agents and groups of agents:
Antimony trioxide 1309-64-4 20A43
Carbon black 1333-86-4 20A38, 20A30
Cobalt and cobalt compounds 7440-48-4 20A31
Cobalt sulfate and other soluble cobalt (II) salts 10026-24-1 20A33
Lead 7439-92-1 20A42, 20A36
Nickel, metallic and alloys 7440-02-0 20A32
Titanium dioxide 13463-67-7 20A43, 20A30
Vanadium pentoxide 1314-62-1 20A33
Exposure circumstances:
Cobalt metal without tungsten carbide 20A33

Agents, groups of agents, mixtures and exposure circumstances (associated with metals and nonmetals, or tobacco) evaluated in IARC Monographs
Volumes 1-95. This list contains all agents evaluated as of November-December 2006 that are considered: Carcinogenic to humans (Group 1), probably
carcinogenic to humans (Group 2A), and possibly carcinogenic to humans (Group 2B). For details of the evaluation, the relevant Monograph should be
consulted, see http://monographs.iarc.fr/ENG/Classification/crthgr01.php.

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 Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts 915
As, usually considered as As2O3 in tobacco, was removed from
tobacco agronomy in 1952. Between 1917 and 1951 the As level
in tobacco rose from about 12 to 57 μg/g (1459). By 1968 the
As level in tobacco had decreased from the 1951 value of more
than 50 μg/g to a 1968 value of 0.5 to 1.0 μg/g, a value similar
to that reported by Griffin et al. (1391). Some of these chrono-
logical data were summarized by the U.S. Surgeon General in
1979 (20A107) and IARC (1871). In 1957, Cogbill and Hobbs
(769) reported the transfer of As from a cigarette containing
7.1 μg of As to MSS to be 3.5%. With the tobaccos analyzed
for As by Griffin et al. (1391), the As content of the MSS would
range from 0.018 to 0.035 μg/cigarette. In 1968, Guthrie (1457)
reported the As transfer from cigarette tobacco to its MSS var-
ied between 4% and 12%. In 1990, Tso (3973) noted that for
most tobaccos at that time the As level was around 0.1 to 0.5
μg/g (3300).
XX.C.1.b Beryllium (Be)
Studies on laboratory animals exposed to high Be dose and
epidemiological data have indicated that Be may cause can-
cer, although Be has been classified as a Group 1 substance
by IARC. However, IARC noted a number of limitations in
the epidemiological studies, namely poor exposure charac-
terization, relatively low excess cancer risk, and the lack of
discussion of exposure to other lung carcinogens. The poten-
tial of Be to induce developmental effects has not been inves-
tigated adequately (20A02). No literature information was
found on the toxicity of Be by ingestion (20A116). The level
of Be reported in cigarette MSS ranges from 0 to 0.5 ng/
cigarette (1742, 1744, 3711).
XX.C.1.c Chromium (Cr), Cadmium (Cd),
and Lead (Pb)
The possible roles of Cr, Cd, and Pb in tobacco carcinogen-
esis are difficult to evaluate given the present data base. In
1990, Hoffmann and Hecht (1727) stated: “Taken together,
the evidence for a major role of these materials as etiologic
factors in tobacco carcinogenesis is not compelling.”
XX.C.1.d Chromium VI [Cr (VI)]
Seventeen years have elapsed since the IARC originally eval-
uated the carcinogenicity of Cr and Cr compounds. In 2000
De Flora (20A12) reviewed the toxicology of Cr compounds.
A wealth of results indicate that Cr metal, Cr (III), and Cr
(VI) can induce a variety of genetic and related effects in
vitro (20A12). But there is a lack of carcinogenicity of Cr
metal and Cr (III) compounds in experimental animals and
only a minority of animal carcinogenicity data with Cr (VI)
compounds were positive (30 out of 70, i.e. 42.9%). Moreover,
most positive studies used administration routes that do not
mimic any human exposure and by-pass physiological defense
mechanisms. Typically, positive results were only obtained at
implantation sites and at the highest dose tested. Exposure to
Cr (VI) has been known for more than a century to be associ-
ated with induction of cancer in humans (20A12).
© 2009 by Taylor & Francis Group, LLC
78836_C020.indd 915
De Flora stated:
Carcinogenicity requires massive exposures, as is only
encountered in well defined occupational settings, and is
site specific, being specifically targeted to the lung and, in
some cases, to the sinonasal cavity. Increased death rates for
cancers at other sites, which were occasionally reported in
some epidemiological studies, were almost invariably not
statistically significant and inconsistent (being counterbal-
anced by other studies which apparently showed decreased
rates for the same cancers) (20A12). Chromium (VI) can be
reduced in body fluids and non-target cells, which results in
its detoxification, due to the poor ability of chromium (III) to
cross cell membranes. In target cells, chromium (VI) tends
to be metabolized by a network of mechanisms leading to
generation of reduced chromium species and reactive oxygen
species, which will result either in activation or in detoxifica-
tion depending on the site of the intracellular reduction and
its proximity to DNA. When introduced by the oral route,
chromium (VI) is efficiently detoxified upon reduction by
saliva and gastric juice, and sequestration by intestinal bac-
teria. If some chromium (VI) is absorbed by the intestine, it
is massively reduced in the blood of the portal system and
then in the liver. These mechanisms explain the lack of geno-
toxicity, carcinogenicity, and induction of other long-term
health effects of chromium (VI) by the oral route. Within the
respiratory tract, chromium (VI) is reduced in the epithelial-
lining fluid, pulmonary alveolar macrophages, bronchial tree
and peripheral lung parenchyma cells. Hence, lung cancer
can only be induced when chromium (VI) doses overwhelm
these defense mechanisms. The efficient uptake and reduc-
tion of chromium (VI) in red blood cells explains its lack of
carcinogenicity at a distance from the portal of entry into
the body. All experimental and epidemiological data, and the
underlying mechanisms, point to the occurrence of thresh-
olds in chromium (VI) carcinogenesis (20A12).
Although Cr (VI) has often been alleged to exist in
MSS, it has never been unequivocally identified in tobacco
smoke (20A95).
XX.C.1.e Nickel (Ni)
The USPHS (20A109) made the following statement on the
occurrence of Ni in tobacco smoke: “It is not likely that
nickel plays a significant role in the etiology of lung cancer in
cigarette smokers.”
During the 1960s the Sundermans reported that they had
found Ni in MSS (3837). They speculated that Ni could pos-
sible react with CO in MSS to form nickel carbonyl. The
Sundermans did not successfully induce lung cancer in rats
exposed to tobacco smoke although much furor was raised as
to their allegations (3837, 3838).
XX.C.1.f Cobalt (Co)
Co has been identified in both tobacco and tobacco smoke.
Co and Co-containing compounds have been evaluated by
IARC and are classified as Group 2B (possibly carcinogenic
agents) (20A31).
This category is used for agents for which there is limited
evidence of carcinogenicity in humans and less than sufficient
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 916 The Chemical Components of Tobacco and Tobacco Smoke
evidence of carcinogenicity in experimental animals. It may
also be used when there is inadequate evidence of carcinoge-
nicity in humans but there is sufficient evidence of carcinoge-
nicity in experimental animals. In some instances, an agent
for which there is inadequate evidence of carcinogenicity in
humans and less than sufficient evidence of carcinogenicity
in experimental animals together with supporting evidence
from mechanistic and other relevant data may be placed in
this group. An agent may be classified in this category solely
on the basis of strong evidence from mechanistic and other
relevant data (IARC Preamble, see http://monographs.iarc.fr/
ENG/Preamble/CurrentPreamble.pdf).
XX.C.1.g Mercury (Hg)
Hg has been identified in both tobacco and tobacco smoke.
Hg and inorganic Hg compounds (20A27) are classified by
IARC as Group 3 agents (not classifiable as to carcinogenic-
ity to humans).
This category is used most commonly for agents for
which the evidence of carcinogenicity is inadequate in
humans and inadequate or limited in experimental animals.
Exceptionally, agents for which the evidence of carcinoge-
nicity is inadequate in humans but sufficient in experimen-
tal animals may be placed in this category when there is
strong evidence that the mechanism of carcinogenicity in
experimental animals does not operate in humans. Agents
that do not fall into any other group are also placed in this
category. An evaluation in Group 3 is not a determination
of noncarcinogenicity or overall safety. It often means that
further research is needed, especially when exposures are
widespread or the cancer data are consistent with differing
interpretations (IARC Preamble, see http://monographs.iarc.
fr/ENG/Preamble/CurrentPreamble.pdf).
XX.C.1.h Selenium (Se)
Se has been identified in both tobacco and tobacco smoke.
The MSS yield of Se in the University of Kentucky reference
cigarette 1R4F is 1.2 ng/cigarette (3300). Se and Se com-
pounds (20A36) are classified by IARC as Group 3 agents
(not classifiable as to carcinogenicity to humans). Se is not an
antioxidant nutrient unto itself, but is a component of antioxi-
dant enzymes. It possesses excellent antioxidant, antimuta-
genic, and anticarcinogenic properties (1177a, 3257, 3685,
20A46, 20A92, 20A93, 20A102, 20A113).
El-Bayoumy (20A15) described the protective role of
Se on genetic damage and on cancer. Fiökin et al. (20A22)
conducted research that demonstrated a protective effect of
vitamin E and Se against ETS exposure through reduction
in the occurrence of lipid peroxidation. Clark et al. (20A09)
reported that taking a Se supplement decreased the incidence
of prostate cancer in men by more than 60% (20A09). The
final analysis of the trial, published in 2002, by Duffield-
Lillico et al. (20A14) showed a 52% reduction of prostate
cancer in men taking Se daily.
© 2009 by Taylor & Francis Group, LLC
78836_C020.indd 916
Two large randomized trials on antioxidants (e.g.,
β-carotene and α-tocopherol) and Se to determine their
effects on cancer risk (Chinese Cancer Prevention Study
and the Selenium and Vitamin E Cancer Prevention Trial
(SELECT). The Chinese study showed that a combination
of β-carotene, vitamin E, and Se significantly reduced total
mortality (9%), cancer mortality (13%), gastric cancer mortal-
ity (20%), and mortality of the other cancers (19%) (20A07).
The SELECT is currently taking place in the United States,
Puerto Rico, and Canada to determine if taking Se and/or
vitamin E supplements can prevent prostate cancer in men
aged fifty or older (20A82).
XX.C.1.i 210Polonium (210Po)
For the last quarter of a century there has been a contro-
versy over the presence and health effects of 210Po in tobacco
smoke. The quantities of 210Po found in the lungs of smok-
ers are generally about three times higher than those in
nonsmokers. However, the significance of 210Po in tobacco-
induced lung cancer has been questioned upon comparison
of these data with those obtained in miners (1509, 1727). In
the case of 210Po, a recent in-depth study raises doubts on the
significance of 210Po as a factor contributing to lung cancer
in smokers (3300). 210Po is present in tobacco and tobacco
smoke (0.03 to 1.0 pCi/cigarette); however, it is unlikely that
these traces represent a major risk for the smoker (20A109).
Rodgman and Green (3300) recently published a cancer
risk assessment on toxicants in tobacco and tobacco smoke.
Where there were sufficient data on carcinogenicity (animal
and/or human), incremental lifetime cancer risks (ILCR)
were calculated for those elements and isotopes. None of the
elements (above) called Hoffmann analytes exhibited more
than a low to very low ILCR (3300). For some of the elements
there was insufficient cancer risk information necessary to
calculate an ILRC, for example, Co, Hg, Se, and Cr. For these
elements, either there were few health concerns anticipated by
regulatory bodies (such as the U.S. Environmental Protection
Agency or World Health Organization) or studies document-
ing cancer associated with these elements were not available.
In view of these various uncertainties in published data and
comments made by known authorities and regulatory bodies
(as to either the level of these elements in smoke or their car-
cinogenic potency of the element) it is difficult at the present
time to conclude that any of the metals and metal isotopes
represents a significant hazard to the human smoker.
XX.D Summary
To date, eighty-one elements (metals and nonmetals), forty-
five isotopes, and twenty-four ions have been identified in
tobacco and tobacco smoke. As indicated in Table XX-4, 146
have been identified in tobacco, 116 have been identified in
tobacco smoke, and 112 are found in both tobacco and tobacco
smoke. Table XX-5 provides a tabulation of the metallic and
11/24/08 12:35:15 PM
 Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts 917

Table XX-4
Distribution of Metallic and Nonmetallic Elements, Isotopes and
Ions between Tobacco and Tobacco Smoke
Number of Identified Metallic and Nonmetallic Elements,
Isotopes and Ions between Tobacco and Tobacco Smoke
Component Total Smoke Tobacco Smoke and Tobacco
Elements: 81
Metals 69 68 68 67
Nonmetals 12 12 10 10
Isotopes: 45
Metal isotopes 39 20 39 20
Nonmetal isotopes 6 4 5 3
Ions: 24 24 12 24 12
Totals 150 116 146 112

nonmetallic elements, isotopes, and ions in tobacco, tobacco
smoke, and tobacco substitute smoke.
There are numerous compounds in tobacco and tobacco
smoke that contain metals and nonmetals. No review articles
have been published on these types of compounds in tobacco
and smoke. In most papers, when they are mentioned, they are
collectively called miscellaneous compounds. The compounds
listed in Table XX-6 consist mainly of acid salts of sodium,
potassium, magnesium, and calcium, metal oxides, hydroxides,
carbonates, and carbonyl-containing compounds, halide salts of
organic compounds, a variety of organometallic compounds,
for example, triphenylarsine, aluminum and magnesium phos-
phide, triphenylstannium hydroxide, certain agrochemicals that
contain metals, such as Alloxydim-sodium®, potassium salt
of gibberellic acid, and Zineb®, and several metal-containing
biomolecules, such as globulins, cytochrome c6, and chloro-
phyll a and b. For the sake of completeness, several ammonium
compounds and the acid salts and various ions of nitric, sulfuric,
and phosphoric acids are included in Table XX-6. Overall, Table
XX-6 lists 125 chemical components.

© 2009 by Taylor & Francis Group, LLC

78836_C020.indd 917 11/24/08 12:35:15 PM

 918 The Chemical Components of Tobacco and Tobacco Smoke

Table XX-5



  

  
  







 




Metallic and Nonmetallic Elements and Ions in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke








(%)





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© 2009 by Taylor & Francis Group, LLC

78836_C020.indd 918 11/24/08 12:35:15 PM

 Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts 919

Table XX-5 (continued)

Metallic and Nonmetallic Elements and Ions in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(%)





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(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C020.indd 919 11/24/08 12:35:16 PM

 920 The Chemical Components of Tobacco and Tobacco Smoke

Table XX-5 (continued)

Metallic and Nonmetallic Elements and Ions in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

!"!+!(!,





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© 2009 by Taylor & Francis Group, LLC

78836_C020.indd 920 11/24/08 12:35:17 PM

 Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts 921

Table XX-5 (continued)

Metallic and Nonmetallic Elements and Ions in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

!"!,!)!-





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(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C020.indd 921 11/24/08 12:35:18 PM

 922 The Chemical Components of Tobacco and Tobacco Smoke

Table XX-5 (continued)

Metallic and Nonmetallic Elements and Ions in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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© 2009 by Taylor & Francis Group, LLC

78836_C020.indd 922 11/24/08 12:35:18 PM

 Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts 923

Table XX-5 (continued)

Metallic and Nonmetallic Elements and Ions in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(%)





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(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C020.indd 923 11/24/08 12:35:19 PM

 924 The Chemical Components of Tobacco and Tobacco Smoke

Table XX-5 (continued)

Metallic and Nonmetallic Elements and Ions in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

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((


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© 2009 by Taylor & Francis Group, LLC

78836_C020.indd 924 11/24/08 12:35:20 PM

 Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts 925

Table XX-5 (continued)

Metallic and Nonmetallic Elements and Ions in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(%)





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(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C020.indd 925 11/24/08 12:35:20 PM

 926 The Chemical Components of Tobacco and Tobacco Smoke

Table XX-5 (continued)

Metallic and Nonmetallic Elements and Ions in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

!"!,!)!-





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© 2009 by Taylor & Francis Group, LLC

78836_C020.indd 926 11/24/08 12:35:21 PM

 Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts 927

Table XX-6
Various Ionic and Covalently Bonded Organic and Inorganic Compounds Containing Metals and Nonmetals,
Miscellaneous Ions, and Organometallic Compounds Found in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C020.indd 927 11/24/08 12:35:23 PM

 928 The Chemical Components of Tobacco and Tobacco Smoke

Table XX-6 (Continued)

Various Ionic and Covalently Bonded Organic and Inorganic Compounds Containing Metals and Nonmetals,
Miscellaneous Ions, and Organometallic Compounds Found in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C020.indd 928 11/24/08 12:35:26 PM

 Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts 929

Table XX-6 (Continued)

Various Ionic and Covalently Bonded Organic and Inorganic Compounds Containing Metals and Nonmetals,
Miscellaneous Ions, and Organometallic Compounds Found in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C020.indd 929 11/24/08 12:35:26 PM

 930 The Chemical Components of Tobacco and Tobacco Smoke

Table XX-6 (Continued)

Various Ionic and Covalently Bonded Organic and Inorganic Compounds Containing Metals and Nonmetals,
Miscellaneous Ions, and Organometallic Compounds Found in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C020.indd 930 11/24/08 12:35:27 PM

 Metallic and Nonmetallic Elements, Isotopes, Ions, and Salts 931

Table XX-6 (Continued)

Various Ionic and Covalently Bonded Organic and Inorganic Compounds Containing Metals and Nonmetals,
Miscellaneous Ions, and Organometallic Compounds Found in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C020.indd 931 11/24/08 12:35:30 PM

 932 The Chemical Components of Tobacco and Tobacco Smoke

Table XX-6 (Continued)

Various Ionic and Covalently Bonded Organic and Inorganic Compounds Containing Metals and Nonmetals,
Miscellaneous Ions, and Organometallic Compounds Found in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C020.indd 932 11/24/08 12:35:32 PM

 21 Pesticides and Growth Regulators
Since 2500 BC, farmers have used pesticides to prevent dam-
age to their crops. The first known pesticide was elemen-
tal sulfur, used to dust crops in Sumeria about 4500 years
ago. By the fifteenth century, pesticides containing arsenic,
mercury, and lead were being applied to crops. In the seven-
teenth century, nicotine was extracted from tobacco leaves
as nicotine sulfate for use as an insecticide. In the nine-
teenth century, two more natural pesticides were introduced:
pyrethrum (extracted from chrysanthemums) and rotenone
(extracted from the roots and stems of several tropical and
subtropical plant species of the genus Lonchocarpus or
Derris) [Miller (21A46)].
From the 1860s until the advent in 1942 of DDT (1-chloro-
2-[2,2,2-trichloro-1-(4-chlorophenyl)ethyl]benzene), there
were numerous inorganic and naturally occurring compounds
(inorganic and organic components extracted from plants
and animals) developed and used for control of insects and
plant diseases, particularly fungi. Little progress occurred in
the discovery of natural or chemical means to control weeds.
The chemistry of arsenicals was further exploited to control
insects (Paris Green [copper(II) acetoarsenite]). Bordeaux
mixture (copper sulfate and lime) was found to be extremely
useful in the control of plant diseases, leading to its wide-
spread usage. The invention of the pressure sprayer (both
hand and power driven) made efficient large-scale applica-
tion of pesticides feasible and economical. Aerial application
was also invented (in the early 1920s), leading to expanded
applications in agriculture. The availability of DDT, begin-
ning in 1945 for civilian/agricultural usage, opened a new
era of pest control, leading not only to its extensive usage
but also to the development of numerous other synthetic
organic insecticides, for example, organophosphates in 1946.
About two years earlier in 1944, selective synthetic organic
herbicides were discovered, starting with 2,4-D (2,4-dichlo-
rophenoxyacetic acid), which revolutionized weed control
in agriculture and elsewhere. Also, synthetic organic fungi-
cides (metal based) were developed as effective controls of
plant diseases (and for other applications). During the 1950s
and 1960s, granular pesticide formulations were developed,
which led to large expansions of pesticide usage on major
field crops [Aspelin (21A02)].
Prior to the advent of DDT (and other organic pesticides
which rapidly followed), most pesticides used in agriculture
were applied to protect high value/small acreage crops, prin-
cipally fruits, vegetables, and cotton. This, however, changed
dramatically in the 1950s, as major field crops, for example,
corn, sorghum, grains, tobacco, and soybeans, rapidly began to
account for a majority of pesticide usage [Aspelin (21A02)].
By the 1960s, some very important new families of chem-
icals were discovered as herbicides, for example, triazines,
© 2009 by Taylor & Francis Group, LLC
78836_C021.indd 933
acetanilides, and dinitroanilines. In the 1970s, synthetic
pyrethroids replaced much of the insecticide chemistry
developed during the previous twenty years. During the
1980s, imidazolinone and sulfonylurea herbicides dramati-
cally lowered application rates for weed control. During the
1990s and currently, agrochemical companies are employ-
ing new synthetic methods to produce safer pesticides (and
growth regulators) for use on crops. The emphasis today in
the development and use of pesticide and growth regulators is
towards safer, more effective biological agents and pesticides
applied at lower levels, and enhanced stewardship in use of
available pesticides [Aspelin (21A02)].
Tobacco is an agricultural product processed from the
leaves of plants in genus Nicotiana of the nightshade fam-
ily (Solanaceae). Nicotiana is indigenous to North and South
America but numerous species of Nicotiana (over sixty) are
found throughout the world. The two main species culti-
vated and grown to produce tobacco and tobacco products
worldwide are Nicotiana tabacum and Nicotiana rustica. N.
tabacum is the most widely cultivated and used for production
of tobacco leaf for cigarettes, cigars, chewing tobacco, snuff,
snus, pipe tobacco, and other forms of tobacco products.
N. rustica is the second most widely grown N. species. Its
leaves are extracted for nicotine, pyridine products, and
solanesol (3973).
Tobacco has evolved over the centuries to be resistant
to many types of pests and infections. The plants produce
numerous compounds that provide for its protection. For
example, the plants contain high levels of nicotine. It con-
stitutes 0.3% to 5% in N. tabacum and up to 8% to 10% in
N. rustica based on the dry weight of the tobacco leaves. Its
biosynthesis takes place in the roots, and it accumulates in
the leaves. It is a potent neurotoxin for many pests, with par-
ticular specificity to insects. Therefore, nicotine and salts of
nicotine, for example, Black Leaf 40® (nicotine sulfate), have
been widely used as insecticides in the past (21A06, 21A07,
21A39–21A42), and currently, nicotine derivatives such as
Imidacloprid® [1-((6-chloro-3-pyridinyl)methyl)-N-nitroimi-
dazolidinimine] continue to be widely used (3973).
Pesticides and plant growth regulators are important parts
of modern agricultural and horticultural productivity. These
pesticides can be naturally occurring in the plant or syntheti-
cally produced. Although naturally produced pesticides and
growth regulators are effective, their concentrations in the
plant are often lower than necessary to completely eradi-
cate harmful pests and infections. Some naturally occurring
pesticides are harvested from plants and sold commercially,
for example, Bacillus thuringiensis, Derris (rotenone), pyre-
thrum, Neem oil, and nicotine (nicotine salts) [Environmental
Protection Agency (21A21)]. Over the last sixty to seventy
933
11/13/08 5:45:21 PM
 934 The Chemical Components of Tobacco and Tobacco Smoke
years, hundreds of synthetic pesticides and growth regula-
tors have been developed for application to tobacco at vari-
ous stages in its development and during storage prior to use
in commercial tobacco products to reduce or eradicate certain
pests, for example, insects, mice, and other animals, unwanted
plants (weeds), fungi, microorganisms such as bacteria and
viruses, and infectious proteins. Some of the most effective
pesticides and growth regulators are synthetic. Unfortunately,
a number of highly effective synthetic pesticides are extremely
harmful to both the environment and humans. One signifi-
cant problem with synthetic insecticides is their longevity.
This longevity is mostly due to the fact that many synthetic
insecticides are not biodegradable. Consequently, these pesti-
cides remain in the ecosystem for long periods of time and
can have disastrous consequences on organisms that subse-
quently absorb the insecticide. Arsenic salts (1459, 1460) and
DDT (707–709) are good examples of synthetic pesticides that
remained in the ecosystem for a long time, and that have had
considerable negative consequences. As a result of the possible
harm to both humans and the environment associated with
synthetic pesticides, worldwide regulations are now in place.
These regulations vary from country to country and apply to
both synthetic agrochemicals and harvested natural pesticides
[Environmental Protection Agency (21A21)].
Based on a definition by the U.S. Environmental Protection
Agency (EPA), a pesticide is any substance or mixture of
substances intended for preventing, destroying, repelling, or
mitigating any pest. The term pesticide also applies to herbi-
cides, fungicides, and various other substances used to con-
trol pests. Under U.S. law, a pesticide is also any substance or
mixture of substances intended for use as a plant regulator,
defoliant, or desiccant. Pests are living organisms that are
present where they are not wanted or that cause damage to
crops or humans or other animals. The EPA regulates both
naturally occurring chemicals harvested or extracted from
plants as pesticides and growth regulators, as well as syn-
thetic agrochemicals [EPA (21A21)].
There are five broad chemical classifications or categories
of pesticides (four for synthetic pesticides and one for natural
or plant-derived pesticides). Each of the following five chemi-
cal/biological categories of synthetic and harvested/extracted
natural pesticides and growth regulators includes examples
of commercial pesticides:
• Organochloride pesticides: Aldrin®, Chlordane®,
Dieldrin®, DDT, Endosulfan®, Endrin®, Heptachlor®,
Lindane®, Methoxychlor®, Mirex®, TDE.
• Organophosphorus pesticides: Acephate®, Azinphos-
methyl®, Chlorpyrifos®, Chlorpyriphos-methyl®,
Diazinon®, Dichlorvos® (DDVP), Dicrotophos®,
Dimethoate®, Disulfoton®, Ethoprop®, Fenamiphos®,
Fenitrothion®, Fenthion®, Fosthiazate®, Malathion®,
Methamidophos®,  Methidathion®, Methyl-parathion®,
Mevinphos®, Naled®, Oxydemeton-methyl®, Para-
thion®, Phorate®, Phosalone®, Phosmet®, Pirimiphos-
methyl®, Profenofos®, Terbufos®, Tetrachlorvinphos®,
Trichlorfon®.
© 2009 by Taylor & Francis Group, LLC
78836_C021.indd 934
• Carbamate pesticides: Aldicarb®, Carbofuran®,
Carbaryl®, Methom®.
• Pyrethroid pesticides: Allethrin®, Bifenthrin®,
Deltamethrin®, Permethrin®, Resmethrin®,
Tetramethrin , Tralomethrin .
® ®
• Plant derived pesticides: Azadirachtin A and B
(obtained from Azadirachta indica), Bacillus
thuringiensis, Derris (rotenone), Neem oil
(obtained from Azadirachta indica), nicotine,
pyrethrum, Spinosad (a mixture of spinosyn A
and spinosyn D) derived from soil bacterium
Saccharopolyspora spinosa.
Not every pesticide and growth regulator example listed
above may be approved for use on tobacco.
This chapter provides information on pesticides and
growth regulator residues (synthetic and natural occur-
ring) identified on tobacco and identified in tobacco smoke.
It also provides data on the transfer rates of these residues
on tobacco to tobacco mainstream smoke (MSS) and cer-
tain examples of degradation/decomposition products from
pesticides and growth regulator residues identified in MSS.
Finally, a brief review of analytical methods for the analysis
of pesticides and growth regulator residues on tobacco and in
tobacco smoke is provided.
XXI.A Synthetic Pesticides and
Plant Growth Regulator
Residues on Tobacco
Pesticide and growth regulator residues on tobacco and their
transfer rates to MSS have been the subject of several reviews
and multiple chapters in books. In the late 1960s, Guthrie and
Bowery (21A25) and Guthrie (1457, 1458) reviewed the early
literature dealing especially with residues of arsenic and the
chlorinated hydrocarbon insecticides, as well as those of car-
bamates and organophosphorus compounds used on tobacco.
In another publication, Guthrie (21A24) summarized legisla-
tion on pesticide residues on tobacco and tobacco products in
countries around the world as of 1973. In that paper, he also
included an updated account of residues in U.S. tobacco and
tobacco products. Ladisch in 1973 reviewed the known chlo-
rinated pesticides in tobacco and tobacco smoke (21A31). Two
reviews published in 1979 discuss the influence of growth
regulators and herbicides [Steffens (3811a)] and insecticides
and nematicides [Sheets and Leidy (3634)] on the chemistry
of tobacco. These reviews contained updates on residues
of pesticides. Ishiguro and Sugawara (1884) reviewed the
known pesticides in tobacco and smoke and literature on
decomposition products from pesticides in 1980. In 1986,
Wittekindt (4271a) reviewed the pesticides recommended for
use of tobacco in twenty-two countries, listed the maximum
residues for eleven pesticides allowed on tobacco products
in Germany, and presented a list of maximum amounts rec-
ommended by the German cigarette industry for seventy-one
other pesticides.
11/13/08 5:45:22 PM
 Pesticides and Growth Regulators 935
Davis et al. (21A17) and Meyer et al. (21A45) presented
a detailed analysis of maleic hydrazide (MH) residues in
U.S. tobacco and discussed the toxicological implications of
the residues. In 1989, the 43rd Tobacco Chemists’ Research
Conference (TCRC) symposium was dedicated to the sub-
ject of regulation of insect and pathogen activity in tobacco
and tobacco products. In that symposium, Benezet (21A05)
reviewed chemical means to control pests in tobacco and
tobacco products and their interaction. At that same sym-
posium Danehower (21A16) and Jackson et al. (21A29)
reviewed the role of natural tobacco constituents that are
effective pesticides (21A30). Cousins (21A14a) published a
review on herbicides and suckering agents in 1989. In 1972
and again in 1990 Tso published books on the chemistry and
biology of tobacco (3972, 3973). In both books he devoted
two chapters to pesticides and growth regulators (both com-
pounds native to tobacco and applied agrochemicals). In
1991, Sheets (3633) presented a very thorough review of all
known pesticides to that date. Davis and Nielsen edited a
book in 1999 on tobacco production, chemistry, and technol-
ogy (910a). Several chapters in that book reviewed various
types of pesticides employed in the production of different
types of tobacco (2483a, 2650b, 2892a, 3646a, 3661a). In
2002, Blanc et al. (21A06) reviewed the use of natural insec-
ticides and pesticides for use on tobacco. Mueller (2650a)
reviewed current approaches and tools for the management
of pesticide residues on tobacco in 2005 at the 59th Tobacco
Science Research Conference. Most recently in 2005,
Eberhardt (21A19) prepared an extensive review of pesticides
used on tobacco, the transfer rates of pesticides to MSS and
sidestream smoke (SSS), and decomposition products of pes-
ticide residues identified in MSS.
The most commonly used commercial pesticides and
growth regulators for tobacco, as of 1998, include:
Insecticides: Acephate®, Aldicarb®, Bacillus thur-
ingiensis, Carbaryl®, Carbofuran®, Chlorpyrifos®,
Diazinon®, Disulfoton®, Endosulfan®, Ethoprop®,
Fenamiphos®, Fonofos®, Imidacloprid®, Mala-
thion®, Methidathion®, Methomyl®, Spinosad®,
Trichlorfon®;
Herbicides: Benefin®, Clomazone®, Diphenamid®, Iso-
propalin®, Napropamide®, Pebulate®, Pendimet-
halin®, Sethoxydim®, Sulfentrazone®;
Fungicides: Dimethomorph®, Mancozeb®, Mefenoxam®,
Metalaxyl®;
Plant growth regulators: Ethephon®, Flumetralin®;
Plant growth regulators as herbicides: maleic hydrazide;
Fumigants as insecticides: Chloropicrin®;
Fumigants as insecticides or herbicides: methyl bromide;
Fungicides as insecticides or herbicides: 1,3-dichloro-
propene (1,3-D) (21A59).
Worldwide pesticide use has increased 50-fold since 1950,
and 2.5 million tons of industrial pesticides are now used
each year [Miller (21A46)]. More than 25 million pounds of
pesticides are used in tobacco production in the United States,
© 2009 by Taylor & Francis Group, LLC
78836_C021.indd 935
and tobacco ranks sixth among all agricultural commodities
in the amount of pesticides applied per acre, according to the
U.S. Government Accounting Office (GAO) (21A59).
Tobacco farmers use a considerable quantity of pesticides
and growth regulators to increase leaf yield and quality and,
hence, a greater profit for their crop. Even with the greatest
caution used by farmers in applying the agrochemicals, a cer-
tain level of these pesticides and growth regulators remain on
the leaf after harvesting and curing. Additional pesticides are
often used on tobacco that is stored to control insect popula-
tions and small but detectable levels of pesticides remain on
tobacco prior to its use in manufacture of tobacco products.
Therefore, certain residual pesticides are expected to be pres-
ent on tobacco. Since about 1950 over 200 types of pesticides
and growth regulators have been used on tobacco crops. Some
are no longer used as many technological improvements have
been made during that time and our knowledge of the effec-
tiveness of different agrochemicals on pest has improved. All
the newer pesticides are now regulated and strenuous test-
ing programs exist to assure that these agrochemicals meet
safety (human and environmental [soil and air]) requirements
(21A21). Additionally, agricultural breeding practices have
generated new varieties of tobacco plants that are often more
resistant to certain plant diseases and insects (21A21). Even
with all the safety measures in place residual levels of agro-
chemicals have been identified in both tobacco and tobacco
smoke. Degradation products from the thermal degradation,
pyrolysis, and combustion of these agrochemicals have also
been identified on tobacco and in tobacco smoke. Generally,
the level of residue tobacco pesticides and growth regulators
is very small (ng/kg tobacco, ppm range). The transfer rate of
these pesticides and growth regulators to MSS varies tremen-
dously but is generally less than 30%, in many cases less than
10%, and in some cases less than 1% [Eberhardt (21A19)].
The existence of trace levels of pesticides and growth regula-
tors in tobacco smoke was made possible by the advent of
modern analytical methodologies, particularly gas capillary
gas chromatography (GC/GC), gas chromatography/mass
spectrometry (GC/MS) and high performance liquid chro-
matography (HPLC).
XXI.B Naturally Occurring Plant
Growth Regulators and
Pesticides in Tobacco
Auxins are a class of plant growth substance (often called phy-
tohormones or plant hormones). The most important member
of the auxin family found in all plants is indole-3-acetic acid
(IAA). It generates the majority of auxin effects in intact
plants, and is the most potent native auxin. Naturally occur-
ring auxins include gibberellic acid, IAA, phenylacetic acid
(PAA), and indole-3-butanoic acid (IBA) (3973). Gibberellic
acid and several gibberellins are sold commercially as plant
growth regulators. Auxins play an essential role in coordina-
tion of many growth and behavioral processes in the plant life
cycle. When stimulated during normal plant growth or when
11/13/08 5:45:23 PM
 936 The Chemical Components of Tobacco and Tobacco Smoke
applied to the plant at high concentrations auxins produce
ethylene. Excess ethylene inhibits elongation growth, causes
leaf abscission, and can even kill the plant (21A14). Synthetic
auxins and commercially available auxins are effective her-
bicides by their effective promotion of ethylene in plants.
Synthetic auxin analogs include 1-naphthaleneacetic acid
(NAA), 2,4-dichlorophenoxyacetic acid (2,4-D), indole-3
-butanoic acid, and 2-methoxy-3,6-dichlorobenzoic acid
[Hobbie and Estelle (21A27), Hobbie et al. (21A28), Lomax
et al. (21A35)]. Additionally, compounds such as naturally
occurring pyrethrins (21A15, 21A20, 21A23, 21A32–21A34),
Neem oil (a mixture from Azadirachta indica of more than
135 compounds), Azadirachtin A and B from Azadirachta
indica [Akol et al. (21A01), Biswas et al. (21A05a), Cousins
(21A14a)], rotenone [Chamberlin and Madden (21A11)], and
Bacillus thuringiensis (B.t.) are effective naturally occurring
pesticides (3973, 21A54). Of course, the most plentiful natu-
rally occurring insecticide in tobacco is nicotine [Busbey and
McIndoo (21A07, 21A08), McIndoo et al. (21A40-21A42),
McIndoo (21A39), Steppuhn et al. (21A55)].
In 1989, Danehower (21A16) reviewed the field of naturally
occurring tobacco growth regulators and pesticides at the
43rd TCRC. Numerous effective naturally occurring pesti-
cides are found on the surface of tobacco leaves, including n-,
iso-, and anteiso-paraffinic hydrocarbons; aliphatic alcohols
and acids; wax esters; α- and β-4,8,13-duvatrien-1-ols, the
α- and β-duvatrienediols (12,Z)-labda-12,14-diene-8α-ol,
Z-abienol; (13,E)-labda-12-ene-8α, 15-diol, labdenediol;
numerous sucrose esters (C2-C8 acids); several labdane diter-
penes (sclareol-type); nicotine; nornicotine; formylnornico-
tine; acetylnornicotine; 3-hydroxy- acylnornicotines (C12-C16);
acyl nornicotines (C12 to C13) with n-, iso-, and anteiso-methyl
branching; and numerous phenolic compounds derived from
shikimic acid, for example, caffeic acid, ferulic acid, gentisic
acid, cichoriin, isoquercitin, rutin and their glucosides, and
the mevalonic acid, for example, capsidol, solavetivone, sola-
nascone, occidol, and numerous other sequiterpenoids cre-
ated from diverse biological pathways in tobacco.
XXI.C Transfer Rates of Pesticides and
Plant Growth Regulators to MSS
Tobacco, because it is subject to many types of pests, can be
damaged both physically and chemically. Serious infections
can result and have led to total crop failures. Efforts are con-
tinually being made to breed new varieties of tobacco resis-
tant to disease and various pests (aphids, hornworms, various
nematodes, etc.). Additionally, herbicides of various types are
widely used to control unwanted vegetation in the fields. As a
result, the use of pesticides and various plant growth regula-
tors is widespread and at present is the primary means used
by tobacco farmers to improve tobacco quality and yield.
The level of pesticide (and plant growth regulator) residues
on tobacco has always been a concern to tobacco growers,
the tobacco industry, and governmental regulators in terms
of the safety of the resulting tobacco products. Hundreds of
© 2009 by Taylor & Francis Group, LLC
78836_C021.indd 936
tobacco pesticides and plant growth regulators have been
developed and marketed in the past. Fewer than twenty-five
are currently regulated and employed by farmers and the
tobacco industry (3633). Regardless of the intended use of
these pesticides and growth regulators, it seems inevitable
that certain levels remain on the tobacco leaf. This is particu-
larly true today, not necessarily because inordinate levels of
pesticides are employed on tobacco but because tremendous
advances in analytical chemistry have enabled scientists to
detect extremely low levels (picogram to fentagram levels) of
these residues (or their decomposition products). As certain
agrochemicals used for pest control and growth regulation
leave residues on cured tobacco leaves, some residual pesti-
cides and growth regulators have been identified in tobacco
smoke. An important question concerning consumer safety
is whether the residual levels of pesticides (or growth regula-
tors) represent a danger to the public.
At the completion in 1976 of the study of the second set
of experimental cigarettes in the National Cancer Institute
(NCI) decade-long study on the “less hazardous” cigarette, it
was reported that the long-chained alcohols used as sucker-
ing agents on tobacco had no adverse chemical or biological
effect on cigarette MSS. In the 1976 report, Gori (1330) sum-
marized this aspect of the NCI second study:
The fatty alcohol, fatty alcohol × 100, and hand-suckered
blends showed no significant difference among themselves
or from the SEB II blend [see p. 2 in (1330)].
No statistically significant differences were observed among
Hand-suckered, Fatty Acid-Normal, and Fatty Acid × 100
Blends (variables 60, 61, and 62) [see p. 14 in (1330)]
In the fourth NCI study completed in 1980, the chemical
and biological properties of the MSSs from cigarettes made
from pesticide-treated tobacco and pesticide-free tobacco
were compared. Gori wrote [see p. 7 in (1333)]:
No significant differences were observed between cigarettes
made from pesticide-treated tobacco leaves and pesticide-
free tobacco leaves.
The pesticide-treated vs. pesticide-free tobaccos used
in this phase of the NCI study were those grown in Prince
Edward Island, Canada. The commercial pesticides used
on the tobacco included Chlorpyriphos®, Trichlorfon®,
Diphenamide®, Methomyl®, DDT, Carbaryl®, maleic hydraz-
ide, and C10 alcohol. The pesticide-treated tobacco proper-
ties were described in 1980 by Tso et al. (3973, 3977):
It appears that chemicals currently registered for use on
tobacco, when applied as directed, are of no significance in
increasing biological activity of cigarette smoke condensate
[see p. 151 in (3973)].
In 2005, Eberhardt (21A19) reported on pesticide residues
on tobacco, the transfer rates of selected pesticide residues,
and pyrolysis products of some pesticide residues as part
11/13/08 5:45:23 PM
 Pesticides and Growth Regulators 937
of the CORESTA Sub-group study on pesticide residues.
Information on forty agrochemicals (used from the 1950s
to the present) was obtained from sixty-four literature refer-
ences. The agrochemicals evaluated were insecticides, fumi-
gants, fungicides, herbicides, and growth regulators. These
represented a diverse set of compounds, including alcohols,
acids, organophosphates, organohalides, carbamates, dithio-
carbamates, pyrethrins, dinitro compounds, organonitrogen
compounds, and heterocyclics. Prior to the work by Eberhardt
(21A19), Rix (4857, 4858) evaluated the transfer of selected
agrochemicals (Dicamba®, Formothion®, and Thiodan®)
from tobacco to smoke.
For the majority of the commercial pesticides (and plant
growth regulators) reviewed by Eberhardt (21A19), only min-
imal information existed for their transfer into the smoke and
for pyrolysis products. It must be noted that some of the agro-
chemicals listed, for example, Leptophos®, TDE, had only
minor significance in tobacco cultivation and were added to
tobacco for purely experimental reasons to study smoke trans-
fer rates. Additionally, not all authors who provided infor-
mation on transfer rates gave precise details on the pesticide
concentrations in the original material used. There are only
a few pesticides, such as DDT, maleic hydrazide, and several
dithiocarbamates, where the transfer rates seemed to be ade-
quately investigated, that is, in sufficient number and by dif-
ferent research groups [Atallah et al. (1051d, 21A03, 21A04),
Chopra et al. (707, 708, 712, 714, 716), Guthrie et al. (1457,
1458), Hoffmann and Rathkamp (1756), and Hoffmann et al.
(1761, 1767)]. A number of publications by these authors used
labeled agrochemicals (sixteen of the sixty studies), which
provided information on the fate of the original substance in
tobacco MSS and SSS as well as their presence in the vapor
and particulate phases of the smoke streams. As most of
the naturally occurring pesticides and plant growth regula-
tors exist in tobacco, no information on the transfer rates to
tobacco smoke are available. Table XXI-3 lists the majority
of known pesticides and plant growth regulators used on and
identified in tobacco and tobacco smoke. Although Table
XXI-3 lists a great number of natural and synthetic pesticides
and growth regulators found in tobacco and tobacco smoke,
there are still other pesticides and plant growth regulators
that could have been used on tobacco but where no infor-
mation could be found in the literature. Additionally, indi-
vidual pesticides and growth regulators often have multiple
common names. Therefore in reviewing Table XXI-3, pesti-
cides and growth regulators should be searched by Chemical
Abstract number or chemical name. Table XXI-3 contains
only a selected number of naturally occurring pesticides and
plant growth regulators found in tobacco and tobacco smoke.
All of the compounds mentioned in this chapter as naturally
occurring pesticides and plant growth regulators are cov-
ered in other chapters, for example, the hydrocarbons are
discussed in Chapter 1, the duvatrienediols are discussed in
Chapter 2, and the nicotinoids are discussed in Chapter 17.
The evaluation by Eberhardt (21A19) of the available lit-
erature demonstrated that the transfer rate for all residues
© 2009 by Taylor & Francis Group, LLC
78836_C021.indd 937
studied was much less than 100%. In most studies, the transfer
rate of the pesticide to MSS is stated as being <30%. For
a small number of agrochemicals, for example, DDT, TDE,
Lindane®, HCH-alpha®, markedly higher transfer rates were
found, although it should be kept in mind that very broad
ranges in transfer rates exist for many of the pesticides exam-
ined. Only in a few studies were the transfer rates of resi-
dues in plain and filtered cigarettes presented and compared.
The data suggested that the presence of a filter in cigarettes
slightly reduces the transfer into MSS of some pesticides,
e.g., DDT, Disulfoton®, TDE (1127). Several other factors
also influenced the transfer rates, for example, the type of
tobacco tested, the form of the smoking article, whether ciga-
rette, cigar, cigarillo, or pipe, the type of filter employed, the
method of adding the original substance and its amount, vari-
ation in smoking conditions, such as puff volume, number
of puffs, and the analytical methods employed to determine
the agrochemical [Mussalo-Rauhamaa et al. (21A48), Mold
and Walker (2596), Carugno (21A10), Schmid and Rastetter
(21A52), Mestres et al. (21A43), Hengy and Thirion (1619),
Hoffmann et al. (1761), Atallah and Dorough (21A03, 21A04),
Thorstenson and Dorough (3915), Smith et al. (3724), Lorenz
et al. (21A36–21A38), Guthrie (1457), Dickes et al. (21A18),
Dorough and Atallah (1051d), Bowery et al. (415), Hawk et al.
(1553), Ceschini and Chauchaix (644), Clark et al. (21A12),
Moshy and Halter (21A47), Hengy and Thirion (1618), Meikle
(2527), Sitaramaiah et al. (21A53), Thurm (21A57), Stone
(21A56), Barkemeyer et al. (186), Chopra and Domanski
(707), Chopra and Sherman (712), and Underwood (21A58)].
Table XXI-1 shows the percentage transfer of selected
pesticides applied to tobaccos that transfer to MSS. The per-
centage transfers were generally taken from the publication
or were calculated based on data provided in the literature
[Eberhardt (21A19)].
XXI.D Decomposition Products
of Agrochemicals in
Mainstream Smoke
The decomposition products identified in MSS of various
agrochemicals added to tobacco are shown in Table XXI-2.
In some of the published studies reviewed by Eberdardt
(21A19), the determination and quantification of the pyrol-
ysis products were the primary objective of the study, for
example, Hoffmann et al. (1761), Mestres et al. (21A44), and
Higman et al. (1645), and MSS transfer rates for the pesticide
were not determined. In other studies 14C-labeled pesticides
were evaluated, for example, Atallah and Dorough (21A03,
21A04), Frisch et al. (1243), and Clark et al. (21A12). In
most cases the agrochemicals tested were used as purchased,
for example, Comer et al. (21A13), Chopra et al. (716), and
Chopra and Zuniga (717).
For the majority of the pesticides reviewed by Eberhardt
(21A19), only minimal information existed for their transfer
into smoke and for their pyrolysis products. There are only a
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 938 The Chemical Components of Tobacco and Tobacco Smoke

few pesticides, such as DDT, maleic hydrazide, and several

Table XXI-1 dithiocarbamates, where the transfer rates seem to be ade-
Percent Transfer of Intact Agrochemicals quately investigated in a sufficient number of studies by dif-
to Mainstream Smoke (1884, 21A19) ferent research groups [Atallah et al. (1051d, 21A03, 21A04),
Chopra et al. (707, 708, 712, 714, 716), Guthrie et al. (1457,
Percent Transfer of
Pesticide* Intact Compound
1458), Hoffmann and Rathkamp (1756), and Hoffmann et al.
(1761, 1767)].
Anilazine 1
Azinphos-methyl 0.2 - 0.27
Benomyl ND XXI.E Methods for Analysis of Pesticides
Captan ND - 2.7 and Plant Growth Regulators
Carbaryl 1 - 11
Carbofuran 0.3 - 20 Numerous analytical methods, for example, GC-GC, GC-MS
Chlorpyrifos 13.5 - 15 and HPLC, have been published for the determination of
Cyhalothrin 5.2
various classes of pesticides [Haeberer and Chortyk (470,
Cypermethrin 1.51
DDT 1.2 - 83.3 21A26), Schmeltz et al. (3483), Sagredos and Eckert (3379–
Deltamethrin 2.64 3381), Sagredos and Moser (3382), Nesemann and Seehofer
Diamidofos ND (2699), Nesemann et al. (2697, 2698), Schmid and Rastetter
Dieldrin 4 - 32 (21A52), Schmid (3513), Dattilo et al. (904, 905), Guhlmann
Diflubenzuron 6.9 et al. (1451), Cai et al. (21A09), Carpenter and Frost (606),
Disulfoton 6 - 14.8
Dithiocarbamates ND
Nowell and Resek (21A50), Zaugg et al. (21A63), Werner
Endosulfan ND - 15.3 et al. (21A60), Yamazaki and Tomara (21A62), and many
Endosulfan sulfate 15.5 - 16.3 others].
Endrin 18.18 - 31.58
Fenpropathrin 15.5
Fenvalerate 1.72 XXI.F Residues of Synthetic
HCH-alpha 45 Pesticides and Plant Growth
Heptachlor 4-5
3-Hydroxycarbofuran 0.1 - 3.26
Regulators Identified in
Imidacloprid 5.3 Tobacco and Tobacco Smoke
Isobenzan 3.5 - 5.1
Leptophos 3 - 10 The number of pesticide, plant growth regulators, and their
Lindane 3.1 - 40 decomposition products identified in tobacco and tobacco
Linuron 6.7 smoke listed in Table XXI-3 is 298. Of these, 102 have been
Malathion ND - 9.4 identified in tobacco smoke, 294 in tobacco, and 98 in both
Maleic hydrazide ND - 23
tobacco and tobacco smoke. There are more natural pesti-
Methoprene 38.2
Metobromuron 3.7 - 4 cides and growth regulators known than are listed in Table
Mirex 9 - 23 XXI-3 because only selected examples of these natural
Monolinuron 2.5 - 4.5 pesticides and growth regulators, described by Danehower
Naphthol 5.7 - 13.8 (21A16), are given.
Parathion ND - 15.3
Phosphine ND
TDE 0.007 - 63.75

ND = not determined

All the agrochemicals listed are sold commercially and

*

are trademarked/registered. Each should have a ® sym-

bol after the product name, except the following agro-
chemicals: DDT, 3-hydroxycarbofuran, maleic hydra-
zide, phosphine and TDE.

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 938 11/13/08 5:45:25 PM

 Pesticides and Growth Regulators 939

Table XXI-2
Degradation Products of Pesticides in Mainstream Smoke (1884, 21A19)
Pesticide* Degradation Products of the Intact Compound References
Anilazine o-chloroaniline 1457
Azinphos-methyl Oxyguthion 419, 1457
Captan CO2 21A37
Carbaryl degradation products: 7 (not further characterized), CO2 1051d, 21A03, 21A04,
Carbofuran degradation products: 2 (not further characterized), CO2 1051d, 1553, 21A03, 21A04
Chlorpyrifos decomposition into unknown fragments 717
DDT 1,1-dichloro-2,2-bis(p-chlorophenyl)ethane (DDD = TDE), 1,1-dichloro-2,2-bis(p- 644, 707, 712, 714, 708, 758, 1000,
chlorophenyl)ethylene (DDE), 1-chloro-2,2-bis(p-chlorophenyl)ethylene (DDM = 1051d, 1457, 1756, 1767, 2697, 3915,
TDEE, 4,4’-dichlorobenzophenone (DCBP), bis(p-chlorophenyl)methane (BCPM), 21A18, 21A37, 21A38, 21A43
CO2, chloroform, methyl chloride, trans-4,4’-dichlorostilbene (DCS), DDD-olefins
Diamidafos phenol 2527
Dieldrin chlorinated and dechlorinated degradation products 21A57
Diflubenzuron 4-chloroaniline, 4-chlorophenylurea 21A53
Dithiocarbamates CO2, carbon disulphide, COS, ethylene thiourea, hydrogen sulfide 124, 186, 21A10, 21A38, 21A44, 21A51
Endosulfan ether 1619
Imidacloprid CO2, CO (traces), urea compound 21A12
Leptophos degradation products: 4 (not further characterized), CO2 1051d, 21A03, 21A04
Lindane CO2 21A36, 21A38
Linuron 3,4-dichloroaniline 822
Malathion CO2 21A38
Maleic hydrazide acetonitrile, acrylonitrile, aminobutanoic acid, ammonia, aniline, butanoic acid, benzonitrile, 716, 1553, 1761, 2383-2385, 3724,
CO2, CO, cyanide, 1H-pyrrole-2,5-dione, hydrazine (traces), indole, succinimide 3725, 4274, 21A56
Methoprene CO2, CO 1243
Metobromuron 4-bromoaniline 822
Mirex degradation products: 3 (not further characterized), CO2 1051d, 21A03, 21A04
Monolinuron CO2, 4-chloroaniline 822, 21A37
Naphthol degradation products: 6 (not further characterized) 21A03, 21A04
TDE (DDD) dechlorinated TDE, 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), 1-chloro-2,2- 415, 416, 714, 758, 1457, 3915
bis(p-chlorophenyl)ethylene (DDM = TDEE), 4,4’-dichlorobenzophenone (DCBP),
bis(p-chlorophenyl)methane (BCPM), trans-4,4’-dichlorostilbene (DCS)

All the agrochemicals listed are sold commercially and are trademarked/registered. Each should have a ® symbol after the product name, except the fol-
*

lowing agrochemicals: DDT, 3-hydroxycarbofuran, maleic hydrazide, phosphine and TDE.

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 939 11/13/08 5:45:25 PM

 940 The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3
Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke
Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 940 11/13/08 5:45:26 PM

 Pesticides and Growth Regulators 941

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 941 11/13/08 5:45:27 PM

 942 The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 942 11/13/08 5:45:29 PM

 Pesticides and Growth Regulators 943

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 943 11/13/08 5:45:30 PM

 944 The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 944 11/13/08 5:45:32 PM

 Pesticides and Growth Regulators 945

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 945 11/13/08 5:45:33 PM

 946 The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 946 11/13/08 5:45:41 PM

 Pesticides and Growth Regulators 947

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 947 11/13/08 5:45:49 PM

 948 The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 948 11/13/08 5:45:53 PM

 Pesticides and Growth Regulators 949

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 949 11/13/08 5:45:55 PM

 950 The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 950 11/13/08 5:45:57 PM

 Pesticides and Growth Regulators 951

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 951 11/13/08 5:45:59 PM

 952 The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 952 11/13/08 5:46:01 PM

 Pesticides and Growth Regulators 953

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 953 11/13/08 5:46:03 PM

 954 The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 954 11/13/08 5:46:06 PM

 Pesticides and Growth Regulators 955

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 955 11/13/08 5:46:13 PM

 956 The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 956 11/13/08 5:46:15 PM

 Pesticides and Growth Regulators 957

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 957 11/13/08 5:46:17 PM

 958 The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 958 11/13/08 5:46:20 PM

 Pesticides and Growth Regulators 959

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 959 11/13/08 5:46:22 PM

 960 The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 960 11/13/08 5:46:24 PM

 Pesticides and Growth Regulators 961

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 961 11/13/08 5:46:26 PM

 962 The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 962 11/13/08 5:46:28 PM

 Pesticides and Growth Regulators 963

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 963 11/13/08 5:46:31 PM

 964 The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 964 11/13/08 5:46:33 PM

 Pesticides and Growth Regulators 965

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 965 11/13/08 5:46:35 PM

 966 The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 966 11/13/08 5:46:44 PM

 Pesticides and Growth Regulators 967

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 967 11/13/08 5:46:46 PM

 968 The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 968 11/13/08 5:46:48 PM

 Pesticides and Growth Regulators 969

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

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 970 The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 970 11/13/08 5:46:57 PM

 Pesticides and Growth Regulators 971

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

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 972 The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 972 11/13/08 5:47:01 PM

 Pesticides and Growth Regulators 973

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 973 11/13/08 5:47:08 PM

 974 The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 974 11/13/08 5:47:10 PM

 Pesticides and Growth Regulators 975

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

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 976 The Chemical Components of Tobacco and Tobacco Smoke

Table XXI-3 (Continued)

Synthetic and Natural Pesticides and Plant Growth Regulators in Tobacco, Tobacco Smoke, and Tobacco Substitute
Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C021.indd 976 11/13/08 5:47:21 PM

 22 Genes, Nucleotides, and Enzymes
Prior to discussing genes, nucleotides (DNA and RNA
strands), and enzymes identified in tobacco, a general discus-
sion of genetics, genes, nucleotides, and enzymes is appropri-
ate (3973). There are numerous excellent reference texts that
the reader can access for more detailed information on genetics
[Davis and Nielsen (910a), Tso (3973), Acquaah (22A01),
Bernardi (22A03), Griffiths et al. (22A12), Hartl and Jones
(22A14)] and several sources of encyclopedic information
(22A05, 22A17, 22A34). The general discussion will be fol-
lowed by a review of work accomplished over many decades
toward understanding the mysteries of tobacco genetics.
XXII.A General Discussion of Genetics
Genetics is the science of heredity and variation in living
organisms (22A12, 22A14, 22A17). Knowledge that desired
characteristics were inherited has been used implicitly since
prehistoric times for improving crop plants and animals
through selective breeding. The science originated from
human experience to improve crop and animals through the
use of varied methods, such as domestication. However, the
modern science of genetics, which seeks to understand the
mechanisms of inheritance, only began with the work of
Gregor Mendel in the mid-1800s (3973, 22A32).
Inheritance is fundamentally a discrete process with
specific traits that are passed on in an independent manner.
These basic units of inheritance are now known as genes. In
the cells of organisms, genes exist physically in the struc-
ture of the molecule DNA and the information contained in
the genes is used to create and control the components of
cells. Although genetics plays a large role in determining
the appearance and behavior of organisms, it is the interac-
tion of genetics with the environment an organism experi-
ences that determines the ultimate outcome. For example,
Nicotiana tabacum seeds planted and cultivated in different
soils and under different climatic and agronomic conditions
can produce different types of tobacco that have vastly dif-
ferent appearances and chemical composition, for example,
Maryland vs. Virginia tobacco (3973).
A gene is a set of segments of nucleic acid. A nucleic acid
is a complex, high molecular weight biochemical macromol-
ecule composed of nucleotide chains that convey genetic
information. The most common nucleic acids are deoxyribo-
nucleic acid (DNA) and ribonucleic acid (RNA).
Genes are arranged linearly in long chains of DNA
sequences, called chromosomes. In eukaryotic organisms
(which include plants and animals), each cell has its DNA
arranged in multiple linear chromosomes. These DNA strands
are often extremely long. The largest human chromosome, for
example, is about 140 million base pairs in length (22A11).
© 2009 by Taylor & Francis Group, LLC
78836_C022.indd 977
Certain segments of nucleic acid contain the informa-
tion necessary to produce a functional RNA product in a
controlled manner. They contain regulatory regions dictat-
ing under what conditions this product is made, transcribed
regions dictating the sequence of the RNA product, and/
or other functional sequence regions (22A23, 22A24). The
physical development and phenotype, that is, a measurable
characteristic, such as color or disease resistance, of organ-
isms can be thought of as a product of genes interacting with
each other and with the environment, and genes can be con-
sidered as units of inheritance.
In cells, genes consist of a long strand of DNA that con-
tains a promoter, which controls the activity of a gene, and
coding sequences, which determine what the gene produces.
When a gene is active, the coding sequence is copied in a
process called transcription, producing an RNA copy of the
gene’s information. This RNA can then direct the synthesis
of proteins via the genetic code. The genetic code is the set
of rules by which information encoded in genetic material
(DNA or RNA sequences) is translated into proteins, that is,
amino acid sequences and enzymes, by living cells. However,
RNAs can also be used directly, for example, as part of the
ribosome, which is a small, dense organelle in cells that
assembles proteins. Molecules produced from gene expres-
sion, whether RNA or protein, are known as gene products.
Most genes contain noncoding regions that do not code
for the gene products, but can regulate gene expression.
Additionally, there are large segments of the DNA that do
not carry any genetic information. One single gene can lead
to the synthesis of multiple proteins. The total complement
of genes in an organism or cell is known as its genome.
The estimated number of genes in the human genome has
been repeatedly revised downward since the completion of
the Human Genome Project, but current estimates place the
human genome size at just under 3 billion base pairs and
about 20000 to 25000 genes (22A15).
The vast majority of living organisms encode their genes
in long strands of DNA. DNA consists of a chain made from
four types of nucleotide subunits: adenosine (A), cytidine (C),
guanosine (G), and thymidine (T). Each nucleotide subunit
consists of three components: a phosphate group, a deoxyri-
bose sugar ring, and a nucleobase. Thus, nucleotides in DNA
or RNA are typically called bases; consequently they are
commonly referred to simply by their purine (adenine and
guanine) or pyrimidine (cytosine and thymine) original base
components. The most common form of DNA in a cell is a
double helix structure, in which two individual DNA strands
twist around each other in a right-handed spiral. In this struc-
ture, the base pairing rules specify that guanine pairs with
cytosine and adenine pairs with thymine (each pair contains
977
11/13/08 5:48:16 PM
 978 The Chemical Components of Tobacco and Tobacco Smoke
one purine and one pyrimidine). The base pairing between
guanine and cytosine forms three hydrogen bonds, while the
base pairing between adenine and thymine forms two hydro-
gen bonds. The two strands in a double helix must therefore
be complementary, that is, their bases must align such that
the adenines of one strand are paired with the thymines of
the other strand, and so on.
Due to the chemical composition of the pentose residues
of the bases, DNA strands have directionality. One end of a
DNA polymer contains an exposed hydroxyl group on the
deoxyribose; this is known as the 3’ end of the molecule.
The other end contains an exposed phosphate group; this is
the 5’ end. The directionality of DNA is vitally important to
many cellular processes, since double helices are necessarily
directional (a strand running 5’-3’ pairs with a complemen-
tary strand running 3’-5’) and processes such as DNA repli-
cation occur in only one direction. All nucleic acid synthesis
in a cell occurs in the 5’-3’ direction, because new monomers
are added via a dehydration reaction that uses the exposed 3’
hydroxyl as a nucleophile.
The expression of genes encoded in DNA begins by tran-
scribing the gene into RNA, a second type of nucleic acid
that is very similar to DNA, but monomers of which con-
tain the sugar ribose rather than deoxyribose. RNA also
contains the base uracil (U) in place of thymine. Genes that
encode proteins are composed of a series of three-nucleotide
sequences called codons. A codon is a set of any three adja-
cent bases in the DNA or RNA. There are sixty-four different
codons, of which sixty-one specify the incorporation of an
amino acid into a polypeptide chain while the remaining
three are stop codons that signal the end of a polypeptide.
For example, the DNA codon ACG via its complementary
RNA codon CGU specifies the amino acid arginine. For
another example, the DNA codon TAC via its complementary
RNA codon GUA specifies the amino acid valine. There are
three stop codons: uracil-adenosine-adenosine (UAA), uracil-
adenosine-guanosine (UAG), and uracil-guanosine-adenosine
(UGA). They are also called termination codons or nonsense
codons. The genetic code specifies the correspondence dur-
ing protein translation between codons and amino acids. The
genetic code is nearly the same for all known organisms.
Many molecular definitions of a gene relate to their role
in directing the production of specific proteins. Production
of protein itself is made possible via certain enzymes known
as polymerases. Various DNAs and RNAs could not be pro-
duced without these polymerases and therefore they are of
primary importance. Numerous other enzymes are produced
that control metabolic and catabolic processes (enzymati-
cally), provide structural components, and perform regula-
tory functions in cells.
A single gene can encode multiple enzymes, and an
enzyme can have multiple genes. For example, ribulose bis-
phosphate carboxylase-oxygenase in Nicotiana tabacum is
a multimeric protein of sixteen peptides, eight small sub-
units (nuclear encoded) and eight large subunits (chloroplast
encoded), thus two genes are responsible for this enzyme
(3974c, 22A27, 22A35).
© 2009 by Taylor & Francis Group, LLC
78836_C022.indd 978
Metabolic and catabolic enzymes are specialized proteins
that catalyze chemical reactions. In enzymatic catalyzed
reactions, the molecules at the beginning of the process are
called substrates, and the enzyme converts them into different
molecules, or products. Almost all processes in a biologi-
cal cell need enzymes in order to occur at significant rates.
Since enzymes are extremely selective for their substrates
and accelerate only a few reactions from among many pos-
sibilities, the set of enzymes made in a cell determines which
metabolic pathways occur in that cell (3973).
Each type of enzyme is generally geared to interact chemi-
cally with only one particular substance or type of substance,
termed a substrate. The two parts fit together, according to
a widely accepted theory introduced in the 1890s by the
German chemist Emil Fischer (1852–1919), as a key fits into
a lock. Each type of enzyme has a specific three-dimensional
shape that enables it to fit with the substrate, which has a
complementary shape.
The link between enzymes and substrates is so strong that
enzymes often are named after the substrate involved, sim-
ply by adding ase to the name of the substrate. For example,
lactase is the enzyme that catalyzes the breakdown of lac-
tose, while urease catalyzes the chemical breakdown of urea.
Enzymes bind their reactants or substrates at special folds
and clefts, named active sites, in the structure of the sub-
strate. Because numerous interactions are required in their
work of catalysis, enzymes must have many active sites, and
therefore can have molecular weights as high as one million.
XXII.B Tobacco Genetics
Tobacco has been used in one form or another in civilized soci-
ety for nearly five centuries. Eventually in the late nineteenth
century, investigations as to its composition began but they
were not particularly numerous. The major driving force in the
escalation in the mid-twentieth century of studies on tobacco
composition was the attempt to define (1) its components that
contributed to the acceptability of the taste and aroma of
tobacco itself and its smoke to consumers and (2) the precur-
sors in tobacco of the toxicants in its smoke (3973, 22A30).
In 1972, Tso (22A30) remarked:
The characteristics of cigarette smoke are functions of the
physical and chemical properties of leaf tobacco which
make the cigarette. Smoke constituents may be modified
by changing leaf characteristics. The questions are: What
kinds of changes are needed? and, how can these changes
be achieved?
Tobacco genetics is a rather new field of study although
research on tobacco to understand its physical and chemi-
cal makeup has been a goal of tobacco scientists for over a
hundred years. The initial problem in undertaking the goal
of trying to understand the origins of the chemical and physi-
cal essence of tobacco was that our understanding of life
processes, in general, was inadequate prior to the discovery
of the structure and function of DNA. Additionally, the life
11/13/08 5:48:16 PM
 Genes, Nucleotides, and Enzymes 979
processing functions of numerous DNAs and RNAs in tobacco
were not understood. Although scientists had an empirical
knowledge of how the genetics worked via the tobacco breed-
ing program, basic fundamental knowledge was lacking until
technology was developed to execute the search for informa-
tion on the genetic code for tobacco (3973).
Regardless, research directed toward the ultimate goal of
understanding of the fundamental life processes of tobacco
began. The early genetic research was conducted in the areas
of tobacco breeding (as a means to improve leaf characteris-
tics, quality, and disease resistance) and the chemical com-
position of tobacco via identification of extractable material
in tobacco, for example, amino acids, various proteins, and
enzymes (424a, 2341a, 3972, 3973, 22A06, 22A29, 22A30).
It was not until the 1970s and 1980s with the development of
new analytical and genetic tools, such as HPLC and GC-MS,
instrumental polymerase chain reaction (PCR), plant trans-
formation, genetic mapping with molecular markers, gene
tagging, and positional cloning, that significant progress was
possible in the understanding of tobacco genetics directed
towards improved pest resistance, yield, and quality (424a).
The chemical composition of tobacco smoke is highly
dependent on the physical and chemical properties of the
leaf tobaccos used in cigarette manufacture. It is a basic
tenet that the biological properties of cigarette mainstream
smoke (MSS) and cigarette smoke condensate (CSC) can
be improved through changes in the genetics of tobacco.
Numerous types of chemical and physical modifications per-
formed on tobacco, for example, tobacco extraction, tobacco
reconstitution, tobacco expansion, inclusion of tobacco substi-
tutes, have indicated that this tenet is possible (1375a, 1375b).
Thousands of genes, nucleotides, and enzymes have been
identified in tobacco. Although they do not transfer intact to
MSS, hundreds of decomposition products from their com-
bustion and pyrolysis products have been identified. Many
of the combustion and pyrolysis products found in MSS and
CSC have been called “Hoffmann analytes” because of their
alleged adverse biological effects, for example, quinoline,
HCN, and several other undesirable nitrogenous compounds,
certain PAHs, aza-arenes, and phenolics (3974c). It is hoped
that through genetic modifications precursors in tobacco
of the toxicants in its smoke can be altered significantly to
improve the safety of tobacco products (3794b, 3974c, 3975,
3984, 3976, 22A30).
XXII.C Genes, Nucleotides, and
Enzymes Identified in Tobacco
The sixty-five species related to Nicotiana tabacum represent
sources of a divergent germplasm for biochemical and physi-
cal variations (3793, 22A19, 22A30). These species differ
widely in growth habit and in chromosome numbers (3793).
Tobacco breeding via interspecific hybridization has been the
major tool for agricultural scientists to improve the health
and quality of tobacco (22A30). Possible approaches that
plant scientists can take to modify tobacco leaf have been
© 2009 by Taylor & Francis Group, LLC
78836_C022.indd 979
reviewed by Tso (22A31). Modifications discussed by Tso
(3973, 22A31) involved genetic and cultural modification,
nitrogen fertilization technology, leaf and plant population,
the physiological stage of topping, and pesticide treatments.
Post-harvest modifications were also discussed (22A31), as
leaf composition is markedly affected by the curing process,
aging, or other treatment of cured leaves (4005).
The U.S. Nicotiana Germplasm Collection was initiated
by the U.S. Department of Agriculture (USDA) in 1934 as a
resource for tobacco breeders. The collection currently con-
sists of approximately 1244 tobacco introductions, 656 cul-
tivars, and 224 accessions representing fifty-nine Nicotiana
species, fifty interspecific hybrids, and a newly introduced
set of mutants (22A19). The gene pool of the Nicotiana
Germplasm Collection represents enormous possibilities
for researchers in plant pathology, plant molecular biology,
and biotechnology to modify and improve the quality, yield,
and safety of tobacco. It has been estimated that the genetic
makeup of tobacco includes 25000 to 50000 genes (22A22).
Nicotiana tabacum has a very large genome size compared
with other cultivated solanaceous plants (22A13, 22A21,
22A22). At approximately 4.5 billion base pairs, it is 1.5 times
the size of the human genome (22A13, 22A21, 22A22).
There are at least two major (and several minor) initia-
tives to sequence the tobacco genome; the Tobacco Genome
Initiative (TGI) and the European Sequencing of Tobacco
Project (ESTobacco). Both projects have an ultimate goal of
sequencing the greater part of the tobacco genome. Although
tobacco has been cultivated for more than 500 years and is a
crop of great economic significance, relatively little informa-
tion exists on its genome structure and organization.
The overall goal of the TGI is to sequence and annotate
more than 90% of the open reading frames in the genome of
cultivated tobacco, Nicotiana tabacum. Nicotiana tabacum
is an amphiploid species (2n = 48) likely resulting from an
interspecific cross between Nicotiana sylvestris (2n = 24) and
Nicotiana tomentosiformis (2n = 24), and at approximately
4.5 billion base pairs has a very large genome size compared
with other cultivated solanaceous plants. A complete gene
catalog will provide the raw information to investigate physi-
ological and genetic processes in the tobacco plant, a widely
used model in plant biotechnology. Tobacco genomics may
lead to the elucidation of genetic factors that impact constitu-
ents associated with tobacco consumption. Improving our
understanding of these processes may potentially contribute
to achieving the goal of reducing the harm associated with
cigarette smoking. In addition, important agronomic traits
such as disease and pest resistance genes could be identified,
and thus could be available for use in traditional and molec-
ular breeding projects the goal of which is to enhance the
performance of tobacco as a crop in different environments.
Finally, Nicotiana tabacum is a member of the agriculturally
important Solanaceae family, which also includes tomato,
potato, eggplant, and pepper crop plants. All of these plants
may benefit from gene discovery in tobacco. The TGI is
housed in the laboratories of the Plant Pathology Department
of the North Carolina State University (NCSU) Centennial
11/13/08 5:48:17 PM
 980 The Chemical Components of Tobacco and Tobacco Smoke
Campus, College of Agricultural and Life Sciences (Raleigh,
North Carolina). NCSU will make the TGI data available
to authorized academic researchers. The Tobacco Genome
Initiative is supported by Philip Morris USA, Inc. (22A13,
22A21, 22A22).
The TGI has identified a large percentage of genes in
Nicotiana tabacum by utilizing a combination of strate-
gies. Researchers at TGI have employed a methyl filtration
approach to identify gene-rich regions in Nicotiana tabacum
in order to expedite the gene discovery process. As of
2006, TGI had sequenced 1700000 lanes of methyl filtered
clones and observed a dramatic increase in gene discovery
in filtered vs. nonfiltered libraries. TGI has also performed
expressed sequence tag (EST) sequencing from various
Nicotiana libraries and to date has sequenced over 80000
ESTs. Genes tagged by these two strategies have been used
as probes to identify bacterial artificial chromosome (BAC)
clones for more targeted sequencing. Numerous BACs have
been sequenced, revealing information about both gene struc-
ture and genome organization in Nicotiana species (22A13,
22A21). The TGI had a projected completion date in late
2007. The TGI was completed in June 2008.
The second major tobacco genomic project is centered in
Europe and was started in 2006. It is known as the European
Sequencing of Tobacco Project or ESTobacco. This project is
being conducted by Advanced Technologies (Cambridge) Ltd.
(a wholly owned subsidiary of British American Tobacco)
and Institut du Tabac de Bergerac (part of the Altadis Group).
The aim of the ESTobacco project is to be complementary
to other projects currently underway concerning the tobacco
genome. The strategy of ESTobacco is to sequence only
genes expressed in tobacco and not the whole genome. They
believe that the size of the tobacco genome is too large to
be totally sequenced. The tobacco genome is thought to be
about twenty-nine times larger than that of Arabidopsis thali-
ana (Table XXII-1).
The plan of the ESTobacco project is to investigate three
commercial varieties of tobacco used throughout the world:
K326 for the flue-cured type, and Burley 21 and TN86 for
the burley types. To obtain the major genes, the organs of the
plant (seeds, roots, stems, midribs, laminae, and flowers) pre-
pared at different stages of development (germination, young
seedlings, before and after topping, maturity) will be used
as a basis for this work. A large tobacco EST dataset was
obtained from eleven normalized cDNA libraries compris-
ing 56000 clones. It is envisioned that a DNA array designed
with these sequences will allow the large-scale study of
Table XXII-1
Relative Size of Genomes and Number of Genes by
Species
Species Genome Size (Mb) Number of Genes
Arabidopsis thaliana 125 25500
Homo sapiens 3000 20000 to 25000
Nicotiana tabacum 3500 to 4500 (est.) 25000 to 50000 (est.)
© 2009 by Taylor & Francis Group, LLC
78836_C022.indd 980
the genes expressed in tobacco. This new tool should lead
to the acceleration of programs already underway concern-
ing the origins of risks associated with tobacco and provide
strategies for harm reduction. To encourage a wide range of
initiatives on tobacco plant genetic, as with other crops, the
resulting sequences obtained during the ESTobacco proj-
ect will be available to the worldwide scientific community
through public access databases (22A08, 22A26).
As whole gene sequences and nucleotide sequences (DNA
and RNA sequenced strands) become available they are being
entered into GenBank (22A10). GenBank is the National
Institute of Health (NIH) genetic sequence database, an
annotated collection of all publicly available DNA sequences
(22A02). There were approximately 65369091950 bases in
61132599 sequence records in the traditional GenBank divi-
sions and 80369977826 bases in 17960667 sequence records
in the Whole Genome Shotgun (WGS) division as of August
2006. GenBank is part of the International Nucleotide
Sequence Database Collaboration, which comprises the
DNA DataBank of Japan (DDBJ), the European Molecular
Biology Laboratory (EMBL), and GenBank at the National
Center for Biotechnology Information (NCBI). Information
located in GenBank can be accessed on the Internet (1282a).
Within the next few years, our understanding of the
tobacco genome will be greatly improved. It is anticipated
or predicted that advances in tobacco genomics will lead to
the next major improvement in safety and health associated
with cigarette smoking via genetic modifications of vari-
ous Nicotiana species. The symposium at the 61st Tobacco
Science Research Conference featured presentations from
representatives from the TGI and the ESTobacco projects.
Updates on both projects were given, as well as information
on how new types of biotechnologies are being employed to
provide both fundamental and practical information on genes
that could be used to improve pest resistance, quality, yield of
tobacco, and the safety of tobacco products (22A09, 22A20).
In the late 1950s and through the 1960s enormous break-
throughs in DNA enzymology took place. For example, in
1955 Kornberg et al. (22A18) isolated DNA polymerase, and
Weiss and Richardson (22A33) isolated DNA ligase in 1967.
Smith and Wilcox (22A28) and Kelley and Smith (22A16)
isolated and characterized the first sequence specific restric-
tion nuclease in 1970. These enzymes, respectively, play roles
in the synthesis of DNA molecules, the attachment of two or
more DNA molecules to one another, and the breaking of
DNA molecules into fragments. Importantly, these enzymes
make it possible to create entirely new kinds of DNA mol-
ecules and, equally important, to manipulate the functioning
of the genes located on these new molecules. The types of
enzymes that Smith, Wilcox, and Kelley (22A16, 22A28) dis-
covered are called restriction enzymes. Restriction enzymes
recognize and cut specific short sequences of DNA. They are
found in bacteria, which use the enzymes to digest invad-
ing DNA. The bacteria add methyl groups to their own DNA
to protect them from digestion. Molecular biologists began
using these enzymes, along with DNA polymerase and DNA
ligase, in the early 1970s to cut, manipulate, and analyze
11/13/08 5:48:18 PM
 Genes, Nucleotides, and Enzymes 981
pieces of DNA in a predictable and reproducible way. The
enzymes became an important, early tool for mapping
genomes. There are over 900 types of restriction enzymes
that have been isolated from over 230 strains of bacteria.
Some of these enzymes provide specific sequence segments
of DNA and some do not. About 180 restriction enzymes are
commercially available.
There have been hundreds of thousands of nucleotide
sequences (DNA and RNA sequenced strands) that have been
produced via restriction enzymes from various forms of DNA
and RNA in tobacco (22A13, 22A21). Not every DNA strand
holds or is encoded with genetic information. There are con-
siderable lengths of DNA that contain no genetic information
or the function of which has yet to be identified. These seg-
ments are called “junk” or “non-coding” DNA. For example,
about 97% of the human genome has been designated as
“non-coding” (22A24). So, of the hundreds of thousands of
nucleotide sequences that have been produced from various
forms of DNA and RNA in tobacco, only a small percentage
contains the essential genetic information needed to direct its
life processes. However, all of these DNA and RNA strands
serve a very important purpose during the construction of
genomes. By employing sophisticated computer programs
that can identify patterns in the bases in the DNA fragments,
DNA fragments can be sequenced. “Fingerprinting” of large
insert genomic fragment libraries, also known as BAC (bac-
terial artificial chromosomes) clones can lead to the construc-
tion of a physical map of a genome. These maps are critical
to genome sequencing, positional cloning, and understanding
the relative organization of genes and markers. When BAC
libraries are arranged into maps that reflect the DNA sequence
in a chromosome, they provide maximal information and
utility. Generally, these BAC libraries are deposited in the
GenBank. For example, BAC clone libraries for Nicotiana
tabacum, currently being compiled as part of the TGI and
ESTobacco projects, are being deposited in the GenBank.
There are vast arrays of enzymes that have been identi-
fied in tobacco (429b, 429c, 3973). Plant enzymes perform
valuable functions almost as soon as seeds are planted and
continue to be important even through the tobacco curing
process. Enzymes are in fact essential molecules that assimi-
late carbon dioxide from air (via photosynthesis), nitrogen by
roots from the soil, and utilize hydrogen liberated by dehy-
drogenation from the components of the Krebs tricarboxy-
lic acid (TCA) cycle to produce a variety of organic acids,
for example, oxaloacetic and α-ketoglutaric acids. The net
result of nitrogen assimilation is the utilization of a portion
of newly photosynthesized carbon chains into the nitrog-
enous pool. When the nitrogen supply is abundant there will
be more synthesis of amino acids, for example, aspartic and
glutamic acids, and nicotine, and less sugars and starch. If
the nitrogen supply is limited, there will be an excess accu-
mulation of acetate in the TCA cycle, which results in higher
production of carbohydrates, fats, volatile oils, resins, and
polyterpenes. Tobacco enzymes efficiently and effectively
control and regulate the type and level of tobacco constitu-
ents available to the plant for growth. The variations in leaf
© 2009 by Taylor & Francis Group, LLC
78836_C022.indd 981
characteristics, texture, color, porosity, and combustibil-
ity, quality, for example, aroma and flavor based on chemi-
cal composition, and yield (poundage per acre/hectare) are
a reflection of the genetic makeup of the plant, agronomic
practices, soil types, and the environmental conditions (3972,
3973, 22A29, 22A30).
Enzymes can either work individually or in teams. In a
metabolic pathway (like the TCA cycle) several enzymes work
together in a specific order, one enzyme takes the product
of another enzyme as a substrate. Two sources of informa-
tion on hundreds of enzymes that have been identified in
tobacco are BRENDA and KEGG (429b, 429c). BRENDA:
The Comprehensive Enzyme Information System is a data-
base of enzymes and enzyme pathways. It was developed
and is maintained at the Institute of Biochemistry at the
University of Cologne and is available through the Internet at
http://www.brenda.uni-koeln.de/. KEGG stands for the Kyoto
Encyclopedia of Genes and Genomes. KEGG is a bioinfor-
matics resource that was developed and is maintained as part
of the research projects of the Kanehisa Laboratories in the
Bioinformatics Center of Kyoto University and the Human
Genome Center of the University of Tokyo.
The phase of plant growth that extends from maturity
to actual death (called senescence) is characterized by an
accumulation of metabolic products, increase in respiratory
rate, and a loss of dry matter (3973). At the senescence stage,
enzyme activities (especially hydrolytic and other degra-
dative enzyme systems) are intensified. These systems are
responsible for breakdown of functional and structural com-
ponents of the cell, such as proteins, nucleic acids, carbohy-
drates, and lipids. The latter stage of senescence resembles
the early stage of leaf curing. Curing is a vital process which
falls into the category of starvation phenomena or inanition
of excised plant parts (3972, 3973).
The most conspicuous chemical conversions during cur-
ing involve two phases. The first phase is dominated by
hydrolytic enzymes and occurs in either flue curing or air
curing. In this phase, disaccharides and polysaccharides
are hydrolyzed to simple sugars; proteins are hydrolyzed to
amino acids which undergo oxidative deamination; and the
pectins and pentosans are hydrolyzed to pectic acid, uronic
acid, and methyl alcohol. The second phase is dominated by
oxidative reactions and takes place mostly in air-curing pro-
cesses. Among the conversions are the following: oxidation
of simple sugars to acids, oxygen and water; the increased
oxidative deamination of amino acids leads to the formation
of ammonia and amides, particularly asparagine; changes in
organic acids, including conversion of malic to citric acid and
also decarboxylations; and the oxidative and polymerization
of phenols to brown products. There is a small decrease in
alkaloids and some loss of dry weight (3972, 3973).
Although not discussed specifically, the tobacco plant con-
tains many thousands of different proteins that are produced
by the plant to perform both structural and functional roles.
The abundance and types of proteins differ according to the
plant organ and cell type being considered. And at the cel-
lular level, proteins with functional roles in chloroplasts and
11/13/08 5:48:18 PM
 982 The Chemical Components of Tobacco and Tobacco Smoke
mitochondria may be encoded by the small DNA genomes
of those organelles, or may be specified by nuclear genes
and imported into those organelles. A significant percentage
of proteins in the tobacco leaf are those involved in photo-
synthesis. This complex process is mediated by the action
of hundreds of enzymes involved in the capture of energy
from sunlight and the use of that energy to assimilate carbon
dioxide from the atmosphere. A key enzyme responsible for
this process is ribulose-1,5-bisphosphate carboxylase-oxyge-
nase (sometimes referred to as RuBP carboxylase, or simply
“Rubisco”) (22A35). It is an enzyme that has a dual func-
tion in that it catalyzes the carboxylation and oxygenation
of ribulose-1,5-bisphosphate. Therefore, it catalyzes the cru-
cial reactions of both photosynthesis and photorespiration,
the ratio of these two processes determine plant productivity
(3973, 3974c). This important enzyme is the most abundant
individual leaf protein, and has been proposed as the most
important and abundant single protein in nature. On the other
hand, the majority of nicotine biosynthesis occurs in root tis-
sues, so the enzymes involved in that process are expressed
most abundantly in roots.
Before the advent of modern plant biochemistry and
molecular biology, tobacco leaves, as well as the leaves of
other higher plants, were considered to possess two broad
classes of proteins based on their solubility properties during
extraction. Of the total tobacco leaf proteins, approximately
half are “soluble” and half “insoluble.” The most abundant
soluble protein came to be known as “Fraction-1 protein”
(F-1 protein, shown to be primarily RuBP carboxylase),
a material that can constitute as much as 50% of the total
soluble tobacco leaf protein. During the 1980s, this material
was considered as a potential source of food protein and for
a number of other food applications due to its abundance and
a number of other favorable properties. The remaining leaf
protein, consisting of a multitude of smaller soluble proteins
and unfractionated protein in the cytoplasm and chloroplast,
was referred to as “Fraction-2 protein” (F-2 protein) (3973,
3974c). In addition to tobacco proteins having functional roles
such as RuBP carboxylase, tobacco and other plants contain
proteins the primary role of which is structural. For example,
extensins, a family of glycoproteins rich in hydroxyproline
residues, may constitute as much as 15% of the primary cell
wall. Extensins are incorporated into the carbohydrate struc-
ture of cell walls and are thought to help provide structural
support as cell walls develop.
Contemporary research has tended to concentrate on the
identification and function of individual proteins that play key
roles in plant growth, development, and response to environ-
mental cues. While much of this research has shifted from
tobacco to the more easily manipulated model plant system
Arabidopsis thaliana, tobacco continues to be the subject of
considerable research due to the historical database of tobac-
co-specific information, its ease of genetic manipulation, and
© 2009 by Taylor & Francis Group, LLC
78836_C022.indd 982
its interesting biochemical pathways for alkaloid biosynthe-
sis. This research has shown tobacco to possess an amaz-
ing diversity of proteins the roles of which continue to be
elucidated.
Tobacco “leaf protein” by itself contributes little to smok-
ing quality, but it is a major precursor of hundreds of tobacco
smoke components, for example, numerous nitrogenous
compounds and amino acids. Similarly, other major tobacco
components such as the carbohydrates, carboxylic acids,
pigments, polyphenols, fatty compounds, phytosterols, and
many primary or secondary compounds play a significant
role in producing a myriad of tobacco smoke compounds
(3972, 3973, 3974c).
Plant material and smoke composition, are closely interre-
lated. Properties of leaf material can be modified through
genetic and biochemical manipulation from seed to curing
(22A30).
In dealing with an organic material as complex as tobacco,
there are limitations in the range of possible changes that can
be made to improve the biological interaction and metabolic
balance within a plant system, and at the same time improve
or alter the smoke composition and ultimately the biological
activity of the smoke. The challenge that faces the tobacco
industry today in light of the numerous possibilities that will
come from the genetic mapping of Nicotiana tabacum is the
development of new tobacco types that can satisfy farmers,
manufacturers, regulators, and consumers in quality and
tobacco safety.
Solutions to the questions posed by Tso in 1972 (22A30) as
to “what kinds of changes are needed (to produce safer tobacco
products)?” And “how can these changes be achieved?” may
be attainable in the future with the new-found knowledge
from the genetic mapping of the tobacco genome.
Table XXII-2 is a catalog of the genes, nucleotides (DNA
and RNA strands), enzymes, and a few major proteins identi-
fied to date in tobacco. The format of this table differs from
those in most other chapters since only one of the tobacco
constituents is transferred intact to MSS (phytuberin). As a
result, the Tobacco Smoke column was deleted from Table
XXII-2. The catalog contains 491 entries. This number of
entries represents only a very small fraction of the genes
identified and nucleotides created recently during the tobacco
genome projects. As more time passes, the totality of the
genes and nucleotides identified in the tobacco genome will
be published or made available in databases for researchers
to access. The majority of the known enzymes identified in
tobacco are contained in the catalog.
Acknowledgments
The authors are grateful to Dr. Gary Hellmann and Dr.
Lynwood Sawyer for review of this chapter.
11/13/08 5:48:19 PM
 Genes, Nucleotides, and Enzymes 983

 Table XXII-2
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78836_C022.indd 983 11/13/08 5:48:21 PM

 984 The Chemical Components of Tobacco and Tobacco Smoke

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78836_C022.indd 984 11/13/08 5:48:23 PM

 Genes, Nucleotides, and Enzymes 985

Table XXII-2 (Continued)

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 986 The Chemical Components of Tobacco and Tobacco Smoke

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 988 The Chemical Components of Tobacco and Tobacco Smoke

Table XXII-2 (Continued)

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Table XXII-2 (Continued)

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 990 The Chemical Components of Tobacco and Tobacco Smoke

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 992 The Chemical Components of Tobacco and Tobacco Smoke

Table XXII-2 (Continued)

Enzymes, Genes, Clones in Tobacco

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 Genes, Nucleotides, and Enzymes 993

Table XXII-2 (Continued)

Enzymes, Genes, Clones in Tobacco
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 994 The Chemical Components of Tobacco and Tobacco Smoke

Table XXII-2 (Continued)

Enzymes, Genes, Clones in Tobacco

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 Genes, Nucleotides, and Enzymes 995

Table XXII-2 (Continued)

Enzymes, Genes, Clones in Tobacco
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 996 The Chemical Components of Tobacco and Tobacco Smoke

Table XXII-2 (Continued)

Enzymes, Genes, Clones in Tobacco
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 Genes, Nucleotides, and Enzymes 997

Table XXII-2 (Continued)

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 998 The Chemical Components of Tobacco and Tobacco Smoke

Table XXII-2 (Continued)

Enzymes, Genes, Clones in Tobacco

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 Genes, Nucleotides, and Enzymes 999

Table XXII-2 (Continued)

Enzymes, Genes, Clones in Tobacco
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 23 “Hoffmann Analytes”
In essence, the terminology “Hoffmann analyte” or
“Hoffmann-type analyte” or “Hoffmann list compound” had
its beginning over two decades ago in 1985. Early that year,
a Working Group of the International Agency for Research
on Cancer (IARC) met to evaluate the carcinogenic risk of
chemicals to humans, with particular emphasis on tobacco
smoking. The next year, the Working Group’s assessment
of tobacco smoking was published in an IARC monograph
(1870). Among the twenty-eight members of the Working
Group were Ernst L. Wynder and Dietrich Hoffmann from
the American Health Foundation, whose participation in the
discussions on the components of tobacco and particularly
tobacco smoke was obviously quite extensive. The number
of references cited in the various smoke component figures,
tables, and appendixes in the IARC monograph (1870)
reveals the extent of the Wynder-Hoffmann contribution to
the Working Group study (see summary in Table XXIII-1).
Nearly 44% of the citations on smoke components consid-
ered deleterious represented a Hoffmann-related publication.
In all of the forty-four references listed in Table XXIII-1,
Hoffmann was a co-author.
A few months after the IARC 1985 Working Group meet-
ing, Hoffmann and Wynder presented a paper on biologi-
cally active tobacco smoke components at a conference and
its contents were published in 1986 (1808). Deriving their
assessment of various tobacco smoke components from the
conclusions of the IARC 1985 Working Group, Hoffmann
and Wynder listed forty biologically active components in
cigarette mainstream smoke (MSS) and sidestream smoke
(SSS). Over the next decade and half, a series of articles were
published with Hoffmann as a co-author of each and in each
article was a listing of tobacco and/or smoke components
that were classified as biologically active (1808, 1741), car-
cinogenic (1808, 1740, 1743, 1744), cocarcinogenic (1808), or
tumorigenic (1717, 1773).
Table XXIII-2 summarizes the chronology of the articles
and the varied classifications of the activity of the compo-
nents listed. In those publications in which the classification
“biologically  active” was used, no mention was made of the
fact that many biologically active components in tobacco
smoke, for example, α-tocopherol and α- and β-4,8,13-
duvane-1,3-diol, have been demonstrated to exert anticarci-
nogenic or inhibitory effects on the activity of several tobacco
smoke components considered potent tumorigens or mutagens
[see Table 3 in (3255a), Table 6 in (3265), Table 11 in (3300)].
In contrast to the multiple listings of benz[a]anthracene (B[a]
A) as a biologically active MSS component (1741, 1808) or
as a tumorigen (1727, 1773) or as a carcinogen (1740, 1743,
1744), Hoffmann and Wynder (1786) reported in 1959 that,
in their mouse skin-painting study, B[a]A co-administered
© 2009 by Taylor & Francis Group, LLC
78836_C023.indd 1001
with benzo[a]pyrene (B[a]P) reduced the tumorigenicity of
the B[a]P, that is, B[a]A was anticarcinogenic to B[a]P.
Eventually the number of biologically active smoke com-
ponents, primarily the tumorigens, was expanded from the
forty-three listed in 1990 by Hoffmann and Hecht (1727)
to eighty-two listed in 1998 by Hoffmann and Hoffmann
(1740). Much of the increase was due to the inclusion of the
N-heterocyclic amines and several vapor-phase components.
Because of the change in its assessment concerning their tum-
origenicity, chrysene and di(2-ethylhexyl) phthalate were no
longer considered as tumorigens by the IARC. Several other
similar lists, not co-authored by Hoffmann, were issued after
1986. They included the 1994 list by the U.S. Occupational
Health and Safety Administration (OSHA) (2825) and the
2001 list by Fowles and Bates (1217). Neither of these lists
differed significantly from those issued by Hoffmann and his
colleagues between 1986 and 2001.
Table XXIII-3 is a tabulation of the toxicants in tobacco
and tobacco smoke from the IARC 1986 publication (1870)
plus the seven lengthy publications co-authored from 1986
to 2001 by Hoffmann with his American Health Foundation
colleagues. Examination of the various lists reveals several
anomalies, none of which detracts from the meaningfulness
of the publications. The anomalies include:
1. Several instances where the per cigarette yield
range unit was listed as microgram in one article
and nanogram in another, for example, the per cig-
arette yield range for quinoline listed as 1 to 2 ng
in (1743) and 1 to 2 μg in (1744).
2. Several instances where the per cigarette yield
range differs significantly in two different publica-
tions, for example, the per cigarette yield range for
N-nitrosopyrrolidine is listed as 1.5 to 110 ng in
(1727) and 3 to 60 ng in (1740).
3. Several instances where the per cigarette yield
range differs in different tables in the same article,
for example, the per cigarette yield range for cat-
echol is listed as 25 to 360 µg in Table 5 in (1808),
as 100 to 350 µg in Table 11 in (1808), and 140 to
500 µg in Table 13 in (1808).
4. The per cigarette yield range is listed for the wrong
component, for example, the range 1.7 to 3.2 ng is
listed for dibenzo[a,l]pyrene in (1741, 1743, 1744)
but in each case that range should be listed for
the omitted dibenzo[a,i]pyrene [see (1727, 1740,
1773)].
5. In some instances, particularly with several PAHs,
the per cigarette yield ranges include data gener-
ated from cigarettes manufactured in the 1950s
1001
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 1002 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-1
Hoffmann Contributions on Smoke Components to the 1985 IARC Working Group on Tobacco Smoking
No. of No, of
Specific Hoffmann
References et al. References
Item Topic Cited Cited Hoffmann et al. References
Figure 5 Some chemical constituents of tobacco smoke 1 1 3491
Table 20 Concentrations of some PAHs and heterocyclic 33 13 1560, 1699, 1763, 1765, 1766, 1779,
compounds in tobacco smoke 1780, 1800, 1803, 3088, 4308, 4312,
4317
Table 21 Concentrations of some phenols in tobacco smoke 11 3 497, 1703, 4332
Table 22 Concentrations of free fatty acids in cigarette smoke 1 1 1785
Table 23 Concentrations of aromatic amines in cigarette smoke 1 1 2900
Table 24 Concentrations of major pyridines and pyrazines 2 1 512
in mainstream cigarette smoke
Table 25 Concentrations of N-nitrosamines in cigarette smoke 1 1 1696
Table 26 Concentrations of N-nitrosamines in SSS of commercial 2 2 1685, 1696
cigarettes and cigars
Table 30 Physiochemical comparison of MSS and SSS of cigarettes 2 2 1695, 1696
Table 31 Concentrations of selected compounds in nonfilter cigarette 6 1 1720
MSS and the ratio of their relative distribution in SSS
Appendix 2 Chemical compounds identified in tobacco smoke that have 6a 3 4332, 4348, 4348a
been evaluated for carcinogenicity in the IARC monograph
series
a Three of the cited references were to IARC monographs.

and 1960s with “tar” and nicotine yields far in
excess of more recently manufactured cigarettes.
6. The per cigarette yield range is incomplete, for
example, a single value of 4 ng/cigarette is listed for
dibenz[a,h]anthracene (DB[a,h]A) in (1727, 1740,
1741, 1743, 1744, 1773, 1870) but an incorrect single
value of 40 ng is listed in (1808); all DB[a,h] A list-
ings in the references cited fail to take into account
the reporting of a DB[a,h]A yield of 5 ng/cigarette by
Van Duuren in 1958 (4020). The MSS yield of 4 ng/

Table XXIII-2
Hoffmann-Related Lists of Toxicants in Tobacco and Tobacco Smoke
No. of Component
Year Authors Ref. No. Table No. Table Title Listed
1986 International Agency for 1870 19 Concentrations of biologically-active agents 60
Research on Cancer (IARC) in nonfilter cigarette mainstream smoke
1986 Hoffmann and Wynder 1808 5 Carcinogens and cocarcinogens in the smoke 21
of a nonfilter cigarette
1808 6 Organ-specific carcinogens in cigarette 14
smoke
1808 13 Biologically-active agents in mainstream 40
smoke (of nonfilter cigarettes)
1990 Hoffmann and Hecht 1727 3 Tumorigenic agents in tobacco and tobacco 43
smoke
1993 Hoffmann et al. 1773 1 Tumorigenic agents in tobacco and tobacco 41
smoke
1997 Hoffmann and Hoffmann 1740 3 Carcinogens in tobacco and cigarette smoke 60
1998 Hoffmann and Hoffmann 1741 1 Biologically-active agents in the mainstream 82
smoke of nonfilter cigarettes
2001 Hoffmann and Hoffmann 1743 5-4 Carcinogens in cigarette smoke 68
2001 Hoffmann et al. 1744 4 Carcinogens in cigarette smoke 68

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78836_C023.indd 1003

“Hoffmann Analytes”
Table XXIII-3
The Basis for the “Hoffmann Analytes”: The Lists of Toxicants Issued by HOFFMANN et al. from 1986 to 2001
1986 1986 1990 1993 1997 1998 2001 2001

Hoffmann and Hoffmann and Hoffmann and

Hoffmann and Hoffmann and Hoffmann et al. Hoffmann Hoffmann Hoffmann Hoffmann
Component IARC (1870) a Wynder (1808) Hecht (1727) (1773) (1740) (1741) (1743) et al. (1744)
Polycyclic Aromatic Hydrocarbons
Benz[a]anthracene 20-70 ng 40-70 ng g 20-70 ng 20-70 ng 20-70 ng 20-70 ng 20-70 ng 20-70 ng
40-70 ng b 40-60 ng j
4-76 ng c
Benzo[b]fluoranthene 4-22 ng 30 ng g 4-22 ng 4-22 ng 4-22 ng 4-22 ng 4-22 ng 4-22 ng
30 ng b
Benzo[j]fluoranthene 6-21 ng 60 ng g 6-21 ng 6-21 ng 6-21 ng 6-21 ng 6-21 ng 6-21 ng
60 ng b
Benzo[k]fluoranthene 6-12 ng NL e 6-12 ng 6-12 ng 6-12 ng 6-12 ng 6-12 ng 6-12 ng
Benzo[a]pyrene 20-40 ng
10-50 ng b 10-50 ng g 20-40 ng 20-40 ng 20-40 ng 20-40 ng 20-40 ng 20-40 ng
5-78 ng c 10-40 ng i
Chrysene 40-60 ng b 40-60 ng g 40-60 ng 40-60 ng NL NL NL NL
Chrysene, 5-methyl- 0.6 ng 0.6 ng 0.6 ng 0.6 ng 0.6 ng 0.6 ng 0.6 ng 0.6 ng
Dibenz[a,h]anthracene 4 ng 40 ng 4 ng 4 ng 4 ng 4 ng 4 ng 4 ng
Dibenzo[a,e]pyrene Pd, NYLe NLe NL NL NL P, NYLf P, NYLf P, NYLf
Dibenzo[a,h]pyrene Pd, NYLe NLe NL NL NL NL NL NL
Dibenzo[a,i]pyrene 1.7-3.2 ng NL 1.7-3.2 ng 1.7-3.2 ng 1.7-3.2 ng NLf NLf NLf
2-3 ng b
17-32 ng c
Dibenzo[a,l]pyrene g P, NYL P, NYL P, NYL P, NYL P, NYL 1.7-3.2 ng f 1.7-3.2 ng f 1.7-3.2 ng f
Indeno[1,2,3-cd]pyrene 4-20 ng 4 ng 4-20 ng 4-20 ng 4-20 ng 4-20 ng 4-20 ng 4-20 ng

Aza-arenes
Pyridine 16-40 µg NL NL NL 20-200 µg m 10-40 µg 20-200 µg p 20-200 µg s
16-40 µg r
Quinoline NL e NL 1-2 µg 0.2-1.3 µmg 1-2 µg 2-180 ng 1-2 ng x 1-2 µg
Dibenz[a,h]acridine h 0.1 ng 0.1 ng g 0.1 ng 0.1 ng 0.1 ng 0.1 ng 0.1 ng 0.1 ng
Dibenz[a,j]acridine 2.7 ng 3-10 ng g 3-10 ng 3-10 ng 3-10 ng 3-10 ng 3-10 ng 3-10 ng
3-10 ng b
7H-Dibenzo[c,g]carbazole 0.7 ng 0.7 ng g 0.7 ng 0.7 ng 0.7 ng 0.9 ng 0.7 ng 0.7 ng

N-Nitrosamines
N-Nitrosodimethylamine 2-20 ng 1-180 ng h 0.1-180 ng 0.1-180 ng 0.1-180 ng 2-180 ng 2-180 ng 2-1000 ng
1-200 ng b 2-180 ng j
N-Nitrosoethylmethylamine 0-2.7 ng 1-40 ng h 3-13 ng 3-13 ng 3-13 ng 3-13 ng 3-13 ng 3-13 ng
0.1-10 ng b 0,1-40 ng j

1003
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(Continued)

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1004

1004
Table XXIII-3 (continued)
The Basis for the “Hoffmann Analytes”: The Lists of Toxicants Issued by HOFFMANN et al. from 1986 to 2001
1986 1986 1990 1993 1997 1998 2001 2001

Hoffmann and Hoffmann and Hoffmann and

Hoffmann and Hoffmann and Hoffmann et al. Hoffmann Hoffmann Hoffmann Hoffmann
Component IARC (1870)a Wynder (1808) Hecht (1727) (1773) (1740) (1741) (1743) et al. (1744)
N-Nitrosodiethylamine 0-2.8 ng 0.1-28 ng 0-25 ng 0-25 ng 0-2.8 ng 0-2.8 ng 0-2.8 ng 0-2.8 ng
0-10 ng b
N-Nitrosodi-n-propylamine 0-1 ng 0-1 ng NL NL NL 0-1.0 ng 0-1.0 ng 0-1.0 ng
N-Nitrosodi-n-butylamine 0-3 ng 0-3 ng NL NL NL 0-30 ng 0-30 ng 0-30 ng
N-Nitrosopyrrolidine 0-110 ng 2-110 ng h 1.5-110 ng NL 3-60 ng 3-110 ng 3-110 ng 3-110 ng
2-42 ng b 2-42 ng j
N-Nitrosopiperidine 0-9 ng 0-9 ng NL NL NL 0-9 ng 0-9 ng 0-9 ng
N-Nitrosodiethanolamine 0-36 ng 0-40 ng 0-36 ng NL 0-68 ng 0-68 ng 0-68 ng 0-68 ng
0-90 ng b
N-Nitrososarcosine NL NL NL NL NYL ND e NL NL
N’-Nitrosonornicotine 0.2-3.0 µg 0.12-3.7 µg 0.12-3.7 µg 0.12-3.7 µg 0.12-3.7 µg 120-3.700 ng v 0.12-3.7 µg v 0.12-3.7 µg v
0.13-0.25 µg b
4-(N-Methylnitrosamino)- 0.08-0.77 µg 0.12-0.95 µg 0.08-0.77 µg 0.08-0.77 µg 0.08-0.77 µg 0.08-0.77 µg 0.08-0.77 µg 0.08-0.77 µg
1-(3-pyridyl)-1-butanone 0.08-0.7 µg b

N’-Nitrosoanabasine 0-150 ng 40-400 ng h 0.14-4.6 µg 0.14-4.6 µg 0.14-4.6 µg 0-150 ng NL NL

The Chemical Components of Tobacco and Tobacco Smoke

0-200 ng b 120 ng j
N’-Nitrosoanatabine NL NL NL NL NL NL NL NL
0-3.7 µg b
N-Nitrosomorpholine NL NL ND k in MSS ND in MSS ND in MSS ND in MSS NL NL

Aromatic Amines
Aniline NL 360 ng 360 ng NL NL 360-655 ng 360-655 ng r NL
2-Toluidine 32-160 ng 30-160 ng 30-200 ng 30-200 ng 30-200 ng 30-337 ng 30-337 ng 30-337 ng
30-200 ng b
Aniline, 2,6-dimethyl- NL NL NL NL NL NL 4-50 µg x 4-50 ng x
1-Naphthylamine NL NL NL NL NL NL NL NL
3-4 ng b
2-Naphthylamine 1.7-22 ng 4.3-27 ng 1-22 ng 1-22 ng 1-22 ng 1-334 ng 1-334 ng 1-334 ng
1-22 ng b
Biphenyl, 3-amino- NL NL NL NL NL NL NL NL
Biphenyl, 4-amino- 2.4-4.6 ng 2.4-4.6 ng 2-5 ng 2-5 ng 2-5 ng 2-5.6 ng 2-5.6 ng 2-5.6 ng
2-5 ng b
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© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1005

“Hoffmann Analytes”
N-Heterocyclic Aminesk
AaC NL NL NL NL 25-260 ng 25-260 ng 25-260 ng 25-260 ng
MeAaC NL NL NL NL 2-37 ng 2-37 ng NL 2-37 ng
Glu-P-1 NL NL NL NL 0.37-0.89 ng 6.37x-0.89 ng 0.37-0.89 ng 0.37-0.89 ng
Glu-P-2 NL NL NL NL 0.25-0.88 ng 0.25-0.88 ng 0.25-0.88 ng 0.25-0.88 ng
PhIP NL NL NL NL 11-23 ng 11-23 ng 11-23 ng 11-23 ng
IQ NL NL NL NL 0.26 ng 0.3 ng 0.3 ng 0.3 ng
MeIQ NL NL NL NL NL NL NL NL
Trp-P-1 NL NL NL NL 0.29-0.48 ng 0.3-0.5 ng 0.3-0.5 ng 0.3-0.5 ng
Trp-P-2 NL NL NL NL 0.82-1.1 ng 0.8-1.1 ng 0.8-1.1 ng 0.8-1.1 ng

Aldehydes and Ketones

Formaldehyde 70-100 µg 5-100 µg 70-100 µg 70-100 µg 70-100 µg l 70-100 µg 70-100 µg 70-100 µg l
20-88 µg b 20-100 µg m 20-100 µg p 20-100 µg s
Acetaldehyde 500-1200 µg 500-1200 µg 18-1400 µg 18-1400 µg 18-1400 µg l 500-1.400 µg u 500-1400 µg u 500-1400 µg u
18-1400 µg b 400-1400 µg m 400-1400 µg p 400-1400 µg s
Propionaldehyde NL NL NL NL NL NL NL NL
Butyraldehyde NL NL NL NL NL NL NL NL
Crotonaldehyde 10-20 µg NL 10-20 µg 10-20 µg NL 10-20 µg NL NL
Acrolein 60-100 µg 50-100 µg NL NL 60-140 µg m 60-140 µg 60-140 µg p 60-240 µg s
25-140 µg b
Acetone 100-250 µg 100-250 µg NL NL 100-650 µg m NL 100-650 µg p NL
2-Butanone NL NL NL NL NL NL NL NL

Volatile Hydrocarbons
1,3-Butadiene NL NL NL NL 20-75 µg l 20-75 µg 20-75 µg 20-75 µg
25-40 µg m 25-40 µg p 25-40 µg s
Isoprene NL NL NL NL 450-1000 µg l 450-1.00 µg u 450-1000 µg u 450-1000 µg u
200-400 µg m 200-400 µg p 200-400 µg s
Benzene 20-50 µg 20-50 µg 12-48 µg 12-48 µg 12–70 µg l 20–70 µg 20-70 µg 20–70 µg
6-70 µg m 12-50 µg p 6-70 µg s
Toluene NL NL NL NL 5-90 µg m NL 20-60 µg p 5-90 µg s
Styrene 10 µg NL NL NL 10 µg 10 µg 10 µg 10 µg

Miscellaneous Organic Compounds

Acetamide 38-56 µg b NL NL NL NL 38-56 µg 38-56 µg 38-56 µg
Acrylonitrile 3.2-15 µg b 3.2-15 µg 3.2-15 µg 3.2-15 µg 3.2-15 µg 3-15 µg 3-15 µg 3-15 µg
Acrylamide NL NL NL NL P, NYL P, NYL P, NYL P, NYL
Hydrazine, 1,1-dimethyl- P, NYL NL P, NYL P, NYL NYL P, NYL P, NYL P, NYL
Maleic hydrazide NL NL NL NL NL 1.16 µg 1.16 µg r
Methanol NL NL NL NL 80-180 µg m 100-250 µg 80-180 µg p 80-180 µg s
100-250 µg r
Methyl isocyanate NL NL NL NL NL 1.5-5 µg NL NL

(Continued)

1005
11/24/08 12:37:12 PM

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1006

1006
Table XXIII-3 (continued)
The Basis for the “Hoffmann Analytes”: The Lists of Toxicants Issued by HOFFMANN et al. from 1986 to 2001
1986 1986 1990 1993 1997 1998 2001 2001

Hoffmann and Hoffmann and Hoffmann and

Hoffmann and Hoffmann and Hoffmann et al. Hoffmann Hoffmann Hoffmann Hoffmann
Component IARC (1870) a Wynder (1808) Hecht (1727) (1773) (1740) (1741) (1743) et al. (1744)
Nitromethane NL NL NL NL NL NL 0.3-0.6 µg 0.5-0.6 µg
2-Nitropropane 0.2-2.2 µg 0.2-2.2 µg 0.73-1.21 µg 0.73-1.21 µg 0.73-1.21 µg 0.2-2.2 µg 0.7-1.2 µg 0.7-1.2 µg
0.73-1.21 µg b
Nitrobenzene NL NL NL NL NL 25 µg 25 µg 25 µg
Vinyl chloride 1.3-16 ng 1.3-16 ng 1-16 ng 1-16 ng 1-16 ng 11-15 ng 11-15 ng 11-15 ng
1-16 ng b
Ethyl carbamate 20-38 ng 20-38 ng 20-38 ng 20-38 ng 20-38 ng 20-38 ng 20-38 µg 20-38 µg
Ethylene oxide NL NL NL NL 7 µg 7 µg 7 µg 7 µg
Propylene oxide NL NL NL NL NL NL 12-100 ng 0-100 ng
Di(2-ethylhexyl) phthalate NL NL NL NL 20 µg 20 µg NL NL
Furan NL NL NL NL 18-30 µg l 18-30 ng u 18-37 ng u 18-37 µg u
20-40 µg m
Benzo[b]furan NL NL NL NL P, NYL P, NYL P, NYL P, NYL

Phenols
Phenol 60-140 µg 60-140 µg 80-60 NL NL 80-160 µg 80-160 µg r 60-180 µg t

The Chemical Components of Tobacco and Tobacco Smoke

o-Cresol 14-30 µg NL NL NL NL NL NL NL
m-Cresol NL NL NL NL NL NL NL NL
p-Cresol NL NL NL NL NL NL NL NL
Catechol 40-350 µg 25-360 µg g 200-400 µg NL NL 200-400 µg 100-360 µg 90-2000 µg
100-350 µgi 200-400 µg r 100-200 µg t
140-500 µg j
Resorcinol 8-80 µg b NL NL NL NL NL NL NL
Hydroquinone 88-155 µg b 110-300 µg NL NL NL NL NL NL
Methyleugenol NL NL NL NL NL 20 ng 20 ng 20 ng
Caffeic acid NL NL NL NL NL NL < 3 µg < 3 µg

Chloroaromatic Compounds
DDT NL NL NL NL 800-1200 ng 800-1.200 ng u 800-1200 µg 800-1200 µg
0.7-1.2 µg b
DDE NL NL NL NL 200-370 ng 200-370 ng 200-370 µg 200-370 µg
Polychlorodibenzo- NL NL NL NL NL NL NL NL
p-dioxins
Polychlorodibenzofurans NL NL NL NL NL NL NL NL

Inorganic Components
Hydrazine 24-43 ng 24-43 ng 24-43 ng 24-43 ng 24-43 ng 24-34 µg x 24-43 ng 24-43 ng
Hydrogen sulfide NL NL NL NL 20-90 µg m 10-90 µg 20-90 µg p 20-90 µg s
Arsenic 1-25 µg NL 40-120 ng 40-120 ng 40-120 ng 40-120 ng 40-120 µg 40-120 µg
11/24/08 12:37:13 PM

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1007

Beryllium NL NL NL NL NL 0.3 µg 0.5 ng 0.5 ng

“Hoffmann Analytes”
Cadmium 9-70 ng NL 41-62 ng 41-62 ng 41-62 ng NL 7-350 ng 7-350 ng
Chromium (VI) 4-70 ng NL 4-70 ng 4-70 ng 4-70 ng 4-70 ng 4-70 ng 4-70 ng
Cobalt 0.2 ng NL NL NL NL 0.13-0.2 ng 0.13-0.2 ng 0.13-0.2 ng
Nickel 0-600 ng b 20-3000 ng 0-600 ng 0-600 ng 0-600 ng 0-600 ng 0-600 ng 0-600 ng
Mercury NL NL NL NL NL 4 ng NL
Lead Pc NL 35-85 ng 35-85 ng 35-85 ng 34-85 ng 34-85 ng 34-85 ng
Polonium-210 0.03 pCi 0.03-1.0 pCi 0.03-1.0 pCi 0.03-1.0 pCi 0.03-1.0 pCi 0.03-1.0 pCi 0.03-1.0 pCi 0.03-1.0 pCi
Selenium Pc NL NL NL NL NL NL NL

Additional Components
Nicotine 1.0-2.3 mg 1-2.5 mg 1.0-3.0 mg NL 0.1-3.0 mg n 1.0-3.0 mg 1.0-3.0 mg q 0.1-3.0 mg t
Carbon monoxide 10-23 mg 10-23 mg NL NL 14-23 mg m 10-23 mg 14-23 mg p 14-23 mg s
Ammonia 50-130 µg 50-170 µg i NL NL 10-130 µg m 10-130 µg 10-130 µg p 10-130 µg s
50-130 µg j
Nitrogen oxides 100-600 µg 50-600 µg NL NL 100-600 µg m 100-600 µg 100-600 µg p 100-600 µg s
Hydrogen cyanide 400-500 µg 400-500 µg NL NL 400-500 µg m 400-500 µg 400-500 µg p 400-500 µg s
a See Table 19 in (1870).
b See Appendix 2 in (1870).
c See Table 20 in (1870)

d P = present, as listed in Appendix 2 in (1870).

e NL= not listed; NYL = no per cigarette MSS yield listed; ND = not detected.

f The yield range listed for dibenz[a,l]pyrene is incorrect. It is the range usually listed for dibenzo[a,i]pyrene. The P, NYL designation should also apply to dibenzo[a,l]pyrene.

g See Table 5 in (1808).

h See Table 6 in (1808).

i See Table 11 in (1808).

j See Table 13 in (1808).

k AaC = 2-amino-9H-pyrido[2,3-b]indole; MeAaC = 2-amino-3-methyl-9H-pyrido[2,3-b]indole; Glu-P-1 = 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole; Glu-P-2 = 2-aminodipyrido[1,2-a:3’,2’-d]

imidazole; PhIP = 2-amino-1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridine; IQ = 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline; MeIQ = 2-amino-3,4-dimethyl-3H-imidazo[4,5-f]quinoline; Trp-P-1 =

3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole; Trp-P-2 = 3-amino-1-methyl-5H-pyrido[4,3-b]indole
l See Table 3 in (1740).

m See Table 1 in (1740).

n See Table 2 in (1740).

p See Table 5-1 in (1743).

q See Table 5-2 in (1743).

r See Table 5-3 in (1743).

s See Table 2 in (1744).

t See Table 3 in (1744).

u Compare yield listed in Table 1 in (1741), Table 5-4 in (1743), and Table 4 in (1744).

v Compare yield listed in Table 1 in (1741) with those listed in (1727, 1740, 1743, 1744).

1007
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© 2009 by Taylor & Francis Group, LLC

 1008 The Chemical Components of Tobacco and Tobacco Smoke
cigarette of DB[a,h]A was obtained by Hoffmann and
Wynder in the late 1950s (1787, 1788) from a 1959
cigarette and reported as such in 1963 by Wynder and
Hoffmann [see Table 1 in (4317)].
7. A component with no known per cigarette yield
is treated the same as a component with literally
hundreds of per cigarette yield values, for exam-
ple, dibenzo[a,l]pyrene vs. B[a]P.
8. For the identification of dibenzo[a,l]pyrene in
MSS, IARC [see Footnote 33 in Table  20 in
(1870)] cited the footnote in the 1958 publica-
tion by Van Duuren (4020). However, like many
other investigators [Lyons and Johnston (2430),
Rodgman and Cook (3273), Wynder and Wright
(4354), Wynder et al. (4355)], Van Duuren had
reported the identification of dibenzo[a,l]pyrene
in MSS. However, in 1966 Lavit-Lamy and
Buu-Hoï (2314) reported that the compound previ-
ously thought to be dibenzo[a,l]pyrene was actually
its isomer dibenz[a,e]aceanthrylene (dibenz[a,e]
fluoranthene) [see also Lacassagne et al. (2250)].
In 1983, IARC had commented that all pre-1966
studies involved with dibenzo[a,l]pyrene were
actually dealing with dibenz[a,e]fluoranthene not
dibenzo[a,l]pyrene (1868a). Dibenzo[a,l]pyrene
was eventually identified in MSS by Snook et al.
(3756) but no quantitative data were given.
9. The repetitious inclusion in the lists published by
Hoffmann and colleagues (1727, 1740, 1741, 1743,
1744, 1773, 1808) of the aza-arenes dibenz[a,h]
acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]
carbazole reported by Van Duuren et al. despite
the failure of numerous investigators in several
countries between 1970 and 2000 to confirm their
presence in MSS [(3260), also see Table  12-7 in
Baker (172) and Table 4 in Rodgman (3265).
These and other anomalies were described in detail by
Rodgman (3265).
The many publications co-authored by Hoffmann (1727,
1740, 1741, 1743, 1744, 1773, 1808), each of which con-
tained a list of biologically active components identified in
tobacco smoke, led to two interesting episodes as a result of
his efforts. Because of those numerous co-authored publi-
cations and the listing of toxicants in tobacco and tobacco
smoke, Dr. Dietrich Hoffmann was dubbed “The Author
of the List” in 2002 (23A05). This recognition was subse-
quently extrapolated in numerous scientific conference pre-
sentations and journal publications in which Dr. Hoffmann’s
list contributions were acknowledged by the authors in the
title of many scientific conference presentations and journal
publications by inclusion of the term “Hoffmann analytes”
or “Hoffmann-type analytes” or Hoffmann list compounds.”
In some published articles, the term “Hoffmann analytes”
does not appear in the title but does appear in the headings
of tables in the articles, for example, in several publications
by Baker and his colleagues at British American Tobacco
© 2009 by Taylor & Francis Group, LLC
78836_C023.indd 1008
(BAT), the term “Hoffmann analytes” appears in the title
of several tables (174a, 174c). Table XXIII-4 catalogs some
of the presentations and/or publications in which the term
“Hoffmann analyte” or its equivalent was used in tobacco-
related scientific literature from the year 2000 to 2006.
Table XXIII-5 catalogs the components in the various lists
co-authored by Hoffmann. In an attempt at simplification, the
sequence of components in Table XXIII-5 approximates the
sequence in many of the articles. Also in Table XXIII-5, the
various components listed by Hoffmann and colleagues (1727,
1740, 1741, 1743, 1744, 1773, 1808) are listed in the most recently
accepted nomenclature, for example, benzo[b]fluoranthene is
listed as benz[e]acephenanthrylene, dibenzo[a,l]pyrene is listed
as dibenzo[def,p]chrysene, catechol is listed as 1,2-benzenediol.
In each case, the nomenclature used in the Hoffmann articles
accompanies the most recent nomenclature listing.
Also included in Table XXIII-5 are several components
that do not appear in any of the Hoffmann co-authored lists
but recently have been included with analyses of Hoffmann-
listed components, for example, 1-naphthalenamine (1-amino-
naphthalene; α-naphthylamine), 3-aminobiphenyl ([1,1’-bip-
henyl]-3-amine), propionaldehyde (propanal), butyraldehyde
(butanal), and acetone (2-propanone). Table XXIII-5 includes
several tobacco smoke components that the IARC has reclassi-
fied with regard to their tumorigenicity, for example, chrysene
and di(2-ethylhexyl) phthalate. Thus, chrysene no longer appears
on the more recent Hoffmann lists (1740, 1741, 1743, 1744) and
di(2-ethylhexyl) phthalate was omitted from (1743, 1744).
One point of interest in the Table XXIII-5 catalog is the
tremendous number of references that deal with some aspect
of the various Hoffmann-listed components.
Over the years, numerous reports have been issued in
which analytical data were presented on the per cigarette
yields of numerous components in the MSS of the 1R4F
Kentucky Reference Cigarette. Many of the analytes were
defined as “Hoffmann analytes.” Table XXIII-6 summa-
rizes several such analyses on the 1R4F MSS reported by
Baker et al. [see Table 11 in (174b)], Rustemeir et al. (3370),
and R.J. Reynolds Tobacco Company (RJRT) (3190)]. Also
included in Table XXIII-6 are the “Hoffmann analyte” yields
reported by Chen and Moldoveanu (688) for the MSS of the
2R4F Kentucky Reference Cigarette. Similar examples of
“Hoffmann analyte” data are available in Baker et al. [see
Table  12 in (174b)] and Rodgman and Green (3300). Table
XXIII-6 lists the MSS analytes proposed by the Department
of Health (Canada) (23A06). Assessment of all the lists in
Table XXIII-6 reveals that the number of analytes in each
case is in the mid-40s and most of them may be considered,
based on the various listings by Hoffmann and his colleagues,
as “Hoffmann analytes.” The sequence of components in
Table XXIII-6 parallels the component class sequence usu-
ally used in the tables in the various articles by Hoffmann
and colleagues (1727, 1740, 1741, 1743, 1744, 1773, 1808).
Table XXVIII-6 also indicates the many components in
the Hoffmann lists that are not usually analyzed or included
in the “Hoffmann analyte” list of forty-four or forty-five bio-
logically active components.
11/24/08 12:37:13 PM
 “Hoffmann Analytes” 1009

Table XXIII-4
An Abbreviated Chronology of the Use of the Term “Hoffmann Analyte” or Its Equivalent in Tobacco
Smoke-Related Scientific Literature
Year Author(s) and Title of Article

2000 While it did not use the term “Hoffmann analyte” in its report, the Department of Health (Canada) proposed that analytical
data on the following smoke components from tobacco smoke should be a requirement (23A06):
“tar”, nicotine, formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, acrolein, crotonaldehyde, acetone,
benzo[a]pyrene, NNN, NNK, NAB, NAT, 1-aminonaphthalene, 2-aminonaphthalene, 3-aminobiphenyl,
4-aminobiphenyl, pyridine, quinoline, styrene, catechol, resorcinol, hydroquinone, phenol, o-cresol, m-cresol, p-cresol,
eugenol, 1,3-butadiene, isoprene, benzene, toluene, acrylonitrile, NH3, CO, HCN, NO, NOx, As, Cd, Cr, Pb, Hg, Ni, Se.
Examination of the Department of Health (Canada) list reveals that most of its listed components appear in the
biologically-active component lists in the publications co-authored by Hoffmann (1727, 1740, 1741, 1743, 1744,
1773, 1808).
2001 In a memorandum to the Department of Health (Canada), Levine (23A10) described the results of an inter-laboratory
comparison on “Hoffmann analytes” in the MSSs from three different cigarette brands.
2001 At the 55th Tobacco Science Research Conference (TSRC), Purkis et al. (3007) in their description of the reliability of
measurements of smoke analytes discussed the measurement of 44 “Hoffmann analytes.” Their TSRC presentation was
published in 2003.
2002 At the 56th TSRC, Baker and Willoughby (later Bishop) (172a) described the compounds generated by the pyrolysis of
relatively volatile tobacco ingredients. Subsequently, the presentation was published in 2004 and linked to the “Hoffmann
analyte” concept.
2002 At the 56th TSRC, Cashmore (631) presented a paper entitled: Alternative smoking regimes: Hoffmann analyte formation
and prediction as a consequence of changing smoking regimes and filter vent blocking.
2003 At the 57th TSRC, Chang et al. (23A04) presented a paper entitled: Influence of tip ventilation on Hoffmann analyte
deliveries.
2003 In their study of a new Kentucky Reference Cigarette 2R4F, Chen and Moldoveanu (688) described the quantitation of
more than 44 analytes in smoke, including most compounds considered as biologically active and described elsewhere as
“Hoffmann analytes.” They referred to the biologically-active components listed in 1998 by Hoffmann and Hoffmann
(1741).
2003 At the 57th TSRC, Dimandia et al. (23A07) described the analysis of Hoffmann list compounds by comprehensive
two-dimensional gas chromatography/time-of-flight mass spectrometry
2003 Also at the 57th TSRC, Ellisor et al. (23A08) described the variation in the level of Hoffmann analytes for cigarette MSS
when a large volume of air passes through the collection device and Volgger et al. (23A14) described the influence of
different cigarette paper properties on the formation of Hoffmann type analytes in smoke.
2003 Warren presented two papers at the 57th TSRC; both of which dealt with “Hoffmann analytes.” They were entitled: The
Hoffmann analyte to ‘tar’ ratio paradox (4136) and Prediction of mainstream cigarette smoke Hoffmann analyte yields by
statistical modeling (4137).
2004 Baker and Bishop (172a) in their report on the pyrolysis of tobacco ingredients noted the following:
Of the approximately 4800 substances in tobacco smoke (1373), 44 are believed…to be relevant to tobacco-related
diseases (23A06). These include…some volatile carbonyl compounds, tobacco-specific N-nitrosamines, aromatic
amines, phenols, volatile alkenes, benzo[a]pyrene and metals. These substances are sometimes called colloquially
‘Hoffmann analytes’ since similar lists of toxicological substances have been proposed by Dietrich Hoffmann et al.
of the American Health Foundation in New York since the mid 1980s. The latest compilation by Hoffmann et al.
lists 82 substances (1741, 1743, 1744).
From their experimental findings, BAKER and BISHOP concluded:
Particular attention has been paid to assessing the generation of ‘Hoffmann analytes’, i.e., biologically-active
analytes in smoke, from the pyrolysis of the ingredients. In general, the number of ‘Hoffmann analytes’ detected
among the pyrolytic products of the ingredients, and their levels, are low.

(Continued)

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 1010 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-4 (continued)

An Abbreviated Chronology of the use of the Term “Hoffmann Analyte” or Its Equivalent in Tobacco
Smoke-Related Scientific Literature
Year Author(s) and Title of Article

2004 In a series of three papers on the effect of tobacco ingredients on smoke chemistry, Baker et al. (174a, 174b, 174c) did not
include the term “Hoffmann analyte” or its equivalent in the three titles. However, the term “Hoffmann analyte” was used
throughout each of the publications. E.g., in the abstract of Baker et al. (174a), it is stated:
The studies are: pyrolysis of the ingredients; influence of the ingredients on smoke constituents believed by
regulatory authorities to be relevant to smoking-related diseases (“Hoffmann analytes”)…
The term “Hoffmann analytes” also appeared in the title of Table 3 in (174a).
In the abstract of Baker et al. (174b), the following was stated:
The effects of 450 tobacco ingredients added to tobacco on the forty-four “Hoffmann analytes” in mainstream
cigarette smoke have been determined…They are based on lists published by D. Hoffmann and co-workers of the
American Health Foundation…
In their summary of the effect of casing ingredients on smoke composition, Baker et al. (174c) stated:
The effects of 29 casing flavour ingredients and three humectants on the yields of 44 “Hoffmann analytes” in
cigarette smoke have been assessed.
The term “Hoffmann analytes” also appeared in the title of Table 10 in (174c).
2004 Case and Warren (23A03) were issued a European patent on a multivariate regression system for predicting “Hoffmann
analytes” in tobacco smoke. While the term “Hoffmann analyte” did not appear in the title of the patent, in its text the term
was used as follows:
The concentration of yields of a first set of components in a particular tobacco smoke, such as the Hoffmann
analytes, are predicted on the basis of a statistical model.
2004 Imperial Tobacco Co. (23A09) discussed “Hoffmann analytes” as follows:
Additional information may be requested by governmental agencies. This may include measurements of large
numbers of smoke constituents of regulatory interest such as the “Hoffmann analytes” (usually a list of 44 smoke
constituents). We have participated in studies requested by Australian and UK agencies and have provided
information to Health Canada. Our interpretation of these studies, other studies in the literature, and our own
internally-produced data is that these smoke constituents are generally proportional to tar measurements for a given
blend style.
2004 At the 58th TSRC, Loureau et al. (2400d) described the influence of cigarette paper and filter ventilation on the yields of
“Hoffmann analytes.”
2004 At the CORESTA Congress in Japan, Röper et al. (23A11) presented a paper entitled: “Hoffmann” analytes and cigarette
smoke in vitro toxicity revisited – How do the data compare?
2005 Baker and Bishop (172b) did not mention the term “Hoffmann analyte” in the title of their publication on the pyrolysis of
non-volatile tobacco ingredients but did note the following:
The study has concentrated on the biologically active substances produced by pyrolysis, in particular the “Hoffmann
analytes.” These analytes are believed by regulatory authorities in Canada and U.S.A. to be relevant to smoking-
related diseases. They are based on lists published by Hoffmann and co-workers of the American Health Foundation
in New York. For the pyrolysis of many of the non-volatile ingredients, no “Hoffmann analytes” were detected
amongst the products. When they were occasionally formed, they included phenols, benzene, toluene, styrene and
furfural (furfural is biologically active but it does not appear on any of the Hoffmann or regulatory authority lists).
2005 At the CORESTA Joint Study Group Meeting in Stratford-on-Avon, U.K. in 2005, BAT personnel presented the following
three papers under the general heading The effect of cigarette design variables on assays of interest to the Tobacco
Industry:
Case et al. (23A01) presented the first paper subtitled: 1) Experimental design and some initial findings on Hoffmann
analyte yields. Sheppard et al. (23A12) presented the second paper subtitled: 2) Prediction of smoke and Hoffmann
analytes using two different modeling methods. Winter et al. (23A15) presented the third paper subtitled: 3) Tobacco
blend types. Although the latter paper did not include the term “Hoffmann analytes” in its title, its abstract indicated it
involved the examination of the potential relationships between various tobacco blend components and “Hoffmann
analyte” yields across three distinct lamina tobacco blend styles, Virginia, burley, and Oriental plus a 1:1
Virginia:burley mixture.

© 2009 by Taylor & Francis Group, LLC

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 “Hoffmann Analytes” 1011

Table XXIII-4 (continued)

An Abbreviated Chronology of the use of the Term “Hoffmann Analyte” or Its Equivalent in Tobacco
Smoke-Related Scientific Literature
Year Author(s) and Title of Article

2005 At the 59th TSRC, Zemann et al. (4406a) presented a paper entitled: On-line puff-by-puff analysis of gaseous and
Hoffmann analytes in cigarette smoke
2006 At the 60th TSRC, Case et al. (23A02) presented a paper entitled: The role of cigarette paper and other factors that influence
Hoffmann analyte yields in sidestream smoke.
2006 Also at the 60th TSRC, Streibel et al. (23A13) presented a paper entitled: Real-time on-line characterization of selected
Hoffmann analytes in inhaled and exhaled cigarette smoke (mouthspace) by photo ionisation time-of-flight mass
spectrometry.

© 2009 by Taylor & Francis Group, LLC

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 1012 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5
“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke
Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1012 11/24/08 12:37:14 PM

 “Hoffmann Analytes” 1013

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1013 11/24/08 12:37:14 PM

 1014 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1014 11/24/08 12:37:15 PM

 “Hoffmann Analytes” 1015

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1015 11/24/08 12:37:16 PM

 1016 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1016 11/24/08 12:37:17 PM

 “Hoffmann Analytes” 1017

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1017 11/24/08 12:37:18 PM

 1018 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1018 11/24/08 12:37:19 PM

 “Hoffmann Analytes” 1019

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1019 11/24/08 12:37:20 PM

 1020 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1020 11/24/08 12:37:20 PM

 “Hoffmann Analytes” 1021

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1021 11/24/08 12:37:21 PM

 1022 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

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 “Hoffmann Analytes” 1023

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1023 11/24/08 12:37:23 PM

 1024 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1024 11/24/08 12:37:24 PM

 “Hoffmann Analytes” 1025

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1025 11/24/08 12:37:25 PM

 1026 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1026 11/24/08 12:37:26 PM

 “Hoffmann Analytes” 1027

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1027 11/24/08 12:37:27 PM

 1028 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1028 11/24/08 12:37:28 PM

 “Hoffmann Analytes” 1029

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1029 11/24/08 12:37:29 PM

 1030 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1030 11/24/08 12:37:30 PM

 “Hoffmann Analytes” 1031

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1031 11/24/08 12:37:31 PM

 1032 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1032 11/24/08 12:37:31 PM

 “Hoffmann Analytes” 1033

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1033 11/24/08 12:37:32 PM

 1034 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1034 11/24/08 12:37:33 PM

 “Hoffmann Analytes” 1035

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1035 11/24/08 12:37:34 PM

 1036 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1036 11/24/08 12:37:35 PM

 “Hoffmann Analytes” 1037

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1037 11/24/08 12:37:36 PM

 1038 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1038 11/24/08 12:37:37 PM

 “Hoffmann Analytes” 1039

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1039 11/24/08 12:37:38 PM

 1040 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1040 11/24/08 12:37:39 PM

 “Hoffmann Analytes” 1041

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1041 11/24/08 12:37:42 PM

 1042 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

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 “Hoffmann Analytes” 1043

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1043 11/24/08 12:37:43 PM

 1044 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

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 “Hoffmann Analytes” 1045

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1045 11/24/08 12:37:45 PM

 1046 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

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 “Hoffmann Analytes” 1047

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1047 11/24/08 12:37:46 PM

 1048 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-5 (continued)

“Hoffmann Analytes” in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

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 “Hoffmann Analytes” 1049

Table XXIII-6
Reported Yields of “Hoffmann Analytes” in 1R4F (174b, 3190, 3370) and 2R4F (688) Mainstream Smoke;
Proposed MSS “Hoffmann Analyte” Yield Analyses (23A06)
1R4F 1R4F 2R4F Proposed
1988 2002 2004 2003 2000
Baker et al. Chen and Department of
RJRT Rustemeier [Table 11 in Moldoveanu Health (Canada)
Component CAS No. (3190) et al. (3370) (174b)] (688) (23A06)

Polycyclic Aromatic Hydrocarbons

Benz[a]anthracene, ng/cig 56-55-3 10.5 10.1 — — — —
Benzo[b]fluoranthene, ng/cig 205-99-2 — — — — —

(benzo[e]acephenanthrylene) 5.63
Benzo[j]fluoranthene, ng/cig 205-82-3 —  — — — —
Benzo[k]fluoranthene, ng/cig 207-08-9 — — — — —
Benzo[a]pyrene, ng/cig 50-32-8 9.2 5.10 6.51 5.51 6.96 ×
Chrysene, ng/cig 218-01-9 — 14.4 — — — —
Chrysene, 5-methyl-, ng/cig 3697-24-3 — <7.60 — — — —
Dibenz[a,h]anthracene, ng/cig 53-70-3 — <0.60 — — — —
Dibenzo[a,e]pyrene, ng/cig 192-65-4 — — — — — —
(naphtho[1,2,3,4-def]chrysene)
Dibenzo[a,h]pyrene, ng/cig 189-64-0 — — — — — —
(dibenzo[b,def]chrysene)
Dibenzo[a,i]pyrene, ng/cig 189-55-9 — — — — — —
(benzo[rst]pentaphene)
Dibenzo[a,l]pyrene, ng/cig 191-30-0 — — — — — —
(dibenzo[def,p]chrysene)
Indeno[1,2,3-cd]pyrene, ng/cig 193-39-5 — 2.63 — — — —

Aza-Arenes
Pyridine, μg/cig 110-86-1 2.09 — 7.7 7.47 7.02 ×
Quinoline, μg/cig 91-22-5 0.235 — 0.34 0.30 0.23 ×
Dibenz[a,h]acridine, ng/cig 226-36-8 — — — — — —
Dibenz[a,j]acridine, ng/cig 224-42-0 — <2.72 — — — —
7H-Dibenzo[c,g]carbazole, ng/cig 194-59-2 — — — — — —

N-Nitrosamines
N-Nitrosodimethylamine, ng/cig 62-75-9 ND <4.40 — — — —
N-Nitrosoethylmethylamine, ng/cig 10595-95-6 ND — — — — —
N-Nitrosodiethylamine, ng/cig 55-18-5 ND — — — — —
N-Nitrosodi-n-propylamine, ng/cig 621-64-7 — — — — — —
N-Nitrosodi-n-butylamine, ng/cig 924-16-3 — — — — — —
N-Nitrosopyrrolidine, ng/cig 930-55-2 14.0 12.5 — — — —
N-Nitrosopiperidine, ng/cig 100-75-4 — — — — — —
N-Nitrosodiethanolamine, ng/cig 1116-54-7 — <4.30 — — — —
N-Nitrososarcosine, ng/cig 13256-22-9 — — — — — —
N’-Nitrosonornicotine, ng/cig 16543-55-8 101.0 124 106 107.09 133.11 ×
4-(N-Methylnitrosamino)-1-(3- 64091-91-4 84.0 138 96 90.69 115.61 ×
pyridyl)-1-butanone, ng/cig
N’-Nitrosoanabasine, ng/cig 37620-20-5 18.0 18.6 22 19.37 16.28 ×
N’-Nitrosoanatabine, ng/cig 71267-22-6 114.0 104.9 96 122.49 119.02 ×
N-Nitrosomorpholine 59-89-2 — — — — — —

Aromatic Amines
2-Toluidine, ng/cig 95-53-4 — — — — — —
Aniline, 2,6-dimethyl-, ng/cig 87-62-7 — — — — — —
1-Naphthylamine, ng/cig 134-32-7 — — 5.1 15.63 15.06 ×

(Continued)

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1049 11/24/08 12:37:47 PM

 1050 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIII-6 (continued)

Reported Yields of “Hoffmann Analytes” in 1R4F (174b, 3190, 3370) and 2R4F (688) Mainstream Smoke;
Proposed MSS “Hoffmann Analyte” Yield Analyses (23A06)
1R4F 1R4F 2R4F Proposed
1988 2002 2004 2003 2000
Baker et al. Chen and Department of
RJRT Rustemeier [Table 11 in Moldoveanu Health (Canada)
Component CAS No. (3190) et al. (3370) (174b)] (688) (23A06)

2-Naphthylamine, ng/cig 91-59-8 — — 12.6 10.40 10.32 ×

Biphenyl, 3-amino-, ng/cig 2243-47-2 — — 3.3 3.20 2.97 ×
Biphenyl, 4-amino-, ng/cig 92-67-1 — — 2.3 1.94 1.73 ×

N-Heterocyclic Amines
AaC, ng/cig 26148-68-5 — — — — —
MeAaC, ng/cig 68006-83-7 — — — — —
Glu-P-1, ng/cig 67730-11-4 — — — — —
Glu-P-2, ng/cig 67730-10-3 — — — — —
PhIP, ng/cig 105650-23-5 — — — — —
IQ, ng/cig 76180-96-6 — — — — —
MeIQ, ng/cig 77094-11-2 — — — — —
Trp-P-1, ng/cig 62450-06-0 — — — — —
Trp-P-2, ng/cig 62450-07-1 — — — — —

Aldehydes and Ketones

Formaldehyde, μg/cig 50-00-0 16.5 19.5 22.19 21.61 ×
Acetaldehyde, μg/cig 75-07-0 — 518 674 623.88 560.48 ×
Propionaldehyde, μg/cig 123-38-6 — — 56.4 51.54 43.92 ×
Butyraldehyde, μg/cig 123-72-8 — — 35.1 33.93 29.58 ×
Crotonaldehyde, μg/cig 123-73-9 — — 24.9 15.90 16.18 ×
Acrolein, μg/cig 107-02-8 — 46.3 69.0 60.64 58.77 ×
Acetone, μg/cig 67-94-1 — — 338 293.15 264.74 ×
2-Butanone, μg/cig 78-93-3 — — 80.7 68.08 62.72

Volatile hydrocarbons
1,3-Butadiene, μg/cig 106-99-0 — 42.7 30.4 32.10 29.94 ×
Isoprene, μg/cig 78-79-5 — 319 361 308.08 297.68 ×
Benzene, μg/cig 71-43-2 45.2 39.8 49.3 44.33 43.39 ×
Toluene, μg/cig 108-88-5 68.1 67.2 89.6 68.08 64.91 ×
Styrene, μg/cig 100-42-5 2.1 — 7.9 6.13 5.11 ×

Miscellaneous Organic Compounds

Acetamide, μg/cig 60-35-5 2.2 — — — — —
Acrylonitrile, μg/cig 107-13-1 7.6 — 9.4 9.51 8.28 ×
Acrylamide, μg/cig 79-06-1 1.1 — — — —
Hydrazine, 1,1-dimethyl-, ng/cig 57-14-7 — — — — —
Nitromethane, μg/cig 75-52-5 — — — — —
2-Nitropropane, μg/cig 79-46-9 — — — — —
Nitrobenzene, μg/cig 98-95-3 — — — — —
Vinyl chloride, ng/cig 75-01-4 — 30.0 — — —
Ethyl carbamate, ng/cig 51-79-6 — — — — —
Ethylene oxide, μg/cig 75-21-8 — — — — —
Propylene oxide, ng/cig 75-56-9 — — — — —
Di(2-ethylhexyl) phthalate, μg/cig 117-81-7 — — — — —
Furan, μg/cig 110-00-9 — — — — —
Benzo[b]furan, ng/cig 271-89-6 — — — — —

Phenols
Phenol, μg/cig 108-95-2 6.8 11.79 9.80 9.63 7.32
o-Cresol, μg/cig 95-48-7 1.8 3.31 3.04 2.62 1.89

© 2009 by Taylor & Francis Group, LLC

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 “Hoffmann Analytes” 1051

Table XXIII-6 (continued)

Reported Yields of “Hoffmann Analytes” in 1R4F (174b, 3190, 3370) and 2R4F (688) Mainstream Smoke;
Proposed MSS “Hoffmann Analyte” Yield Analyses (23A06)
1R4F 1R4F 2R4F Proposed
1988 2002 2004 2003 2000
Baker et al. Chen and Department of
RJRT Rustemeier [Table 11 in Moldoveanu Health (Canada)
Component CAS No. (3190) et al. (3370) (174b)] (688) (23A06)

m-Cresol, μg/cig
p-Cresol, μg/cig
103-39-4
106-44-5
1.6
4.1
2.55
6.36
{8.55 {7.43 {5.84 ×
×
Catechol, μg/cig 120-80-9 38.0 53.8 35.3 40.57 37.90 ×
Resorcinol, μg/cig 108-46-3 3.0 0.83 <1.1 0.94 0.91 ×
Hydroquinone μg/cig 123-31-9 37.0 43.3 34.9 42.77 32.40 ×
Methyleugenol, μg/cig 93-15-2 — — — — — —
Caffeic acid, μg/cig 331-39-5 — — — — — —

Chloroaromatic Compounds
DDT 50-29-3 — — — — — —
DDE 72-55-0 — — — — — —
Polychlorodibenzo-p-dioxins — — — — — — —
Polychlorodibenzofurans — — — — — — —

Inorganic Components
Hydrazine 302-01-2 — — — — — —
Arsenic, ng/cig 7440-38-2 — 3.33 <15 12.21 10.39 ×
Beryllium 7440-41-7 — — — — — —
Cobalt 7440-48-4 — — — — — —
Nickel, ng/cig 7440-02-0 — <2.63 <12 6.44 5.12 ×
Chromium (VI), ng/cig 7440-47-3 — <1.32 <5 57.74 73.01 ×
Cadmium, ng/cig 7440-43-9 — 24.7 47 55.09 47.82 ×
Mercury ng/cig 7439-97-6 — — 6.5 5.43 3.82 ×
Lead, ng/cig 7439-92-1 — 10.1 36 42.51 32.95 ×
Selenium ng/cig 7782-49-2 — — <20 39.81 34.85 ×
Polonium-210 7440-08-6 — — — — — —

Additional Components
Nicotine, mg/cig 54-11-5 0.79 0.74 0.74 0.80 0.75 ×
Carbon monoxide, mg/cig 630-08-0 11.3 10.0 — 12.26 11.96 ×
Ammonia, μg/cig 7664-41-7 18.0 — — 12.90 11.02 ×
Nitric oxide, μg/cig 10102-43-9 — — — 319.88 223.41 ×
Nitrogen oxides, μg/cig 234 263 — 348.34 268.98 ×
Hydrogen cyanide, μg/cig 74-90-8 89.0 80.8 — 128.93 109.20 ×
“Tar”, mg/cig — — — 9.38 8.91 ×

© 2009 by Taylor & Francis Group, LLC

78836_C023.indd 1051 11/24/08 12:37:48 PM

 24 Tobacco and/or Tobacco Smoke
Components Used as Tobacco Ingredients
For nearly four decades after the early 1950s an exceptional
amount of information was generated on the composition
of the various types of tobacco, the smoke from many of
the types, and the relationship between the two. Although
much of the information has been published, much has not.
Exemplary in this regard was the research conducted by
personnel not only at the R.J. Reynolds Tobacco Company
but also at many other tobacco companies. Much informa-
tion has been published in peer-reviewed journals and the
remainder is available on the Internet. In the early tobacco
and tobacco smoke studies, the chemical nature of one or
two components was defined by means of classical chemical
procedures, for example, the identification of the terpenoid
alcohol solanesol in flue-cured tobacco (3359), the phenols
eugenol and isoeugenol in the mainstream smoke (MSS)
from Oriental tobacco (3280), and maltol in the MSS from
an ingredient-free German tobacco blend (1131). However, as
analytical methodology became more sophisticated and pre-
cise, many more components—sometimes several hundred
newly identified in tobacco or smoke—were reported in a
single publication.
In 1986, each major U.S. cigarette manufacturer listed
the ingredients used at that time in its cigarette products. A
combined list was submitted to the U.S. Office of Smoking
and Health. That list, comprising 599 additives, was sub-
jected by a panel of eminent toxicologists not only to an
extensive literature survey but also to an examination of
unpublished data provided by the tobacco industry members
on the chemistry and toxicology of the ingredients. The
panel assessed the safety of each listed ingredient with
regard to its pyrolysate components and its possible effect
when added to cigarette tobacco on the chemical and bio-
logical properties of the cigarette mainstream smoke. The
results were summarized in 1994 by Doull et al. (1053). Of
the 599 ingredients, 460 (∼77 %) are individual compounds.
The remaining items are mixtures such as natural oils, plant
extracts, oleoresins, etc. Many investigators have noted in
their publications that numerous compounds on the list of
ingredients are tobacco and/or cigarette mainstream smoke
(MSS) components. The following pages chronicle such
a relationship between individual added components and
their presence in untreated tobacco and/or its smoke. While
Paschke et al. (2896) attempted to catalog every material
ever added to tobacco and its effect on MSS chemical and/
or biological properties, this chapter deals only with those
materials in the list by Doull et al. Although some of the addi-
tives cataloged by Paschke et al. did reduce the responses in
specific bioassays and the levels of some MSS components
© 2009 by Taylor & Francis Group, LLC
78836_C024.indd 1053
considered toxic, they also rendered the MSS unacceptable
to the consumer. Obviously, the ingredients listed by Doull
et al. did not suffer from such a problem since their addition
was specifically designed to enhance the acceptability to
consumers of the MSS from the product.
As a beginning, Doull et al. (1053) in their report noted:
Many of the ingredients added to cigarettes are identical or
essentially similar in composition to natural leaf tobacco
components.
In their 1998 report of the effect on rats of inhalation of
MSS from ingredient-treated tobacco cigarettes, Gaworski et
al. (24A04) expressed a similar view:
The addition of flavoring ingredients to the cigarette prior
to smoking did not significantly alter the type or extent of
biologic changes normally seen in smoke-exposed rodents.
Given the fact that many of the added flavoring ingredients
are structurally similar or identical to natural constituents
of tobacco leaf or of tobacco smoke itself [Lloyd et al.
(2389)], these results are not totally unexpected.
Later, Rustemeier et al. (3370) in their description of the
chemistry of MSS from ingredient-treated tobacco cigarettes
noted:
Many of these compounds or mixtures are also natural con-
stituents of the tobacco leaf.
Rodgman (3263) concurred with the preceding statements
when he wrote:
Many flavorful tobacco additives listed by Doull et al. are
structurally identical with or similar to highly polar, volatile
components identified in the aqueous alcohol-soluble portion
of cigarette MSS and tobacco.
More recently, Rodgman and Green (3300) wrote:
With the capability to isolate and identify highly polar and
volatile components of tobacco and its MSS, it was obvi-
ous that many were identical with or similar to ingredients
of flavor formulations added to specific tobacco blends
to impart unique smoking characteristics … Many “top-
dressing” components are structurally identical with or
similar to identified tobacco components. With no evidence
to the contrary, it is assumed that such an individual added
flavorant would behave during the smoking process (in
terms of direct transfer to smoke or degradation, reaction,
etc.) much in the same manner as the naturally occurring
tobacco component.
While many investigators considered many individual
compounds added to cigarette tobacco filler to be tobacco
and/or tobacco smoke components, it seemed worthwhile
to catalog the extent to which this was true. Obviously, if
1053
11/13/08 5:53:13 PM
 1054 The Chemical Components of Tobacco and Tobacco Smoke
a specific flavorful compound is already a tobacco compo-
nent, then its addition to tobacco is an attempt to enhance
its flavorful effect. If it is a compound generated during the
smoking process, then its addition to tobacco enhances the
level in the smoke by tobacco-to-smoke transfer.
The compounds added as ingredients to cigarette tobacco
may fall into one of the following categories:
• It is a component of one or more of the tobacco
types (flue-cured, Oriental, burley, Maryland)
commonly used in cigarette blends.
• It is a component of cigarette MSS.
• It is a component of both tobacco and tobacco
smoke.
• It is not a component of either the tobaccos or their
smoke.
An ingredient compositionally similar to but not identical
with a tobacco leaf or smoke component may be categorized
as an isomer or an homolog of a compound identified in natu-
ral tobacco leaf and/or its smoke. In the broad spectrum of
chemistry, biochemistry, and biology, cases exist where the
properties of one homolog vary significantly from those of
another or where the properties of one isomer differ signifi-
cantly from those of another.
For example, whether classified as a “Group 2A carcino-
gen” by the International Agency for Research on Cancer
(IARC) (1868a), or a significant carcinogen in cigarette MSS
by Hoffmann and Hecht (1727), or overall as a borderline car-
cinogen by others, for example, Dipple et al. (983), the specific
tumorigenicity of mice skin painted or subcutaneously injected
with benz[a]anthracene (B[a]A) is insignificant compared to
that of its homolog, 7,12-dimethylbenz[a]anthracene (DMB[a]
A). The isomeric C20H12 polycyclic aromatic hydrocarbons
(PAHs) benzo[a]pyrene (B[a]P) and benzo[e]pyrene (B[e]
P) differ markedly in their specific tumorigenicities in stud-
ies involving mouse skin painting or subcutaneous injection
(983). B[a]P under appropriate laboratory conditions is one of
the most potent tumorigens known, whereas the isomeric B[e]
P under the same conditions is essentially nontumorigenic.
In the 1950s, the organic solvent extraction of tobacco was
studied extensively with the purpose of removing PAH pre-
cursors from the tobacco. One process involved an aqueous
ethanol-hexane partition to separate the polar, more flavor-
ful tobacco components from the lipophilic PAH precursors.
At that time, little was known about the nature of the polar
tobacco components although it was apparent they made a
considerable positive contribution to the flavor and aroma
of cigarette MSS. Despite the lack of knowledge about the
precise nature of the polar components, it was demonstrated
they were not significant PAH precursors (3262). The lack
of knowledge about the polar tobacco components was due
to our inability to separate highly polar compounds in a
complex mixture. This situation continued during years of
intensive effort on cigarette MSS composition but was finally
resolved and utilized by Schumacher et al. (3553) in the 1970s.
© 2009 by Taylor & Francis Group, LLC
78836_C024.indd 1054
Among 1545 MSS components identified by Schumacher et
al. (3553), Newell et al. (2769), and Heckman and Best (1587)
were over 800 components new to the tobacco smoke litera-
ture, many of which were highly polar. By glass capillary
gas chromatography, Grob (1416) also identified many polar
components in the MSS from cigarettes containing additive-
free tobacco. Later, it was shown that some of the identified
polar components reported in MSS by Grob are also in the
Doull et al. list (1053).
With regard to tobacco, Lloyd et al. (2389) identified 275
previously unidentified components of additive-free flue-
cured tobacco, 132 new to all tobacco types. Many of these
compounds were highly polar and considered significant con-
tributors to MSS flavor and aroma. Similar studies were con-
ducted on the composition of burley (3219), Oriental (3561,
and Maryland (3550) tobaccos. Later, it became apparent that
many of the highly polar components of tobacco and tobacco
smoke were identical with or similar to many of the com-
ponents used in the flavor additive formulations, that is, the
“top dressing,” added to a specific tobacco blend to impart its
unique smoking characteristics (1053).
As previously mentioned, in the mid-1980s, each major
U.S. cigarette manufacturer listed the ingredients added to
its cigarette products at that time. In 1986, a combined list,
comprising 599 entities, was submitted to the U.S. Office of
Smoking and Health. From an extensive literature survey and
examination of much unpublished data from the cigarette
manufacturers on the chemistry and toxicology of the ingre-
dients, a panel of eminent toxicologists assessed the safety
of each listed ingredient with regard to its pyrolysis products
and its possible effect when added to cigarette tobacco on the
chemical and biological properties of cigarette mainstream
smoke. Subsequently, Doull et al. (1053) listed the ingredi-
ents assessed and summarized the conclusions of the panel
on their effect on the chemical and biological properties of
cigarette smoke.
In their assessment of available information on these
ingredients variously used as cigarette tobacco ingredients,
Doull et al. concluded that none of the materials used as fla-
vorants on smoking tobacco products, particularly cigarettes
marketed by U.S. manufacturers, imparted any significant
adverse chemical or biological properties to the MSS from
the ingredient-treated tobacco. However, Doull et al. did not
publish an overview of the studies and reports they had exam-
ined or provide any details on their analysis. In their detailed
assessment of reported chemical and biological properties
of the MSS from cigarettes fabricated with tobacco with or
without one or more additives, Paschke et al. (2895) reached
a similar conclusion; namely, that in general, no significant
increase in the biological activity of tobacco was reported
from cigarettes containing specifically described added
ingredients. In his examination of extensive laboratory data
generated from additives and additive-treated cigarettes
between the mid-1950s and the late 1970s, Rodgman (3263,
3264) reached a conclusion similar to that of Doull et al.
(1053) and Paschke et al. (2896).
11/13/08 5:53:14 PM
 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1055
Previously [see Table  1 in (3266)], the individual com-
pounds listed by Doull et al. (1053) as possible U.S. cigarette
ingredients were assigned a number somewhat indicative of
the alphabetical order in which the 460 individual compo-
nents were listed. That numerical listing is provided in Table
XXIV-1A. A similar number assignment [see Table  7A in
(3266)] was made in the case of individual components used
as tobacco ingredients by cigarette manufactures outside of
the United States. That numerical listing appears in Table
XXIV-1B. In each case, a few citations on the identification
of the component in tobacco and/or smoke were included
in the previous publication [see Tables  1 and 7A in (3266)]
to indicate that the ingredient was indeed a tobacco and/or
tobacco smoke component. A more complete listing of cita-
tions on the identification of the ingredient in tobacco and/
or smoke is included in Table XXIV-2. Examination of the
Reference column in Table XXIV-2 indicates that the number
of references for many of the tobacco and/or tobacco smoke
components used as ingredients is substantial. They not only
include reports on the identification of the component in addi-
tive-free tobacco and/or its tobacco smoke but also reports on
the effect of the added ingredient on MSS composition, par-
ticularly references dealing with “Hoffmann analyte” yields.
In several instances, ingredients not previously included as
tobacco and/or smoke components in (3266) are cataloged in
Table XXIV-2 because of their identification in tobacco after
the publication of (3266), for example, previously unidenti-
fied 2-hexenol and several naphthalene derivatives identified
in tobacco by Peng et al. (2917a) and several esters identified
in tobacco by Leffingwell and Alford (2339a).
Examination of the data presented previously [see
Tables 1 and 7A in (3266)] permits verification of the state-
ments by numerous investigators that many of the ingredients
in the Doull et al. list have been identified as components in
untreated tobacco types and/or the MSS from cigarettes con-
taining such tobaccos. Such an examination also permits an
assessment of the effect of a number of the listed ingredients
that have been reported in a variety of studies to not adversely
affect the chemical or biological properties of the MSS from
cigarettes containing such ingredients or the chemical prop-
erties of the pyrolysates from individual ingredients.
Table XXIV-2 catalogs those individual compounds that
have been identified in untreated tobacco and/or its tobacco
smoke and are listed by Doull et al. (1053) as tobacco addi-
tives used by U.S. cigarette manufacturers in and prior to
1994. The references cited are pertinent not only to their
tobacco/tobacco smoke identification but also to their effect
on the chemical and biological properties of the MSS from
cigarettes containing ingredient-treated tobacco. The compo-
nents are cross-referenced to the numbers assigned to their
listing in the Doull et al. (1053) and Baker et al. (174b, 174c,
24A01) articles (see Tables XXIV-1A and 1B). Over 260 of
the 460 compounds (57%) listed by Doull et al. and nineteen
of the fifty compounds (38%) in the Baker et al. list have
been identified as components in additive-free tobacco and/
or its smoke.
© 2009 by Taylor & Francis Group, LLC
78836_C024.indd 1055
In 1957, Wynder (4296) proposed that reduction of the
per cigarette “tar” yield by about 50% would have beneficial
health-related results. By the late 1970s to the early 1980s
the tobacco industry had exceeded the suggested reduction
by generating the low-“tar” and ultralow-“tar” cigarette. This
led to the criticisms and assertions that (1) some commercial
low-“tar” brands might have additive levels much higher than
those in previous high- and medium-“tar” cigarettes and (2)
the fates during the cigarette smoking process of many indi-
vidual added components were unknown.
The criticisms and assertions of the early 1980s about
tobacco additives were not new but an extension of those
made earlier, for example, in 1967, Wynder and Hoffmann
wrote about additives [see pp. 488 and 628 in (4332)]:
The importance of flavor-enhancing agents as contributors
to the tumorigenicity in the experimental animals varies for
different tobacco products. For cigarettes it may be a minor
factor compared to the overwhelming effects of other con-
stituents and variables. Nevertheless, one should emphasize
that further studies on the toxicity of flavorants and their
combustion products could provide a scientific basis for
the selection of less harmful additives … In evaluating the
effect of tobacco additives, we need to consider whether such
additions may contribute to the production of tumorigenic
agents during the smoking of a tobacco product. If an addi-
tive increases the formation of carcinogenic substances dur-
ing smoking to an analytically significant extent, it would, of
course, be most undesirable. If, however, an additive should
inhibit the production of tumorigenic agents during smok-
ing and at the same time not yield other types of toxic sub-
stances, it may represent an effective and useful agent.
However, the proponents of problems with added tobacco
ingredients became more vocal when the nearly 70% reduction
in sales-weighted MSS “tar” yield achieved by 1985 not only
answered the “tar” criticisms of the late 1950s and early 1960s
but exceeded the goal that halving the “tar” yield was a means
to lower lung cancer incidence in cigarette smokers (4296).
In 1980, LaVoie et al. (24A07) wrote:
The development of the low-tar, low-nicotine cigarette
required cigarette fillers with a potential for smoke flavor
contribution to make these cigarettes acceptable to the
consumer. Such products can be realized either by select-
ing tobaccos rich in flavor or by addition of tobacco extracts
or certain plant extracts, addition of synthetic flavor com-
pounds, or a combination of several of these factors … New
cigarettes should be assayed for toxicity and tumorigenicity,
so that the reduction of toxic and tumorigenic effects in the
smoke of low-tar, low-nicotine cigarettes is not offset by the
introduction of unknown factors.
Despite their criticism of the possible increased use of fla-
vorants in the filler of low-“tar,” low-nicotine cigarettes, the
authors admitted that prior to 1980, the U.S. cigarette manu-
facturers had, apparently achieved a “reduction of toxic and
tumorigenic effects in the smoke of low-‘tar,’ low-nicotine
cigarettes.”
11/13/08 5:53:15 PM
 1056 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-1A
As Listed by Doull et al. (1053), Individual Ingredient Components Used in U.S. Smoking Products
Note: The assigned numbers are those assigned by Rodgman (3266) to the individual component ingredients listed alphabetically in
their more or less common name by Doull et al. (1053).
Assigned Name in Doull Assigned Name in Doull Assigned Name in Doull
No. et al. (1053) No. et al. (1053) No. et al. (1053)
49 1,3-Butanediol 97 Diethyl malonate
1a Acetanisole
2 Acetic acid 50 2,3-Butanedione 98 Diethyl sebacate
3 Acetoin 99 Diethylpyrazine (3 isomers)
51 1-Butanol
4 Acetophenone 52 2-Butanone 100 Dihydroanethole
5 6-Acetoxydihydrotheaspirane 53 4-(2-Butylidene-3,5,5-trimethyl)- 101 5,7-Dihydro-2-methylthieno[3,4-d]
2-cyclohexen-1-one pyrimidine
6 2-Acetyl-3-ethylpyrazine 54 Butyl acetate 102 m-Dimethoxybenzene
7 2-Acetyl-5-methylfuran 55 Butyl butyrate 103 p-Dimethoxybenzene
8 Acetylpyrazine 56 Butyl butyryl lactate 104 2,6-Dimethoxyphenol
9 2-Acetylpyridine 57 Butyl isovalerate 105 Dimethyl succinate
10 3-Acetylpyridine 58 Butyl phenylacetate 106 3,4-Dimethyl-1,2-
cyclopentanedione
11 2-Acetylthiazole 59 Butyl undecylenate 107 3,5-Dimethyl-1,2-
cyclopentanedione
12 Aconitic acid 60 3-Butylidenephthalide 108 3,7-Dimethyl-1,3,6-octatriene
13 dl-Alanine 61 Butyric acid 109 4,5-Dimethyl-3-hydroxy-
2,5-dihydrofuran-2-one
14 Allyl hexanoate 62 Cadinene 110 6,10-Dimethyl-5,9-undecadien-
2-one
15 Allylionone 63 Caffeine 111 3,7-Dimethyl-6-octenoic acid
16 Ammonia 64 Calcium carbonate 112 2,4-Dimethylacetophenone
17 Ammonium bicarbonate 65 Camphene 113 a,p-Dimethylbenzyl alcohol
18 Ammonium hydroxide 66 Carbon dioxide 114 a,a-Dimethylphenethyl acetate
19 Ammonium phosphate dibasic 67 b-Carotene cis-trans- 115 a,a-Dimethylphenethyl butyrate
20 Ammonium sulfide 68 Carvacrol 116 2,3-Dimethylpyrazine
21 Amyl alcohol 69 4-Carvomenthenol 117 2,5-Dimethylpyrazine
22 Amyl butyrate 70 1-Carvone 118 2,6-Dimethylpyrazine
23 Amyl formate 71 b-Caryophyllene 119 Dimethyltetrahydrobenzofuranone
24 Amyl octanoate 72 b-Caryophyllene oxide 120 d-Dodecalactone
25 a-Amylcinnamaldehyde 73 Cellulose 121 g-Dodecalactone
26 Anethole trans- 74 Cinnamaldehyde 122 p-Ethoxybenzaldehyde
27 Anisyl acetate 75 Cinnamic acid 123 Ethyl 10-undecenoate
28 Anisyl alcohol 76 Cinnamyl acetate 124 Ethyl 2-methylbutyrate
29 Anisyl formate 77 Cinnamyl alcohol 125 Ethyl acetate
30 Anisyl phenylacetate 78 Cinnamyl cinnamate 126 Ethyl acetoacetate
31 l-Arginine 79 Cinnamyl isovalerate 127 Ethyl alcohol
32 Ascorbic acid 80 Cinnamyl propionate 128 Ethyl benzoate
33 l-Asparagine monohydrate 81 Citral 129 Ethyl butyrate
34 l-Aspartic acid 82 Citric acid 130 Ethyl cinnamate
35 Benzaldehyde 83 dl-Citronellol 131 Ethyl decanoate
36 Benzaldehyde glyceryl acetal 84 Citronellyl butyrate 132 Ethyl fenchol
37 Benzoic acid 85 Citronellyl isobutyrate 133 Ethyl furoate
38 Benzoin 86 Cuminaldehyde 134 Ethyl heptanoate
39 Benzophenone 87 p-Cymene 135 Ethyl hexanoate
40 Benzyl alcohol 88 l-Cysteine 136 Ethyl isovalerate
41 Benzyl benzoate 89 trans, trans-2,4-Decadienal 137 Ethyl lactate
42 Benzyl butyrate 90 d-Decalactone 138 Ethyl laurate
43 Benzyl cinnamate 91 g-Decalactone 139 Ethyl levulinate
44 Benzyl propionate 92 Decanal 140 Ethylmaltol
45 Benzyl salicylate 93 Decanoic acid 141 Ethyl methylphenylglycidate
46 Bisabolene 94 1-Decanol 142 Ethyl myristate
47 Borneol 95 3-Decenal 143 Ethyl nonanoate
48 Bornyl acetate 96 Dehydromenthofurolactone 144 Ethyl octadecanoate

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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1057

Table XXIV-1A (continued)

As Listed by Doull et al. (1053), Individual Ingredient Components Used in U.S. Smoking Products
Assigned Name in Doull Assigned Name in Doull Assigned Name in Doull
No. et al. (1053) No. et al. (1053) No. et al. (1053)
145 Ethyl octanoate 193 2-Heptenal 241 Isobutyric acid
146 Ethyl oleate 194 Heptyl acetate 242 dl-Isoleucine
147 Ethyl palmitate 195 w-6-Hexadecenlactone 243 a-Isomethylionone
148 Ethyl phenylacetate 196 g-Hexalactone 244 2-Isopropylphenol
149 Ethyl propionate 197 Hexanal 245 Isovaleric acid
150 Ethyl salicylate 198 Hexanoic acid 246 Lactic acid
151 Ethyl trans-2-butenoate 199 2-Hexen-1-ol 247 Lauric acid
152 Ethyl valerate 200 3-Hexen-1-ol 248 Lauric aldehyde
153 Ethylvanillin 201 cis-3-Hexen-1-yl acetate 249 l-Leucine
154 2-Ethyl-3-methoxypyrazine 202 2-Hexenal 250 Levulinic acid
155 2-Ethyl-5-methoxypyrazine 203 2-Hexenoic acid 251 Linalool
156 2-Ethyl-6-methoxypyrazine 204 3-Hexenoic acid 252 Linalool oxide
157 2-Methyl-3-methoxypyrazine 205 3-Hexenyl formate 253 Linalyl acetate
158 2-Methyl-5-methoxypyrazine 206 Hexyl 2-methylbutyrate 254 l-Lysine
159 2-Methyl-6-methoxypyrazine 207 Hexyl acetate 255 Malic acid
160 2-Ethyl-1-hexanol 208 Hexyl alcohol 256 Maltol
161 3-Ethyl-2-hydroxy-2- 209 Hexyl phenylacetate 257 Maltyl isobutyrate
cyclopenten-1-one
162 2-Ethyl-3,5-dimethylpyrazine 210 l-Histidine 258 p-Mentha-8-thiol-3-one
163 2-Ethyl-3,6-dimethylpyrazine 211 5-Hydroxy-2,4-decadienoic acid 259 l-Menthol; l-menthol (synthetic)
d-lactone
164 5-Ethyl-3-hydroxy-4-methyl- 212 2,5-Dimethyl-4-hydroxy-3(2H)- 260 l-Menthone
2(5H)-furanone furanone
165 2-Ethyl-3-methylpyrazine 213 2-Hydroxy-3,5,5-trimethyl-2- 261 Menthyl acetate
cyclohex-1-one
166 4-Ethylbenzaldehyde 214 4-Hydroxy-3-pentenoic acid lactone 262 dl-Methionine
167 4-Ethylguaiacol 215 2-Hydroxy-4-methylbenzaldehyde 263 Methoprene
168 p-Ethylphenol 216 4-Hydroxybutanoic acid lactone 264 2-Methoxy-4-methylphenol
169 3-Ethylpyridine 217 Hydroxycitronellal 265 2-Methoxy-4-vinylphenol
170 Eucalyptol 218 6-Hydroxydihydrotheaspirane 266 p-Methoxybenzaldehyde
171 Farnesol 219 4-(p-Hydroxyphenyl)-2-butanone 267 1-( p-Methoxyphenyl)-1-penten-
3-one
172 d-Fenchone 220 a-Ionone 268 4-(p-Methoxyphenyl)-2-butanone
173 Furfurylmercaptan 221 b-Ionone 269 1-(p-Methoxyphenyl)-2-propanone
174 4-(2-Furyl)-3-buten-2-one 222 a-Irone 270 Methoxypyrazine
175 Geraniol 223 Isoamyl acetate 271 Methyl 2-furoate
176 Geranyl acetate 224 Isoamyl benzoate 272 Methyl 2-octynoate
177 Geranyl butyrate 225 Isoamyl butyrate 273 Methyl 2-pyrrolyl ketone
178 Geranyl formate 226 Isoamyl cinnamate 274 Methyl anisate
179 Geranyl isovalerate 227 Isoamyl formate 275 Methyl anthranilate
180 Geranyl phenylacetate 228 Isoamyl hexanoate 276 Methyl benzoate
181 l-Glutamic acid 229 Isoamyl isovalerate 277 Methyl cinnamate
182 l-Glutamine 230 Isoamyl octanoate 278 Methyl dihydrojasmonate
183 Glycerol 231 Isoamyl phenylacetate 279 Methyl isovalerate
184 Glycyrrhizin, ammoniated 232 Isobornyl acetate 280 Methyl linoleate
185 Guaiacol 233 Isobutyl acetate 281 Methyl linolenate
186 2,4-Heptadienal 234 Isobutyl alcohol 282 Methyl naphthyl ketone
187 g-Heptalactone 235 Isobutyl cinnamate 283 Methyl nicotinate
188 Heptanoic acid 236 Isobutyl phenylacetate 284 Methyl phenylacetate
189 2-Heptanone 237 Isobutyl salicylate 285 Methyl salicylate
190 3-Hepten-2-one 238 2-Isobutyl-3-methoxypyrazine 286 Methyl sulfide
191 2-Hepten-4-one 239 a-Isobutylphenethyl alcohol 287 3-Methylcyclopentadecanone
192 4-Heptenal 240 Isobutyraldehyde 288 4-Methyl-1-phenyl-2-pentanone

(Continued)

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 1058 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-1A (continued)

As Listed by Doull et al. (1053), Individual Ingredient Components Used in U.S. Smoking Products
Assigned Name in Doull Assigned Name in Doull Assigned Name in Doull
No. et al. (1053) No. et al. (1053) No. et al. (1053)
289 5-Methyl-2-phenyl-2-hexenal 337 9,12,15-Octadecatrienoic acid 383 Potassium sorbate
290 5-Methyl-2- 338 d-Octalactone 384 l-Proline
thiophenecarboxaldehyde
291 6-Methyl-3,5-heptadien-2-one 339 g-Octalactone 385 5-Propenylguaethol
292 2-Methyl-(p-isopropylphenyl)- 340 Octanal 386 Propionic acid
propionaldehyde
293 5-Methyl-3-hexen-2-one 341 Octanoic acid 387 Propyl acetate
294 4-Isopropyl-3-methoxy- 342 1-Octanol 388 Propyl p-hydroxybenzoate
1-methylbenzene
295 4-Methyl-3-penten-2-one 343 2-Octanone 389 Propylene glycol
296 2-Methyl-4- 344 3-Octen-2-one 390 3-Propylidenephthalide
phenylbutyraldehyde
297 6-Methyl-5-hepten-2-one 345 1-Octen-3-ol 391 Pyridine
298 4-Methyl-5-thiazoleethanol 346 1-Octen-3-yl acetate 392 Pyroligneous acid
299 4-Methyl-5-vinylthiazole 347 2-Octenal 393 Pyrrole
300 Methyl-a-ionone 348 Octyl isobutyrate 394 Pyruvic acid
302 4-Methylacetophenone 349 Oleic acid 395 Rhodinol
303 p-Methylanisole 350 Palmitic acid 396 Salicylaldehyde
304 a-Methylbenzyl acetate 351 w-Pentadecalactone 397 Sclareolide
305 a-Methylbenzyl alcohol 352 2,3-Pentanedione 398 Skatole
306 2-Methylbutyraldehyde 353 2-Pentanone 399 Sodium acetate
307 3-Methylbutyraldehyde 354 4-Pentenoic acid 400 Sodium benzoate
308 2-Methylbutyric acid 355 2-Pentylpyridine 401 Sodium bicarbonate
309 a-Methylcinnamaldehyde 356 a-Phellandrene 402 Sodium carbonate
310 Methylcyclopentenolone 357 2-Phenethyl acetate 403 Sodium chloride
311 2-Methylheptanoic acid 358 Phenethyl alcohol 404 Sodium citrate
312 2-Methylhexanoic acid 359 Phenethyl butyrate 405 Sodium hydroxide
313 3-Methylpentanoic acid 360 Phenethyl cinnamate 406 Solanone
314 4-Methylpentanoic acid 361 Phenethyl isobutyrate 407 Sucrose octaacetate
315 2-Methylpyrazine 362 Phenethyl isovalerate 408 Sugar alcohols
316 5-Methylquinoxaline 363 Phenethyl phenylacetate 409 Sugars b
317 2-Methyltetrahydrofuran-3- 364 Phenethyl salicylate 410 Tannic acid
one
318 Methyl methylthiopyrazine 365 1-Phenyl-1-propanol 411 d-Tartaric acid
319 3-Methylthiopropionaldehyde 366 3-Phenyl-1-propanol 412 a-Terpineol
320 Methyl 367 2-Phenyl-2-butenal 413 Terpinolene
3-methylthiopropionate
321 2-Methylvaleric acid 368 4-Phenyl-3-buten-2-ol 414 a-Terpinyl acetate
322 Myristaldehyde 369 4-Phenyl-3-buten-2-one 415 5,6,7,8-Tetrahydroquinoxaline
323 Myristic acid 370 Phenylacetaldehyde 416 1,5,5,9-Tetramethyl-13-
oxatricyclo[8,3,0,0(4,9)]tridecane
324 b-Naphthyl ethyl ether 371 Phenylacetic acid 417 2,3,4,5-
Tetramethylethylcyclohexanone
325 Nerol 372 l-Phenylalanine 418 3,4,5,6-
Tetramethylethylcyclohexanone
326 Nerolidol 373 3-Phenylpropionaldehyde 419 2,3,5,6-Tetramethylpyrazine
327 2,6-Nonadienal 374 3-Phenylpropionic acid 420 Thiamine hydrochloride
328 2,6-Nonadien-1-ol 375 3-Phenylpropyl acetate 421 Thiazole
329 g-Nonalactone 376 3-Phenylpropyl cinnamate 422 l-Threonine
330 Nonanal 377 2-(3-Phenylpropyl)tetrahydrofuran 423 Thymol
331 Nonanoic acid 378 Phosphoric acid 424 a-Tocopherol
332 2-Nonanone 379 a-Pinene 425 o-Tolualdehyde
333 2-Nonen-1-ol 380 b-Pinene 426 m-Tolualdehyde
334 2-Nonenal 381 d-Piperitone 427 p-Tolualdehyde
336 9,12-Octadecadienoic acid 382 Piperonal 428 p-Tolyl 3-methylbutyrate

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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1059

Table XXIV-1A (continued)

As Listed by Doull et al. (1053), Individual Ingredient Components Used in U.S. Smoking Products
Assigned Name in Doull Assigned Name in Doull Assigned Name in Doull
No. et al. (1053) No. et al. (1053) No. et al. (1053)
429 p-Tolylacetaldehyde 441 2,6,6-Trimethylcyclohexa-1,3-dienyl- 452 Valencene
methane
430 p-Tolyl acetate 442 4-(2,6,6-Trimethylcyclohexa-1,3- 453 Valeraldehyde
dienyl)-but-2-en-4-one
431 p-Tolyl isobutyrate 443 2,6,6-Trimethylcyclohexanone 454 Valeric acid
433 Triacetin 445 l-Tyrosine 455 g-Valerolactone
434 2-Tridecanone 446 d-Undecalactone 456 Valine
435 2-Tridecenal 447 g-Undecalactone 457 Vanillin
436 Triethyl citrate 448 Undecanal 458 Veratraldehyde
437 3,5,5-Trimethyl-1-hexanol 449 2-Undecanone 459 Water
438 p,a,a-Trimethylbenzyl alcohol 450 10-Undecenal 460 3,4-Xylenol
439 4-(2,6,6-Trimethylcyclohex-2- 451 Urea
enyl)-but-2-en-4-one
440 2,6,6-Trimethylcyclohex-2-
ene-1,4-dione
a A number in bold print indicates the component has been identified as a tobacco and/or a tobacco smoke component (see Table XXIV-2).
b Sugars include glucose, fructose, sucrose, galactose, and mannose

Table XXIV-1B
As Listed by Baker et al. (174a), Individual Ingredient Components Not Used in U.S. Smoking Products but Used
Outside of the U.S.
Assigned
No. Name In Assigned No. Name In Assigned No. Name In

1A Ambroxide 18A Ethyl isobutyrate 35A Methylcyclopentenolone

2A Ammonium glycyrrhizinatea 19A Hexen-2-al 36A 6-Methyl-5-hepten-2-one
3A Amyl hexanoate 20A 2-Hexenol 37A Methyl 2-octynate
4Ab Anisole 21A 2-Hexenyl acetate 38A 4-Methyl-5-thiazole ethanol
5A Anisyl propionate 22A Ionone 39A Neryl acetate
6A Benzyl formate 23A Isoamyl propionate 40A d-Nonalactone
7A Benzyl isobutyrate 24A Isoamyl salicylate 41A Pectin
8A Benzyl isovalerate 25A Isobutyl butyrate 42A Pent-4-en-4-olide
9A Bornyl isovalerate 26A dl-Isomenthone 43A Potassium citrate
10A Butyl valerate 27A Isopropyl myristate 44A Rose oxide
11A d-Carvone 28A Linalyl benzoate 45A Sodium ethyl
4-hydroxybenzoate
12A Cinnamyl isobutyrate 29A Linalyl isobutyrate 46A Sodium methyl
4-hydroxybenzoate
13A Citronellal 30A Methional 47A Sodium propyl
4-hydroxybenzoate
14A Citronellyl acetate 31A 5H-5-Methyl-6,7- 48A Sorbic acid
dihydrocyclopenta-[b]pyrazine
15A Cyclamen aldehyde 32A Menthyl isovalerate 49A Sorbitol
16A Dextrin 33A Methyl anthranilate c 50A Tetradecalactone
17A 3-Ethyl-4-hydroxy-5-methyl- 34A 1-Methyl-2,3-cyclohexadione
3(2H)-furanone
a The Doull et al. list dos not include this item per se but does include glycyrrhizin, ammoniated (see Table XXIV-1A, item No. 184).
b A number in bold print indicates the component has been identified as a tobacco and/or a tobacco smoke component (see Table XXIV-2).
c Methyl anthranilate, a component in the Doull et al. list, was inadvertently listed in Table 7A in (3266)

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 1060 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2
Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients
Note: The number is square brackets [ ] is that previously assigned (3266) to the tobacco ingredient component listed by Doull et al. (1053);
The number with an A in square brackets [ ] is that previously assigned (3266) to the tobacco ingredient component listed by Baker et al.
(174b, 174c, 24A01)

The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke.

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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1061

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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 1062 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1063

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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 1064 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1065

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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 1066 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1067

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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 1068 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1069

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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 1070 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1071

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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 1072 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1073

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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 1074 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1075

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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 1076 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1077

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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 1078 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1079

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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 1080 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1081

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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 1082 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1083

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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 1084 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1085

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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 1086 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1087

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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 1088 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1089

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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 1090 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1091

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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 1092 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1093

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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 1094 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1095

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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 1096 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1097

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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 1098 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1099

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

(Continued )

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 1100 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1101

Table XXIV-2 (Continued)

Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients

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 1102 The Chemical Components of Tobacco and Tobacco Smoke
In the U.S. Surgeon General’s 1979 report [see pp. 63–64
in (4005)] the following was written:
The trend toward low-tar, low-nicotine cigarettes and toward
a reduction of undesirable volatile smoke compounds has
brought about major changes in the smoke flavor of ciga-
rettes. The use of rolled stems and reconstituted tobacco sheet
admixed with leaf lamina and the use of effective filter tips
are major factors inducing changes in smoke flavor. All of
these developments have led to increased use of flavor addi-
tives, especially for low-tar, low-nicotine cigarettes. In fact,
these new cigarettes require flavor corrections by additives
in order to be acceptable to the consumer. Tobacco extracts
as well as nontobacco flavors, such as licorice, cocoa, fruit,
spices, and floral compositions, are used … At present,
the selection of tobacco flavor additives from the GRAS
(Generally Regarded As Safe) List or from natural extract
and the screening of their smoke decomposition products for
toxicity or other biological activity are not required by law
and are done voluntarily by manufacturers.
Temperatures to which flavorants added to tobacco are
exposed and the duration of the exposure during the smok-
ing process range from 500 to 700ºC and the few seconds
of the puff duration, respectively. Many of the flavor addi-
tives listed by the Surgeon General are used in cooking and/
or baking where the exposure temperatures are lower than in
the smoked cigarette but the exposure time to the elevated
temperature is much longer. This raises the question: Will
more toxic compounds be formed from a given flavorant
during food preparation or during cigarette smoking? When
questioned about the need to determine the generation of toxic
substances from a GRAS list additive used in cooking and/or
baking, the FDA stated such studies were not required of the
foodstuff manufacturer nor could they be done by the FDA
since it had neither the staff, facilities, nor funds to undertake
such studies.
In the U.S. Surgeon General’s 1981 report [see pp. 51–52
in (4009)] it was noted:
Humectants and flavoring agents have long been used as
additives in cigarette manufacture … In recent years, ciga-
rette manufacturers’ advertisements have focused on the
flavor of new lower “tar” and nicotine cigarettes, enhanced
presumably by the addition of tobacco constituents or by
the addition of new flavoring materials, such as natural and
synthetic chemicals. The identities and amounts of the addi-
tives actually used in the manufacture of U.S. cigarettes are
not known. Systematic information has not been published
or made available on the influence of these additives on the
composition or biological activity of cigarette smoke.
A similar comment was made in the 1982 Surgeon
General’s report [see pp. 217–218 in (4010)]:
The development of the low-tar cigarette required enrich-
ment of smoke flavors in order to make the product accept-
able to the consumer. The flavor is enhanced by addition of
undescribed materials that may include concentrates of flavor
precursors obtained from tobacco, licorice, extracts from
other plants, or semisynthetic or fully synthetic flavor com-
ponents. Because these additives have not been identified, no
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78836_C024.indd 1102
judgment can be made as to whether they result in new com-
pounds or higher concentrations of hazardous components
in the smoke. The practice of flavor enrichment requires
detailed toxicological studies that are not available at present
for scientific evaluation of their impact [LaVoie et al. (2314c);
USPHS (4005)].
In the 1994 report by Doull et al. (1053) and the 2000
report by Paschke et al. (2895) on their analysis of reports
on the effects of added cigarette tobacco ingredients on the
chemical and biological properties of its MSS, both groups
essentially reached the same conclusion: The added ingre-
dients under the conditions of use contributed no adverse
chemical or biological properties to the MSS.
In their 1997 review of the “changing cigarette,” Hoffmann
et al. (1716) did not discuss low-“tar” cigarettes or the pre-
sumed use of additional flavoring materials, identity unknown.
In a second 1997 article on cigarette design changes imple-
mented between 1950 and 1995, Hoffmann and Hoffmann
[see pp. 345–346 in (1740)] discussed the casing additives
sugars and humectants (glycerol, propylene glycol, diethylene
glycol) but did not mention that some cigarette manufacturers
do not use diethylene glycol. The transfer of humectants to
cigarette MSS and their significant contribution to FTC “tar”
yield were ignored. On flavor additives, they wrote:
In April 1994, the major U.S. cigarette companies released a
list of 599 additives used at that time for the manufacture of
cigarette [Doull et al. (1053)]. However, in the past, additional
reactive flavor additives have been used (such as angelica lac-
tone and linalool oxide; Leffingwell (2336)). An exception is
menthol, which amounts to less than 2.5 mg in U.S. mentho-
lated cigarette [Perfetti and Gordin (2923)]. Menthol is not
carcinogenic in rodents [National Cancer Institute (24A10)],
nor does this readily volatilized compound give rise to mea-
surable amounts of carcinogenic hydrocarbons during smok-
ing of cigarettes [Jenkins et al. (1936)]. Yet it is possible that
the spraying of tobacco with menthol affects the burning
characteristics of a cigarette and thus changes the concentra-
tion of toxic and/or tumorigenic agents in the smoke.
The Hoffmanns obviously ignored what Wynder and
Hoffmann [see p. 527 in (4332)] wrote about the findings of
Bock et al. (355) on the specific tumorigenicity of the MSS
from menthol cigarettes:
The results of Bock et al. [355] suggest no difference in tum-
origenic activity of heptane-soluble “tar” from a mentho-
lated cigarette compared with a plain cigarette when tested
on a gram-to-gram basis.
Over the years it has been repeatedly asserted that cigarette
ingredients added at normal levels to pre-1980 cigarettes or at
slightly increased levels to more recent lower-“tar” cigarettes
might adversely modify the chemistry and biology of the MSSs
from such cigarettes. However, despite these repeated assertions,
no chemical or biological evidence has been presented by those
authorities making such assertions in support of their assertions.
Table XXIV-3 summarizes many of the chemical and bio-
logical studies conducted since 1994 on the effect of tobacco
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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1103

Table XXIV-3
A Summary of Tobacco Ingredient Studies Conducted from 1997 to Date
Number of
Ingredients Reported Findings/
Analysis Date Studied Conclusions Reference

Detailed literature 1994 599 It was concluded that there was no evidence that any Doull et al. (1073)
survey of ingredient added to commercial cigarette tobacco
ingredients added produces harmful effects under the conditions of use
to U.S. tobacco in cigarettes.
products

Effect of added 2002 333 The smoke chemistry data revealed changes towards Carmines (603);
tobacco both higher and lower amounts of various smoke Rustemeier et al. (3370)
ingredients on constituents…This suggests that the addition of 333
cigarette MSS commonly used ingredients to cigarettes in three
chemistry groups did not add to the toxicity of the smoke, even
at the exaggerated levels tested…
An overall assessment of our data suggests that
these ingredients, when added to the tobacco, do not
add to the toxicity of smoke, even at the elevated
levels used in this series of studies.
2002 482 In most cases, the flavour mixtures had no statistically Baker and Smith (24A01)
significant effect on the smoke yields relative to the
control cigarette. In a few cases, the small increases or
decreases were observed for some analytes relative to
the control cigarette. The smoke yields of the
experimental cigarettes were well within the ranges
observed in the three reference cigarettes.
2004 450 The significances of differences between the test and Baker et al. (174b)
control cigarettes were determined using both the
variability of the data on the specific occasion of the
measurement, and also taking into account the
long-term variability of the analytical measurements
over the one-year period in which analyses were
determined in the present study. This long-term
variability was determined by measuring the levels of
the 44 “Hoffmann analytes” in a reference cigarette
MSS on many occasions over the one-year period of
this study.
The effects of 450 tobacco ingredients (many
were individual compounds listed in Tables
XXIV-IA and IB) added to tobacco as seven
different mixtures on the yields of 44 “Hoffmann
analytes” in cigarette MSS were determined. In most
cases, the flavoring ingredient mixtures had no
significantly statistical effect on the MSS “Hoffmann
analyte” yields vs. those from the control cigarette.
Occasionally, with some mixtures, differences would
be observed in some “Hoffmann analyte” yields.
2004 32 The effects of 29 casing ingredients and three humectants Baker et al. (174c)
added to tobacco as eight different mixtures on the
yields of 44 “Hoffmann analytes” were determined.
Many of the ingredient mixtures had no statistically
significant effect on the MSS “Hoffmann analyte”
yields vs. those from the control cigarette. An increase
in one “Hoffmann analyte”, formaldehyde, was reported
when the ingredient mixture contained sugar.

(Continued)

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 1104 The Chemical Components of Tobacco and Tobacco Smoke

Table XXIV-3 (CONTINUED)

A Summary of Tobacco Ingredient Studies Conducted from 1997 to Date
Number of
Ingredients Reported Findings/
Analysis Date Studied Conclusions Reference

Effect of added 1997, ≈152 Although the mutagenic activities appeared to be Bioresearch [for RJRT]
tobacco 2002 similar, there were statistically significant (24A02); Rodgman
ingredients on differences in mutagenic activities among the (3263, 3264)
cigarette MSS samples.
biology: [The differences were primarily due to the
a) in vitro increase in mutagenicity of the CSC when the
genotoxicity and humectants (glycerol, propylene glycol) were not
cytotoxicity added to the cigarette tobacco and thus were not
present as diluents in the CSC].
2002 333 Within the sensitivity and specificity of the test Carmines (603);
systems, the in vitro mutagenicity and cytotoxicity Roemer et al. (24A11)
of the cigarette smoke were not increased by the
addition of the ingredients.
2002 482 The data has been analyzed and demonstrates no Massey et al. (24A09)
additional activity from the flavored cigarettes above
that of the control products.
b) MSS smoke 1997, 2 (glycerol, It was concluded that addition of the tested Heck et al. (24A06)
inhalation 2002 propylene humectants singly or in combination had no
glycol) meaningful effect on the site, extent or frequency of
respiratory tract changes associated with smoke
exposure in rats.
1997 1 The results of this 13-week inhalation study indicated Gaworski et al. (24A03)
(menthol) that the addition of 5000 ppm menthol to tobacco
had no substantial effect on the character or extent of
the biological responses normally associated with
inhalation of mainstream cigarette smoke in rats.
1998 170 The results indicate that the addition of flavoring Gaworski et al. (24A04)
ingredients to cigarette tobacco had no discernible
effect on the character or extent of the biologic
responses normally associated with inhalation of
mainstream cigarette smoke in rats.
2002 333 The data indicate that the addition of these 333 Carmines (603) ;
commonly used ingredients, added to cigarette in Vanscheeuwijck et al.
three groups, did not increase the inhalation toxicity (24A12)
of the smoke, even at the exaggerated levels used.
c) MSS CSC and 1999 150 While tumor incidence, latency and multiplicity data Gaworski et al. (24A05)
skin painting occasionally differed between test and comparative
reference CSC groups, all effects appeared to be
within normal variation for the model system.
Furthermore, none of the changes appeared to be
substantial enough to conclude that the tumor
promotion capacity of CSC obtained from cigarettes
containing ingredients was discernibly different
from the CSC obtained from reference cigarettes
containing tobacco processed without ingredients.
Pyrolysis of 2002/2004 291 The results are compatible with parallel studies in Baker and Bishop (172a)
tobacco which the ingredients are added to tobacco and the
ingredients under effect on cigarette smoke constituents are measured.
conditions In general, the number of “Hoffmann analytes”
simulating those detected among the pyrolysis products of the
in the cigarette ingredients, and their levels, are low…Of the 291
burning zone tobacco ingredients pyrolyzed, almost a third
transfer out of the pyrolysis zone intact, and almost
two thirds transfer at least 95% intact.

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 Tobacco and/or Tobacco Smoke Components Used as Tobacco Ingredients 1105

Table XXIV-3 (CONTINUED)

A Summary of Tobacco Ingredient Studies Conducted from 1997 to Date
Number of
Ingredients Reported Findings/
Analysis Date Studied Conclusions Reference

2003 A review of the pre-2003 studies on the effect of Baker and Smith (174e)
added ingredients on the chemical and biological
properties of cigarette MSS with emphasis on the
yields of the “Hoffmann analytes.” Their discussion
included various published (603, 1053, 3263, 3264,
3266, 24A03, 24A04, 24A05, 24A06) and pre-
published (172a, 174a, 174b, 3314a, 3370, 24A09,
24A11, 24A12) manuscripts on tobacco ingredients.
2004 482 This publication summarized the reported findings on Baker et al. (174a)
the 482 tobacco ingredients studied by Baker et al.
(174b, 174c). The major conclusion: Many of the
added tobacco ingredient mixtures produced no
significant effect on the yields of many of the
“Hoffmann analytes” in the cigarette MSS. In a
series of three biological studies on genotoxicity and
cytotoxicity, the response due to MSS exposure was
not distinguishable between the ingredient-treated
cigarette and the control.
2004 1 (glycerol) A study to determine the effect of different levels of Liu (2380)
added glycerol on cigarette MSS yields: The
glycerol transfer was proportional to that added to
the tobacco blend.
2005 159 non-volatile With a system simulating cigarette combustion Baker and Bishop (172b)
and complex conditions, pyrolysis of many of the non-volatile
ingredients ingredients gave no “Hoffmann analytes.” When
(these occasionally formed, the “Hoffmann analytes”
ingredients included phenols, benzene, toluene, and styrene.
were not Biologically-active furfural, never listed as a
individual significant biologically-active smoke component by
compounds) Hoffmann and his colleagues (1727, 1740, 1741,
1743, 1744, 1773, 1808), was occasionally formed.
2006 1(sugar) This study was an extension of the previously Baker et al. (172c)
reported effect (174c) of sugar ingredients on the
MSS yield of formaldehyde.

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 1106 The Chemical Components of Tobacco and Tobacco Smoke
ingredients on the chemical and biological properties of the
MSS from cigarette containing a particular added ingredient
or ingredient mixture. Many of the scientific criteria sug-
gested by the Life Sciences Research Office (LSRO) person-
nel (24A08) are incorporated in the tabulated investigations.
It is interesting that the LSRO in its 2004 monograph [see
p. 50 in (24A08)] wrote about the Doull et al. list of 460 indi-
vidual compounds: “However, the fate of very few of these
chemicals has been studied in cigarettes.”
This statement was made about the “very few” chemicals
despite the listing by LSRO [see pp. 45–46 in 24A08)] of the
studies by Baker et al. (174b, 174c), Massey et al. (24A09),
and Baker and Smith (24A01) on 482 ingredients, the studies
by Gaworski et al. (24A03, 24A04, 24A05) and Heck et al.
(24A06) on over 170 ingredients, the studies by Carmines
(603), Roemer et al. (24A11), Rustemeier et al. (3370), and
Vanscheeuwijck et al. (24A12) on 333 ingredients. In the latter
studies (603, 3370, 24A11, 24A12), over 210 of the 333 ingre-
dients (63%) were listed by Doull et al. as individual tobacco
ingredients. Can more than 210 vs. 333 be considered “very
few” agents in the smoke? LSRO is probably correct in its
assessment of the number of individual components with a
precise fate study but examination and understanding of the
pyrolysis data and effect of many of them on MSS chemical
and biological properties provide much significant data on
© 2009 by Taylor & Francis Group, LLC
78836_C024.indd 1106
their behavior in a smoked cigarette. To date, there is much
more known on the effect of added tobacco ingredients on
MSS properties than there is on the effect of foodstuff addi-
tives on the properties of cooked foodstuffs.
Despite the wealth of information now available from the
studies outlined in Table XXIV-3 that indicate that the ingre-
dients—whether tobacco compounds or nontobacco com-
pounds—added to cigarette tobacco do not significantly alter
the MSS chemical or biological properties, none of the critics
of tobacco ingredients has challenged the scientific findings
presented in the publications listed, provided any contradictory
scientific data, or suggested any additional definitive studies.
This raises the question: Is this oft-repeated assertion about the
deleterious effect of added tobacco ingredients like the many
other anti-tobacco-smoking assertions that have no supporting
data or for which contradictory data or equivocal data have
been generated [see Table 1 in Rodgman et al. (3307)]?
ACKNOWLEDGMENT
The authors are extremely grateful to the late Richard R.
Baker for his meaningful contributions to several sections of
this chapter that were included in part in previous ingredient
publications.
11/13/08 5:55:10 PM
 25 Pyrolysis
For many years, the fate during smoking of a compound added
to cigarette tobacco was defined by its fate during pyrolysis
as an individually pyrolyzed compound. The stimulus for
this assertion was twofold: (1) many publications were avail-
able that indicated the pyrolysis of a large number of com-
pounds—from relatively low molecular weight ones, such
as acetylene, to much higher molecular weight ones, such as
the sterols—yielded tumorigenic polycyclic aromatic hydro-
carbons (PAHs); (2) the ingredients to improve the smoking
quality of a cigarette were added at such a low level that ana-
lytical data on their effect on smoke composition was almost
impossible to generate. Because of this analytical problem
with additives to the cigarette filler, many investigators uti-
lized pyrolysis of individual tobacco components or additives
in an attempt to define the spectrum of products and their
influence on tobacco smoke composition and properties.
The assertion of the equivalence of the fate of a compound
on pyrolysis vs. its fate in a cigarette tobacco filler during
smoking persisted for over twenty years after the mid-1950s.
As proponents of this equivalence, Wynder and Hoffmann
[see pp. 346–347 in (4332)] wrote:
Most pyrolysis studies with tobacco, tobacco extracts,
extract fractions, individual components, and tobacco addi-
tives are performed in a nitrogen atmosphere. This proce-
dure has often been criticized on the grounds that many of
the toxic constituents formed during smoking of tobacco
products occur as a result of combustion in air rather than
in a nitrogen atmosphere. This criticism, however, cannot be
maintained in view of studies by Newsome and Keith (2780)
which demonstrated that a reducing rather than an oxidizing
atmosphere exists at the cone region of a burning cigarette.
Consideration of the effect of pyrolysis and the cigarette
smoking process reveals the following: in both cases, a given
compound may undergo a variety of reactions. In the case
of pyrolysis, fragments produced from the compound dur-
ing pyrolysis only have the opportunity to react with the
unchanged compound itself or with each other. In the case of
a smoked cigarette, the compound, either inherent in tobacco
or added, generates fragments during the smoking process
which have the opportunity not only to react with intact vola-
tilized tobacco components (over 5300 of which have been
identified) but also to react with the reaction fragments pro-
duced from them.
If it is assumed that a given compound X during pyroly-
sis is not only transferred in part to the pyrolysate but also
yields three pyrosynthetic fragments (A, B, and C), then these
four entities (X, A, B, and C) may transfer to the pyrolysate
intact or interact in a variety of ways to form a mixture of
pyrolysate components.
© 2009 by Taylor & Francis Group, LLC
78836_C025.indd 1107
entities interact
with one another
X X + A + B + C pyrolysate
plus transfer
of intact X
If it is assumed not only that the same type of reaction
occurs in a cigarette during the smoking process in the case
of compound X, either added (Xa) to or inherent (X) in the
tobacco blend, but also that similar degradation reactions
occur with the other tobacco components (X1, X2, X3, … Xn)
the situation described in the following equations could exist,
where n could be as high as or higher than 5300, the approxi-
mate number of identified tobacco components.
In the study of the addition of compound X to a cigarette
tobacco filler, the added compound is designated as Xa. The
inherent tobacco compound X and its fragments A, B, and C
plus the added compound Xa and its fragments Aa, Ba , and
Ca have the opportunity not only to react with each other but
also to interact with X1, X2, X3, … Xn, A1, A2, A3, … An, B1, B2,
B3, … Bn, and C1, C2, C3, … Cn, the fragments from hundreds
of other tobacco components. In both the pyrolysis case and
the cigarette smoke formation case, the number of fragments
may, of course, be many more than the three designated as
A, B, and C.
X X + A + B + C 
Xa Xa + Aa + Ba + Ca 
X1 X1 + A1 + B1 + C1 entities interact
X2 X2 + A2 + B2 + C2 with one another
X3 X3 + A3 + B3 + C3    cigarette smoke
… . . . . . plus transfer of
… . . . . . intact X and Xa,
as well as
… . . . . . intact
Xn Xn + An + Bn + Cn X1, X2, X3,...Xn
Obviously, pyrolysis of an individual compound (X) at
a specific temperature and during the smoking process in
a machine-smoked cigarette whose blend contains inherent
compound X and added compound Xa, are entirely different
situations and will yield qualitative and quantitative differ-
ences between the compositions of the pyrolysates and the
cigarette smoke. Qualitatively there may be some similari-
ties in the two compositions. Quantitatively, the probability
of any similarity is extremely low. It should be noted that
during the pyrolysis of compound X, a specific temperature
such as 700°C or 600°C is usually maintained. During the
smoking process occurring in the compound X- and (X + Xa)-
containing cigarette, compound X and Xa and their pyro-
genetically generated fragments are exposed to a range of
temperatures varying from nearly 1000°C at the fire cone to
1107
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 1108 The Chemical Components of Tobacco and Tobacco Smoke
50 to 60°C near the butt. In addition, Britt et al. (435) noted
that the residence time during most pyrolysis studies of
tobacco components was much longer than that encountered
by the tobacco components during the smoking process.
The reactions depicted above in pyrolysis of a component
vs. those in the cigarette smoking process with a component
added to the tobacco exist despite the assertion that the pyrol-
ysis procedure has been specifically designed to simulate the
smoking process (172b, 1648, 3616).
In 1979, Schmeltz et al. (3512) reported on the fate of radi-
olabeled nicotine during pyrolysis and its fate during actual
smoking of a cigarette containing the radiolabel nicotine rev-
eals at least two of the co-authors (Hoffmann and Schmeltz)
had changed their long-held view on the supposed equivalence
of compound behavior during pyrolysis and actual smoking.
Schmeltz et al. wrote:
Products obtained from the thermal degradation of [14C]
nicotine in a combustion tube (under pyrolytic conditions)
and in a cigarette (undergoing machine smoking) were
examined by gas-liquid chromatography (GLC), by GLC-
mass spectrometry, and by radiochromatography. Under
pyrolytic conditions in a combustion tube, nicotine under-
went extensive degradation to pyridines, quinoline, aryl-
nitriles, and aromatic hydrocarbons. In contrast, in a burning
cigarette, a substantial portion of nicotine remained intact
(≈41%), 12.5% underwent oxidation to CO2, up to 11% was
degraded to volatile pyridine bases, and negligible amounts
were converted to neutral or acidic particulate components.
A major portion of nicotine and its degradation products was
also diverted to sidestream smoke. These results suggest to
us that pyrolysis experiments may be limited for establishing
the fate of nicotine and possibly other tobacco components
in a burning cigarette.
On the basis of numerous pyrolysis studies, it has been
postulated that a number of tobacco leaf components are
the major precursors of components in tobacco smoke.
Throughout this chapter, smoke components alleged by some
investigators to play a role in the smoking-health issue have
Table XXV-1
Precursor Relationships between Tobacco Leaf Components and Tobacco Smoke Components
Smoke Component Leaf Component
Monocyclic Aromatic Hydrocarbons
Benzene, toluene, xylenes, etc. tobacco extracts
paraffin hydrocarbons
aliphatic acids
sugars
amino acids
Polycyclic Aromatic Hydrocarbons
Naphthalenes, anthracenes, solanesol
© 2009 by Taylor & Francis Group, LLC
78836_C025.indd 1108
been emphasized, particularly those smoke components sup-
posedly involved in the causation of lung cancer or other
respiratory tract disorders. Carbon monoxide and nicotine
have been proposed as cigarette mainstream smoke (MSS)
components involved in cardiovascular problems. Nicotine
occurs in cigarette smoke as a result of its transfer from the
cut tobacco leaf where it is considered to be present in the
so-called “bound” form as a variety of nicotine salts with
organic acids (citric, malic, oxalic, palmitic, stearic, etc.). As
noted by Perfetti (2918a, 25A47), these nicotine salts may
have various structures, depending on the nature of the acid,
for example, the molar ratio of acid to nicotine may be 3:1,
2:1, or 1:1. During the cigarette smoking process, these salts,
depending on their composition, are considered to decompose
to yield products ranging from mainly nicotine plus the acid
in the salt to traces of nicotine plus various nicotine reaction
and degradation products plus the acid. It has been proposed
that the nicotine in the smoke again “binds” with acidic
components of the smoke and is considered to be present
primarily in the mainstream particulate phase as “bound”
nicotine, but the binding in cigarette MSS is different from
that in the tobacco. In cigarette smoke, the “binding” or salt
formation is considered to be primarily with the stronger ali-
phatic organic acids such as formic, acetic, etc., whose levels
in smoke are substantial compared to those of palmitic acid,
stearic acid, etc.
Table XXV-1, modified and updated from similar tables
by Chortyk and Schlotzhauer (722) and Baker (171a), sum-
marizes the major precursor relationships proposed and/or
demonstrated for tobacco leaf components and tobacco
smoke components. These proposals are based in part on the
results of numerous pyrolysis studies. In some cases, the vali-
dation of the proposals is based on results obtained by addi-
tion of leaf components to tobacco and assessing the effect
on the yields of specific MSS components when the “spiked”
tobacco is smoked as a cigarette.
As noted previously, equivalence of the reaction mecha-
nisms involved in pyrolysis and those involved in the tobacco
smoking process was debated for many years, with the current
References
Schlotzhauer and Schmeltz (3465, 3466),
Schlotzhauer et al. (3456)
Schlotzhauer and Schmeltz (3466)
Schlotzhauer and Schmeltz (3466)
Schlotzhauer and Schmeltz (3466)
Patterson et al. (2902),
Schlotzhauer and Schmeltz (3466),
Higman et al. (1647)
Severson et al. (3616),
Rodgman and Cook (3269, 3291)
11/13/08 5:56:14 PM
 Pyrolysis 1109

Table XXV-1 (Continued)

Precursor Relationships between Tobacco Leaf Components and Tobacco Smoke Components
Smoke Component Leaf Component References

phenanthrenes, pyrenes, chrysenes, fluoranthenes, terpenes Schlotzhauer and Schmeltz (3466),

benzopyrenes, etc. Severson et al. (3616)
tobacco extracts Rodgman and Cook (3269, 3291),
Rodgman (3246),
Schlotzhauer and Schmeltz (3465),
Schlotzhauer et al. (3466),
Severson et al. (3615, 3616)
paraffin hydrocarbons Rodgman and Cook (3269, 3291),
Rodgman (3246),
Lam (2255, 2257),
Schlotzhauer and Schmeltz (3466),
Severson et al. (3616)
polysaccharides (pectin, cellulose, starch) Wright (4281),
Gilbert and Lindsey (1289),
Higman et al. (1647)
phytosterols Rodgman and Cook (3269, 3291),
Wynder et al. (4355),
Rodgman (3246),
Severson et al. (3616),
Schlotzhauer and Schmeltz (3466)
long-chained esters Severson et al. (3616)
amino acids Patterson et al. (2902);
Higman et al. (1647)
sugars Gilbert and Lindsey (1289),
Higman et al. (1647)
Polycyclic Aromatic Hydrocarbons (cont.) triglycerides Rodgman and Cook (3269)

Phenols
Phenol, cresols, xylenols, lignin Rodgman and Mims (3305),
  dihydroxybenzenes, etc. Schlotzhauer et al. (3468),
Higman et al. (1647),
Schlotzhauer et al. (3466)
sugars Bell et al. (246),
Spears et al. (3767),
polysaccharides (cellulose, pectin, starch) Higman et al. (1647),
Schlotzhauer et al. (3466)
protein Higman et al. (1647)
amino acids Higman et al. (1647)
tobacco extracts Schlotzhauer et al. (3466)
extracted tobacco Rodgman and Cook (3277),
Rodgman and Mims (3305),
Severson et al. (3616)
chlorogenic acid Schlotzhauer et al. (3462)

Aldehydes and Ketones

Formaldehyde, acetaldehyde, acrolein, acetone, sugars
α,β-dicarbonyls, quinolines, carbolines, etc.
polysaccharides (cellulose, pectin)
triglycerides
glycerol
Gager et al. (1264, 1265),
Houminer and Patai (1835d),
Johnson et al. (1960),
Higman et al. (1647)
Zamorani et al. (4398d),
Fredrickson (1228),
Fredrickson et al. (1238)
Kitamura (2111a)
Doihara et al. (1023, 1024),
Kröller (2192, 2196)

Hydrogen Cyanide
amino acids Patterson et al. (2902, 2905),
Higman et al. (1647),
Johnson et al. (1967)

(Continued)

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 1110 The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-1 (Continued)

Precursor Relationships between Tobacco Leaf Components and Tobacco Smoke Components
Smoke Component Leaf Component References

Aliphatic Nitrogen Compounds

Aliphatic amines, volatile amino acids Smith et al. (3729)
  N-nitrosamines protein Higman et al. (1647)
nicotine Kaburaki et al. (2006),
Schmeltz et al. (3512)
nicotine + nitrate Tso et al. (3985),
Hecht et al. (1564),
Hoffmann et al. (1696)

Monocyclic Nitrogen Compounds

amino acids Patterson et al. (2902),
Higman et al. (1647)
Anilines, pyrazines, pyridines, amino acids + sugars Green et al. (1369)
  pyrroles, tobacco-specific N- nitrosamines, etc. protein Higman et al. (1647),
Schmeltz et al. (3499)
nicotine Schmeltz et al. (3512)

Polycyclic Nitrogen Compounds

Indoles, carbazoles, acridines, quinolines, nicotine Van Duuren et al. (4027),
carbolines, etc. Kaburaki et al. (2006),
Schmeltz et al. (3512)
amino acids Patterson et al. (2902),
Higman et al. (1647),
Yamamoto et al. (4365a),
Sugimura (3828c)
protein Higman et al. (1647)

N-Heterocyclic Amines
Trp-P-1, Trp-P-2, Glu-P-1, Glu-P-2, IQ, amino acids Chortyk et al. (726),
AaC, MeAaC, etc. Patterson et al. (2902),
Akimoto (25A01),
Dong et al. (1041),
Sugimura et al.(3829a),
Kosuga et al. (2178a),
Sugimura (3828a, 3828b),
Takeda et al. (3863a, 25A73),
Yasuda et al. (4382a),
Yoshida and Matsumoto (4387a, 4387b, 4388),
Yamazoe et al. (4370a),
Conner and Dominguez (25A17),
Coleman and Perfetti (25A14),
Coleman et al. (25A15)
protein Yoshida et al. (4389A, 4390)

Sulfur-Containing Compounds
sulfur-containing amino acids Fujimaki et al. (25A23),
Kato et al. (2048, 2049),
Smith et al. (3729)

Acids, Aliphatic
Formic to nonanoic esters of mono- and disaccharides Wynder and Hoffmann (4332)
and aliphatic and terpenoid alcohols

Acids, Aliphatic
Decanoic and higher esters of phytosterols, aliphatic alcohols, Wynder and Hoffmann (4332),
and terpenoid alcohols Severson et al. (3616)

Acids, Aromatic
lignin Wynder and Hoffmann (4332)

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 Pyrolysis 1111
consensus being that these processes are not equivalent.
Also included are the results of research in the mid-1950s
on the major tobacco and cigarette paper component, cellu-
lose, either smoked in cigarette configuration [Fredrickson
(1228), Fredrickson et al. (1238)] or burned or pyrolyzed in
bulk. When the primary focus of the early research was on
the pyrogenesis of PAHs, Wright (4281) demonstrated that
the amount of benzo[a]pyrene (B[a]P) generated during bulk
burning or bulk pyrolysis of cellulose was much greater than
that generated during the burning of the cellulose (cigarette
paper) in a cylindrical form, simulating its configuration in
the cigarette.
XXV.A Individual Tobacco Types
In the early 1930s, Roffo (3320, 25A50, 25A51, 25A52)
reported the production of skin tumors in laboratory animals
by the repeated application of a “tar” obtained by the
“destructive distillation” of tobacco. This “destructive distil-
late” from tobacco, as noted by Wynder and Hoffmann (4319,
4332), is in no way comparable to the smoke condensate gen-
erated from cigarettes during a smoking procedure simulat-
ing that used by the human smoker in terms of puff duration,
puff frequency, and puff volume. Despite the fact that the
puff volume, puff duration, and puff frequency were usually
set at 35 ml, 2 sec, and 1 puff/min, respectively, after the
1937 publication by Bradford et al. (1937) on human smok-
ing parameters, Wynder et al. (1953a, 1953b) elected to use a
puff frequency of 3 puff/min for the generation of cigarette
smoke condensate (CSC) for their mouse skin-painting stud-
ies, despite their assertion that the smoking regime simulated
that of the human smoker.
In addition, the destructive distillation procedure used by
Roffo is not comparable to the pyrolysis procedures used sev-
eral decades later by other investigators, for example, Lam
(2255, 2257) and Wynder et al. (4355). Roffo’s work is pre-
sented here for the sake of historical completeness. In later
reports, Roffo (3323, 3325) and his son (3316, 3318) claimed
the identification of B[a]P in the destructive distillate of
tobacco, but these claims were subsequently challenged by
Wynder et al. (4306a) who noted:
Roffo … claimed to have identified benzpyrene in tobacco tar,
but this could not be confirmed by Hirst and his coworkers
(813), and more recently that substance could not be detected
by Waller (25A81). An examination by Eby (25A21) of the
tobacco tar used in this study [the mouse skin-painting study
by Wynder, Graham, and Croninger (4306a)] did not reveal
any spectroscopic evidence of the known carcinogenic
hydrocarbons.
Roffo (25A60) also claimed that the biological results in
his painting results with the effect on the levels of “destruc-
tive distillate” from tobacco were the same no matter which
type of tobacco was subjected to his destructive distillation
process. That his destructive distillation was not comparable
to the actual cigarette smoking process was demonstrated
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78836_C025.indd 1111
in later studies by Wynder and Hoffmann (4317, 4332), who
reported that the different types of tobacco (flue-cured, burley,
Maryland, and Oriental) generated CSCs whose specific
tumorigenicities were different, as were their contents of B[a]
P and phenol. The specific tumorigenicities and phenol levels
per milligram of CSC were found to be in the sequence
flue-cured = Oriental > Maryland > burley
whereas the B[a]P levels per milligram of condensate were
found to be in the sequence
flue-cured > Oriental > Maryland > burley.
More recent confirmation of the differences among
tobacco types in another bioassay has been obtained with
regard to the specific mutagenicities (as measured in the
Ames test with Salmonella typhimurium) of their smoke con-
densates generated under standard conditions. Results of both
in-house studies [Smeeton et al. (3707)] and external stud-
ies [Mizusaki et al. (2568), Yoshida and Matsumoto (4388),
DeMarini (933)] indicate the response of different strains of
Salmonella typhimurium in the Ames test to smoke conden-
sates from cigarettes fabricated with different tobacco types
not only are dissimilar but also are in a sequence opposite
that found for specific tumorigenicities determined in mouse
skin-painting studies, that is, the mutagenicities based on an
equivalent weight of smoke condensate were found to be in
the sequence
flue-cured < Oriental < Maryland < burley.
Critical reviews of the Roffo work have been published
by Wynder et al. (4306a), Wynder and Hoffmann (4332),
and Larson et al. (2264). All three groups asserted that the
“destructive distillate” from tobacco, as prepared by Roffo,
is not comparable to CSC generated under conditions more
closely approximating those in the human smoking of a
cigarette. Larson et al. also noted that the number of malig-
nant tumors produced in all of the Roffo skin-painting stud-
ies with the destructive distillate from tobacco was so few
(three malignant tumors, two carcinomas and one sarcoma,
in nearly 1000 treated animals) as to be almost within experi-
mental error.
Over the years, pyrolysis studies with tobaccos under a
variety of conditions have provided diverse results with regard
to the level of B[a]P found in the pyrolysate, for example,
Kröller (2196), Green and Best (1357), and Severson et al.
(3616). The phenol:B[a]P ratios were also much compared in
pyrolysates and MSSs and they too provided diverse results,
for example, Wynder and Hoffmann (4319, 4332), R.J.
Reynolds Tobacco Company (3190). Adams et al. (31) used
catechol rather than phenol as an “indicator” for phenols and
provided MSS and SSS B[a]P and catechol data on four dif-
ferent types of commercial cigarettes. From these data, the
calculated catechol:B[a]P ratios for the combined MSS and
SSS were widespread, ranging from 1074:1 to 2680:1. The
data reported by Severson et al. on the yields of phenol and
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 1112 The Chemical Components of Tobacco and Tobacco Smoke
benzopyrenes in the pyrolysates (and the ratios derivable
from their data) demonstrated that the process involved in
the generation of a tobacco pyrolysate is not comparable to
the process involved in the generation of CSC from cigarettes
made with the same tobacco and smoked under conditions
simulating the human smoking process.
XXV.B Extracts from Tobacco
The 1953 report of the successful production of carcinomas
in mice repeatedly painted for their life span with daily doses
of CSC generated by a smoking process supposedly simu-
lating that used by human cigarette smokers [Wynder et al.
(4306a)] led to a search for the smoke component(s) respon-
sible for the biological response. No carcinogenic, cocarci-
nogenic, or promoting compound identified in CSC, when
considered at its concentration in CSC, can explain the bio-
logical response obtained in mouse skin-painting studies nor
can it be explained when the carcinogenic, cocarcinogenic,
and promoting components at their CSC concentrations are
considered to be acting in concert.
The finding in 1913 by Staudinger et al. (25A68) that pyrol-
ysis of isoprene yielded a “tar” was utilized a decade later
by Kennaway (2073–2076). He reported that heating organic
compounds (acetylene, isoprene, cholesterol, foodstuffs) at
high temperatures (in air or an inert atmosphere) yielded
“tars” or “pyrolysates” which were tumorigenic to the skin
of laboratory animals. After the discoveries of the tumorige-
nicity of dibenz[a,h]anthracene (DB[a,h]A) and B[a]P, many
such generated pyrolysates were shown to contain various
tumorigenic PAHs [Rodgman (3233, 25A48)]. In the early
1950s, a controversy arose about the presence of such PAHs
in CSC, a material generated by the exposure of tobacco—a
mixture of many organic compounds—to temperatures rang-
ing from slightly above ambient to over 900°C. By the late
1950s, this controversy was resolved by the identification in
CSC of a variety of PAHs, including several [B[a]P, chrysene,
benz[a]anthracene (B[a]A), 7,12-dimethylbenz[a]anthracene
(DMB[a]A), DB[a,h]A] reported to give positive responses
in skin-painted laboratory animals, albeit at dose levels far in
excess of their levels in CSC. Wynder and Hoffmann (4332)
reviewed much of the early research on the identification of
PAHs in CSC.
Demonstration that PAHs were present in CSC then led to
research on their source(s). Cigarette paper [Wright (4281)],
the lighting source (matches, flammable organic solvent-
charged cigarette lighters), and PAHs in environmental pol-
lutants to which tobacco might be exposed during growth,
harvesting, and transportation [Campbell and Lindsey (583),
Lyons (2426), Bentley and Burgan (285)] were eliminated as
sources or precursors of PAHs in cigarette smoke. Extensive
research subsequently determined that tobacco itself and/or
its components were precursors of the PAHs in CSC.
As noted previously, in the 1930s, Roffo (3320, 25A50)
claimed the production of malignant tumors in laboratory ani-
mals skin painted with a “destructive distillate” from tobacco.
Roffo (3323, 3325) and his son [Roffo (3316, 3318)] also
© 2009 by Taylor & Francis Group, LLC
78836_C025.indd 1112
claimed identification of a benzopyrene or a “benzopyrene-
like” substance in the distillate. Subsequently, Roffo reported
that organic-solvent extraction of tobacco yielded an organic
solvent-insoluble tobacco residue whose “destructive distil-
late” was less tumorigenic in skin-painting studies than the
“destructive distillate” prepared from the unextracted (con-
trol) tobacco (3327). Roffo postulated that the major tobacco
precursor of the “distillate” component responsible for the
tumorigenicity observed in laboratory animals was the
phytosterols.
Coincident with general acceptance of biologically active
PAHs in CSC were extensive pyrolysis studies not only on
organic solvent-extractable materials from tobacco but also
individual components and classes of components in the
solvent-extracted materials. The organic solvent (pentane,
hexane, heptane, petroleum ether) used as extractant removed
wax-like organic components from the tobacco. These waxy
materials comprised several series of long-chained saturated
(1308, 3807) and unsaturated aliphatic hydrocarbons (3247,
3345) and alcohols (812, 3276), phytosterols and their long-
chained fatty acid esters (3247), terpenoid alcohols such
as solanesol (3344, 3359) and the duvanediols (3195, 3220,
3221, 3283, 3351, 3361), solanesyl esters with long-chained
fatty acids (3296, 3358, 3616), and a series of esters of long-
chained alcohols and long-chained fatty acids (3294).
Contradictory results were obtained on the yields of the
allegedly tumorigenic PAHs and the biological properties of
the CSCs from cigarettes fabricated from organic solvent-
extracted tobaccos. With relatively nonpolar solvents such
as pentane, hexane, and heptane, from 5% to 10% of the
tobacco weight was removed by extraction with these sol-
vents. Reductions in per cigarette PAH yields were reported
for the MSSs from solvent-extracted tobaccos by numerous
investigators, for example, Campbell and Lindsey (583),
Neukomm and Bonnet (2716), Rodgman (3241–3243, 3246,
3251), and Wynder and his co-workers [Wynder (4294),
Wright (4282), Wynder et al. (4355), Wynder and Hoffmann
(4307, 4309)] on solvent extractions of tobaccos and their
effect on the PAH yields in the CSC. Initially, the reduc-
tions in the MSS yields of the PAHs, particularly those with
four or more fused rings, were reported as being significant
when considered on a per cigarette yield basis. Subsequently,
the same investigators (Wynder and colleagues) claimed
that the reductions in PAH yields should be viewed as
only marginal when the PAH yields were considered on
a per gram of CSC basis. The percent reduction in tum-
origenicity (expressed as % tumor-bearing animals [TBA]
in skin-painting experiments) of the mainstream CSCs
from cigarettes fabricated with solvent-extracted tobaccos
was usually less than the percent reduction in the levels of
PAHs (with B[a]P, expressed in micrograms per gram or
nanograms per gram of CSC, used as an “indicator” for the
levels of PAHs with four or more fused rings). It was obvi-
ous from data already in the literature describing tobacco
smoke and tobacco pyrolysate compositions that B[a]P was
not a valid “indicator” for the tetracyclic and higher PAHs
demonstrated to be tumorigenic to mouse skin.
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 Pyrolysis 1113
American investigators [Rayburn and Wartman (3091),
Rayburn et al. (3092)] as well as French investigators [Cuzin
et al. (885)] reported slight to no reductions in the levels of
mainstream CSC PAHs, particularly B[a]P, as a result of
organic solvent-extraction of tobacco. Much of the early
research on organic solvent extraction of tobacco to reduce
the yields of PAHs in mainstream CSCs was reviewed by
Wynder and Hoffmann (4319, 4332) and Hoffmann and
Wynder (1798).
Organic-solvent extraction of tobacco to control PAH
levels in MSS fell from grace around 1960 when it was described
by its early proponents, Wynder and Hoffmann (4309), as a pro-
cess “impractical both technically and economically” and later
was classified as “only of academic interest” by Wynder and
Hecht (4306d), a view reported by the U.S. Surgeon General
[see Table 26, p. 14: 114 in (4005)]. Pyrolysis studies have been
conducted not only on the material extracted from the tobacco
but also on the unextracted (control) tobaccos and the residual
extracted tobaccos in attempts to define the precursor(s) of
PAHs (and phenols) in cigarette MSS. In some respects, the
differences between the compositions of the pyrolysates from
solvent-extracted tobacco and from unextracted tobacco paral-
leled the differences between the compositions of the MSSs
from cigarettes fabricated with solvent-extracted tobacco and
with unextracted tobacco.
In 1958, Wynder et al. (4355) described the effect of vary-
ing the pyrolysis temperature on the yield of pyrolysate from
an n-hexane extract from tobacco. The extracted material
constituted 5.4% of the original tobacco weight and consisted
of long-chained saturated and unsaturated aliphatic hydro-
carbons, glycerides and other esters, solanesol and phytos-
terols and their esters, long-chained aliphatic esters, and
α-tocopherol. Major findings from their study included (see
also Table XXV-2):
The pyrolysate yields varied inversely as the pyrolysis
temperature, that is, the pyrolysate yield decreased
as the temperature of pyrolysis was increased.
Presumably, this is due to less decomposition of the
extracted components to vapor-phase components
Table XXV-2
Pyrolysis Studies on n-Hexane Extract from Tobacco
Pyrolysis Conditions Pyrolysate,
Temp. °C Medium % of Extract
560 N2 50
640 N2 35
720 N2 32
800 N2 28
880 N2 28
880 air 30
a % Tumor-bearing animals (mice) with carcinoma at skin-painted site; similar percentages were found with skin-painted rabbits
© 2009 by Taylor & Francis Group, LLC
78836_C025.indd 1113
(water, carbon monoxide, carbon dioxide, methane,
etc.) at the lower pyrolysis temperatures.
The percent conversion of the extracted components
to PAHs decreased as the pyrolysis temperature
decreased.
The specific tumorigenicities of the pyrolysates, applied
as 1% and 5% solutions in acetone in skin-painting
studies involving both mice and rabbits, decreased
as the pyrolysis temperature was lowered.
Pyrolysis of the extract in either an inert atmosphere
(nitrogen) or an oxygenated atmosphere (air) at
880°C did not markedly affect the findings with
respect to the yield of pyrolysate, the generation of
PAHs, or the specific tumorigenicity (mouse skin-
painting bioassay) obtained with a solution of 1%
pyrolysate in acetone.
Studies on organic-solvent extraction of tobacco con-
ducted from the mid- to-late 1950s by Rodgman (3241, 3242,
3246, 3251), Ashburn (116, 117), and Ashburn and Rodgman
(121) provided analytical data on the PAHs in mainstream
CSC that in some ways paralleled the findings reported by
Wynder (4294). Rodgman (3251) summarized the RJRT
R&D findings:
Organic-solvent extraction of various tobacco types (flue-
cured, burley, Oriental) and blends reduced the yields of both
total and individual PAHs, e.g., B[a]P in mainstream CSC
both on a per cigarette basis and on a weight of tobacco con-
sumed basis. The per cigarette “tar” yields were also reduced
in every instance.
Partition of the organic-solvent extractables between a
solvent system consisting of a polar solvent (aqueous etha-
nol) and a nonpolar solvent (hexane or pentane) and returning
each partition fraction separately to the organic solvent-ex-
tracted tobacco residue indicated:
Addition of the nonpolar solvent-soluble material
(which contained the bulk of the tobacco waxes)
Tumorigenicity Studies, % Tumor-Bearing
Tumorigenic Animalsa Painted with Pyrolysate
PAHs 1% Solution 5% Solution
0 0
0 17
present 0 60
60 97
present 77
present 67 67
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 1114 The Chemical Components of Tobacco and Tobacco Smoke
to the extracted tobacco residue returned the CSC
PAH yield almost to that of the CSC from the unex-
tracted (control) tobacco.
Addition of the polar solvent-soluble material (which
consisted primarily of oxygen- and/or nitrogen-
containing flavor-contributing tobacco components)
to the extracted tobacco produced very little change
in the PAH (both total and individual) level of the
CSC.
These results were interpreted as an indication that the rela-
tively high molecular weight, nonvolatile tobacco wax com-
ponents were the major precursors in tobacco of the PAHs in
smoke, whereas the moderate to low molecular weight and
volatile flavorful components in tobacco did not contribute
significantly to the PAH levels in smoke.
Addition of the organic solvent-soluble tobacco compo-
nents, for example, long-chained aliphatic hydrocarbon frac-
tion, solanesol, or β-sitosterol, to unextracted (control) tobacco
increased the levels of the total and some individual PAHs in the
CSC. Thus, removal of tobacco wax components reduced the
levels of both the total and individual PAHs in CSC, whereas
addition of tobacco wax components increased the levels of
both the total and individual PAHs in CSC (3251, 3269).
Examination of the relationship of the level of B[a]P to that
of other individual PAHs in the various CSCs from the solvent-
extracted tobaccos or from the component-“spiked” tobaccos
confirmed what was already obvious from other literature
data: B[a]P is not a valid “indicator” for either total PAHs or
other individual PAHs with fewer than four fused rings, with
four fused rings, or with more than four fused rings.
From the mid-1960s to the early 1970s, the USDA group
described the pyrolysis of organic-solvent extractables from
tobacco. In the earlier studies, the pertinence of the pyroly-
sis results in defining the precursors in tobacco of the PAHs
in the CSC was emphasized (3465, 3455), but subsequent
research dealt with the precursors in tobacco of the simple
phenols in cigarette smoke (3456, 3468).
In 1968, Schlotzhauer and Schmeltz (3465) noted that
hexane extractables from tobacco constituted about 6% of
the original tobacco weight, whereas the extracted tobacco
residue constituted about 94% of the original tobacco weight.
Pyrolysis of the hexane extractables and the extracted
tobacco residue indicated that, of the total B[a]P determined
in these two pyrolysates, about 60% was found in the hexane
extractables pyrolysate (6% of the original tobacco) and 40%
in the pyrolysate of the extracted tobacco residue (94% of
the original tobacco). Schlotzhauer and Schmeltz (3466) also
demonstrated by pyrolysis of individual components isolated
from the hexane extract that the following were precursors
of the PAHs in the pyrolysates: n-dotriacontane, stearic acid
and linoleic acid, phytol, squalene, and β-sitosterol.
In 1973, Chortyk and Schlotzhauer (722) reviewed the
pyrogenesis of tobacco smoke components. They discussed
the extraction/pyrolysis results described above plus results
of their studies on the pyrolysis (800°C) of fractions sequen-
tially extracted from tobacco with a series of increasingly
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78836_C025.indd 1114
polar solvents (hexane, acetone, ethanol, water) (3458).
Chortyk and Schlotzhauer (722) noted:
The sources of about 70% of the aromatic hydrocarbons
ranging from benzene to BaP, in the pyrolysates, were due to
leaf components extractable with hexane and acetone: these
extracts amounted to less than 25% of dry leaf weight. The
hexane extractables (7.2% of leaf weight) accounted for 33%
of the neutral products. The hexane-soluble material of cured
leaf tobacco is known to include aliphatic and cyclic paraf-
fins, fatty acids, phytosterols, steryl esters, and terpenes, all
preferred precursors of aromatic hydrocarbons. The acetone
extract (17.5% of leaf weight) contributed another 35% of
aromatic hydrocarbons to the pyrolysate, indicating a further
extraction of similar polycyclic aromatic hydrocarbons pre-
cursors. Together, these two extracts contributed 86% of the
BaP content of the tobacco pyrolysate. The disproportion-
ate contribution of these fractions to BaP formation becomes
apparent from the following data: the hexane and acetone
fractions, containing hydrocarbons and lipids, yielded about
700 mg BaP per gram of material pyrolyzed, while the resid-
ual tobacco, consisting mostly of cellulose materials, yielded
less than 34 mg of BaP per gram pyrolyzed.
They also demonstrated that the major volatile phenols
(phenol, cresols) were produced primarily by pyrolysis of the
alcohol extractable and the final tobacco residue. These frac-
tions accounted for 38% and 44%, respectively, of the total
phenols yield. The alcohol extractables included polyphenolic
tobacco pigment and low molecular weight sugars, whereas
the final tobacco residue contained the polysaccharides cel-
luloses, starch, pectins, and lignin. All these yield the simple
phenols on pyrolysis or during tobacco smoking (248, 2043,
3277, 3305, 3453, 3468, 3767).
In 1978, Severson et al. (3616) revisited the organic-
solvent extraction of tobacco. They noted [see p. 277 in
(3616)]:
Numerous pyrolytic studies have shown that the hexane or
petroleum ether … extract of tobacco contains the major pre-
cursors of smoke polycyclic aromatic hydrocarbons [Wynder
et al. (4355), Schlotzhauer et al. (3468), Schlotzhauer and
Chortyk (3451)]. However, many of these studies were made
under conditions which produced optimum PAH yields
[Schmeltz and Hoffmann (3489)]; thus, the PAH distribu-
tions were not comparable to those in [CSC] and the data
obtained could not be exactly correlated with PAH produc-
tion during the smoking process.
Severson et al. (3616) determined the pyrolytic condi-
tions that gave the PAH profiles of tobacco pyrolysates that
they claimed “could be correlated with [CSC] PAH pro-
files.” Examination of their data indicates that this claim is
not valid. Severson et al. conducted two major experiments.
They examined:
The effect of petroleum ether extraction on the PAH
levels in the pyrolysates from the petroleum ether
extractables, PEE (8% of the original tobacco weight),
the extracted tobacco residue, RES (92% of the orig-
inal tobacco weight), and the original tobacco.
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 Pyrolysis 1115

Table XXV-3
Comparison of Polycyclic Aromatic Hydrocarbon Fraction Levels, Phenol Yields, and Acid Yields in 700°C
Pyrolysates from Tobacco, Petroleum Ether Extractables (PEE), and the Tobacco Residue (RES) after Extraction
Amount From
Tobacco PEE RES Total PEE + RES % Diff.,
Pyrolysate Components μg/1000 mg μg/80 mg μg/920 mg μg/1000 mg Total vs. Tobacco

PAH Group
Naphthalene 3200 3900 1300 5200 63
Fluorene 1100 1100 860 1960 78
Phenanthrene 1600 1500 780 2280 43
Pyrene 630 820 350 1170 86
Chrysene 180 260 80 340 89
Benzopyrene 190 140 50 190 0
Totals 6900 7720 3420 11140 61

Phenol Group
Phenol 3610 50 2620 2670 26
o-Cresol 750 50 630 680 20
m- + p-Cresol 1620 50 1180 1230 24
Ethyl-/dimethylphenols 910 130 700 830 -9
1-Naphthol 160 30 110 140 -13
2-Naphthol 140 20 110 130 -7
Totals 7190 330 5350 5680 -21

Acids
Volatile acids (C1-C7) 330 140 230 370 12
Nonvolatile acids (C11-C34) 12 11 4 15 25
Totals 342 151 234 385 13

The effect of chromatography of the petroleum ether
extractables PEE with eight increasingly polar sol-
vent systems, ranging from petroleum ether to an
acetone:methanol solution, on the composition of
each of the eight chromatographic fractions, and on
the PAH levels in the pyrolysates from each of the
eight fractions.
Table XXV-3, adapted from (3616), indicates that, at the
optimum pyrolysis conditions specified (700°C, N2), the
totals of the PAH groups (except for the benzopyrene group)
in the pyrolysates from the PEE and the RES are substan-
tially higher (42% to 89%) than the levels of the same PAH
groups in the pyrolysate from unextracted tobacco. Table
XXV-3 also shows that the sum of the total PAHs in the
pyrolysates from the two fractions was 61% greater than the
total PAHs in the control tobacco pyrolysate. Similar studies
on individual and total acids and individual and total phenols
in the same pyrolysates reveal that the sum of the total phe-
nols in the pyrolysate of the PEE and RES was 21% less than
the total phenols in the control tobacco pyrolysate, for acids,
the sum of total acids in the pyrolysates from the two frac-
tions (PEE plus RES) was 13% greater than the total acids in
the control tobacco pyrolysate.
If this situation prevails in the relatively simple situation
(petroleum ether extractables, extracted tobacco residue, and
unextracted control tobacco) described above, then it is highly
likely that the discrepancy will be enhanced when individual
compounds are considered, that is, there will be substantial
uncertainty in any attempt to extrapolate from pyrolysis data
on a specific compound, either present in or proposed to be
added to tobacco, to what will actually happen to that com-
pound during the smoking of a cigarette.
Since Severson et al. (3616) defined the composition of
the eight chromatographic fractions, the remainder of their
research findings will be discussed in the following section.
XXV.C Individual Tobacco Components
The research conducted from the early 1950s to the mid-
1960s on the organic solvent-soluble precursors in tobacco
of the PAHs in cigarette MSS has been described in detail
by Wynder and Hoffmann [see pp. 345–351, 518 in (4332)]
and Hoffmann and Wynder (1798). Despite the fact that the
tumorigenic PAHs at their levels in cigarette smoke and act-
ing in concert with promoting and/or cocarcinogenic but
nontumorigenic PAHs, phenols, acids, etc., at their levels in
cigarette smoke explain only a small fraction (less than 2%)
of the biological response (measured as % TBA) observed in
skin-painted laboratory animals, efforts to define the major
precursors in tobacco of the tumorigenic PAHs in cigarette
smoke were continued into the late 1970s, particularly by the
USDA group at Athens, Georgia (3616). Despite the advances
during this period in the laboratory techniques for (1)

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 1116 The Chemical Components of Tobacco and Tobacco Smoke

successful fractionation of complex mixtures such as those licorice, cocoa, and other flavorants are added to impart
found in cigarette MSS and in the pyrolysates from various other consumer acceptable organoleptic properties to the
tobaccos, tobacco fractions, and tobacco components and (2) smoke (2341).
the quantitation of the levels of individual identified PAHs,
phenols, aldehydes, ketones, etc., no revolutionary new pre-
cursor in tobacco of PAHs in tobacco smoke was discovered. XXV.C.1  Nicotine
The organic solvent-soluble tobacco components that yielded
Over the years, the results of numerous studies on the
PAHs on pyrolysis were essentially those or structurally sim-
pyrolysis of nicotine have been published. Many of them,
ilar to those that had been proposed several decades earlier in
for example, those of Frank et al. (25A22) and Woodward
the 1950s. Several tobacco components, structurally similar
et al. (4275a, 25A84, 25A85) in the early 1940s, preceded
to those proposed earlier, had not been identified as tobacco
the escalation in the 1950s of the interest in the cigarette
components in the 1950s, but once they were identified, logic
smoke-health issue. Other early studies of nicotine pyrolysis
dictated they would yield PAHs either on pyrolysis or during
in air or nitrogen included those in the early 1960s by Jarboe
the tobacco smoking process. For example, in the late 1950s,
and Rosene (1923a) and Kobashi et al. (25A37, 25A38). In
Wright [(4282), see also Rodgman (3243)] theorized that the
1964, pyrolysis products generated from nicotine during the
high molecular weight terpenes (other than the phytosterols)
tobacco smoking process were summarized by Kuhn (2228).
and the phytosterols themselves were major precursors in
In 1960, Van Duuren et al. (4027) extended their stud-
tobacco of the PAHs in tobacco smoke. These proposals were
ies on tumorigenic PAHs in mainstream CSC to identify
subsequently confirmed. In 1958, Rodgman and Cook (3269,
three tumorigenic N-heterocyclic compounds: the aza-arenes
3291) demonstrated in a “spiking” experiment with solanesol,
dibenz[a,h]acridine, dibenz[a,j]acridine, and 7H-dibenzo
that it was an effective precursor of total and individual
[c,g]-carbazole. Their yields were 0.1, 2.7, and 0.7 ng/ciga-
PAHs in cigarette MSS as indicated by the increased levels
rette, respectively, substantially less than that of the nano-
in the PAHs in the MSS from solanesol-“spiked” tobacco
gram per cigarette yield reported for B[a]P in the early
cigarettes vs. those in the MSS from control tobacco ciga-
1960s. These three N-heterocyclics had also been reported as
rettes. Similarly, Rodgman and Cook reported that results
mouse-skin tumorigens [see tabulation in Hartwell (1544)].
from phytosterol-“spiked” tobacco cigarettes indicated the
Dibenz[a,h]acridine and dibenz[a,j]acridine were also iden-
phytosterol was a major precursor of PAHs in MSS. In 1979,
tified by Van Duuren et al. in pyrolysates from nicotine and
Severson et al. (3616) demonstrated that solanesol pyrolysis
pyridine (750°C, N2).
generated substantial amounts of PAHs vs. other organic sol-
However, the presence of these aza-arenes in tobacco
vent-soluble tobacco components.
smoke or nicotine pyrolysate has been questioned. Of the
In subsequent sections, pyrolysis studies on various tobacco
numerous reports on this class of compound in tobacco
components categorized as follows will be discussed:
smoke, only one report describes the identification of one
of the three, dibenz[a,j]acridine: Wynder and Hoffmann
Nicotine
(4319, 4332) reported that their group, Candeli et al. (587),
Organic solvent-soluble components: long-chained
was able to confirm the presence of dibenz[a,j]acridine but
aliphatic saturated and unsaturated hydrocarbons;
not dibenz[a,h]acridine in mainstream CSC. The per ciga-
terpenoid alcohols such as the duvanediols, phytos-
rette yield for dibenz[a,j]acridine reported by Candeli et al.
terols, phytol, and solanesol; normal long-chained
(587) was almost four times that reported by Van Duuren
aliphatic alcohols; esters of these groups of alcohols
et al. Since 1963, no other investigator has reported these
with long-chained aliphatic acids (palmitic, stearic,
three compounds in tobacco smoke or a nicotine pyrolysate.
oleic, etc.)
In 1970, Kaburaki et al. (2006) reported the results of
Structural components of tobacco (the biopolymers
their pyrolysis of nicotine at various temperatures in air and
such as lignin and the polysaccharides cellulose,
in N2. The two tumorigenic benzacridines reported in a nico-
starch, and pectins and their constituent monosac-
tine pyrolysate by Van Duuren et al. as components of their
charides such as glucose and fructose)
nicotine pyrolysate were not found by Kaburaki et al.
Acids
Schmeltz et al. (3499) described the results of their pyrol-
Proteins and amino acids
ysis of several nitrogenous tobacco components, including
nicotine:
Nicotine (as well as the other nicotine-related alkaloids in
tobacco, usually present in trace amounts) is the one tobacco We could not detect benzo(a)pyrene in nicotine pyrolyzates,
component whose level in tobacco is sometimes controlled nor could we confirm the presence of the physiologically
by removal in a denicotinization process. In contrast to the active dibenzacridines and dibenzcarbazole reported in
removal or reduction of its level in the case of nicotine, mate- tobacco smoke and in nicotine and pyridine pyrolyzates by
rials such as simple sugars, glycerol, and some flavorants are Van Duuren [4027].
added to the tobacco blend to augment their existing levels
in the tobacco and to enhance certain consumer accept- In their review of the pyrogenesis of tobacco smoke com-
able organoleptic properties of the MSS. Materials such as ponents, Chortyk and Schlotzhauer (722) emphasized the

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 Pyrolysis 1117
failures of several investigators to confirm the two dibenzacri-
dines and 7H-dibenzo[c,g]carbazole in nicotine pyrolysates:
Since nicotine is the most abundant and best known tobacco
alkaloid, its pyrolysis has been thoroughly studied [Woodward
et al. (4275a), Jarboe and Rosene (1923a)]. More recent work
[Kaburaki et al. (2006)] on the pyrolysis of nicotine and vari-
ous alkylpyridines has resulted in a proposed mechanism for
the thermal degradation of nicotine … Schmeltz [Schmeltz
et al. (3499)] also studied nicotine and identified a number of
previously unreported compounds in the nicotine pyrolysates
… These included pyrrole, acenaphthene, indole, skatole,
and anthracene and/or phenanthrene. However, the presence
of dibenzacridines and dibenzcarbazole, previously reported
in nicotine and pyridine pyrolysates, could not be confirmed
[Van Duuren et al. (4027)].
In 1977, Schmeltz and Hoffmann (3491) in their review of
N-containing components of tobacco and tobacco smoke dis-
cussed the generation of various pyridines from nicotine dur-
ing both the actual smoking process and pyrolysis. Schmeltz
and Hoffmann (3491) did report the identification by Van
Duuren et al. (4027) of the two dibenzacridines in cigarette
smoke and nicotine pyrolysate. They did not, however, com-
ment on the inability of other investigators (587, 2006, 3499)
to confirm the findings of Van Duuren et al.
In 1979, Schmeltz et al. (3512) reported their major find-
ings from a study of the fate of radiolabeled nicotine during
pyrolysis and during the actual smoking of a radiolabeled
nicotine-treated cigarette:
Under combustion tube pyrolysis conditions, nicotine in
either silica gel matrix (pyrolysis temperature = 600°C,
750°C, or 900°C) or tobacco matrix (600°C) underwent
extensive degradation to pyridines, quinolines, arylnitriles,
and aromatic hydrocarbons.
In a burning cigarette during actual smoking, a substantial
portion of the nicotine (about 41%) remains intact, 12.5% is
oxidized to carbon dioxide, as much as 11% is degraded to
volatile alkylpyridines, and negligible amounts are converted
to neutral or acidic components of the particulate phase.
Dibenz[a,h]acridine and dibenz[a,j]acridine reported nearly
two decades earlier by Van Duuren et al. (4027) were not
identified in this study.
Schmeltz et al. (3512) noted:
In ongoing studies we are now identifying those compounds
that are formed from nicotine only as minor compounds
(<0.1%) which nevertheless can contribute to the toxicity of
the smoke. To this group of minor smoke constituents having
nicotine as a precursor belong the dibenzacridines.
From their experimental results, Schmeltz et al. (3512) con-
cluded: “These results suggest to us that pyrolysis experi-
ments may be of limited value for establishing the fate of
nicotine and possibly other tobacco components in a burning
cigarette.”
The pyrolysis system in this study [see Higman et al.
(1648)] was designed to be the optimum simulation of the
© 2009 by Taylor & Francis Group, LLC
78836_C025.indd 1117
smoking process. Obviously, nicotine did not behave in this
pyrolysis system as it did in the burning cigarette during
actual smoking. Examination of the 1979 Schmeltz et al.
publication on the fate of nicotine during pyrolysis vs. actual
smoking reveals at least two of the authors (Hoffmann and
Schmeltz) definitely changed their opinion on their long-held
view on the equivalence of compound behavior during pyrol-
ysis and actual smoking, for example, Wynder and Hoffmann
(4332) earlier wrote:
Most pyrolysis studies with tobacco, tobacco extracts,
extract fractions, individual components, and tobacco addi-
tives are performed in a nitrogen atmosphere. This proce-
dure has often been criticized on the grounds that many of
the toxic constituents formed during smoking of tobacco
products occur as a result of combustion in air rather than
in a nitrogen atmosphere. This criticism, however, cannot be
maintained in view of studies by Newsome and Keith [2780]
which demonstrated that a reducing rather than an oxidizing
atmosphere exists at the cone region of a burning cigarette.
With regard to the dibenzacridines and dibenzocarbazole
from nicotine during pyrolysis and the smoking process,
Table XXV-4 summarizes the state of knowledge. None of
the investigations conducted from 1963 through 2000 on
the levels of these three aza-arenes in mainstream CSC con-
firmed the 1960 findings of Van Duuren et al. (4027).
Another aspect of the involvement of nicotine (and related
tobacco alkaloids) in the generation of allegedly harm-
ful tobacco and/or smoke components is the formation of
tobacco-specific N-nitrosamines (TSNAs).* It is claimed
by Hoffmann and his co-workers that TSNAs such as
N’-nitrosonornicotine (NNN) and 4-(N-methylnitrosamino)-
1-(3-pyridyl)-1-butanone (NNK) are formed from nicotine
and other minor nicotine-related alkaloids during various
stages of tobacco development and treatment (growing, cur-
ing, and aging) [Hecht et al. (1563, 1564), Adams et al. (22)].
TSNAs appear in cigarette MSS as a result of two mecha-
nisms: (1) direct transfer of the TSNAs from the tobacco to
the smoke, and (2) pyrogenesis during the smoking process.
For example, Hoffmann et al. (1734) and Adams et al. (29)
estimated that 40% to 46% of the NNN in MSS was a result
of its transfer from the tobacco blend. The remainder, 54% to
60%, in MSS was due to pyrogenesis of NNN from nicotine
and nornicotine during the smoking process. Similar data
were generated for NNK: 26% to 37% by direct transfer; 63%
to 74% by pyrogenesis.
The levels in MSS of TSNAs such as NNN can presum-
ably be reduced by reduction in the level of nicotine and/or
nitrate in the tobacco blend (499). However, Brunnemann et
al. (511) have presented contradictory data on the significance
of the correlations among the levels of nitrate, nicotine, and
TSNAs in tobacco.
* TSNAs include N’-nitrosonornicotine (NNN) from nicotine and norni-
cotine, 4-(N-methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) from
nicotine, N’-nitrosoanatabine (NAT) from nicotine and anatabine, and
N’-nitrosoanabasine (NAB) from anabasine.
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 1118 The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-4
Dibenz[a,h]acridine, Dibenz[a,j]Acridine, and 7H-Dibenzo[c,g]Carbazole in Nicotine Pyrolysates (Pyr) and
Mainstream Cigarette Smoke Condensate (CSC)
Dibenz[a,h]Acridine Dibenz[a,j]Acridine 7H-Dibenzo[c,g]Carbazole
Investigators Pyr CSC Pyr CSC Pyr CSC

Van Duuren et al. (4027) yes yes yes yes No yes

Candeli et al. (587), Wynder and Hoffmann (4319, 4332) NE no NE yes NE NE
Kaburaki et al. (2006) no NE no NE NE NE
Schmeltz et al. (3499) no NE no NE No NE
Schmeltz et al. (3512) no no no no No no
Snook (3733) NE no NE no NE no
Snook et al. (3750) NE no NE no NE no
Grimmer et al. (1409) NE no NE no NE no
Kamata et al. (2021) NE no NE no NE NE
Sasaki and Moldoveanu (3414) NE no NE no NE NE
Rustemeier et al. (3370) NE no NE yes NE NE

yes = Compound identified.

no = Compound not found or identified.
NE = Substrate not examined for compound in question.

Since the TSNAs are components of the MSS particulate
phase, control of their levels in smoke is also possible by any
means that controls the yield of the MSS particulate matter.
These include:
• Use of reconstituted tobacco sheet;
• Expanded tobacco;
• High filtration efficiency;
• Air dilution by increased paper porosity and/or
ventilated filter tips (Hoffmann et al., 1984).
Unlike the volatile N-nitrosamines such as dimethylnitro-
samine (DMNA), the TSNAs are not amenable to selective
filtration by use of plasticized filter tips.
XXV.C.2 Organic Solvent-Soluble Components
(Long-Chained Aliphatic Hydrocarbons,
Phytosterols, Solanesol, High
Molecular Weight Esters, etc.)
The tobacco smoke components “known” in 1954 numbered
fewer than 100 (2170). At that time, the chemical composi-
tion of tobacco was as equally ill-defined as that of its smoke.
Pyrolyses conducted throughout the 1950s involved the
organic solvent-soluble material from tobacco and were lim-
ited either to the total extractables or to a few classes of known
tobacco components, for example, phytosterols and long-
chained saturated aliphatic hydrocarbons. These relatively
high molecular weight compounds were present in tobacco at
levels usually exceeding 0.5% and presented little problem in
collecting sufficient material for study. Subsequent research
on tobacco (and tobacco smoke) composition resulted in the
isolation and elucidation of the structures of numerous classes
of organic solvent-soluble compounds, including those listed
in Table XXV-5.
The early work of Roffo (3327) on the reduction of tumori-
genicity of a “destructive distillate” from a solvent-extracted
tobacco (ethyl alcohol), his claim that alcohol extraction
removed the tumorigen precursor from the tobacco, and his
proposal of the phytosterols as the tumorigen precursor(s)
were described previously. Despite the fact that the “destruc-
tive distillate” from tobacco was not equivalent to cigarette
smoke particulate matter, the proposal of the phytosterols as
precursors in tobacco of PAHs was based on sound reasoning
and previous experimental findings. Nearly two decades ear-
lier, Kennaway (2073–2075) had demonstrated that pyrolysis
of isoprene, acetylene, and cholesterol yielded pyrolysates
tumorigenic to mouse skin. Cholesterol was once considered
unique to animal tissue but subsequently, trace amounts were
found in plant tissue, including tobacco [Stedman (3797),
Grunwald et al. (1434)]. Of the tobacco and tobacco smoke
sterols, the two present at the highest level are stigmasterol
and β-sitosterol. These differ from each other and cholesterol
in the structure and configuration of the side chain on the
cyclopentane ring. They occur in tobacco as free phytosterols
and phytosteryl derivatives (esters, glycosides). Pyrolysis of
sterols generates high levels of chrysene. Its four rings are
configurationally similar to that of the sterol ring system.
In the mid-1920s, Kennaway and others were concerned
about the fate of cholesterol when animal tissue was heated
during roasting and broiling. Cholesterol pyrolysis experi-
ments were crude attempts to duplicate what happened to
it during the cooking process. Here again, the presence of
other tissue components (amino acids, proteins, lipids, and
carbohydrates) with cholesterol during cooking would cer-
tainly have affected the results when compared to the results
obtained from pyrolysis of cholesterol alone.
In 1928, Kennaway and Sampson (2080) also demon-
strated that the specific tumorigenicities of pyrolysates from
cholesterol and other organic compounds increased as the

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 Pyrolysis 1119
Table XXV-5
Organic Solvent-Soluble Components of Tobacco Identified Post-1955
Compound Reported in Tobacco by
Solanesol Rowland et al. (3359)
Neophytadiene Rowland (3345)
α-Tocopherol Rowland (3347)
Squalene Fredrickson (1229)
Solanesenes — Rodgman et al. (3297)
Solanesyl esters Rowland and Latimer (3358)
Phytosteryl esters Rowland and Latimer (3358)
Long-chained aliphatic alcohols Cook et al. (812)
Long-chained aliphatic esters Rodgman et al. (3294),
Arrendale et al. (103)
Duvanediols Roberts (3195), Roberts and Rowland (3220, 3221),
Rowland and Roberts (3360),
Rowland et al. (3361)
Phytyl esters Severson et al. (3616)
Wynder and Wright (4354) reported geraniol as a cigarette smoke constituent. However, the infrared spectrum of the isolate was identical with that
a
of solanesol, not geraniol (Wright, private communication to Rodgman).
pyrolysis temperature was increased. This observation was
later confirmed with saturated aliphatic hydrocarbons (2257)
and phytosterols [Wynder et al. (4355, 4356)] isolated from
tobacco. In the latter two studies, the yield of PAHs gener-
ated during pyrolysis of the compounds in question increased
as the pyrolysis temperature increased. Wynder et al. (4355)
and Wynder and Hoffmann (4332) reported that pyrolyses
of a hexane extract of tobacco gave decreasing yields of
pyrolysate “tar” as the pyrolysis temperature increased:
560°C, 50%; 640°C, 35%; 720°C, 32%; 800°C, 28%; and
880°C, 28%. They also reported that pyrolysis at 880°C of
the hexane extractables in air vs. their pyrolysis in N2 gave
pyrolysates whose yields were essentially the same (30% in
air vs. 28% in N2) and whose specific tumorigenicities were
comparable in skin-painting studies with the mouse and
rabbit. Similar findings were reported for aliphatic tobacco
hydrocarbons pyrolyzed either in air or in N2 at 800°C with
regard to PAH composition and specific tumorigenicity in
skin-painting studies.
Table XXV-6, adapted from Lam (2257), demonstrates the
relationship between PAH generation and pyrolysis tempera-
ture for aliphatic tobacco hydrocarbons pyrolyzed in air at sev-
eral temperatures. Calculation of the yield ratios [PAH, mg/g:
B[a]P, mg/g] of the other PAHs vs. B[a]P reveals significant
information: In this case of pyrolysis, there was no consistency
between the change in ratios of PAH/B[a]P as the temperature
was increased from 700°C to 800°C, for example, in the case
of the tetracyclic PAHs, the PAH/B[a]P ratio decreased for
pyrene and chrysene but increased for fluoranthene; for the
pentacyclic PAHs, the ratio decreased for both perylene and
B[e]P; for the hexacyclic PAH dibenzo[def,mno]chrysene, the
ratio increased. These same trends existed whether PAH/B[a]
© 2009 by Taylor & Francis Group, LLC
78836_C025.indd 1119
Reported in Tobacco Smoke By
Mold and Booth (2590),
Wynder and Wright (4354)a,
Rodgman and Cook (3270)
Rodgman (3247)
Rodgman and Cook (3271)
Van Duuren and Schmitt (4033), Rodgman et al. (3297)
Rodgman and Cook (3270),
Rodgman et al. (3296)
Rodgman et al. (3296)
Cook et al. (812)
Rodgman et al. (3294)
Rowland et al. (3361)
Rodgman and Cook (3287)
P ratios were calculated as molar yields or, as in Table XXV-6,
as absolute quantities (micrograms of PAHs generated per
gram of aliphatic tobacco hydrocarbons pyrolyzed).
The significance of these data and calculations is their
demonstration in 1956 that in even the simplest pyrolysis sit-
uation, B[a]P is not a valid “indicator” for the PAHs with four
or more rings and their supposed relationship to tumorigenic
activity [Wynder and Hoffmann (4317, 4319, 4332)]. In addi-
tion to these data by Lam, other contrary data that demon-
strated the invalidity of the concept of B[a]P as an “indicator”
for PAHs with four or more rings and the tumorigenicity of
the substrate (CSC, pyrolysate) containing them were gen-
erated not only by Wynder et al. (4355, 4356) but also by
Campbell and Lindsey (583), Rodgman and Cook (3286),
Gori (1329, 1330, 1332, 1333), National Cancer Institute
(2685), and Severson et al. (3616).
The lack of correlation between CSC content of B[a]P
and specific tumorigenicity was demonstrated by Lazar et al.
(2320), who reported that a 30-fold increase in B[a]P content
by its addition to CSC produced no increase in the specific
tumorigenicity to mouse skin of the B[a]P-enhanced CSC vs.
the control CSC applied at equal dose levels. This lack of cor-
relation between the B[a]P concentration in CSC and its spe-
cific tumorigenicity was also recognized by the U.S. Surgeon
General, who wrote in 1981 [see p. 36 in (4009)]:
The contribution of BaP or PAH in general to mouse skin
carcinogenesis by cigarette smoke condensate cannot be
fully measured at this time. Wynder and Hoffmann [4332]
found a correlation between BaP levels and carcinogenic
activity of smoke condensates from several types of ciga-
rettes. A much larger series of experimental cigarettes was
studied in the smoking and health program of the National
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 1120 The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-6
Polycyclic Aromatic Hydrocarbons from Aliphatic Tobacco Hydrocarbons Pyrolyzed in Air at Various
Temperatures
Quantity (µg) of PAH Formed on Pyrolysis (in air) of Aliphatic Tobacco Hydrocarbons (1.0 gram)

Polycyclic Aromatic At 800°C At 700°C At 600°C

Hydrocarbon PAH, µg/g PAH/B[a]Pa PAH, µg/g PAH/B[a]Pa PAH, µg/g

Naphthalene 14260 41.94 [2/5]b 4760 158.7 0

Acenaphthene 0 0 [3/5]c 0 0 0
Acenaphthylene 3520 10.35 [3/5]c 480 16.00 0
Phenanthrene 3840 11.29 [3/5]c 580 19.33 0
Anthracene 580 1.71 [3/5]c 110 3.67 0
Pyrene 960 2.82 [4/5]d 320 10.67 0
Fluoranthene 1700 5.00 [4/5]d 24 0.80 0
Chrysene 400 1.18 [4/5]d 86 2.87 0
Perylene 34 0.10 [5/5]e 4 0.13 0
Benzo[a]pyrene 340 1.00 30 1.00 0
Benzo[e]pyrene 400 1.18 [5/5]e 80 2.67 0
Dibenzo[def,mno]chrysene 42 0.12 [6/5]f <1 <0.03 0
Totals 26076 86.87 6474 21.47 0
a B[a]P = benzo[a]pyrene b [2/5] = bicyclic/pentacyclic B[a]P
c [3/5] = tricyclic/pentacyclic B[a]P d [4/5] = tetracyclic/pentacyclic B[a]P
e [5/5] = pentacyclic/pentacyclic B[a]P f [6/5] = hexacyclic/pentacyclic B[a]P

Cancer Institute. No significant dependence of carcinogenic
potency on BaP content was observed [Gori (1329, 1330,
1332, 1333), National Cancer Institute (2683].
The post-1930 stimulus for PAH research was provided by
the following events: the independent syntheses of DB[a,h]A
in 1929 by Clar (760) and Fieser and Dietz (1184); the demon-
stration of its mouse-skin tumorigenicity by Kennaway and
Hieger (2078); the early 1930s reports by Cook et al. (726,
727) on several PAH isolates from coal tar, known to be tum-
origenic to the skin of mice and rabbits; identification of two
coal tar isolates as B[a]P and B[a]A; and the demonstration
of the tumorigenicity to mouse skin of B[a]P (194, 726).
In addition to Kennaway and Sampson (2080), numer-
ous investigators after 1932–1933 examined the pyrolysates
from sterols in conjunction not only with the alleged tum-
origenicity and PAH content of “destructive distillates” from
tobacco, CSCs, and pyrolysates of tobacco, tobacco extract-
ables, and individual tobacco components but also with the
alleged tumorigenicity and PAH content of heated foodstuffs
and their role in digestive tract cancer. For example, Roffo,
in addition to his tumorigenicity studies with “destructive
distillates” from various tobaccos types (3320, 3324, 25A51)
and organic solvent-extracted tobaccos (3327), investigated
the tumorigenicity of heated or oxidized fats (25A53, 25A55,
25A59) and the “tars” and phenanthrene derivatives from
cholesterol pyrolyzed (25A56, 25A57, 25A58) or irradiated
in air (25A54).
Other investigators who examined the chemical and bio-
logical properties of cholesterol pyrolysates included Steiner
et al. (25A69), Falk et al. (1171), and Bischoff and Rupp
(25A10). Previously, Veldstra (4042a) had demonstrated that
3,5-cholestadiene, produced pyrolytically from choles-
terol, was tumorigenic to skin-painted laboratory animals.
Subsequently, cholesten-4-one was found to be both tumori-
genic to mouse skin and a component of the pyrolysate from
cholesterol and/or its derivatives. These and other pyrolysate
findings on composition (PAHs in the pyrolysate) and prop-
erties (tumorigenicity of pyrolysate and/or the components
of pyrolysates generated from cholesterol or its natural-
occurring derivatives) were summarized by Rodgman
(3233, 3242). Although the pentacyclic PAH 1,2-dihydro-3-
methylbenz[j]aceanthrylene (previously known as 3-methyl-
cholanthrene or 20-methylcholanthrene), a potent mouse-skin
tumorigen, may be prepared by a series of chemical reactions
from a sterol-derived compound structurally related to cho-
lesterol, it has never been identified in a sterol pyrolysate.
Although Kröller (2191) claimed the identification of 1,2-di-
hydro-3-methylbenz[j]aceanthrylene (3-methylcholanthrene)
in mainstream CSC, his identification of it was questioned
by Wynder and Hoffmann (4332), who asserted that it and
other alkylated PAHs had never been reported as a combus-
tion or pyrolysis product. Wynder and Hoffmann (4332) also
questioned the reports by Pietzsch (2962) and Kröller (2191)
of the presence in CSC of the methylated PAH DMB[a]
A. It and other methylated PAHs in mainstream CSC were
reported in 1960 by Rodgman and Cook (3273). In addition,
in 1963 Grossman et al. (1431, 1432) reported alkylated naph-
thalenes in the pyrolysate from solanesol, a major tobacco
component. In the 1970s, Snook et al. reported not only sev-
eral dimethylbenz[a]anthracenes in CSC (3756) but also a
great number of alkylated PAHs in CSC (3757). Thus, the

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 Pyrolysis 1121
Table XXV-7
Total, Free, and Bound Sterols in Cigarette Tobacco
Total
Free, µg/g Bound, µg/g
Sterol Tobacco µg/g Tobacco Tobacco
Stigmasterol 326 262 588
β-Sitosterol 185 366 551
Campesterol 129 173 302
Cholesterol 79 86 165
Total 719 887 1,606
Wynder-Hoffmann assertion about the presence of alkylated
PAHs in MSS was incorrect.
Campesterol, stigmasterol, β-sitosterol, and cholesterol
have been identified both free and/or bound (as esters, etc.) in
tobacco and CSC [see Grunwald et al. (1434) for a summary of
the early research on tobacco sterols and their derivatives]. In
their study, Grunwald et al. found that these four sterols con-
stituted about 0.16% of the tobacco weight and about 15% of
them were transferred to MSS. According to Grunwald et al.,
the remainder of the sterols were “lost in the smoke side-
stream, pyrolyzed during the smoking process and/or depos-
ited in the butt.” Thus, a cigarette containing 1.0 g of the
tobacco studied by Grunwald et al. would contain 1600 µg of
these sterols and deliver about 240 µg to MSS. About 82 µg
of the 240 µg would be β-sitosterol, a compound reported to
be anticarcinogenic to several N-nitrosamines [Wattenberg
(4149a)} and PAHs [Yasukawa et al. (25A86)]. Table XXV-7,
adapted from Grunwald et al. (1434), indicates the relative
proportions of these four sterols in tobacco: cholesterol is the
least plentiful of the four tobacco sterols in Table XXV-7.
Except for minor differences in the side-chain structure,
the cholesteryl oleate studied by Veldstra (4042a) is struc-
turally similar to the phytosteryl ester fraction isolated from
tobacco by Rowland and Latimer (3358) and from CSC by
Rodgman et al. (3296). It was subsequently identified as a
mixture of esters of stigmasterol and β-sitosterol with long-
chained saturated (palmitic, stearic) and unsaturated (oleic,
linoleic) acids. In the late 1950s to the early 1960s, Rodgman
and Cook were unsuccessful in their CSC study to identify
the stigmasterol- or β-sitosterol-derived dienes or ketones
corresponding to the tumorigenic 3,5-cholestadiene and
cholesten-4-one generated during pyrolysis of cholesterol or
its esters. However, Benner et al. (273) subsequently identi-
fied 3,5-campestadiene (VIb) and 3,5-stigmastadiene (VId]
in tobacco smoke, [see Eatough et al. (1099, 1100)]. The fol-
lowing paragraphs summarize the relationships, both known
and proposed, between a sterol such as cholesterol and its
various pyrolysis products.
Because of the results of the studies by Kennaway (2073–
2076), Kennaway and Sampson (2080), and Roffo (25A56,
25A57, 25A58) on the generation of tumorigenic pyrolysates
from cholesterol or cholesterol-containing foodstuffs, the
© 2009 by Taylor & Francis Group, LLC
78836_C025.indd 1121
question was raised: What is the relationship between these
observations on tumorigenic cholesterol pyrolysates and the
incidence of stomach and digestive tract cancers? When many
studies, beginning in 1934 [see summary in Hartwell (1544)],
revealed that 1,2-dihydro-3-methylbenz[j]aceanthrylene
(3-methylcholanthrene) was a potent tumorigen equivalent
%
in potency in mouse skin-painting bioassays to B[a]P and
37 DB[a,h]A, extensive research was conducted in attempts to
34 determine whether it was generated from cholesterol dur-
19 ing various cooking processes. Examination of the entries
10
in the catalogs by Hartwell (1544) and Shubik and Hartwell
100 (3664) for the four PAHs considered to be potent tumorigens
revealed 474 studies involving 1,2-dihydro-3-methylbenz[j]
aceanthrylene (3-methyl-cholanthrene) between 1934 and
1953, 410 studies involving B[a]P between 1932 and 1953,
275 studies involving DB[a,h]A between 1930 and 1953, and
91 studies involving DMB[a]A between 1938 and 1953.
One of the most potent PAHs in mouse skin-tumor induction
is 1,2-dihydro-3-methylbenz[j]aceanthrylene (3-methylcholan-
threne) which theoretically could be formed pyrogeneti-
cally from sterols such as cholesterol {Ia}. In addition to the
trace level of cholesterol present in tobacco, tobacco usually
contains substantial levels of several phytosterols [campes-
terol {Ib}, β-sitosterol {Ic}, stigmasterol {Id}, and ergosterol
{Ie}] structurally similar to cholesterol. These phytosterols
differ from cholesterol {Ia} in the structure of the long side
chain. Stigmasterol {Id} is structurally similar to β-sitosterol
{Ic} except for a double bond at the C22 carbon. The legend
to Figure XXV-1 indicates the differences among cholesterol,
campesterol, β-sitosterol, ergosterol, and stigmasterol. These
sterols, present in tobacco in both the free and bound form (as
glycosides and esters), are transferred intact to MSS.
These sterols constitute about 0.2% of the tobacco weight.
Table XXV-7 illustrates the relative proportions of these
sterols in tobacco. These data indicate that cholesterol and
cholesteryl derivatives are the least plentiful of the free and
bound sterols in tobacco. These levels are similar to those of
the standard and reference cigarettes in the National Cancer
Institute (NCI) “Less Hazardous” Program (1329, 1330, 1332
1333, 2683).
As shown in Figure XXV-1, pyrolysis of cholesterol
{Ia} yields chrysene {III} and a Diels’ hydrocarbon {IV}, a
methylcyclopentaphenanthrene. Both PAHs have also been
isolated from pyrolysates of the major tobacco phytosterols.
While cholesterol {Ia} and the tobacco phytosterols [campes-
terol {Ib}, β-sitosterol {Ic}, and stigmasterol {Id}] have not
been shown to generate 3-methylcholanthrene {II} on pyrol-
ysis, cholesterol {Ia} and its esters with long-chained acids
do generate the mouse-skin tumorigens 4-cholesten-3-one
{Va} and 3,5-cholestadiene {VIa} (1171). Veldstra (4042a)
reported that the pyrolysis of cholesteryl oleate also yielded
3,5-cholestadiene {VIa}. Cholesteryl oleate was probably a
component of the mixture of steryl esters described in flue-
cured tobacco by Rowland and Latimer (3358) and in tobacco
smoke by Rodgman et al. (3296). The steryl esters included
sterols esterified with a series of saturated (palmitic, stearic,
etc.) and unsaturated (oleic, linoleic, etc.) acids.
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 1122 The Chemical Components of Tobacco and Tobacco Smoke

R
CH3 CH3
CH3

CH3

H3C
O
IV R V R
CH3
CH3 CH3
CH3 CH3

CH3 CH3

HO
II I VI

III

LEGEND

Sterol, R=

Ia cholesterol -(CH2)3-CH(CH3)2
Ib campesterol -(CH2)2-CH(CH3)-CH(CH3)2
Ic β-sitosterol -(CH2)2-CH(C2H5)-CH(CH3)2
Id stigmasterol -CH=CH-CH(C2H5)-CH(CH3)2
Ie ergosterola -CH=CH-CH(CH3)-CH(CH3)2

II 1,2-dihydro-3-methylbenz[j]aceanthrylene
(3-methylcholanthrene)

III chrysene IV Diels´ hydrocarbon

Va 4-cholesten-3-one VIa 3,5-cholestadiene

Vb 4-campesten-3-one VIb 3,5-campestadiene
Vc β-4-sitosten-3-one VIc β-3,5-sitostadiene
Vd stigmasten-3-one VId 3,5-stigmastadiene
Ve ergostadien-3-one VIe 3,5,7-ergostatriene
a Ergosterol has a double bond at the 7-position

Figure XXV-1  Possible sterol degradation products.

In the late 1950s, Rodgman proposed that on thermal
degradation during the smoking process, campesterol, stig-
masterol, and β-sitosterol and their esters might generate the
ketones {Vb, Vc, Vd} and dienes {VIb, VIc, VId} analogous
to 4-cholesten-3-one {Va} and 5-cholestadiene {VIa} and
they might also be mouse-skin tumorigens like their choles-
terol counterparts.
Several PAHs other than chrysene and Diels′ hydrocarbon
(Figure XXV-1) were subsequently identified in sterol
pyrolysates. In 1959, Wynder et al. (4355, 4356) reported that
PAHs were generated at both temperatures when tobacco
sterols were pyrolyzed in air at 720°C and 850°C. At these
temperatures, the pyrolysates constituted 28% and 22%,
respectively, of the phytosterols pyrolyzed; B[a]P constituted
0.1% and 1.0%, respectively, of the pyrolysates. These results
with phytosterols pyrolyzed at two different temperatures
are similar to those reported for the pyrolyses of aliphatic
tobacco hydrocarbons (2255–2258).
In 1962, Van Duuren (4022) described the identification of
pyrene and B[a]P in a stigmasterol pyrolysate. Badger et al.
(142) in their pyrolysis study of tobacco phytosterols reported
the identification of some thirty PAHs, all previously reported
as CSC components. They also noted the accentuated produc-
tion of chrysene vs. its generation by pyrolysis of aliphatic
tobacco hydrocarbons. Chrysene, reported to be tumorigenic
to mouse skin, is a sterol pyrolysis product characteristically
generated at a high level compared to that for other PAHs
in the pyrolysate. The four-ring arrangement in chrysene is

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 Pyrolysis 1123
similar to that of the sterol rings. The International Agency
for Research on Cancer (IARC) eventually removed chrysene
from the tumorigen list.
From a precursor “spiking” experiment involving addition
to tobacco of aliphatic tobacco hydrocarbons, a phytosterol
(β-sitosterol), or solanesol, it was noted that the increase in the
chrysene yield in the CSC was much more pronounced with
phytosterol-treated tobacco than with aliphatic hydrocarbon-
or solanesol-treated tobacco (3251, 3269, 3291). Doubling the
levels of solanesol, aliphatic tobacco hydrocarbons, and phyto-
sterols by addition of each to a control tobacco blend resulted in
increases in the B[a]P yields in the mainstream CSCs of 13%,
13%, and 16%, respectively. However, the chrysene yields were
increased by 16%, 28%, and 183%, respectively. Tripling the
addition levels increased the B[a]P levels in the mainstream
CSCs by 18%, 20%, and 28%, respectively, and the chrysene
levels by 22%, 50%, and 239%, respectively.
In their study of the petroleum ether-extractable material
(8% of tobacco weight) from tobacco which was chromato-
graphically separated into eight fractions (see Table XXV-8),
Severson et al. (3616) identified PAHs in the pyrolysates from
fractions F-2 and F-3 (containing phytosterol derivatives) and
from fractions F-5 and F-6 (containing unbound phytoster-
ols). Their PAH data for these four pyrolysates from phytos-
terol-rich tobacco fractions showed high yields of chrysene
vs. those in the pyrolysates from the essentially phytosterol-
free fractions (F-1, F-2, F-7, and F-8).
Although their study dealt with pyrolysis of tobacco phy-
tosterols, Schmeltz et al. (3511) did determine the percent
conversion of phytosterols (and other components) to MSS
PAHs by use of radiolabeled phytosterols generated by grow-
ing tobacco in an atmosphere containing radiolabeled CO2,
isolating radiolabeled tobacco components, and adding them
individually to cigarettes which were then smoked and the
MSS analyzed. Their data are summarized in Table XXV-9.
Their 1978 finding with radiolabel techniques (<1% conver-
sion to PAHs) for the tobacco phytosterols is comparable to
Table XXV-8
Component Distribution in Eight Subfractions
from a Petroleum Ether Extract of Tobacco
(8% of Tobacco Weight)
Chromatographic
Fraction
No. % Major Component(s)
F-1 5.3 Long-chained saturated hydrocarbons,
neophytadiene
F-2 4.3 Esters of sterols and terpenoid alcohols
F-3 8.9 Esters of sterols and solanesol
F-4 29.2 Solanesol
F-5 6.6 Solanesol, sterols, and long-chained fatty acids
F-6 20.3 Sterols and long-chained fatty acids
F-7 15.8 Polar esters of fatty acids
F-8 9.6 Polar esters of fatty acids
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78836_C025.indd 1123
Table XXV-9
Conversion of Tobacco Leaf Constituents
to Total Mainstream Smoke Polycyclic
Aromatic Hydrocarbons
Leaf Constituent % Conversion to Mainstream PAHs
Phytosterols <1.0
Palmitic acid <1.0
Neophytadiene 0.10
Polar fraction 0.15
Alkaloids 0.10
the 1958 data of Rodgman and Cook (3269, 3291) who, using
classical chemical techniques in a “spiking” experiment,
reported the conversion of β-sitosterol to PAHs to be about
0.6%.
As noted by Wynder and Hoffmann (4319, 4332), the first
group of tobacco components studied by pyrolysis was the
“tobacco paraffins.” Subsequently, these were shown to con-
sist of a mixture of n- (normal), iso- (2-methyl-), and anteiso-
(3-methyl-) saturated hydrocarbons CnH2n+2, the bulk of
which comprised hydrocarbons ranging from ten or twelve
to more than forty carbon atoms. These hydrocarbons were
also extractable from tobacco by pentane, hexane, or petro-
leum ether. Pyrolysis studies in air or an inert atmosphere
(N2, He) with either the tobacco-derived saturated aliphatic
hydrocarbon fraction or individual components of the frac-
tion [see Lam (2255, 2256, 25A39), Wynder et al. (4356)] or
individual hydrocarbons [see Lam et al. (2260) for n-pen-
tacosane, Haefele and Giles (1480) for n-hentriacontane,
Badger and Novotny (151) for n-decane, Badger et al. (142)
and Lam (2256) for n-dotriacontane (dicetyl)] indicated that
these tobacco components yielded pyrolysates reported to be
tumorigenic in mouse skin-painting bioassays and to contain
many PAHs, several of which were tumorigenic in long-term
mouse skin-painting bioassays.
The PAHs identified in the various pyrolysates ranged in
complexity from bicyclic (naphthalenes), tricyclic (acenaph-
thenes, anthracenes, phenanthrenes), tetracyclic (pyrenes, fluo-
ranthenes, chrysenes, benzanthracenes), pentacyclic (perylenes,
benzopyrenes, dibenzanthracenes, benzofluoranthenes), hexacy-
clic (dibenzochrysenes), and heptacyclic (coronene). Eventually,
all the PAHs identified in the various pyrolysates were identified
in mainstream CSC. In every case where the pyrolysis tempera-
ture was lowered, the yields of the PAHs in the pyrolysate also
decreased (see Table XXV-6).
From data they generated, Rayburn and Wartman (3091)
and Rayburn et al. (3092) challenged the concept that the satu-
rated aliphatic hydrocarbons in tobacco were precursors of the
PAHs in mainstream CSC. Wynder and Hoffmann (4319, 4332),
in turn, criticized the experimental procedures that provided
the data upon which Rayburn et al. based their argument:
The experimental findings (of Rayburn et al.) are partially
based on total polycyclic hydrocarbons of similar ultraviolet
11/13/08 5:56:27 PM
 1124 The Chemical Components of Tobacco and Tobacco Smoke
spectra and not on analytical data. The report did not men-
tion counting techniques for C14-labeled paraffins nor their
quenching effects. These, as well as other factors, appear
to weaken considerably the challenge of a concept based on
extensive experimental data.
In 1979, Severson et al. (3616), in their study of the petro-
leum ether extractables (8% of tobacco weight) chromato-
graphically separated into eight fractions (see Table XXV-8),
reported the identification of PAHs in the pyrolysate from
fraction F-1, the fraction containing the saturated aliphatic
hydrocarbons extracted from the tobacco.
As recently as 1985, Lam et al. (2260) identified numerous
PAHs in the pyrolysate from n-pentacosane, a known compo-
nent of the saturated aliphatic hydrocarbon fraction present
in tobaccos.
In 1958, Rodgman and Cook (3269, 3291) added tobacco-
derived saturated aliphatic hydrocarbons to a tobacco blend
in a “spiking” experiment and determined the effect of
the addition on the PAH levels in mainstream CSC. They
reported the added saturated hydrocarbons increased the
yield of PAHs in cigarette MSS and thus were precursors of
the smoke PAHs.
The structure of the unsaturated C45 polyisoprenoid alco-
hol, solanesol, was established in 1956 by Rowland et al.
(3359). Despite the fact that solanesol was one of the major
individual components of the extractable waxes from tobacco,
its pyrolysis was not reported until 1962. While Lam (2255)
favored the saturated hydrocarbons as the major precursors
in tobacco of PAHs in smoke, Wynder (4294) considered
both the saturated hydrocarbons and the phytosterols to be
the major precursors. Wright (4282) proposed that the phy-
tosterols and other terpenoids such as solanesol were the
major precursors in tobacco of PAHs in smoke. In spite of
their differences of opinion on the relative importance of
these tobacco components in their contribution to smoke
PAHs, they collaborated on several studies in the late 1950s
(4355, 4356). Subsequently, the saturated hydrocarbons, the
phytosterols, and other terpenoids such as solanesol were
shown to be important in the formation of PAHs in tobacco
smoke (3251, 3269, 3291, 3616).
In the early 1960s, Grossman et al. (1431, 1432) examined
the pyrolysate from solanesol and reported the identifica-
tion of monocyclic hydrocarbons (benzene and cyclopen-
tene derivatives) (1431) and bicyclic aromatic hydrocarbons
(naphthalenes) (1432). No tricyclic PAHs were reported. In
1963, Gil-Av and Shabtai (1286) postulated that solanesol in
tobacco was a source of tobacco smoke PAHs and proposed
a mechanism for their generation from solanesol. Solanesol
and other similarly configured terpenoid compounds, for
example, neophytadiene, squalene, and duvane derivatives,
depolymerized during the smoking (or pyrolytic) process
to produce isoprene which, in turn, reacted with itself and
subsequent reaction products to generate a tumorigenic
“tar” such as that described in the mid-1920s by Kennaway
(2073–2075). This “tar” derived from solanesol via isoprene
would contain the requisite tumorigenic PAHs such as B[a]P.
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78836_C025.indd 1124
Although Gil-Av and Shabtai (1286) demonstrated the pres-
ence of B[a]P in an isoprene pyrolysate, they did not study
the pyrolysis of solanesol.
Severson et al. (3616) described the pyrogenesis of PAHs
from solanesol in their study of the petroleum ether tobacco
extractables (8% of tobacco weight) which they chromato-
graphically separated into eight fractions (see Table XXV-8).
Fraction F-4 was primarily solanesol. Fraction F-3 contained
solanesyl esters. Severson et al. (3616) summarized the contri-
bution of solanesol to PAHs in its pyrolysate (and in CSC):
The carotenoids and solanesol are most like responsible for
the high levels of the multialkylated PAH found in the [petro-
leum ether]-extract pyrolyzate and, by analogy, in CSC.
Because of its relative abundance in leaf, solanesol may con-
tribute as much as 40% of the benzopyrenes produced on
pyrolysis of the [petroleum ether] extract of tobacco.
As noted previously, 1958 precursor experiments (3251,
3269, 3291), in which solanesol was added at several levels
in a “spiking” experiment and the effect of this addition on
the levels of total and individual PAHs in cigarette MSS
were determined, demonstrated that solanesol in tobacco was
indeed a precursor of PAHs in cigarette MSS.
Phytol, a terpenoid alcohol, is a known component of
tobacco leaf. It and its structurally similar dehydration product,
neophytadiene, probably occur in tobacco leaf through the
degradation of chlorophyll whose structure includes phytol
(3345). Neophytadiene (3247), phytol (3285), and phytyl
esters (3287) are present in tobacco smoke (see Table XXV-5).
Schmeltz et al. (3511), in their 1978 radiolabel study, deter-
mined the contribution of neophytadiene to PAHs in cigarette
MSS. They estimated that about 0.1% of the tobacco neophyta-
diene is converted during the smoking process to PAHs in the
MSS (see Table XXV-9). The pyrolysis products of neophyta-
diene and phytol were examined in 1985 by Lam et al. (2260).
Numerous PAHs were identified in both pyrolysates.
Normal long-chained aliphatic alcohols, known minor
components of tobacco (614, 615, 25A18, 25A80) and tobacco
smoke (812), may not play a significant role as PAH precur-
sors. In fact, Carruthers and Johnstone (614, 615), who iden-
tified 1-docosanol in tobacco, found little of its dehydration
product, 1-docosene, in tobacco smoke. They postulated that
long-chained primary alcohols such as 1-docosanol were lit-
tle affected by pyrolysis. Severson et al. (3616) cataloged the
major components in eight chromatographic fractions of the
petroleum ether extractables from tobacco (see Table XXV-8).
Each fraction was subjected to pyrolysis. Surprisingly,
Severson et al. did not list long-chained primary alcohols in
any of the eight chromatographic fractions!
XXV.C.3 Structural Components of Tobacco
(Cellulose, Lignin, Pectins, etc.)
Since cellulose, the pectins, starch, lignin, and proteins—
the so-called structural components of tobacco—are organic
compounds, that is, contain carbon, with one or more of the
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 Pyrolysis 1125

Table XXV-10
Polycyclic Aromatic Hydrocarbons from Tobacco Components Pyrolyzed in a N2 Atmosphere at 650°C
Quantity (ng) of PAH Formed on Pyrolysis of Tobacco Componenta (1.0 mg) at 650°C (in N2)
PAHb Cell Lign Pect Star Sucr Gluc Fruc Mal Citr Oxal

Acenaphthylene 1.60 0.80 0.20 0.56 0.24 0.27 1.04 0.16 0.50 0.15
Fluorene 5.84 80.00 2.87 0.32 0.12 0.07 1.18 6.32 1.73 0.03
Anthracene 3.37 5.44 5.39 1.04 0.70 0.36 1.39 0.70 0.98 0.30
Pyrene 1.29 0.33 1.33 0.35 0.24 0.66 0.35 1.66 0.24 0.20
Pyrene, 3-methyl- 1.31 0 0.29 0.11 0.15 0.01 0.11 1.19 0.89 0.01
Fluoranthene 1.64 0.58 1.52 0.94 0.35 0.45 1.06 1.36 0.06 0
Benz[a]anthracenec 1.86 0.44 2.73 1.16 0.41 0.43 1.20 1.30 0.05 0
Benzo[a]pyrenec 0.78 0.47 0.45 0.17 0.10 0.29 0.33 0.35 0.17 0.01
Benzo[e]pyrenec 0.85 0.22 0.34 0.04 0.02 0.11 0.02 0.08 0.37 0
Dibenzo[def,mno]chrysene 0.10 0 0.09 0.01 0 0.05 0.05 0.01 0.02 0.003
Coronene 0.44 0 0.15 0.03 0.03 0.01 0.05 0.06 0.11 0.02
a Cell = cellulose; Lign = lignin; Pect = pectin; Star = starch; Sucr = sucrose; Gluc = glucose; Fruc = fructose; Mal = malic acid; Citr = citric acid;
Oxal = oxalic acid.
b Several other PAHs were found in some, but not all, of the pyrolysates, namely, azulene, naphthalene, alkylnaphthalenes, acenaphthene, phenanthrene,
and perylene.
c Tumorigenic to mouse skin in skin-painting studies.

carbons linked to hydrogen,* they will generate PAHs dur-
ing high-temperature pyrolysis much in the same manner as
the compounds studied in the mid-1920s and early 1930s by
Kennaway (2073–2076). In his studies, Kennaway demon-
strated that pyrolysis of various organic compounds—from
simple ones such as acetylene or isoprene to more complex
ones—would generate pyrolysates tumorigenic to mouse skin.
Subsequently, these and similar organic compound-derived
pyrolysates were shown to contain a variety of PAHs (1286,
2264b), some of which were potent mouse-skin tumorigens.
Obviously, PAHs should be generated from the structural
components of tobacco during the reactions occurring when
tobacco is smoked in a cigarette. Interest in the major precur-
sors in tobacco of the PAHs in MSS eventually led to the con-
clusion that the major precursors in tobacco of cigarette MSS
PAHs in cigarette MSS were the organic solvent-extractable,
high molecular weight tobacco components, such as the satu-
rated aliphatic and unsaturated aliphatic hydrocarbons, the
phytosterols, and terpenoid alcohols such as solanesol (3251,
3269, 3291, 3616, 4332).
During the search for the major PAH precursors in tobacco,
all of the above-mentioned organic solvent-soluble tobacco
components (see Table XXV-5) that were examined by pyrol-
ysis were shown to yield PAHs. In 1957, Gilbert and Lindsey
* Examination of the data reported by Gilbert and Lindsey (1289) on the
pyrogenesis of PAHs from various tobacco constituents would appear to
contradict this statement. Gilbert and Lindsey reported the generation of a
series of PAHs in the pyrolysate (see Table XXV-10) from the dicarboxy-
lic acid oxalic acid [(COOH)2] which obviously has no carbon-hydrogen
bond. However, it is known that a major product of the thermal decom-
position of oxalic acid is formic acid [H-COOH] via decarboxylation.
Formic acid does have the requisite carbon-hydrogen bond.
(1289) reported their results on the amounts of various PAHs
in the pyrolysates (650°C, N2) from the major structural
components from flue-cured tobacco. These included cellu-
lose, pectins, starch and lignin, the simple sugars sucrose,
glucose, and fructose, and the acids malic acid, citric acid,
and oxalic. Their data, modified to indicate nanograms of
individual PAHs generated per milligram of tobacco compo-
nent pyrolyzed,† are summarized in Table XXV-10.
Numerous pyrolysis experiments were conducted from
the mid-1950s to the mid-1980s on tobacco components and
tobacco fractions and residues obtained by solvent extraction
of tobacco. However, meaningful comparison of the results
has been difficult because of the lack of uniformity in the
pyrolysis conditions employed in the studies. Even when
some similarity existed between experimental conditions
used in two separate experiments, precise comparison was
confounded by the fact that different tobaccos or blends were
used in the experiments, for example, Gilbert and Lindsey
(1289) examined the PAH yields in the pyrolysates (650°C,
N2) from the structural components of a flue-cured tobacco
grown a year or two prior to their 1957 study; Severson et
al. (3616) examined the pyrolysates (produced at a variety of
temperatures including 650°C, N2) from a flue-cured tobacco
probably grown a few years before their 1979 publication and
from a tobacco blend.
In their detailed study, Severson et al. (3616) examined
the following pyrolysates: a flue-cured tobacco; its petroleum
ether extractables (8% of the tobacco weight), PEE; the tobacco
† Nanogram of PAH generated per milligram of tobacco component pyro-
lyzed = microgram of PAH generated per gram of tobacco component
pyrolyzed = parts per million (ppm) of PAH from the tobacco component
pyrolyzed.

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 1126 The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-11
Conversion of Components in Tobacco to Benzo[a]pyrene during Pyrolysis
Theoretical Contribution toa
Level in Tobacco Pyrolysis Benzo[a]pyrene Total Benzopyrenesb
Tobacco Component of Fraction % mg/g T, °C Atmos ng/mg ng ng/mg ng

Flue-Cured Tobacco Components (1289)

Cellulose 9.0 90 650 N2 0.78 70.2 1.43 128.7
Lignin 3.5 35 650 N2 0.47 16.5 0.69 24.2
Pectin 10.7 107 650 N2 0.45 48.2 0.79 84.5
Starch 4.0 40 650 N2 0.17 6.8 0.21 8.4
Sucrose 4.2 42 650 N2 0.10 4.2 0.12 5.0
Glucose 11.0 110 650 N2 0.29 31.9 0.40 44.0
Fructose 7.8 78 650 N2 0.33 25.7 0.35 27.3
Malic acid 10.1 101 650 N2 0.35 35.4 0.43 43.4
Citric acid 0.6 6 650 N2 0.17 1.0 0.54 3.2
Oxalic acid 1.0 10 650 N2 0.01 0.1 0.01 0.1
Total 61.9 619 240.0 368.8
Fractions From Flue-Cured Tobacco (3616)
F-1 Aliphatic hydrocarbons 0.42 42 650 N2 29 122
F-4 Solanesol 2.34 234 650 N2 930 21762
F-6 Phytosterols 1.62 162 650 N2 670 10854
Fractions From University of Kentucky 1R1 Tobacco Blend (3616)
Petroleum ether extractables 8.0 80 650 N2 320 25600
Petroleum ether extractables 8.0 80 700 N2 380 30400
Petroleum ether extractables 8.0 80 800 N2 1140 91200
1R1 tobacco blend 100.0 1000 700 N2 190 190000
Petroleum ether extractables 8.0 80 700 N2 1750 140000
Petroleum ether extractables 92.0 920 700 N2 54 50000
Other Studies with Tobacco Components (2257)
Saturated aliphatic hydrocarbons c 0.5 5 600 Air 0 0 0 0
Saturated aliphatic hydrocarbons c 0.5 5 700 Air 30 30 110 550
Saturated aliphatic hydrocarbons c 0.5 5 800 Air 340 1700 740 700

Flue-Cured Cigarette Smoke Condensate (4317) 90 d

a It is assumed that 1 g of tobacco is consumed during the cigarette smoking.
b Total BP = B[a]P + B[e]P
c Saturated aliphatic hydrocarbons isolated from flue-cured tobacco.

d Estimated total of B[a]P in MSS (4317) plus SSS from an all-flue cured tobacco cigarette is 45 ng in MSS plus an estimated 45 ng in SSS.

residue after petroleum ether extraction, RES; and eight chro-
matographic fractions (F-1 through F-8) derived from the PEE.
Unfortunately, Severson et al. conducted several key pyroly-
sis experiments at 700°C only. It should also be noted that
tobaccos, such as the flue-cured tobaccos used by Gilbert and
Lindsey and by Severson et al., would not be identical because
of the differences in agronomic conditions and practices for
the tobaccos grown in the mid-1950s vs. the mid-1970s.
Table XXV-11 summarizes pyrolysis data from Lam
(2257), Gilbert and Lindsey (1289), and Severson et al. (3616)
with particular emphasis on the somewhat similar experi-
mental conditions (pyrolysis temperature, atmosphere) and
on the yields of B[a]P and B[e]P from the pyrolysis of differ-
ent tobaccos, blend, components, and/or fractions.
The data in Table XXV-1l, plus additional data in the pub-
lications cited, indicate that the structural components as well
as other components and fractions (organic solvent-soluble
or insoluble) from tobacco yielded a variety of PAHs on
pyrolysis, but the structural components—the biopolymers—
such as cellulose, pectins, starch, lignin, etc., on a per unit
weight pyrolyzed basis generated much lower yields of PAHs
than did the organic solvent-soluble components and/or frac-
tions. Even in the cases where tobacco components are not
only soluble in organic solvents but also are relatively highly
oxygenated, they show a low propensity to generate PAHs
on pyrolysis. This fact was demonstrated by Severson et al.
(3616) in their study of the pyrolysates from the eight chro-
matographic fractions from the petroleum ether extractables
from flue-cured tobacco. They noted:
Extraction fractions F-1 and F-8 yielded relatively low
yields of PAH on pyrolysis, the former because of its ther-
mally stable hydrocarbon content, and the latter because of
its polar oxygenated constituent content. Such oxygenated
compounds, having a relatively low carbon content yield low

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 Pyrolysis 1127

amounts of the alkyl residues essential for PAH formation

[see Badger et al. (148), Schmeltz and Hoffmann (3489)]. Table XXV-12
Conversion of Pectins, Starch, and Cellulose to
The F-8 components that Severson et al. in their pyrolysis Specific Polycyclic Aromatic Hydrocarbons and
studies demonstrated to have a low propensity to yield PAHs Phenols during Smoking
on pyrolysis are similar both structurally and property-wise
Percent of Added Tobacco Component
(molecular weight, volatility) to some of the compounds used
Converted during Smoking
in “top dressing” formulations for tobacco smoking products
to Smoke Component
[see tabulations in Doull et al. (1053), Leffingwell et al.
Smoke Component Pectins Starch Cellulose
(2341)]. Presumably, “top dressing” components applied to
tobacco products on pyrolysis would behave similarly dur- Polycyclic Aromatic Hydrocarbons
ing pyrolysis to the F-8 oxygenated tobacco components Pyrene NDb ND 0.0000546
described by Severson et al. [see pp. 284–285 in (3616)]. Benzo[a]pyrene 0.0000014 0.0000136 0.0000021
Even though the structural components of tobacco on Benz[e]acephenanthrylene a 0.0000018 0.0000017 0.0000060
Benzo[k]fluoranthene 0.0000032 ND ND
pyrolysis did yield PAHs, albeit at a much lower level than
other classes of tobacco components, their contribution to Phenols
tobacco smoke composition became important from another Phenol 0.00125 0.0034 0.0036
o-Cresol 0.0010 0.0030 0.0046
point of view: when only a small portion (about 2% to 3%)
m-Cresol + p-Cresol 0.00077 ND 0.0048
of the biological response observed in mice (or other rodents) Guaiacol 0.00115 ND 0.0024
skin-painted with CSC could be explained by its content of the 2,5-Xylenol ND ND 0.0022
PAHs reported to be tumorigenic to mouse skin [see pp. 14–52 a Benz[e]acephenanthrylene was formerly known as benzo[b]fluor-
in (4005), Wynder et al. (4303)] additional explanations for the
anthene
observed biological response were sought. The concepts of pro- b ND = not determined
motion and co-carcinogenesis were introduced into the theory
of CSC tumorigenicity in an attempt to explain the observed
biological response in the mouse skin-painting studies.
In the 1950s, Boutwell et al. (414) and Boutwell and Bosch grown in a radiolabeled CO2 atmosphere. Among these radi-
(414) reported that low molecular weight phenols such as olabeled components studied were the cell-wall components
phenol itself and the cresols, nontumorigenic per se in skin- or biopolymers [pectin (2764), starch (2764), α-cellulose
painting experiments, enhanced the tumorigenicity in mouse (2764] of the tobacco. Each component was added individu-
skin-painting studies of PAHs reported to be tumorigens. In ally to cigarette tobacco and their contributions to various
1959, Roe et al. (3314) reported the promoting effect of a phe- classes of MSS components, particularly the PAHs and the
nolic fraction from cigarette MSS. Two years later, Wynder phenols, were determined. Table XXV-12 summarizes the
and Hoffmann (4313) examined phenol as a promoter of sev- Newell-Best findings on the percent conversion during smok-
eral PAHs (B[a]P, DMB[a]A) and concluded: ing of these three structural components to specific PAHs
and phenols.
Promoting substances present in tobacco smoke can increase Examination of these data indicates that the percent con-
and accelerate the tumor yield of carcinogenic polynuclear
version of these structural components to phenol ranges from
hydrocarbons that by themselves are not present in sufficient
concentration to yield any tumors or yield them only after a one (0.0013%) to about four (0.0036%) one-thousandths of a
prolonged latent period. percent, whereas the conversion of these three components to
benzo[a]pyrene ranges from about one (0.0000014%) to about
The low molecular weight phenols are extremely low-level fourteen (0.0000136%) one-millionth of a percent. Such data
components of tobacco but are present in cigarette MSS at may be used to estimate the conversion to PAHs and phenols
levels many times those in tobacco. This led to the search in of a flavorant (structurally similar to but of lower molecular
the late 1950s and early 1960s for precursors in tobacco of weight and higher volatility than these biopolymers) added to
the alleged biologically active phenols in tobacco smoke. the tobacco blend.
Studies by Rodgman and Cook (3277), Rodgman and Numerous pyrolysis studies were conducted on these pre-
Mims (3305), and Rodgman (3251) on the effect of tobacco cursors of phenols. In each case, the generation of simple phe-
components (lignin, pectin) added to a cigarette tobacco blend nols (phenol, cresols, and numerous xylenols) was observed.
on low molecular weight phenols levels in MSS and similar Kato et al. (2043) reported the pyrolysis of tobacco lignin
studies [Spears et al. (3767), Bell et al. (248)] on the effect yielded phenol, cresols, xylenols, and guaiacol—all known
of tobacco carbohydrates (glucose, sucrose, starch, cellulose, components of cigarette MSS. Examination of the structure of
or pectin) added to cigarette tobacco filler on phenols levels lignin reveals why it would readily yield these phenols as well
in MSS demonstrated that these tobacco components were as other substituted phenols such as vanillin [Ball (176a)].
major precursors of the simple phenols in cigarette MSS. From the mid-1960s to the early 1980s, the USDA tobacco
From 1962 through 1971, Newell and Best conducted research group—initially at Philadelphia, Pennsylvania, and
studies with radiolabeled components isolated from tobaccos subsequently at Athens, Georgia—described the pyrolysis of

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 1128 The Chemical Components of Tobacco and Tobacco Smoke
various tobacco components and the yield of phenols in the
pyrolysates. Tobacco components examined for their propen-
sity to generate the simple phenols during pyrolysis included:
• Cellulose, pectin, lignin, and the so-called tobacco
pigment (3468).
• The major tobacco polycarboxylic acids—malic,
citric, and fumaric plus the sodium salts of citric
and lactic acids (3486). In the late 1950s, a mix-
ture of sodium and potassium citrates was used as
an additive on cigarette paper to control its com-
bustion properties.*
• Tobacco and tobacco extracts [Kennedy and Riehl
(25A35), Schlotzhauer et al. (3456), Severson et al.
(3616)].
• Cellulose, glucose, and fructose [Higman et al.
(1647)]. The latter two sugars† are used in casing
materials applied to cigarettes during manufacture
[Leffingwell et al. (2341)].
With regard to the generation of phenols by the tobacco
acids, Schmeltz et al. (3486) noted:
The data show that citric, malic and related acids give rise
to phenols on pyrolysis. The yields, however, are lower
than those from other phenol-forming materials present in
tobacco leaf.
Despite the repeated assertions of the promoting potency
for PAHs of the CSC phenolic fraction [Roe et al. (3314)]
and the simple phenols, particularly phenol itself [Wynder
and Hoffmann (4313, 4332)], contradictory evidence was
reported. In 1962, Bock and Moore (25A11) challenged the
concept that the weakly acidic portion of CSC was a tumor
promoter. In fact, Wynder and Hoffmann (4319), strong pro-
ponents in 1964 of the promoting effect of the phenols in
smoke, wrote “Definite tumor-promoting activity for a vari-
ety of phenols may be regarded as established.”
However, this statement was omitted from their 1967
book in which Wynder and Hoffmann [see p. 626 in (4332)]
wrote:
Phenol and some of its derivatives have been shown to possess
tumor-promoting activity … However, a reduction of phenols
in tobacco smoke condensate has not led to a concomitant
reduction of tumorigenicity in the corresponding “tars.”
* A mixture of sodium and potassium salts of citric acid was used as a ciga-
rette paper additive, initially at RJRT and subsequently throughout the
U.S. tobacco industry since the late 1950s. This additive ensured that the
cigarette paper combustion char line slightly preceded the tobacco com-
bustion char line. In the late 1950s, Rodgman (3246) demonstrated that
inclusion of sodium and potassium citrates in the cigarette paper additive
system reduced the levels of PAHs in the MSS.
† Glucose and fructose are naturally occurring components present at rela-
tively high levels (10% to 25%) in Oriental and flue-cured tobaccos but at
relatively low levels (usually less than 2%) in burley and Maryland tobac-
cos, for example, see Wynder and Hoffmann (4332). For many years, the
two simple sugars glucose and fructose were added as such or in the form
of “invert sugars” to the cigarette blend as part of the casing materials
formulation. Low levels of the disaccharide sucrose, a known naturally
occurring component of tobacco, were also added.
© 2009 by Taylor & Francis Group, LLC
78836_C025.indd 1128
In 1971, Van Duuren et al. (4035), in a discussion of
tumor promoters and the complexity of CSC and its potential
role in carcinogenesis, reported: “Phenol, which is a weak
tumor-promoting agent, is indeed an inhibitor of tumorigen-
esis when applied simultaneously with benzo[a]pyrene.”
Two years later, Van Duuren et al. (4029) concluded from
their cocarcinogenesis research: “Phenol has been regarded
as an important ‘tumor promoter’ in [cigarette smoke con-
densate] … [but our] work indicates that it is inactive in
cocarcinogenesis and, indeed, has a slight inhibitory effect
on benzo[a]pyrene carcinogenesis.”
Chortyk and Schlotzhauer (722) reviewed the studies
reported during the preceding two decades on pyrolysis of
tobacco components and the relationship of the pyrolysis
results to the pyrogenesis of tobacco smoke components.
In 1979, Martin et al. (2468a) not only reported the results
of their own research on the generation of a variety of phenols
during the pyrolysis of lignin derived from several sources
but also reviewed the results of their own and earlier studies
by other investigators on lignin pyrolysis.
From their 1981 and 1982 studies on pyrolysis, Schlotzhauer
and Chortyk (3453) and Schlotzhauer et al. (3452) reported the
pyrogenesis of phenols not only from cellulose and lignin but
also from chlorogenic acid and other polyphenols. Cellulose
was defined as a major precursor of cresols and xylenols in
smoke; lignin as a major precursor of guaiacol, eugenol, and
catechol in smoke; the polyphenols, such as chlorogenic acid,
as major precursors of the catechols in smoke.
In 1975, Schlotzhauer and Chortyk (3452), emphasiz-
ing the toxicants in tobacco smoke, reported that the yields
of PAHs and phenols in the pyrolysate from reconstituted
tobacco sheet (RTS) were significantly lower than those
from flue-cured tobacco leaf when generated under the same
experimental conditions. Extrapolating their pyrolysis results
to the formation of specific components of tobacco smoke,
Schlotzhauer and Chortyk noted that “the continued use
of reconstituted tobacco sheet in tobacco products appears
warranted.”
Comparison of data obtained under different pyrolysis
conditions with cellulose, glucose, and fructose with data gen-
erated under actual smoking conditions reveals the problem
of attempting such a comparison. In Table XXV-13 are sum-
marized data from Gilbert and Lindsey (1289), Higman et al.
(1647), and Newell and Best (2764) on the conversion (ppm or
μg/g) of such tobacco components to B[a]P during pyrolysis
under two different conditions (650°C and 840°C, N2) and
when smoked in a cigarette under actual smoking conditions
(35-ml puff, 2-sec puff duration, 1 puff/min). The degree of
conversion of tobacco components such as cellulose to B[a]
P under different pyrolysis conditions parallels the degree of
conversion of other tobacco components such as the saturated
aliphatic hydrocarbons to B[a]P under different pyrolysis
conditions; for example, Lam (2257) and his findings sum-
marized in Table XXV-11. The conversion of cellulose to B[a]
P increases several hundredfold as the pyrolysis temperature
increased nearly 200°C (from 650°C to 840°C). Under actual
smoking conditions, the cellulose-to-B[a]P conversion was
11/13/08 5:56:32 PM
 Pyrolysis 1129

in cigarette smoke and cellulose in tobacco was a major pre-

Table XXV-13
Pyrolysis vs. Actual Smoking Conditions: Conversion of
Glucose, Fructose, and Cellulose to Benzo[a]pyrene
Conversion (ppm or µg/g) of Tobacco
Component to Benzo[a]pyrene
Experimental Conditions Glucose Fructose
Pyrolysis (650°C, N2) 0.29 0.33
[Gilbert and Lindsey (1289)]
Pyrolysis (840°C, N2) 47.5 98.4
[Higman et al. (1647)]
Actual smoking conditions NDa ND
(35-ml puff, 2-sec duration,
1 puff/min) [Newell and
Best (2764)]
a ND = not determined
less than 30%* of the conversion at 650°C. Similarly, under
actual smoking conditions, the conversion of cellulose to B[a]
P was only 0.073% of the conversion at 840°C. Thus, these
data from several sources indicate that the fate of a tobacco
component on pyrolysis is not equivalent to its fate under
actual smoking conditions [see the conclusion of Schmeltz et
al. (3512) on the fate of nicotine on pyrolysis vs. its fate during
actual smoking].
As noted in reviews of the thermal degradation products
from tobacco carbohydrates (cellulose, pectins, starch, and
sugars) by Roberts et al. (3225) and by Schumacher (3551),
pyrolysis of the carbohydrate components of tobacco results
in generation of several classes of compounds other than
PAHs and phenols. Among these were aldehydes and ketones,
considered significant in smoking-respiratory tract issues. It
was asserted during the 1960s that aldehydes and ketones,
shown to be ciliastatic in vitro to ciliated tissue, were impor-
tant because of their significant impairment (by extrapo-
lation) of the action of human respiratory tract cilia. Such
impairment was considered part of the mechanism of lung
cancer causation by cigarette smoke. However, their impor-
tance diminished after the reported findings of Dalhamn et
al. (892) that these cigarette smoke-derived, water-soluble in
vitro ciliastats were removed in large part by the “scrubbing
action” of the fluids coating the surfaces of the oral cavity
and laryngeal area, a phenomenon demonstrated several
years earlier by Rodgman et al. (3306).
Early studies (1955–1959) on carbonyl components included
those of Fredrickson (1228), who examined the volatile MSS
components from all-cellulose cigarettes. Many were identi-
fied as aldehydes and ketones (1238, 1239). In 1959, Laurene
et al. (2310) reported the unequivocal identification of acrolein
* Conversion of cellulose to B[a]P under actual smoking conditions = 0.21
mg/g; conversion of cellulose to B[a]P at 650°C = 0.78 mg/g. Percent ratio
for 650°C pyrolysis = 100 × 0.21/0.778 = 27%; for 840°C pyrolysis = 100
× 0.21/288.8 = 0.073%.
cursor of it in smoke. Grob (1413) subsequently demonstrated
in 1962 that, during smoking, cellulose generated high levels
not only of acrolein but also the ketone 3-buten-2-one.
In 1966, Latimer (25A40) reported several aldehydes
(acetaldehyde, acrolein) and ketones (acetone, 2-butanone) in
the pyrolysate from tobacco-derived starch. At Philip Morris
Cellulose
R&D, Gager et al. (1264, 1265) noted from their study with
0.78 radiolabeled sugars added to cigarette tobacco that acetalde-
hyde and acetone were formed during the smoking process
288.8 in the highest yields from added sugars but their levels were
reduced because of the levels generated from other major
0.21
tobacco components, such as cellulose, pectins, and starch.
In their 1976 literature review of pyrolysis products from
carbohydrates, Roberts et al. (3225) noted that, of the more
than 140 compounds identified in the pyrolysates from glucose,
fructose, sucrose, cellulose, and starch, twenty-one were
aldehydes and thirty were ketones. Of these fifty-one pyroly-
sis products identified at that time, forty had been identified
as cigarette MSS components.
In 1977, Ohnishi and Kato (2850) described the identifica-
tion of several carbonyl compounds in the pyrolysates from
the tobacco cell-wall polysaccharides cellulose, hemicellu-
lose, and pectins. They noted that these biopolymeric poly-
saccharides constituted 30% to 50% of the dry weight of the
tobacco they were studying. Sakuma et al. pyrolyzed tobacco-
derived cellulose (3401), chlorogenic acid, and rutin (3400)
and reported various aldehydes and ketones plus numerous
phenols in the pyrolysates. Many of the pyrolysate compo-
nents identified have also been identified in cigarette MSS.
XXV.C.4 Acids
The research findings of Gilbert and Lindsey (1289) on the
generation of a variety of PAHs during the pyrolysis of major
components of tobacco, including several polycarboxylic
acids (oxalic, malic, and citric acids), were discussed previ-
ously (see Table XXV-10). These acids may constitute from
3% to 12% of dry tobacco weight (1289, 1329, 1330, 1332,
1333). At RJRT R&D, the fate of these acids during smoking
in a cigarette was determined by Newell and Best in stud-
ies with radiolabeled acids added individually to cigarette
tobacco (2763). In 1967, Schmeltz et al. (3486), in their
attempt to define precursors in tobacco of several classes of
compounds in cigarette smoke, studied the nature and levels
of phenols generated in the pyrolysates of malic, citric, aco-
nitic, and fumaric acids or their sodium salts. Thus, pyrolysis
of tobacco leaf acids yielded phenols (3486) and PAHs (1289).
Although direct comparison is somewhat difficult because
of the 50°C pyrolysis temperature difference in the Gilbert-
Lindsey vs. Schmeltz et al. studies, the PAHs appeared to be
generated in much lesser amounts per gram of tobacco leaf
acid pyrolyzed than were the phenols. Table  XXV-14 sum-
marizes data obtained from the studies.
Pyrolysate products obtained from several short-chained
aliphatic acids or their sodium salts were examined. Schmeltz
and Schlotzhauer (3498) pyrolyzed sodium acetate at 500°C

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 1130 The Chemical Components of Tobacco and Tobacco Smoke
Table XXV-14
Pyrolysis of Leaf Acids: Generation of Selected
Phenols and Polycyclic Aromatic Hydrocarbons
Compound Pyrolysis
Generated, ng/mg Conditions Acid Pyrolyzed
of Acid Pyrolyzed
T, °C Atm. Malic Citric
Polycyclic Aromatic Hydrocarbons [Gilbert and Lindsey (1289)]
Benz[a]anthracene 650 N2 1.30 0.35
Benzo[a]pyrene 650 N2 0.33 0.17
Phenols [Schmeltz et al. (3486)
Phenol 700 N2 89 25
o-Cresol 700 N2 79 38
m-Cresol + p-Cresol 700 N2 79 51
a ND = not determined
and 800°C. The 800°C pyrolysate was much more complex
than that produced at 500°C. This was true for the numbers
of pyrolysate components generated and those with aromatic
structures. Among the latter were several alkylbenzenes and
phenols. Rudenko and Konsinska (25A61) reported simi-
lar findings from their pyrolysis of propionic acid, present
in tobacco in bound form. At the USDA, Geisinger et al.
(1279) demonstrated that pyrolysis of malic and lactic acids
at temperatures from 500°C to 900°C (in 100°C increments)
yielded both aromatic hydrocarbons and phenols. With
malic acid, the aromatic hydrocarbon complexity increased
(increased methylation) as the temperature increased.
Bicyclic indene was the only PAH detected in the 500°C and
600°C pyrolysates. Indene and naphthalene were detected
in the 700°C pyrolysate. Tricyclic acenaphthylene, anthra-
cene, phenanthrene, and fluorene were detected in the 800°C
pyrolysate, tetracyclic pyrene and chrysene in the 900°C
pyrolysate. Pyrolytic products from several aromatic acids
present either free or bound in tobacco were investigated, for
example, Zane and Wender (4403) demonstrated in 1963 that
pyrolysis of rutin, quercetin, and chlorogenic acid (tobacco
polyphenols with bound caffeic acid) yielded catechol as the
major product, alkylcatechols, resorcinol plus several furan-
carboxaldehydes. Similar results were reported by the USDA
group (3462) at Athens, Georgia.
In 1969, Jones and Schmeltz reported catechol as the major
pyrolysis product (32%) from free caffeic acid (1981) and
stilbene as the major pyrolysis product from trans-cinnamic
acid (1983). trans-Cinnamic acid pyrolysate also contained
low yields of several bicyclic and tricyclic PAHs. The results
of these and similar pyrolysis studies with tobacco acids were
reviewed by Chortyk and Schlotzhauer (722).
Indirect evidence that major leaf acids such as malic, citric,
and oxalic acids in tobacco contributed low PAH levels to
pyrolysates from tobacco fractions was provided by Severson
et al. (3616). When tobacco was extracted with hexane or
petroleum ether, the bulk of these acids did not appear in
© 2009 by Taylor & Francis Group, LLC
78836_C025.indd 1130
the extract but remained in the insoluble tobacco residue.
Severson et al. reported that the pyrolysate from the extract-
ables (8% of tobacco weight) contained more than twice the
amount of total PAHs than did the pyrolysate from residual
tobacco (92% of tobacco weight). In the same study, Severson
et al. (3616) examined the levels of various PAHs (bicyclic
to pentacycylic) in the pyrolysates of eight chromatographic
Oxalic
fractions from the petroleum ether extractables. Several frac-
tions consisted primarily of free fatty acid mixtures, such
 0 as myristic, palmitic, stearic, oleic, and linoleic acids (frac-
0.01 tions F-5 and F-6) and esters of long-chained saturated and
unsaturated alcohols with these acids (fractions F-7 and F-8,
see Table XXV-8). As described previously, Schmeltz et al.
NDa
(3511) demonstrated that less than 1% of radiolabeled palm-
ND
ND
itic acid, isolated from tobacco grown in a radiolabeled-CO2
atmosphere and added to cigarette tobacco filler, was con-
verted to PAHs during the smoking process.
Pyrolysis products from esters such as ethyl acetate and
isobutyl acetate, both possible flavorants for tobacco smok-
ing products, have been reported [Leffingwell et al. (2341),
Miyagawa (2563)]. The principal pyrolysis products from
both acetates were CO, CO2, methane, acetic acid, and
acetone. Isobutyl acetate yielded isobutylene as a major
product. Products from pyrolysis of the esters formed from
long-chained fatty acids* and glycerol (triglycerides) were
described by Higman et al. (1646) (tripalmitin, tristearin) and
Kitamura (2111a) (trilaurin, tripalmitin). In the early 1970s,
Halaby and Fagerson (25A28) pyrolyzed palmitic, oleic, and
linoleic acids plus their triglycerides. Numerous PAHs were
identified in the pyrolysates. They reported that B[a]P was
generated from each acid and from each triglyceride at about
100 ppm of the compound pyrolyzed. In their studies on pre-
cursors in tobacco of PAHs in tobacco smoke, Rodgman and
Cook (3269) demonstrated that addition of 0.4% (4.0 mg/g
of tobacco) of trimyristin to tobacco produced, under actual
smoking conditions, a 6% increase in total PAHs in the MSS.
The changes in individual PAH yields are shown in Table
XXV-15. These changes are also expressed in Table XXV-15
in terms of the conversion (ng/mg or ppm) of the added
trimyristin to individual PAHs. The changes observed in the
levels of individual PAHs are well within the experimental
error for PAH analyses in the late 1950s.
XXV.C.5 Proteins and Amino Acids
Amino acids, both as free acids and as acids bound within
protein molecules, are present in all of the tobacco types
(flue-cured, burley, Oriental, and Maryland). The diversity
and levels of amino acids in various tobaccos have been
* The major long-chained fatty acids, either free or bound, in tobacco are
lauric acid (C12), myristic acid (C14), palmitic acid (C16), stearic acid (C18),
oleic acid (C18, 1 carbon-carbon double bond), linoleic acid (C18, 2 carbon-
carbon double bonds), and linolenic acid (C18, 3 carbon-carbon double
bonds). However, bound and free acids in tobacco (and in tobacco smoke)
are not limited to acids with even-numbered carbon chains [Bellin (258,
259), Rodgman et al. (3294), Swain and Stedman (3842, 25A72), Wynder
and Hoffmann (4332)].
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 Pyrolysis 1131
Table XXV-15
Conversion of Trimyristin Added to Tobacco to Polycyclic Aromatic Hydrocarbons
during Actual Cigarette Smoking (3269)
Mainstream Smoke Delivery of
PAH, µg/cig, at Trimyristin Addition
Level to Tobacco Blend, mg/g
Polycyclic
Aromatic Hydrocarbon 0 4.0
Naphthalenes a 15.8 b 17.7 b
Anthracene 0.247 0.255
Pyrene 0.051 0.045
Fluoranthene 0.213 0.207
Chrysene 0.018 0.018
Benzo[a]pyrene 0.081 0.086
a Naphthalenes represent a mixture of naphthalene plus several methyl-, dimethyl-, and trimethylnaphthalenes.
b Micrograms produced per gram of tobacco burned.
c Within experimental error of analytical procedure.
d ng/mg = parts per million (ppm)
presented by Gori (1329, 1330) and Tso and Chaplin (3975).
The amino acids occurring free and/or bound in tobaccos
include alanine, α-aminobutyric acid, arginine, aspartic acid,
cystine, glutamic acid, glycine, histidine, isoleucine, leucine,
lysine, methionine, ornithine, phenylalanine, proline, serine,
threonine, tryptophan, tyrosine, and valine.
The presence in cigarette MSS of numerous free amino
acids and amino acid-derived compounds was demonstrated
in the mid-1950s. This occurred soon after the publication of
the results of several cigarette smoke-related epidemiological
and biological studies led to a massive escalation in tobacco
smoke composition studies; for example, Buyske et al. (562)
identified glutamic acid and its derivative glutamine (glutamic
acid 5-amide) in tobacco smoke. Other amino acids identified
in tobacco smoke [see Ishiguro and Sugawara (1884)] include
alanine, aspartic acid (and asparagine), cysteine, glycine,
leucine, ornithine, phenylalanine, proline, serine, threonine,
and valine.
In the early 1960s, pyrocoll (dipyrrolo[a,d]pyrazine-5,
10-dione) was identified in cigarette MSS by Mold et al.
(2592), who proposed that either free or bound proline was
its precursor. During their study of the isolation and iden-
tification of N-heterocyclic components (the indoles and
carbazoles) in cigarette MSS, Rodgman and Cook (3279)
confirmed the presence of pyrocoll. Two decades earlier, Van
Order and Linwall (25A78) had demonstrated that dry distil-
lation of tryptophan yielded indole and 3-methylindole (ska-
tole), both of which were subsequently identified in tobacco
smoke (3279) and in burley tobacco by Roberts [see citation
in Rodgman and Cook (3279)].
From their pyrolysis studies (850°C, N2) with lysine, leu-
cine, and tryptophan, Patterson et al. (2902) reported that
each yielded the N-heterocyclic compounds indole, quino-
line, isoquinoline, several nitriles, and PAHs ranging from
bicyclic to tetracyclic (see Table XXV-16). B[a]P was found
© 2009 by Taylor & Francis Group, LLC
78836_C025.indd 1131
PAH Increase
In ng/4.0 mg of In ng/mgd of
Trimyristin Added Trimyristin Added
1900 475
8c 2
6c 1.5
(6) c 0
0c 0
5c 1.25
only in the leucine pyrolysate. From their own findings and
from a previous report by Jarboe and Rosene (1923a) that
quinoline and isoquinoline were components of a nicotine
pyrolysate, Patterson et al. suggested that the precursors
in tobacco of quinoline and isoquinoline in tobacco smoke
might be nicotine and/or the amino acids. They also reported
that tryptophan, per mole pyrolyzed, yielded a phenol frac-
tion weighing about five times that generated from lysine and
about thirty times that from leucine.
Patterson et al. (2903) reported the effect of temperature on
the pyrolysate composition from phenylalanine, with empha-
sis on PAHs yields, and the effect of tryptophan or pyrrole
on the pyrolysate composition when equimolar quantities of
phenylalanine + tryptophan or phenylalanine + pyrrole were
pyrolyzed (see summary of results in Table XXV-17). The
difference between the pyrogenesis of PAHs from phenylala-
nine and equimolar quantities of phenylalanine + tryptophan
mixture prompted Patterson et al. (2903) to propose amino
acid addition to tobacco to control the PAH content of the
CSC:
These results suggest the possibility that aromatic hydro-
carbon content of tobacco “tar” may be affected by the
amino acid composition of the tobacco and that it might be
possible to affect deliberately the amount of aromatics and
bases formed by adding suitable additives, such as amino
acids, to the tobacco.
In 1971 when Patterson et al. made this suggestion, the
presence in amino acid pyrolysates of the N-heterocyclic
amines and the inordinately high mutagenicity of several of
them were unknown.
Higman et al. (1647) reported the generation of PAHs, phe-
nols, pyridines, indole, quinoline, and other aromatic bases
during pyrolysis of tobacco amino acids and proteins [see the
review on pyrogenesis of smoke components by Chortyk and
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 1132 The Chemical Components of Tobacco and Tobacco Smoke

(Salmonella typhimurium]. Initial impetus for amino acid

Table XXV-16 pyrolyses was not the definition of the relationship between
Components in Pyrolysates from Lysine, Leucine, tobacco precursors and smoke components but the observa-
and Tryptophan (2902) tion that extracts of broiled, fried, or roasted foodstuffs were
highly mutagenic (Ames bioassay). These N-heterocyclic
Yield, mg/mole of Amino Acid Pyrolyzed
amines, derived from amino acids and/or proteins in heated
Pyrolysate Component Lysine a Leucine Tryptophan
foodstuffs, were defined as “cooked food” mutagens. These
Nitrogen Compounds studies in the 1970s on the tumorigenicity and mutagenicity
Hydrogen cyanide +b + + of extracts of cooked foodstuffs are reminiscent of the stud-
Aniline 60 5 — ies in the 1920s by Kennaway (2073–2076), who reported the
Quinoline 160 8 17.7 tumorigenicity of extracts of heated foodstuffs or pyrolysates
Isoquinoline 80 6 2.4
Benzonitrile 470 40 1370
from compounds such as cholesterol, and by Roffo (25A56,
o-Tolunitrile 30 + 610 25A57, 25A58), who reported the tumorigenicity of pyro-
m-Tolunitrile 30 30 + lyzed cholesterol. Subsequently, pyrolysates from many
p-Tolunitrile 20 + + foodstuffs and cholesterol were shown to contained various
Phenylacetonitrile 6 — 400 PAHs, including B[a]P. Identification of highly mutagenic
Indole 20 + 610 N-heterocyclic compounds in amino acid pyrolysates was
1-Naphthonitrile 10 30 350
followed by their identification not only in heated foodstuffs
2-Naphthonitrile — — 170
but also in mainstream CSC.
Cyclic Hydrocarbons In 1977, Sugimura et al. (3829) reported the identification
Styrene 5 20 —
of the potent mutagens 3-amino-1-methyl-5H-pyrido[4,3-b]
Biphenyl 10 30 +
indole (Trp-P-2) and 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]
Bibenzyl 2 — +
Indene 40 70 — indole (Trp-P-1) in tryptophan pyrolysate. The next year,
Naphthalene 210 620 1100 Yamamota et al. (4365a) identified two potent mutagens in
Naphthalene, 1-methyl- 10 40 + glutamic acid pyrolysate: aminodipyrido[1,2-a:3’,2’-d]imida-
Naphthalene, 2-methyl- 10 50 — zole (Glu-P-2) and 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]
Acenaphthene 20 — — imidazole (Glu-P-1).
Acenaphthylene 30 19 3
Table XXV-19 lists several N-heterocyclic amines that
Fluorene 10 80 140
Anthracene/phenanthrene 30 250 7900 exhibit high mutagenicity in the Ames bioassay, are amino
Fluoranthene 10 90 210 acid pyrolysis products, and have been identified in heated
Pyrene 10 110 270 foodstuffs and CSC (3828c). On a per microgram basis, B[a]
Pyrene, methyl- 2 20 — P in the Ames bioassay with Salmonella typhimurium (TA 98
Benzofluorene 10 30 150 strain) shows about 200 revertants/µg. Several of the amino
Chrysene 10 50 110
acid-derived compounds in Table XXV-19 exceed the B[a]
Criphenylene + + +
Benz[a]anthracene + + +
P effect (TA 98 strain) by factors ranging from about 10 to
Benzopyrene — 30 — over 2100.
Yoshida and Matsumoto (4387a) reported the identifica-
a Pyrolyzed as lysine monohydrochloride
tion of two α-carbolines in CSC: 2-amino-9H-pyrido[2,3-b]
b + indicates the presence of compound; — indicates the absence of the
compound.
indole (AαC) and 2-amino-3-methyl-9H-pyrido[2,3-b]indole
(MeAαC). These and several other compounds were repor-
ted in CSC by Yamashita et al. (4367, 4368). The quantita-
tive levels of the possibly amino acid-derived, mutagenic
N-heterocyclics in CSC are shown in Table XXV-19. In their
Schlotzhauer (722)]. The results reported by Higman et al. studies they emphasized in particular the identification and
are summarized in Table XXV-18. quantitation of 2-amino-3-methylimidazo[4,5-f]quinoline
Tryptophan was found to be the precursor in tobacco of (IQ) because of its inordinately high mutagenicity (433000
harman (1-methyl-9H-pyrido[3,4-b]indole) and norharman and 490000 revertants/µg in the Ames bioassay, Salmonella
(9H-pyrido[3,4-b]indole) in tobacco smoke, compounds orig- typhimurium strain TA 98).
inally identified in tobacco and tobacco smoke by Poindexter Demonstration of the mutagenicity of the compounds in
and Carpenter (2972). That tryptophan was indeed a precur- Table XXV-19 was followed by demonstration of their tum-
sor in tobacco of the harmans in smoke was demonstrated by origenicity in laboratory animals. Ohgaki et al. (2849a) dem-
addition of radiolabeled tryptophan to tobacco and identifica- onstrated the tumorigenicity of IQ in mice. Takayama et al.
tion of radiolabeled harman and norharman in the MSS. (3862c) and Tanaka et al. (3865c) reported its tumorigenicity
More recent amino acid pyrolysis studies led to the iso- in rats. Trp-P-1 and Trp-P-2 were reported to be tumorigenic
lation and identification of several N-heterocyclic amines in mice by Matsukura et al. (2491a) and in rats by Hosaka et al.
reported not only to be tumorigenic to mouse skin but also (1835a) and Takayama et al. (3862d). Ohgaki et al. (2849b)
to show inordinately high mutagenicity [Ames bioassay reported that Glu-P-1, Glu-P-2, AαC, and MeAαC were

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 Pyrolysis 1133

Table XXV-17
Pyrolysis of Phenylalanine. A. Effect of Pyrolysis Temperature B. Effect of Equimolar Addition of
Tryptophan (Try) or Pyrrole (Pyr) (2903)
Material Pyrolyzed
Phenylalanine (Phe) Pyrolyzed at Phe Phe + Try b Phe + Pyrc
Pyrolysate Component a 450°C 650°C 850°C 950°C 850°C 850°C 850°C

Monocyclic Aromatic Hydrocarbons

Biphenyl — 1270 10300 4360 10300 2980 2240
Bibenzyl 10300 12000 2550 + 2550 — 345

Polycyclic Aromatic Hydrocarbons

Indene — 360 2,730 — 2730 — 170
Naphthalene 120 1450 3500 1270 3500 3525 5600
Naphthalene, 1-methyl- — + — — — — 730
Naphthalene, 2-methyl- — — — — — 2980 345
Acenaphthene — 485 1940 <180 1940 54 86
Acenaphthylene — 1700 2550 730 2550 400 990
Fluorene 425 1330 4500 850 4,500 780 650
Phenanthrene/anthracene 4120 9700 20000 7900 20000 1440 2410
Benzofluorene — 485 1940 2600 1940 220 390
Fluoranthene — 485 1270 600 1270 160 40
Pyrene — 3500 3200 1200 3200 300 390
Pyrene, methyl- — — 3200 <600 3200 220 +
Chrysenes — 485 2550 1580 2550 160 300

N-Containing Compounds
Benzonitrile 1270 850 7880 1270 7880 3800 1465
o-Tolunitrile — 360 2850 60 2850 680 260
m-Tolunitrile — 60 — 60 — 1380 260
p-Tolunitrile — 180 180 — 180 380 260
Phenylacetonitrile — 1400 — — — 220 130
1-Naphthonitrile — 1400 — — — 1140 1000
Indole — 2300 725 — 725 17350 860
Quinoline — 1800 12000 300 12000 25750 1300
Isoquinoline — 3000 10900 180 10900 1100 430
a Yield of pyrolysis component in µg/g of compound or mixture pyrolyzed.
b Pyrolysis involved equimolar quantities of phenylalanine and tryptophan (total mol. wt. = 369).
c Pyrolysis involved equimolar quantities of phenylalanine and pyrrole (total mol. wt. = 232).

tumorigenic in mice, and Takayama et al. (3862b) reported
Glu-P-1 and Glu-P-2 to be tumorigenic in rats.
Hoffmann and Hecht (1727) discussed the amino acid-
derived aromatic amines in cigarette smoke:
Of the known carcinogenic pyrolysis products of the amino
acids, so far only 2-amino-3-methylimidazo(4,5-f)quinoline
has been detected in trace amounts of 0.26 ng in the smoke of
a Japanese filter cigarette [Yamashita et al. (4368)].
Apparently, Hoffmann and Hecht had overlooked not
only the reports of the identification in CSC of several other
known “carcinogenic” pyrolysis products of amino acids,
for example, AaC and MeAaC [Yoshida and Matsumoto
(4387a)] or Trp-P-1 and Trp-P-2 [Yamashita et al. (4367)]
but also the reports on their tumorigenicity in several ani-
mal species [Matsukura et al. (2491a), Hosaka et al. (1835a),
Ohgaki et al. (2849a, 2849b), Takayama et al. (3862c, 3862d),
Tanaka et al. (3865c)].
Table XXV-20 summarizes the MSS yields of N-hetero-
cyclic amines considered to be significant tumorigens
[Hoffmann and Hoffmann (1740, 1741)] plus the assessment
of the IARC (1870) on their tumorigenicity in laboratory ani-
mals and humans.
Table XXV-21 illustrates precursor relationships, either
demonstrated or proposed, between N-containing compo-
nents such as the amino acids and proteins and tobacco smoke
components. The tabulation of possible flavorants for tobacco
smoking products by Leffingwell et al. (2341) included con-
tributions to tobacco smoke taste and aroma of twenty-three
amino acids added individually to the cigarette filler.
During tobacco growth, curing, aging, and/or the smok-
ing process, tobacco sugars may react with ammonia and/
or amino acids to yield Amadori compounds which, when
heated during the smoking process, will generate a variety of
pyrazines [Green et al. (1369)]. Many pyrazines identified in
tobacco smoke are highly flavorful and contribute uniquely

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 1134 The Chemical Components of Tobacco and Tobacco Smoke

growth inhibitors (see Chapter XXI). Acceptable use levels

Table XXV-18 of these are prescribed in the United States by appropriate
Components in Pyrolysates from Amino Acids government agencies. Comments, for example, see Wynder
(Proline and Glycine) and Proteins (Casein and and Hoffmann* (4332), Guthrie (1457), and Guthrie and
Collagen) (1647) Sheets (1460) on the use of pesticides, etc., were published
in increasing numbers, after the mid-1960s when smoke
Pyrolysate Amino Acid or Protein
Component
components or classes of components allegedly responsible
Casein Collagen Proline Glycine
for the effects of cigarette smoke in the smoke-disease asso-
Nitrogen Compounds ciation could not explain the observed effects at the levels in
Hydrogen cyanide + + + + cigarette smoke.
Pyridine + + + + Two types of materials have been examined in greater
Pyridine, 2-methyl- + + + + detail than most of the others. These are discussed in this sec-
Pyridine, 3-methyl- + + + + tion because there is substantial information on their pyroly-
Pyridine, 4-methyl- + + + +
sis products, their transfer per se from cigarette tobacco to its
Pyridine, 3-vinyl- + + — —
MSS, their degradation during the actual smoking process,
Aniline + + + —
Pyrrole + + + +
and/or their effect as either transferred or degraded materials
Quinoline + + + — on the biological activity. Even in these two cases, no attempt
Isoquinoline + + + — has been made to include all the available references. These
Indole + + + — classes of materials include:
Benzonitrile + + — +
o-Tolunitrile + + + — Sucker growth inhibitors: Representative sucker
m-Tolunitrile + + + — growth inhibitors or suckering agents include maleic
Cyclic Hydrocarbons hydrazide, currently used as an alkali metal salt, and
Benzene + + + — the normal, even-numbered carbon chain saturated
Toluene + + + + alcohols, ranging in carbon chain length from (C6)
Styrene + + — + 1-hexanol through C12 (1-dodecanol) (4332).
Xylenes + + — + Pesticides: Particularly those pesticides that are chlo-
Indene + + — + rinated; for example, DDT, Aldrin®, and Dieldrin®
Naphthalene + + — —
(4332).
Fluorene + + — —
Phenols
Phenol + + — —
XXV.D.1.a  Sucker Growth Inhibitors
o-Cresol + — — —
m-Cresol + + — — The pyrolysis of long-chained saturated alcohols such as
p-Cresol + + — — 1-docosanol and long-chained unsaturated alcohols such as
Phenol, ethyl- + + — — phytol and solanesol, known to be naturally occurring com-
Xylenol + + — — ponents of tobacco, was discussed previously.
One of the most widely used and effective commercial prep-
a +
 indicates the presence of compound; — indicates the absence of the
compound. In the publication by Higman et al. (1647), actual pyrolysis
arations for inhibition of sucker growth is “Off-Shoot-T®,” a
yield data are listed for each compound. mixture consisting primarily of the even-numbered straight-
chained alcohols 1-hexanol, 1-octanol, 1-decanol, and 1-do-
decanol [Collins et al. (25A16)]. Pyrolysis studies by Higman
et al. (1644, 1645) with individual alcohols of “Off-Shoot-T®”
to the aroma and taste not only of tobacco smoke but also of a revealed that much of the alcohol was transferred intact to the
variety of consumer food products such as coffee, tea, cocoa, pyrolysate. Much of the remainder was converted to the cor-
roasted peanuts, and roasted, broiled, or fried meats, poultry, responding alkene; for example, 1-decanol yielded 1-decene.
and fish [Maga and Sizer (2439)]. Because of their volatility and low molecular weight, conver-
sion of the alcohols to PAHs was minimal.
Definitive evidence that the alcohol sucker growth inhibi-
XXV.D  Tobacco Additives tors added to tobacco did not augment the tumorigenicity of
XXV.D.1 Additives Used in Tobacco Production cigarette MSS was provided in the second set of experimen-
tal cigarettes studied in the NCI “Less Hazardous” Cigarette
Much information exists in the tobacco literature on the use
and levels of use of a various materials added to tobacco dur-
ing growth, harvesting, and storage and on such materials * It should be noted that, in their earlier review, Wynder and Hoffmann
that either remain unchanged on the tobacco as residual (4319) discussed pesticide-derived arsenic in tobacco and tobacco smoke,
but they did not discuss tobacco production additives such as sucker
material or are chemically altered. These materials include
growth inhibitors, pesticides, etc., and their effects on tobacco and
insecticides, herbicides, fungicides, fumigants, and sucker tobacco smoke properties.

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 Pyrolysis 1135

Table XXV-19
Amino Acid-Derived N-Heterocylic Amines
Compound Mutagenicitya, rev/µg Level in CSC,
Code Name TA 98 TA 100 ng/cig b

IQ Imidazo[4,5-f]quinoline, 2-amino-3-methyl- 433000 7000 0.26

490000
Trp-P-1 5H-Pyrido[4,3-b]indole, 3-amino-1,4-dimethyl- 39000 1700 0.29-0.48
Trp-P-2 5H-Pyrido[4,3-b]indole, 3-amino-1-methyl- 104200 1800 0.82-1.1
Glu-P-1 Dipyrido[1,2-a:3’,2’-d]imidazole, 2-amino-6-methyl- 49000 3200 0.37-0.89
Glu-P-2 Dipyrido[1,2-a:3’,2’-d]imidazole, 2-amino- 1900 1200 0.25-0.88
AaC 9H-Pyrido[2,3-b]indole, 2-amino- 300 20 25-260
MeAaC 9H-Pyrido[2,3-b]indole, 2-amino-3-methyl- 200 120 2-37
a Salmonella typhimurium, strain TA 98 or TA 100, with S-9 mix.
b See Hoffmann and Hoffmann (1740, 1741).

Program (1330, 2683). The chemical and biological proper-
ties of the MSSs from three samples (hand-suckered tobacco,
tobacco treated with the recommended level of alcohol sucker
growth inhibitor, and tobacco treated with 100 times the rec-
ommended level) were compared among themselves and with
the Standard Experimental Blend, SEB II. Data obtained are
shown in Table XXV-22. Examination of the data indicates
that neither the normal use level of the alcohol nor a use level
100 times normal had any significant adverse effect on the
mainstream CSC properties. The MSS phenol yields were
increased from the hand-suckered and both alcohol-treated
tobacco samples, but the increase elevation had no signifi-
cant effect on the CSC biological properties. The results were
described by Gori (1330):
No statistically significant differences were observed among
Hand-suckered, Fatty Alcohol-Normal and Fatty Alcohol x
100 Blends (variables 60, 61, and 62).
In the summary report (2683) on the four sets of NCI
Tobacco Working Group (TWG) experimental cigarettes,
this statement was expanded:
The fatty alcohol, fatty alcohol × 100, and hand-suckered
blends showed no significant differences among themselves
or from the SEB II blend.
It is interesting to note that biological responses (% TBA),
ranging from a high of the average of 48% for the four rep-
licate SEB II CSCs to a low of 36% for the CSC from the
sample treated with alcohol at the normal use level, were
considered to show “no significant difference.”
Maleic hydrazide, another growth inhibitor used as a
suckering agent on tobacco, is used in the United States
as its potassium salt. Prior to 1982, use on tobacco
involved application of maleic hydrazide as its dietha-
nolamine salt. Such use was banned in 1981 by the

Table XXV-20
Summary of Lists of Tumorigenic N-Heterocyclic Amines Identified in Tobacco Smoke
IARCa Evaluation of Evidence
re Tumorigenicity in
Hoffmann and OSHA Hoffmann and MSS Yield Laboratory
Component Hecht (1727) (2825) Hoffmann (1740, 1741) ng/ciga Animals Humans

Glu-P-1 — — + 0.37-0.89 ng sufficient —

Glu-P-2 — — + 0.25-0.88 ng sufficient —
Trp-P-1 — — + 0.29-0.48 ng sufficient —
Trp-P-2 — — + 0.82-1.1 ng sufficient —
AaC — — + 25-260 ng sufficient —
MeAaC — — + 2-37 ng sufficient —
IQ — — + 0.26 ng sufficient probable
PhIP — — + 11-23 ng sufficient possible
IQ — — + 0.26 ng sufficient probable
a Data from Hoffmann and Hoffmann (1740, 1741)

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 1136 The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-21
Precursor Relationships between N-Containing Tobacco Leaf Components and Tobacco Smoke Components

Demonstrated or Biological Activity

Code Component Proposed Precursor Tumorigen Mutagen Cocarcinogen Anticarcinogen

Tryptophan trp — — — —
pyrocoll Dipyrrolo[a,d]pyrazine-5,10-dione prol — — — —
9H-Pyrido[2,3-b]indole trp — — — —
9H-Pyrido[2,3-b]indole, 2-methyl- trp — — — —
9H-Pyrido[2,3-b]indole, 2-pentyl- trp — — — —
9H-Pyrido[2,3-b]indole, 2-(2-methyl-propyl)- trp — — — —
AaC 9H-Pyrido[2,3-b]indole, 2-amino- trp yes yes — —
MeAaC 9H-Pyrido[2,3-b]indole, 2-amino-3-methyl- trp yes yes — —
norharman 9H-Pyrido[3,4-b]indole trp — yes — —
harman 9H-Pyrido[3,4-b]indole, 1-methyl- trp — yes — —
9H-Pyrido[3,4-b]indole, 1-ethyl- trp — ? — —
9H-Pyrido[3,4-b]indole, 1-propenyl- trp — ? — —
9H-Pyrido[3,4-b]indole, 1-butyl- trp — ? — —
Trp-P-2 5H-Pyrido[4,3-b]indole, 3-amino-1-methyl- trp yes yes — —
Trp-P-1 5H-Pyrido[4,3-b]indole, 3-amino-1,4-dimethyl- trp yes yes — —
IQ Imidazo[4,5-f]quinoline, 2-amino-3-methyl- creat (?) yes yes — —
Glu-P-1 Dipyrido[1,2-a:3’,2’-d]imidazole, 2-amino-6-methyl- glut yes yes — —
Glu-P-2 Dipyrido[1,2-a:3’,2’-d]imidazole, 2-amino- glut yes yes — —
Indole trp
lys
leuc
Indole, 3-acetonitrile trp — a — yes
Indole, 2,3-dimethyl- trp — yes — —
Indole, 1-methyl- trp — — yes —
Indole, 3-methyl- trp — — — —
Quinoline trp yes yes — —
lys
leuc

Isoquinoline trp — — — —
lys
leuc
aAcetonitrile has been designated as a mutagen precursor.
Abbreviations: trp = tryptophan; prol = proline; lys = lysine; leuc = leucine; creat = creatinine; glut = glutamic acid

Environmental Protection Agency (EPA) (1147) soon
after it was reported that tobacco treated with it gener-
ated N-nitrosodiethanolamine (NDELA) during smoking.
NDELA was subsequently reported to be a potent, tissue-
specific tumorigen in laboratory animals [see Hoffmann et
al. (1696) and references therein].
Over the years, the pyrolysis of maleic hydrazide has been
much studied, for example, by Patterson et al. (2907), Smith
et al. (3728), Harke et al. (1507), and Clough et al. (25A13).
Also studied has been its transfer (estimated at ≤4%) as intact
maleic hydrazide from tobacco to cigarette MSS [Haeberer
(1470), Liu and Hoffmann (2383, 2384)] and its generation
of hydrazine during smoking (2385). However, in his 1979
report, the U.S. Surgeon General (4005) noted that maleic
hydrazide was not a significant precursor of either hydrazine
or 1,1-dimethylhydrazine in cigarette smoke. Smith et al.
(3728) reported that the pyrolysis of maleic hydrazide at 600°C
yielded CO2 (24%), CO (2%), HCN (3%), NH3 (9%), and N2
(3%), hydrazine (trace), and a black residue (50%), structure
unknown, whose empirical formula was C15H15N5O2.
In the fourth set of experimental cigarettes in the NCI “Less
Hazardous” Cigarette Program, the chemical and biological
(mouse skin-painting bioassay) properties of mainstream
CSC from a “pesticide”-treated tobacco cigarette were com-
pared to those of the CSC from a control cigarette, SEB IV
(1333, 2683). Gori (1333) listed the pesticides, sucker growth
inhibitors, etc., used and described the chemical analyses and
bioassays of the pesticide-treated and control tobaccos and
their MSSs. Among the additives used in the treatment of the
“pesticide”-treated tobacco were maleic hydrazide (MH-30),
a 10-carbon alcohol (“Contak®”), and DDT. Because both
maleic hydrazide and DDT were on the tobacco, the chemical
and biological results from the MSSs from these samples are
discussed later.

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 Pyrolysis 1137

Table XXV-22
NCI Study (Second Set of Experimental Cigarettes): Effect of Long Chained Alcohols Sucker Growth Inhibitors
on Cigarette Smoke Properties (1330, 2683)
Phenol, PAH, µg/g of CSC % TBAd at Daily CSC Dose of
Code No. Cigarette Filler µg/g of CSCa B[a]Ab B[a]Pc 25 mg 50 mg

42 SEB II 3.83 1.08 0.58 50 54

43 SEB II 3.66 0.89 0.82 52 40
44 SEB II 3.90 0.90 0.79 41 49
45 SEB II 3.81 0.86 0.65 47 50
Avg. (Code Nos. 42-45) 3.80 0.93 0.71 47.5 48

60 Hand-suckered 4.42 0.89 0.73 54 45

61 Alcohole level: normal application rate 4.46 0.73 0.50 43 36
62 Alcohol level: 100 times normal application rate 4.83 0.79 0.51 49 41
a CSC = cigarette smoke condensate
b B[a]A = benz[a]anthracene
c B[a]P = benzo[a]pyrene

d TBA = tumor-bearing animals

e Alcohol = long-chained alcohols in sucker inhibiting reagent

XXV.D.1.b  Pesticides examination not only for their contribution to cigarette

As mentioned in earlier chapters, the biological response
observed in mice skin painted with CSC or its fractions can-
not be explained on the basis of the identified components
and their levels in the CSC. In an attempt to define the bio-
logical response, Wynder and Hoffmann fractionated CSC
and determined that the major part of the tumorigenicity
that could be accounted for (only a few percent) arose from
a PAH-rich fraction designated as fraction B [Wynder and
Hoffmann (4332, 4342), Hoffmann and Wynder (1798, 1800)].
In addition to thirty-nine PAHs, totally or partially identified,
among which were several known to be mouse-skin tumori-
gens, fraction B contained twenty-seven N-heterocyclic com-
pounds (indoles, carbazoles, and acridans), five O-heterocyclic
compounds (dibenzofurans), and six chlorinated compounds
that were either insecticides (DDD, DDT) or their chlori-
nated derivatives (trans-4,4’-dichlorostilbene) [Hoffmann
and Wynder (1800)]. According to Hoffmann and Wynder
(1800), trans-4,4’-dichlorostilbene (DCS) is one of the major
pyrolysis products of the most important tobacco insecticides
DDT and DDD. They also stated:
DCS is neither a complete carcinogen nor a tumor initiator,
nor a tumor promoter, but the DCS (0.3%) can accelerate
significantly the tumorigenicity of a BaP solution (0.003%)
when both agents are applied concurrently.
However, it should be noted that the use in tobacco cul-
ture of chlorinated insecticides such as DDD and DDT in
the United States was discontinued in the late 1960s. For
example, between 1968 and 1974, the residual DDT levels
per gram of U.S. flue-cured tobacco decreased rapidly and
substantially (over 200-fold) as follows: 1968, 52 μg/g; 1970,
6 μg/g; 1974, 0.23 μg/g [USPHS (4005), IARC (1870)].
From 1967 through 1973, the organochlorine-containing
pesticides such as DDT and TDE were subjected to detailed
MSS composition by direct transfer and/or degradation to
simpler compounds during the smoking process but also to
the composition of their pyrolysates. Investigators involved
included Nesemann et al. (1968) from BAT (West Germany),
Hoffmann et al. (1756, 1767) from the Sloan Kettering
Institute and American Health Foundation, Carpenter and
Frost (606) from Carreras Tobacco, Chopra and colleagues
from North Carolina A&T [Chopra and Osborne (709,
25A12), Chopra and Domanski (707), Chopra et al. (708),
Chopra and Thekkekandam (713, 714)] and Kennedy et al.
(25A36) from Mississippi State.
Chopra and Osborne (709) initially studied the pyrolysis
of p,p′-DDT to identify degradation products. They com-
pared the pyrolysis data with those from actual smoking
studies and commented on the differences observed:
There are two differences in the pyrolysis of DDT reported
earlier and the degradation of DDT in tobacco smokes: the
concentration of DDT is much greater in the former and
hydrogen in the latter. The DDT degradation products as we
have found are as would be expected from the difference in
the reaction conditions. It is thus possible to predict the fate
of a pesticide in tobacco smoke by studying its pyrolysis pat-
tern. Also these investigations show that at the combustion
zone hydrogen plays a very important role in the reactions
taking place.
Chopra and his colleagues employed these pyrolysis
data to identify the transfer and degradation products gen-
erated from pesticide-treated tobaccos during the smoking
process [Chopra and Domanski (707), Chopra et al. (708),
Chopra and Osborne (25A12), Chopra and Thekkekandam
(713, 714)]. The results reported indicated the effect of added
pesticides on MSS composition primarily in terms of the

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 1138 The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-23
NCI Study (Fourth Set of Experimental Cigarettes): Effect of Pesticides Addition on Cigarette Smoke
Properties (1333, 2683)
PAH, µg /g of CSC % TBAd at Daily CSC Dose of
Code No. Cigarette Filler Phenol, µg/g of CSCa B[a]Ab B[a]Pc 12.5 mg 25 mg

04 SEB IV 3.79 0.99 0.72 24 49

14 SEB IV 2.98 1.11 0.79 36 56
29 SEB IV 3.95 0.96 0.71 24 55
32 SEB IV 3.19 1.55 0.60 27 55
Avge (04,14,29,32) 3.48 1.15 0.70 27.8 53.8
69 Pesticide-free control 5.33 1.05 0.83 34 54
39 Pesticide-treated 6.21 1.21 0.79 27 43
a CSC = cigarette smoke condensate
b B[a]A = benz[a]anthracene
c B[a]P = benzo[a]pyrene

d TBA = tumor-bearing animals

transfer of intact pesticides from tobacco to smoke or the
products generated from them during the smoking process.
In the National Cancer Institute (NCI) study of the fourth
set of cigarettes (1333, 2683), the effect of added pesticides
on chemical and biological properties (mouse skin painting)
was examined. As noted previously, the “pesticides” included
the sucker growth inhibitors maleic hydrazide (MH-30) and
“Contak®” (1-decanol) in addition to DDT (1333). Other
compounds present in the mix used in the tobacco treatment
according to government-approved procedures and treat-
ment levels included Lorsban®, Dylox®, Enide®, Lannate®,
and Carbaryl®. According to Smith et al. (3727), pyrolysis
of Carbaryl® (methyl carbamic acid, 1-naphthyl ester) gave
three major products in the pyrolysate: unchanged Carbaryl®
(»40%), 1-naphthol, and methyl isocyanate.
Some results from the NCI study of the MSS from the
“pesticide”-treated tobacco are shown in Table XXV-23. The
conclusions were [see p. 29 in (1333)]:
Pesticide-Free and Pesticide-Treated Tobaccos: Two ciga-
rettes tested in the fourth experiment were made from
tobacco grown [in] Prince Edward Island (PEI) [Canada].
One of the tobaccos was pesticide-free and the other was
pesticide-treated … There are no statistically significant dif-
ferences among the [probability of survival] values at either
dose level … Relative condensate yields from these ciga-
rettes are presented … These yields confirm the [probability
of survival] values, namely: there is no clear cut difference
between the pesticide-free and pesticide-treated tobaccos.
It was also noted in the summary (2683) of the NCI 10-year
“Less Hazardous” Cigarette Program:
No significant differences were observed between cigarettes
made from pesticide-treated tobacco leaves and pesticide-
free tobacco leaves.
These findings, at least with respect to the maleic hydraz-
ide added, are in agreement with the comments of Chopra
(704) in his theoretical discussion of the relationships among
pyrolysis, maleic hydrazide, the actual smoking of tobacco
treated with maleic hydrazide, and B[a]P:
Evidence and data so far available on maleic hydrazide are
not sufficient to suggest the MH [maleic hydrazide] is a health
hazard to the smoker … Thus far it is reasonable to assume
that there is not enough data or justification to consider the
use of MH as a health hazard to the smoker.
In the late 1970s, two excellent reviews on reagents used
to treat tobacco and their effects on tobacco chemistry were
authored by Steffens (3911a) and by Sheets and Leidy (3634).
The latter review included considerable information on the
effect of such compounds added to tobacco on MSS com-
position. Sheets and Leidy (3634) summarized the data,
which indicated the gradual decline in the levels on tobacco
of insecticides such as DDT following the government’s
proscription of their use on tobacco (and other crops) in the
United States. Their summary is similar to that provided ear-
lier by Guthrie (1457) on the gradual decline of the tobacco
arsenic level following the discontinuance in 1952 of arsen-
ate use on tobacco. By 1968, the arsenic level in U.S. tobacco
had decreased from a 1951 level of ≈50 μg/g of tobacco (dry
weight) to 0.5–1.0 μg/g [USPHS (4005), IARC (1870)]. In
1975, Griffin et al. (1391) reported arsenic values of 0.5 to 0.9
μg/g for U.S. tobaccos.
A pesticide used to control cigarette beetles in stored tobac-
cos and tobacco products was methoprene (Altosid®) or in the
formulation Kabat®. The use of the well-studied methoprene
(5-isopropyl(2E,4E)-11-methoxy-3,7,11-trimethyl-2,4-dodeca-
dienoate) escalated markedly in the 1990s. Methoprene is also
acceptable for controlling pests on various foodstuffs as well
as mosquito larvae in water supplies. Using radiolabeled meth-
oprene in a cigarette, Frisch et al. (1242, 1243) reported that
38.2% to 39.4% of the activity was found in the MSS, 52.3%
to 52.4% in the sidestream smoke (SSS), and 8.1% to 8.4% in

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 Pyrolysis 1139
the 23-mm butt. Of the activity in the MSS, 96.8% was due
to methoprene transferred from the treated tobacco. Of 1.3%
total activity found in mainstream vapor phase, 86% consisted
of radioactive CO plus CO2; the remaining 14% of the activity
was distributed among ten vapor-phase components, all nor-
mally found as vapor-phase components of cigarette MSS.
XXV.D.2 Additives Used in Cigarette Manufacture
The pyrolysate compositions from various tobacco additives,
including casing materials and humectants, and their effect
on cigarette MSS composition and properties were described
by Roberts et al. (3225, 3226) and by Schumacher (3551). In
this section, additional data are discussed.
XXV.D.2.a  Casing Materials (Sugars, Cocoa, Licorice)
Casing materials used in cigarette products in the United
States are licorice, cocoa, and the sugars, including the
invert sugars (glucose plus levulose) and sucrose. Although
they did not discuss the topic in their 1964 review (4319),
Wynder and Hoffmann (4332) did discuss the possible
effects on cigarette MSS properties of inclusion of casing
materials in the tobacco filler with particular emphasis on
licorice because of its glycyrrhizin content. Glycyrrhizin,
the potassium and calcium salt of glycyrrhizic acid, is poly-
cyclic, with five cyclohexane rings in the picene configura-
tion. (Figure XXV-2). Picene is a PAH identified in several
pyrolysates by Badger et al. (142) and Kröller (2195) and in
CSC by Snook et al. (3756).
According to an assertion by Wynder and Hoffmann
(4332), glycyrrhizin in licorice added to tobacco could be a
precursor of PAHs in smoke. In an ill-defined experiment,
Hoffmann et al. (1766) compared the B[a]P yield in the MSS
from pipe tobacco (containing 30% casing materials, includ-
ing licorice, level unspecified) smoked in a pipe (2 puff/min)
with the B[a]P level in the MSS from cigarette tobacco (no
licorice added) smoked identically, that is, in a pipe. The
B[a]P levels were 27 and 10.5 μg/100 g of tobacco smoked,
respectively. Later, Hoffmann and Rathkamp (1754) stated
that the pyrolysis of licorice yielded PAHs. This finding was
subsequently confirmed by Green and Best (1356, 1357),
whose data on B[a]P generated during identical pyrolyses
of licorice and flue-cured tobacco are summarized in Table
XXV-24. They also identified thirty-five other compounds in
the licorice pyrolysate [Green and Best (1356, 1357), all of
which had previously been identified in cigarette MSS. Ten
Figure XXV-2  The picene configuration present in glycyrrhizic
acid.
© 2009 by Taylor & Francis Group, LLC
78836_C025.indd 1139
Table XXV-24
Pyrolysis of Licorice vs. Flue-Cured Tobacco:
Benzo[a]pyrene Generation
Material Pyrolysate wt., Benzo[a]pyrene
Pyrolyzed mg/g Pyrolyzed Total, ng ng/mg of Pyrolysate
Licorice 117 24.8 0.21
Flue-cured tobacco 133 70.5 0.53
of the licorice pyrolysate components were phenols; four
were dimethyl- or trimethylnaphthalenes.
Many of the compounds identified in licorice are the same
as those identified in tobacco (3551, 3555). Thus, there will
be similarities in their contributions to the composition of
either pyrolysates from licorice vs. tobacco or the MSSs
from a licorice-containing vs. a licorice-free tobacco blend.
Differences will be reflected by the components unique to
the material being investigated, for example, glycyrrhizin
in licorice, theobromine in cocoa, and nicotine in tobacco.
As noted by Schumacher et al. (3555), 172 (83%) of the 209
components identified in licorice by 1981 had also been iden-
tified in tobacco and/or tobacco smoke. Later, a similar situa-
tion between cocoa composition and tobacco/tobacco smoke
compositions will be discussed.
Sakuma et al. (25A62) reported the pyrolysis products
from several naturally occurring polyphenols (chlorogenic
acid, rutin). Rutin is a major polyphenol in both licorice and
different tobacco types. It and chlorogenic acid yield substan-
tial levels of catechol and substituted catechols on pyrolysis.
All the identified volatile pyrolysis products from rutin have
been identified in cigarette MSS.
In the late 1970s, Harllee and Leffingwell (1512, 1513)
cataloged cocoa components identified to that date with par-
ticular emphasis on the volatile, flavorful components com-
mon to cocoa and tobacco or its smoke. Both tobacco and
tobacco smoke, as well as cocoa, contain numerous fatty
acid triglycerides (1512) and many of the same fatty acids
(1512). At least nineteen amino acids are common to cocoa
and tobacco (1512). Of 352 volatile components identified in
cocoa by 1979, 209 (59%) had also been identified in tobacco
and tobacco smoke (1513).
From his pyrolysis study on cocoa, Schlotzhauer (3447)
reported that his results suggested:
Cocoa powder added as tobacco flavorant would not signifi-
cantly increase the phenol yield of smoke, but may affect the
higher fatty acid content.
In the NCI study of the third set of experimental cigarettes
(1332), the cigarette MSS composition and biological proper-
ties (mouse skin-painting studies) of four cigarette samples
were compared. These included three samples to each of which
had been added individually a specified amount of glycerol
(Code No. 80), sugar (Code No. 81), and cocoa (Code No. 82).
11/13/08 5:56:43 PM
 1140 The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-25
NCI Study (Third Set of Experimental Cigarettes): Effect of a Humectant (Glycerol) or Casing Material
(Sugar or Cocoa) on Cigarette Smoke Properties (1332, 2683)
Relative to CSCa
Additive, % µg/g µg/g % TBAb at Daily Dose of
Code No. Filler Glyc
c Sugar Cocoa Acr d Phenol B[a]A e B[a]P f 12.5 mg 25 mg

72 SEB III 2.80 5.30 0 3.36 3.86 1.43 1.16 28 50

73 SEB III 2.80 5.30 0 3.62 3.70 1.42 0.97 22 44
74 SEB III 2.80 5.30 0 3.30 3.90 1.36 0.95 30 46
75 SEB III 2.80 5.30 0 3.45 3.90 1.44 1.01 11(?) 44
Avge 72-75 2.80 5.30 0 3.44 3.84 1.41 1.02 23 46
Avge 72-74 2.80 5.30 0 3.44 3.82 1.40 1.03 27 47
83 SEB III 0 0 0 3.61 4.33 1.21 1.00 22 31
80 SEB III 2.95 0 0 3.46 3.82 1.23 1.09 22 47
81 SEB III 0 5.42 0 3.54 4.34 1.50 1.08 19 41
82 SEB III 0 0 1.00 3.22 4.46 1.40 1.06 28 49
a CSC = cigarette smoke condensate d Acr = acrolein
b TBA = tumor-bearing animals e B[a]A = benz[a]anthracene
c Glyc = glycerol f B[a]P = benzo[a]pyrene

The fourth sample was a control (Code No. 83) to which none These changes usually are perceived by the consumer to be
of these casing materials/humectants had been added (1332, detrimental and unacceptable [Townsend (25A76)].
2683). The results are summarized in Table XXV-25 together The pyrolysis of humectants, including glycerol and pro-
with data from four Standard Experimental Blend III sam- pylene glycol, was studied in the mid-1960s by Doihara et al.
ples (SEB III, Code Nos. 72–75), the controls for the third (1023, 1024) and Kröller (2192, 2195, 2196). Kröller exam-
set of experimental cigarettes. Variations in the analytical ined the pyrolysates from nine humectants (including glyc-
and biological data among these four control samples (Code erol and propylene glycol, the most commonly used in the
Nos. 72–75) raised questions about any attempt to compare United States) for the yields of B[a]P and other PAHs gener-
on a one-to-one basis the data from individual samples, for ated during the pyrolysis. His B[a]P data are summarized in
example, the cocoa-treated sample (Code No. 82) vs. its con- Table XXV-26.
trol (Code No. 83), the sugar-treated sample (Code No. 81) vs. In the early studies of methods to control cigarette MSS
its control (Code No. 83), etc. Additional comments will be composition and yield, particularly with regard to PAHs,
made about these data in the following section where humec- Bentley and Burgan (286) asserted addition of glycerol at
tants are discussed. the 3% level to the tobacco blend substantially decreased
The phenol data (Code No. 82 vs. Code No. 83) in Table (by as much as ≈ 60%) the B[a]P yield when the CSCs
XXV-25 indicate the prediction by Schlotzhauer (3447) from glycerol-treated cigarettes vs. untreated tobacco were
appears to be valid: Inclusion of nominal levels of cocoa in
the cigarette blend produced little change in the MSS phenol
yield. Addition of 1% cocoa (Code No. 82 vs. Code No. 83) Table XXV-26
increased the phenol yield (mg/g of CSC) by 0.13 mg/g. This Benzo[a]pyrene in the Pyrolysates from Various
is about a 3% increase relative to Cigarette coded No. 83; well Humectants Used or Proposed for Use in Cigarette
within the experimental error of the phenol determination. Fabrication
XXV.D.2.b  Humectants (Glycerol, Propylene Glycol) Humectant Benzo[a]pyrene, ng/g Pyrolyzed
Humectants (glycerol, propylene glycol) are added to the
Diethylene glycol 15
tobacco blend to diminish the rate of post-cigarette-manu- Triethylene glycol 30
facture moisture loss. Cigarettes are usually manufactured Glycerol 60
with the blend at a 12% moisture content. As the cigarette 1,2-Propylene glycol 60
loses moisture, that is, becomes “dry” during transportation 1,3-Propylene glycol 80
Polyethylene glycol 400 105
and shelf storage, its yield of smoke components changes
Sorbitol 130
adversely, with increased yields not only of particulate-phase Polyethylene glycol 600 289
entities such “tar” and nicotine but also vapor-phase com- Polyethylene glycol 1000 420
ponents such as the aldehydes (acetaldehyde, acrolein) and Tobacco, no additives 20–40
ketones (acetone, methyl vinyl ketone) [Green et al. (1364)].

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 Pyrolysis 1141
compared. Their finding was challenged by Wynder and
Hoffmann (4332). Subsequently, with a reproducible analyti-
cal method for B[a]P determination, Scherbak et al. (3440)
and de Souza and Scherbak (953) reported that such levels of
added glycerol did not have the dramatic effect claimed by
Bentley and Burgan on PAHs (or B[a]P) generation during
smoking. Scherbak et al. (3440) reported:
Addition of glycerol to flue-cured tobacco up to the 6%
level does not modify the formation of 3,4-benzpyrene or
smoke particulate.
The effect of glycerol added to the cigarette blend on MSS
composition and properties was studied by the NCI TWG
in the third set of experimental cigarettes (1332, 2683). The
results were summarized in Table XXV-26. At the glycerol
level (nearly 3%) used in the glycerol-treated sample (Code
No. 80), it would be expected that the total particulate matter
(TPM) would contain sufficient transferred glycerol to dilute
other components by about 10% to 12% [Greene et al. (1382),
Laurene et al. (2300), Wynder and Hoffmann (4332), Hege
(1603)]. This was not observed with B[a]A and B[a]P yields
but was with the phenol yield, see the data in Table XXV-26
for sample Code Nos. 80 and 83. The effect of transfer of
humectants from the tobacco blend to smoke plus their dilu-
tion of the products formed during the cigarette smoking
process affects the biological properties (mutagenicity in the
Ames bioassay with Salmonella typhimurium) of the MSS
particulate matter.
In a detailed study of the effect of various casing ingredi-
ents (sugars, cocoa, humectants) on smoke chemistry, Baker
et al. (174c) determined the yields of various “Hoffmann ana-
lytes” when such ingredients were added in various mixtures.
They concluded:
Many of the casing ingredient mixtures either had no sta-
tistically significant effect on the level of analytes investi-
gated in smoke relative to a control cigarette or the produced
decreases of up to 44% in some case.
Sugars did increase the yield in MSS of formaldehyde.
XXV.E Cigarette Construction
Materials (Paper, Adhesives, etc.)
Interest in cigarette MSS components possibly responsible
for the epidemiological cigarette smoking-lung cancer asso-
ciation and the biological response observed in mice skin
painted with massive CSC doses led to studies of the con-
tribution of cigarette paper to MSS composition, primarily
because as a cigarette construction factor, other than the
tobacco blend, it contributed substantially (6% to 7%) to the
weight of a 1.0-g cigarette. In 1954, Cooper and Lindsey (819),
based on fragmentary UV data, reported the presence of sev-
eral PAHs, including B[a]P, in a “tar” obtained by burning
cigarette paper in bulk. Similar findings on PAHs (and B[a]P)
in the combustion products of cigarette paper, tobacco, and
© 2009 by Taylor & Francis Group, LLC
78836_C025.indd 1141
cigarettes were reported by Lefemine et al. (2335), Cardon
et al (594), and Alvord and Cardon (57). They also proposed
an additive (ammonium sulfamate) for paper and/or tobacco
to reduce pyrogenesis of PAHs. The ammonium sulfamate
efficacy in decreasing B[a]P production in a burning cigarette
was discussed by Wynder and Hoffmann [see pp. 521–523,
528 in (4322)], who noted that the additive gave discordant
results in different investigations [no significant B[a]P reduc-
tion reported by Bentley and Burgan (286) or Pyriki et al.
(3046) vs. substantial B[a]P reduction reported by Alvord and
Cardon (57), Lindsey et al. (2370), and Candeli et al. (589].
Whether cigarette paper contributed significantly to the
PAHs in cigarette MSS was finally resolved by Wright (4281),
who reported that PAHs (and particularly B[a]P) were indeed
generated when cigarette paper was burned in bulk or pyro-
lyzed, but when it was burned in a cylindrical configuration
such as that encountered around the cigarette tobacco rod,
the yields of PAHs (particularly B[a]P) were insignificant.
Between 1963 and 1966, Kröller (2184–2195, 2200, 2203)
reported the pyrolysis products from cigarette components
permitted in cigarette fabrication in Germany. He estimated
the amount of B[a]P generated by pyrolysis of each material
at 700°C in air. In addition to tobacco itself (2191), the mate-
rials he studied included cellulose, starch, and a number of
humectants, adhesives, and dyes consumed during the actual
cigarette smoking process.
Kröller (2191, 2192) asserted his pyrolysis and the actual
cigarette smoking process were qualitatively and quantita-
tively identical processes. Kröller’s opinion of the equivalence
of the fate of a material on pyrolysis in an inert atmosphere
vs. its fate in the tobacco rod of a smoked cigarette parallels
that of Wynder and Hoffmann (4332). In addition to phenan-
threne, 4,5-methylenephenanthrene, and fluoranthene, Kröller
reported the identification of four potent PAH mouse-skin
tumorigens in his tobacco pyrolysate: DMB[a]A, 3-methyl-
cholanthrene (now known as 1,2-dihydro-3-methylbenz[j]
aceanthrylene), B[a]P, and DB[a,h]A. Despite their agree-
ment with Kröller (2191, 2192) on the equivalence of the fate
of a material in an inert atmosphere pyrolysis and the smok-
ing process, Wynder and Hoffman were critical of several of
Kröller’s findings. For example, Wynder and Hoffman (4332)
questioned Kröller’s identification of the methyl derivatives
(DMB[a]A, 30-methylcholanthrene) in his pyrolysates and
smoke samples. However, a methylbenz[a]anthracene had
been identified in CSC by Rodgman and Cook (3273) in the
late 1950s and numerous methyl- and dimethylbenz[a]anthra-
cenes were subsequently reported in CSC in the late 1970s by
Snook et al. (3756, 3757).
Table XXV-27, adapted from Kröller (2195), summa-
rizes his data on the amounts of B[a]P generated during
the pyrolysis of tobacco and numerous components used in
cigarette fabrication.
More recently, several studies on the pyrolysis of vari-
ous adhesives either used or proposed for use as seam pastes
in cigarette fabrication were conducted by Best (25A06,
25A07). He reported that, in contrast to a starch pyrolysate,
the pyrolysate from polyvinyl acetate showed high levels of
11/13/08 5:56:44 PM
 1142 The Chemical Components of Tobacco and Tobacco Smoke

Certain casing agents, saucing materials, and humectants are

Table XXV-27 widely used in the manufacture of tobacco products. For all
Benzo[a]pyrene in the Pyrolysates from Various we know at this time, it is certainly a possibility that PAH
Materials Used or Proposed for Use in Cigarette may also be formed from these agents. One should keep in
Fabrication (2195) mind, however, that only small amounts of these materials
are used for most smoking products.
Material Benzo[a]pyrene, ng/g Pyrolyzed
Their latter statement would also apply to cigarette fabrica-
Natural Dyes
tion materials consumed during the smoking process, such as
Logwood extract < 10
the adhesives used on the cigarette paper seam, printing inks
Buckthorn berry extract 20
Madder lake 120 on the paper, etc.
Humic acid, sodium salt 270 The data from Kröller (2195) on the B[a]P yields gener-
ated during cellulose and starch pyrolysis may be compared
Humectants
Diethylene glycol 15
with those of Gilbert and Lindsey (1289), see Table XXV-28,.
Triethylene glycol 30 This provides an excellent example of the effect of changing
Glycerol 60 pyrolysis conditions (pyrolysis at 650°C in air vs. pyrolysis
1,2-Propylene glycol 60 at 700°C in N2) when two different materials are consid-
1,3-Propylene glycol 80 ered. The different pyrolysis conditions give a ratio of 9.75
Polyethylene glycol 400 105
(0.78/0.080) for the B[a]P yields from cellulose, but a ratio of
Sorbitol 130
Polyethylene glycol 600 289 2.43 (0.17/0.070) for the B[a]P yields from starch.
Polyethylene glycol 1000 420 Cellulose was included in the Kröller studies because it
constitutes the major part of cigarette paper, much of which
Adhesives and Starches
Alginic acid 30
is consumed during the smoking process. It was not included
Carob bean flour 60 because cellulose, as wood pulp, is sometimes added by some
Starch 70 manufacturers to their reconstituted tobacco sheet (RTS) to
Cellulose 80 improve integrity and reduce fragmentation.
Carboxymethylcellulose, 120 The effect of cellulose added to cigarette filler on cigarette
sodium salt MSS composition and properties in a mouse skin-painting
Methylcellulose 180
Tragacanth 230
bioassay was examined in the mid-1970s in the NCI study of
Dialdehyde starch 235 the first set of cigarettes (1329, 2683). The results are poorly
Cellulose monoacetate 285 defined because the cellulose was added (as wood pulp) at a
Carboxymethylstarch 300 7.5% level to fillers made from the Standard Experimental
Guava gum 300 Blend (SEB I) reconstituted into sheet material at three dif-
Gum arabic 320
ferent densities.
Hydroxyethylcellulose 340
Agar-agar 470

Tobacco XXV.F Flavoring Ingredients

Tobacco (no additives) 20–40
As outlined in Chapter 24 dealing with tobacco and/or
smoke components used as flavorful additives, the numer-
ous assertions about the possibly adverse effect of flavorful
acetic acid and B[a]P. Best also examined the pyrolysates compounds added to tobacco were never accompanied by
from a variety of proposed new cigarette papers (25A04, any supporting laboratory evidence. None of the information
25A05, 25A08). generated over the past decade that the added flavorants had
In 1967, Wynder and Hoffmann [see pp. 350–351 in (4332)] little, if any, adverse effect on the chemical and biological
noted that pyrolysis data on cigarette components should be properties of the smoke generated from the treated tobacco
considered carefully: has been criticized by any investigator, governmental agency,

Table XXV-28
Pyrolysis of Cellulose and Starch: Comparison of Benzo[a]pyrene Data from Kröller with Those
from Gilbert and Lindsey
Pyrolysis Conditions Benzo[a]pyrene, ng/mg of Material Pyrolyzed
Investigator Temp., °C Atmosphere Cellulose Starch

Gilbert and Lindsey (1289) 650 N2 0.78 0.17

Kröller (2195) 700 air 0.080 0.070

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 Pyrolysis 1143
or medical institute or any contradictory data presented. In
an exemplary study by Baker and Bishop (172a), 291 flavor-
ful additives were pyrolyzed and, in each case, the yields of
the major components of the pyrolysate were determined. As
outlined in Chapter 24, many of the compounds used as fla-
vor additives are already components of tobacco and/or its
smoke. The behavior of such an additive will not differ from
its tobacco inherent counterpart. In addition to the pyrolysis
study of Baker and Bishop (172a), there are also many stud-
ies in which the effect of added flavorants on the chemical
and biological properties of cigarette MSS was determined.
Many were summarized in 2004 by Rodgman [see Tables 1
and 7A in (3266)] but since then much additional data have
been published. Table XXV-29 lists a variety of references
pertinent to the use of tobacco and/or smoke components
as additives, their pyrolysis, their effect on smoke compo-
sition when added individually to tobacco, and their effect
on smoke composition when added as a component of a fla-
vorant formulation. Among the references cited is that of
Paschke et al. who, in their report on the effect of ingredients
on the chemical and biological properties of MSS, tabulated
detailed pyrolysis data on a number of individual tobacco
and/or smoke components plus detailed pyrolysis data on
a variety of materials studied as tobacco additives [see pp.
226–241, Table 5 in (2896)].
Table XXV-30 lists a variety of references pertinent to
compounds used as tobacco additives where the compounds
are not known to be present in tobacco or its smoke. Included
are references to their pyrolysis plus their effect on smoke
composition when added as a component of a flavorant
formulation.
© 2009 by Taylor & Francis Group, LLC
78836_C025.indd 1143
Although Table XXV-31 does not involve individual
tobacco and/or tobacco smoke compounds, it is included
because of the relationship of the entities to tobacco and/or
tobacco products. The results of many of the studies cited
were published in the early days of the examination of
tobacco composition and the attempts to define the precur-
sors in tobacco of various components in MSS. The studies
on cocoa and licorice are included because of their level of
use in tobacco products.
Table XXV-29 deals with individual components that are
either tobacco and/or tobacco smoke components, many of
which are listed and discussed by Doull et al. (1053), Baker
et al. (172a, 174a), Carmines (603), and Rodgman (3266)
as additives in tobacco products. Table XXV-30 deals with
compounds not identified to date in tobacco and/or tobacco
smoke but listed as tobacco product additives. Since our pri-
mary concern throughout this project was the discussion of
the contribution of individual tobacco components to smoke
properties, neither Table XXV-29 nor Table XXV-30 includes
the many complex mixtures (oils, extracts, resins, etc.) used
as flavorful cigarette tobacco additives that have also been
studied in detail with regard to their pyrolysates (172a, 172b)
and their effect as tobacco additives on the chemical (174a,
174b, 630, 3370) and biological properties (174a, 25A24,
25A25, 25A27, 25A43, 25A49, 25A79) of cigarette smoke.
Table XXV-32 [updated from Table 6 in (3266)] summarizes
the specific conclusions from many of such studies conducted
between 1994 and 2005. A more detailed summary of the
chemical and biological studies through mid-2004 of the
complex mixture additives was presented by Rodgman [see
Tables 2 and 7B in (3266)].
11/13/08 5:56:46 PM
 1144 The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-29
Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to
Tobacco

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 Pyrolysis 1145

Table XXV-29 (Continued)

Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to
Tobacco

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C025.indd 1145 11/13/08 5:56:48 PM

 1146 The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-29 (Continued)

Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to
Tobacco

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78836_C025.indd 1146 11/13/08 5:56:58 PM

 Pyrolysis 1147

Table XXV-29 (Continued)

Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to
Tobacco

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C025.indd 1147 11/13/08 5:57:00 PM

 1148 The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-29 (Continued)

Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to
Tobacco

© 2009 by Taylor & Francis Group, LLC

78836_C025.indd 1148 11/13/08 5:57:01 PM

 Pyrolysis 1149

Table XXV-29 (Continued)

Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to
Tobacco

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C025.indd 1149 11/13/08 5:57:04 PM

 1150 The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-29 (Continued)

Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to
Tobacco

© 2009 by Taylor & Francis Group, LLC

78836_C025.indd 1150 11/13/08 5:57:07 PM

 Pyrolysis 1151

Table XXV-29 (Continued)

Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to
Tobacco

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C025.indd 1151 11/13/08 5:57:09 PM

 1152 The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-29 (Continued)

Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to
Tobacco

© 2009 by Taylor & Francis Group, LLC

78836_C025.indd 1152 11/13/08 5:57:12 PM

 Pyrolysis 1153

Table XXV-29 (Continued)

Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to
Tobacco

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C025.indd 1153 11/13/08 5:57:22 PM

 1154 The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-29 (Continued)

Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to
Tobacco

© 2009 by Taylor & Francis Group, LLC

78836_C025.indd 1154 11/13/08 5:57:37 PM

 Pyrolysis 1155

Table XXV-29 (Continued)

Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to
Tobacco

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C025.indd 1155 11/13/08 5:57:38 PM

 1156 The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-29 (Continued)

Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to
Tobacco

© 2009 by Taylor & Francis Group, LLC

78836_C025.indd 1156 11/13/08 5:57:41 PM

 Pyrolysis 1157

Table XXV-29 (Continued)

Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to
Tobacco

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C025.indd 1157 11/13/08 5:57:43 PM

 1158 The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-29 (Continued)

Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to
Tobacco

© 2009 by Taylor & Francis Group, LLC

78836_C025.indd 1158 11/13/08 5:57:52 PM

 Pyrolysis 1159

Table XXV-29 (Continued)

Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to
Tobacco

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C025.indd 1159 11/13/08 5:57:54 PM

 1160 The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-29 (Continued)

Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to
Tobacco

© 2009 by Taylor & Francis Group, LLC

78836_C025.indd 1160 11/13/08 5:57:56 PM

 Pyrolysis 1161

Table XXV-29 (Continued)

Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to
Tobacco

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C025.indd 1161 11/13/08 5:57:59 PM

 1162 The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-29 (Continued)

Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to
Tobacco

© 2009 by Taylor & Francis Group, LLC

78836_C025.indd 1162 11/13/08 5:58:01 PM

 Pyrolysis 1163

Table XXV-29 (Continued)

Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to
Tobacco

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C025.indd 1163 11/13/08 5:58:04 PM

 1164 The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-29 (Continued)

Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to
Tobacco

© 2009 by Taylor & Francis Group, LLC

78836_C025.indd 1164 11/13/08 5:58:06 PM

 Pyrolysis 1165

Table XXV-29 (Continued)

Pyrolysis of Tobacco and Tobacco Smoke Components Plus Their Effect on Smoke Composition When Added to
Tobacco

© 2009 by Taylor & Francis Group, LLC

78836_C025.indd 1165 11/13/08 5:58:09 PM

 1166 The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-30
Pyrolysis of Non-Tobacco and Non-Tobacco Smoke Components and/or Their Effect on Smoke Composition
When Added to Tobacco
References to
Pyrolysis of Effect on Mainstream
Individual Smoke Composition, When
CAS No. Name (per CA Collective Index) Component Component Added in a Mixture
105-87-3 Acetic acid, 3,7-dimethyl-2,6-octadien-1-yl ester {geranyl acetate} 172a 174a, 174b, 603, 3370
150-84-5 Acetic acid, 3,7-dimethyl-6-octenyl ester {citronellyl acetate} 172a 174a, 174b
151-05-3 Acetic acid, 1,1-dimethyl-2-phenylethyl ester {α,α-dimethylphenethyl acetate} 603, 3370
3681-71-8 Acetic acid, 3-hexen-1-yl ester, (Z)- {cis-3-hexen-1-yl acetate} 172a 174b
140-39-6 Acetic acid, 4-methylphenyl ester {p-tolyl acetate} 172a 174b, 603, 3370
143-13-5 Acetic acid, nonyl ester {nonyl acetate} 603, 3370
2442-10-6 Acetic acid, 1-octen-3-yl ester {1-octen-3-yl acetate} 603, 3370
24851-98-7 Acetic acid, 2-pentyl-3-oxo-1-cyclopentyl-, methyl ester {methyl dihydrojasmonate} 172a 174a, 174b
103-54-8 Acetic acid, 3-phenyl-2-propenyl ester {cinnamyl acetate} 172a 174a, 174b
76-49-3 Acetic acid, endo-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl ester {bornyl acetate} 603, 3370
141-97-9 Acetoacetic acid, ethyl ester {ethyl acetoacetate} 172a 174a, 174b
53956-04-0 Ammonium glycyrrhizinate a 174a, 174b
1336-21-6 Ammonium hydroxide 172a
10031-82-0 Benzaldehyde, 4-ethoxy-{p-ethoxybenzaldehyde} 172a 174a, 174b
1319-88-6 Benzaldehyde glyceryl acetal 172a 174a, 174b
698-27-1 Benzaldehyde, 2-hydroxy-4-methyl-{2-hydroxy-4-methylbenzaldehyde} 172a 174a, 174b
151-10-0 Benzene, 1,3-dimethoxy-{m-dimethoxybenzene} 172a 174a, 174b, 603, 3370
1076-56-8 Benzene, 3-methoxy-1-methyl-4-(1-methylethyl)- {4-isopropyl-3-methoxy-1- 172a 174a, 174b
methylbenzene}
104-87-0 Benzeneacetaldehyde, 4-methyl- {p-tolylacetaldehyde} 174b
122-43-0 Benzeneacetic acid, butyl ester {butyl phenylacetate} 603, 3370
102-22-7 Benzeneacetic acid, 3,7-dimethyl-2,6-octadieny-1-yl ester {geranyl phenylacetate} 603, 3370
5421-17-0 Benzeneacetic acid, hexyl ester {hexyl phenylacetate} 603, 3370
101-94-0 Benzeneacetic acid, 4-methylphenyl ester {p-tolyl phenylacetate} 603, 3370
102-13-6 Benzeneacetic acid, 2-methylpropyl ester {isobutyl phenylacetate} 172a 174a, 603, 3370
105-13-5 Benzenemethanol, 4-methoxy-{anisyl alcohol} 172a 174a, 174b, 603, 3370
122-91-8 Benzenemethanol, 4-methoxy-, formate {anisyl formate} 172a 174a, 174b, 603, 3370
102-17-0 Benzenemethanol, 4-methoxy-, phenylacetate {anisyl phenylacetate} 172a 174a, 174b, 603, 3370
7549-33-9 Benzenemethanol, 4-methoxy-, propanoate {anisyl propionate} 172a 174a, 174b
93-92-5 Benzenemethanol, α-methyl-, acetate {α-methylbenzyl acetate} 172a 174a, 174b
104-53-0 Benzenepropanal {3-phenylpropionaldehyde} 172a 174a, 174b
13341-72-5 Benzofuranone, dimethyltetrahydro- {dimethyltetrahydrobenzofuranone-} 603, 3370
134-20-3 Benzoic acid, 2-amino-, methyl ester {methyl anthranilate} 603, 3370
87-19-4 Benzoic acid, 2-hydroxy-, 2-methylpropyl ester {isobutyl salicylate} 603, 3370
118-58-1] Benzoic acid, 2-hydroxy-, phenylmethyl ester {benzyl salicylate} 603, 3370
120-47-8 Benzoic acid, 4-hydroxy-, ethyl ester {ethyl p-hydroxybenzoate} 2208, 2896
94-13-3 Benzoic acid, 4-hydroxy-, propyl ester {propyl p-hydroxybenzoate} 603, 3370
121-98-2 Benzoic acid, 4-methoxy-, methyl ester {methyl anisate} 172a 174a, 174b
94-46-2 Benzoic acid, 3-methylbutyl ester {isoamyl benzoate} 603, 3370
126-64-7 Benzoic acid, 3,7-dimethyl-1,6-octadien-3-yl ester {linalyl benzoate} 172a 174a, 174b
532-32-1 Benzoic acid, sodium salt {sodium benzoate} 2208, 2896 174a, 174b
125-12-2 Bicyclo[2,2,1]heptan-2-ol, 1,7,7,-trimethyl-, acetate {isobornyl acetate} 172a 174a, 174b
87-69-4 Butanedioic acid, 2,3-dihydroxy- {l-tartaric acid} 172a, 2201, 174a, 174c
2896,
7492-70-8 Butanoic acid, 2-butoxy-1-methyl-2-oxoethyl ester {butyl butyryl lactate} 603, 3370
109-21-7 Butanoic acid, butyl ester {butyl butyrate} 172a 174a, 174b, 603, 3370
106-29-6 Butanoic acid, 3,7-dimethyl-2,6-octadien-1-yl ester {geranyl butyrate} 172a 174a, 174b, 603, 3370
10094-34-5 Butanoic acid, 1,1-dimethyl-2-phenylethyl ester {α,α-dimethylphenethyl butyrate} 603, 3370
539-90-2 Butanoic acid, 2-methylpropyl ester {isobutyl butyrate} 172a 174a, 174b
540-18-1 Butanoic acid, pentyl ester {amyl butyrate} 172a 174b, 603, 3370
106-27-4 Butanoic acid, 3-methylbutyl ester {isoamyl butyrate} 172a 174a, 174b, 603, 3370
10032-15-2 Butanoic acid, 2-methyl-, hexyl ester {hexyl 2-methylbutyrate} 603, 3370
109-19-3 Butanoic acid, 3-methyl-, butyl ester {butyl isovalerate} 172a 174a, 174b, 603, 3370
55066-56-3 Butanoic acid, 3-methyl-, 4-methylphenyl ester {p-tolyl 3-methylbutyrate}
16409-46-4 Butanoic acid, 3-methyl-, 5-methyl-2-(1-methylethyl)- cyclohexyl ester {menthyl isovalerate} 172a 174b

© 2009 by Taylor & Francis Group, LLC

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 Pyrolysis 1167

Table XXV-30 (Continued)

Pyrolysis of Non-Tobacco and Non-Tobacco Smoke Components and/or Their Effect on Smoke Composition
When Added to Tobacco
References to
Pyrolysis of Effect on Mainstream
Individual Smoke Composition, When
CAS No. Name (per CA Collective Index) Component Component Added in a Mixture
103-52-6 Butanoic acid, phenylethyl ester {phenethyl butyrate} 172a 174a, 174b, 603, 3370
104-20-1 2-Butanone, 4-(4-methyoxyphenyl)- {4-(p-methoxyphenyl)-2-butanone} 172a 174a, 174b
10544-63-5 2-Butenoic acid, ethyl ester; (E)- {ethyl trans-2-butenoate} 172a 174a, 174b
3-Buten-2-ol, 4-phenyl- {4-phenyl-3-buten-2-ol} ?????
76-69-6 3-Buten-2-one, 4-(2,5,6,6-tetramethyl-2-cyclohexen-1-yl)- {α-irone} 172a 174a, 174b
3008-43-3 2,3-Cyclohexanedione, 1-methyl- {1-methyl-2,3-cyclohexadione} 172a 174a, 174b
16409-45-3 Cyclohexanol, 5-methyl-2-(1-methylethyl)-, acetate {menthyl acetate} 172a 174a, 174b
89-48-5
38462-22-5 Cyclohexanone, 2-(1-mercapto-1-methylethyl)-5-methyl- {p-Mentha-8-thiol-3-one} 172a 174a, 174b
491-07-6 Cyclohexanone, 2-methyl-5-(1-methylethyl)- {dl-isomenthone} 172a 174a, 174b
495-62-5 Cyclohexene, 4-(1,5-dimethyl-4-hexenylidene)-1-methyl- {bisabolene} 603, 3370
586-62-9 Cyclohexene, 1-methyl-4-(methylethylidene)- {terpinolene} 172a 174a, 174b, 603, 3370
2244-16-8 2-Cyclohexen-1-one, 2-methyl-5-(1-methylethyl)- {d-carvone} 172a 174a, 174b
23747-48-0 5H-Cyclopenta[b]pyrazine, 6,7-dihydro-5-methyl- {5H-5-methyl-6,7- 172a 174a, 174b
dihydrocyclopenta[b]pyrazine}
21835-01-8 2-Cyclopenten-1-one, 3-ethyl-2-hydroxy- {3-ethyl-2-hydroxy-2-cyclopenten-1-one} 172a 174a, 174b
110-40-7 Decanedioic acid, diethyl ester {diethyl sebacate} 603, 3370
111-46-6 Ethanol, 2,2’-oxybis- {diethylene glycol} 2192, 2896
89-74-7 Ethanone, 1-(2,4-dimethylphenyl)- {2,4-dimethylacetophenone} 603, 3370
24295-03-2 Ethanone, 1-(2-thiazolyl)-(2-acetylthiazole} 172a 174a, 174b, 603, 3370
105-86-2 Formic acid, 3,7-dimethyl-2,6-octadien-1-yl ester {geranyl formate} 172a 174a, 174b, 603, 3370
33467-73-1 Formic acid, 3-hexenyl ester, (E)- {3-hexenyl formate, (E)-} 172a 174b
638-49-3 Formic acid, pentyl ester {amyl formate} 603, 3370
28664-35-9 2(3H)-Furanone, 2,5-dihydro-4,5-dimethyl-3-hydroxy- {4,5-dimethyl-3-hydroxy-2,5- 172a 174a, 174b
dihydrofuran-2-one}
104-67-6 2(3H)-Furanone, dihydro-5-heptyl- {γ-undecalactone} 172a 174a, 174b, 603, 3370
2305-05-7 2(3H)-Furanone, dihydro-5-octyl- {γ-dodecalactone} 172a 174a, 174b, 603, 3370
3658-77-3 3(2H)-Furanone, 2,5-dimethyl-4-hydroxy- {2,5-dimethyl-4-hydroxy-3(2H)-furanone} 172a 174a, 1974b, 603, 3370
27538-09-6 3(2H)-Furanone, 3-ethyl-4-hydroxy-5-methyl- {3-ethyl-4-hydroxy-5-methyl-3(2H)- 172a 174a, 174b
furanone}
698-10-2 2(5H)-Furanone, 5-ethyl-3-hydroxy-4-methyl- {5-ethyl-3-hydroxy-4-methyl-2(5H)- 172a 174a, 174b, 603, 3370
furanone}
1405-86-3 2-O-β-D-Glucopyranuronysyl-α-D-glucopyranosiduronic acid (3β,20β)-20-carboxy- 2896,
11-oxo-30-norolean-12-en-3-yl- {glycyrrhizic acid; glycyrrhizin} 25A87
106-30-9 Heptanoic acid, ethyl ester {ethyl heptanoate} 172a 174a, 174b, 603, 3370
6728-31-0 4-Heptenal {4-heptenal} 172a 174b
1119-44-4 3-Hepten-2-one {3-hepten-2-one} 603, 3370
7779-50-2 ω-6-Hexadecenlactone {ω-6-Hexadecenlactone} 172a 174a, 174b, 603, 3370
590-00-1 2,4-Hexadienoic acid, potassium salt {potassium sorbate} 2208, 2896 174a, 174b, 603, 3370
24634-61-5
2198-61-0 Hexanoic acid, 3-methylbutyl ester {isoamyl hexanoate} 172a 174a, 603, 3370
540-07-8 Hexanoic acid, pentyl ester {amyl hexanoate} 172a 174a, 174b
3452-97-9 1-Hexanol, 3,5,5-trimethyl- {3,5,5-trimethyl-1-hexanol} 172a 3 174a, 174b
21834-92-4 2-Hexenal, 5-methyl-2-phenyl- {5-methyl-2-phenyl-2-hexenal} 603, 3370
13419-69-7 2-Hexenoic acid, (E)- {2-hexenoic acid, (E)-} 172a 174b, 603, 3370
551-08-6 1(3H)-Isobenzofuranone, 3-butylidene {3-butylidenephthalide} 603, 3370
17369-59-4 1(3H)-Isobenzofuranone, 3-propylidene {3-propylidenephthalide} 172a 174a, 174b, 603, 3370
3738-00-9 Naphtho[2,1-b]furan, dodecahydro-3a,6,6,9a-tetramethyl- {ambroxide} 172a 174a, 174b
7786-44-9 2,6-Nonadien-1-ol {2,6-nonadien-1-ol} 172a 174a, 174b
31502-14-4 2-Nonen-1-ol {2-nonen-1-ol} 120 603, 3370
141-12-8 2,6-Octadien-1-ol, 3,7-dimetyyl-, acetate, (Z)- {neryl acetate} 172a 174a, 174b
107-75-5 Octanal, 3,7-dimethyl-7-hydroxy- {hydroxycitronellal} 172a 174a, 174b

(Continued)

© 2009 by Taylor & Francis Group, LLC

78836_C025.indd 1167 11/13/08 5:58:11 PM

 1168 The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-30 (Continued)

Pyrolysis of Non-Tobacco and Non-Tobacco Smoke Components and/or Their Effect on Smoke Composition
When Added to Tobacco
References to
Pyrolysis of Effect on Mainstream
Individual Smoke Composition, When
CAS No. Name (per CA Collective Index) Component Component Added in a Mixture
2035-99-6 Octanoic acid, 3-methylbutyl ester {isoamyl octanoate} 172a 174a, 174b
502-47-6 6-Octenoic acid, 3,7-dimethyl- {3,7-dimethyl-6-octenoic acid} 172a 174a, 174b, 603, 3370
6812-78-8
141-25-3 7-Octen-1-ol, 3,7-dimethyl- {rhodinol} 172a 174a, 174b, 603, 3370
111-12-6 2-Octynoic acid, methyl ester {methyl 2-octynoate} 172a 174a, 174b
591-68-4 Pentanoic acid, butyl ester {butyl valerate} 172a 174a, 174b
127-42-4 4-Penten-3-one, 5-(2,6,6-trimethyl-2-cyclohexen-1-yl)- {methyl-α-ionone} 172a 174a, 174b
94-86-0 Phenol, 2-ethoxy-5-(1-propenyl)- {5-propenylguaethol} 172a 174a, 174b, 603, 3370
2785-89-9 Phenol, 4-ethyl-2-methoxy- {4-ethylguaiacol} 174a, 174b
103-95-7 Propanal, 2-methyl-3-[4-(1-methylethyl)]phenyl-{2-methyl-(p-isopropylphenyl)- 172a 174a, 174b
propionaldehyde; cyclamen aldehyde}
105-53-3 Propanedioc acid, diethyl ester {diethyl malonate} 172a 174a, 174b
866-84-2 1,2,3-Propanetricarboxylic acid, 2-hydroxy-, potassium salt {potassium citrate} 174a, 174b
68-04-2 1,2,3-Propanetricarboxylic acid, 2-hydroxy-, sodium salt {sodium citrate} 174a, 174b
26446-35-5 1,2,3-Propanetriol, monoacetate {monoacetin} 2206, 2896
102-76-1 1,2,3-Propanetriol, triacetate {triacetin} 172a, 2896 174a, 174b, 603, 3370
105-68-0 Propanoic acid, 3-methylbutyl ester {isoamyl propionate} 172a 174a, 174b
97-89-2 Propanoic acid, 2-methyl-, 3,7-dimethyl-6-octenyl ester {citronellyl isobutyrate} 603, 3370
97-62-1 Propanoic acid, 2-methyl-, ethyl ester {ethyl isobutyrate} 172a 174a, 174b
65416-14-0 Propanoic acid, 2-methyl-, 2-methyl-4-oxo-4H-pyran-3-yl ester {maltyl isobutyrate} 603, 3370
103-93-5] Propanoic acid, 2-methyl-, 4-methylphenyl ester {p-tolyl isobutyrate} 172a 174a, 174b, 603, 3370
78-35-3 Propanoic acid, 2-methyl-, 3,7-dimethyl-1,6-octadien-3-yl ester {linalyl isobutyrate} 172a 174a, 174b
109-15-9 Propanoic acid, 2-methyl-, octyl ester {octlyl isobutyrate} 603, 3370
103-48-0 Propanoic acid, 2-methyl-, phenylethyl ester {phenethyl isobutyrate} 172a 174a, 174b, 603, 3370
103-28-6 Propanoic acid, 2-methyl-, phenylmethyl ester {benzyl isobutyrate} 172a 174a, 174b
103-59-3 Propanoic acid, 2-methyl-, 3-phenyl-2-propenyl ester {cinnamyl isobutyrate} 174a, 174b
13532-18-8 Propanoic acid, 3-(methylthio)-, methyl ester {methyl 3-methylthiopropionate} 172a 174a, 174b
122-63-4 Propanoic acid, phenylmethyl ester {benzyl propionate} 603, 3370
122-84-9 2-Propanone, 1-(4-methoxyphenyl)- {1-(p-methoxyphenyl)-2-propanone} 172a 174a, 174b
122-40-7 2-Propenal, 3-phenyl-, α-pentyl- {α-amylcinnamaldehyde} 172a 174a, 174b
499-12-7 1-Propene, 1,2,3-tricarboxylic acid {aconitic acid} 3486 603, 3370
122-67-8 2-Propenoic acid, 3-phenyl-, 2-methylpropyl ester {isobutyl cinnamate} 172a 174a, 174b, 603, 3370
103-53-7 2-Propenoic acid, 3-phenyl-, phenylethyl ester {phenethyl cinnamate} 172a 174a
16409-43-1 Pyran, 4-methyl-2-(2-methylpropen-1-yl)-tetrahydro- {rose oxide} 172a 174a, 174b
3301-94-8 2H-Pyran-2-one, 6-butyltetrahydro- {δ-nonalactone} 172a 174a, 174b
713-95-1 2H-Pyran-2-one, 6-heptyltetrahydro- {δ-dodecalactone} 172a 174a, 174b, 603, 3370
710-04-3 2H-Pyran-2-one, 6-hexyltetrahydro- {δ-undecalactone} 172a 174a, 174b
823-22-3 2H-Pyran-2-one, 6-methyltetrahydro- {δ-hexalactone} 172a 174a, 174b
2721-22-4 2H-Pyran-2-one, 6-nonyltetrahydro- {tetradecalactone} 172a 174a, 174b
705-86-2 2H-Pyran-2-one, 6-pentyltetrahydro- {δ-decalactone} 172a 174b, 603, 3370
2847-30-5 Pyrazine, 2-methoxy-3-methyl- {2-methyl-3-methoxypyrazine} 172a 174b, 603, 3370
2882-22-6 Pyrazine, 2-methoxy-5-methyl- {2-methyl-5-methoxypyrazine} 172a 174b
2882-21-5 Pyrazine, 2-methoxy-6-methyl- {2-methyl-6-methoxypyrazine} 172a 174b
13708-12-8 Quinoxaline, 5-methyl- {5-methylquinoxaline} 172a 174a, 174b
34413-35-9 Quinoxaline, 5,6,7,8-tetrahydro- {5,6,7,8-tetrahydroquinoxaline} 172a 174a, 174b
110-27-0 Tetradecanoic acid, 1-methylethyl ester {isopropyl myristate} 172a 174a, 174b
137-00-8 5-Thiazoleethanol, 4-methyl- {4-methyl-5-thiazole ethanol} 172a 174a, 174b

© 2009 by Taylor & Francis Group, LLC

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 Pyrolysis 1169

Table XXV-31
Pyrolysis of Miscellaneous Tobacco Product Components Plus Their Effect on Smoke Composition When Added
to Tobacco
References to
Effect on Mainstream Smoke
Composition, When Component Added
CAS No. Name (per CA Collective Index) Pyrolysis of Individual Component Individually In a Mixture

Cocoa 172b, 2896, 3447 174a, 174c, 603,

3370
Hydrocarbons, aliphatic, 2257, 3616 3269, 3291
tobacco-derived
Licorice 172b, 743, 1356, 2204, 2896 174a, 174c
Phytosterols, tobacco derived 4346
Polyphenol pigment, tobacco-derived 725a, 726
Tobacco 162, 163, 170, 171a, 172c, 276, 277, 369, 521, 522, 532,
536, 1357, 1651, 2071, 2072, 2196, 3190, 3468, 3616,
4150-4153, 4279, 4319, 4332, 25A35, 25A63
Tobacco extract 722, 3456, 3458, 3465-3467, 3470, 3472, 3616, 3877,
4355, 25A35

Table XXV-32
Summary of Tobacco Ingredient Studies from 1994–2005
Number of
Ingredients
Analysis Date Studied Reported Findings/Conclusions Reference

Detailed literature survey
of ingredients added to
U.S. tobacco products
Effect of added tobacco 2002
ingredients on cigarette
MSS chemistry
1994 599 “…it was concluded that there was no evidence that any Doull et al. (1053)
ingredient added to cigarette tobacco produces harmful effects
under the conditions of use in cigarettes.”
333 “The smoke chemistry data revealed changes towards both higher Carmines (603);
and lower amounts of various smoke constituents…This suggests Rustemeier et al.
that the addition of 333 commonly used ingredients to cigarettes (3370)
in three groups did not add to the toxicity of the smoke, even at
the exaggerated levels tested…
“An overall assessment of our data suggests that these
ingredients, when added to the tobacco, do not add to the toxicity
of smoke, even at the elevated levels used in this series of studies.”
2002 482 “In most cases, the flavour mixtures had no statistically significant Baker and Smith
effect on the smoke yields relative to the control cigarette. In a (25A03)
few cases, the small increases or decreases were observed for
some analytes relative to the control cigarette. The smoke yields
of the experimental cigarettes were well within the ranges
observed in the three reference cigarettes.”
(Continued )

© 2009 by Taylor & Francis Group, LLC

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 1170 The Chemical Components of Tobacco and Tobacco Smoke

Table XXV-32 (Continued)

Summary of Tobacco Ingredient Studies from 1994–2005
Number of
Ingredients
Analysis Date Studied Reported Findings/Conclusions Reference

2004 482 “The significances of differences between the test and control Baker et al. (174b)
cigarettes were determined using both the variability of the data
on the specific occasion of the measurement, and also taking into
account the long-term variability of the analytical measurements
over the one-year period in which analyses were determined in
the present study. This long-term variability was determined by
measuring the levels of the 44 “Hoffmann analytes” in a
reference cigarette on many occasions over the one-year period
of this study.
“…It was found that, in most cases, the mixtures of flavouring
ingredients (generally added in parts per million levels) had no
statistically significant effect on the analyte smoke yields relative
to the control cigarette.”
Effect of added tobacco 1997, ≈152 “Although the mutagenic activities appeared to be similar, there were Bioresearch [for
ingredients on cigarette 2002 statistically significant differences in mutagenic activities among the RJRT] (25A09);
MSS biology: sample.” Rodgman (3263,
3264)
a) in vitro genotoxicity [Note: The differences were primarily due to the increase in
and cytotoxicity mutagenicity of the CSC when the humectants (glycerol,
propylene glycol) were not added to the cigarette tobacco and
thus were not present as diluents in the CSC].
2002 333 “Within the sensitivity and specificity of the test systems, the in Carmines (603);
vitro mutagenicity and cytotoxicity of the cigarette smoke were Roemer et al.
not increased by the addition of the ingredients.” (25A49)
2002 482 “The data has been analyzed and demonstrates no additional Massey et al.
activity from the flavoured cigarettes above that of the control (25A43)
products.”
b) MSS inhalation 1997, 2 “It was concluded that addition of the tested humectants singly or Gaworski et al.
2002 (glycerol, in combination had no meaningful effect on the site, extent or (25A27)
propylene frequency of respiratory tract changes associated with smoke
glycol) exposure in rats.”
1997 1 “The results of this 13-week inhalation study indicated that the Gaworski et al.
(menthol) addition of 5000 ppm menthol to tobacco had no substantial (25A24)
effect on the character or extent of the biological responses
normally associated with inhalation of mainstream cigarette
smoke in rats.”
1998 170 “The results indicate that the addition of flavoring ingredients to Gaworski et al.
cigarette tobacco had no discernible effect on the character or (25A25)
extent of the biologic responses normally associated with
inhalation of mainstream cigarette smoke in rats.”
2002 333 “The data indicate that the addition of these 333 commonly used Carmines (603);
ingredients, added to cigarette in three groups, did not increase Vanscheeuwijck et
the inhalation toxicity of the smoke, even at the exaggerate levels al. (25A79)
used.”

© 2009 by Taylor & Francis Group, LLC

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 Pyrolysis 1171

Table XXV-32 (Continued)

Summary of Tobacco Ingredient Studies from 1994–2005
Number of
Ingredients
Analysis Date Studied Reported Findings/Conclusions Reference

c) Mainstream CSC 1999 150 “While tumor incidence, latency and multiplicity data Gaworski et al.
and skin painting occasionally differed between test and comparative reference (25A26)
CSC groups, all effects appeared to be within normal variation
for the model system. Furthermore, none of the changes
appeared to be substantial enough to conclude that the tumor
promotion capacity of CSC obtained from cigarettes containing
cigarettes with ingredients was discernibly different from the
CSC obtained from reference cigarettes containing tobacco
processed without ingredients.”
Pyrolysis of tobacco 2004 291 “The results are compatible with parallel studies in which the Baker and Bishop
ingredients under ingredients are added to tobacco and the effect on cigarette [see pp. 245-246 in
conditions simulating smoke constituents are measured. In general, the number of (172a)]
those in the cigarette “Hoffmann analytes” detected among the pyrolysis products of
burning zone the ingredients, and their levels, are low…Of the 291 tobacco
ingredients pyrolysed, almost a third transfer out of the pyrolysis
zone intact, and almost two thirds transfer at least 95% intact.”
2005 159 “…a further 159 non-volatile and complex ingredients, as well as Baker and Bishop
ingredient mixtures have been pyrolyzed…For the pyrolysis of (172b)
many of the non-volatile ingredients, no “Hoffmann analytes”
were detected among the products.

© 2009 by Taylor & Francis Group, LLC

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 26 Carcinogens, Tumorigens, and
Mutagens vs. Anticarcinogens,
Inhibitors, and Antimutagens
Because of the diverse nature of this chapter, the following
listing of its contents is provided:
Carcinogens, Tumorigens, and Mutagens:
The polycyclic aromatic hydrocarbons:
Other classes of carcinogens, tumorigens,
and mutagens:
Aza-arenes
N-Nitrosamines
N-Heterocyclic amines
Anticarcinogens, Inhibitors, and Antimutagens:
Alternate exposure to carcinogens:
Alternate exposures to polycyclic aromatic
hydrocarbons
Alternate exposures to aza-arenes
Alternate exposures to N-nitrosamines
Alternate exposures to N-heterocyclic amines
Summary:
XXVI.A Carcinogens, Tumorigens,
and Mutagens
In 1990, the U.S. Environmental Protection Agency (EPA)
issued several draft documents in which it defined environ-
mental tobacco smoke (ETS) as a carcinogen and designated
it as a “Group A Carcinogen” (1148, 1148a). Subsequently,
EPA issued a final report on this topic (1148b). Data from vari-
ous epidemiological studies on the incidence of lung cancer
in nonsmokers exposed to ETS were interpreted by the EPA
as indicating that ETS was causally related to lung cancer
in the ETS-exposed nonsmokers. In addition to these epide-
miological data, EPA relied on data from studies on tobacco
smoke composition, particularly the many studies dealing
with the composition of mainstream smoke (MSS) as well as
the smaller number of studies dealing with sidestream smoke
(SSS) composition. Of the limited number of SSS components
for which quantitative data have been obtained on per ciga-
rette yields, many are delivered at higher per cigarette levels
in SSS than in MSS. Many of the SSS components quanti-
fied are those that have been considered as contributors to
respiratory tract or other disease problems, based on results
reported from laboratory animal experiments with individual
compounds. EPA extrapolated these SSS (and MSS) qualita-
tive and quantitative composition data directly to ETS with
little regard for the profound quantitative differences between
MSS and SSS composition and the highly diluted ETS system
© 2009 by Taylor & Francis Group, LLC
78836_C026.indd 1173
and the biological implications of these differences (3255,
3255a, 3257). Of prime concern to EPA were those mss and
sss components that, in one biological system or another, had
been described as tumorigenic at doses far in excess of those
encountered in mss and sss (1148).
The cigarette MSS components of greatest concern to
EPA were thirty-five MSS components listed by Hoffmann
and Wynder (1808) in 1986, a list derived from the 1986
International Agency for Research on Cancer (IARC) mono-
graphs on tobacco smoking (1869, 1870) and expanded in 1990
to forty-three MSS (and tobacco) components by Hoffmann
and Hecht (1727). The Hoffmann and Hecht list was the first
of many lists issued from 1990 through 2001 by Hoffmann
and his colleagues (1727, 1740, 1741, 1743, 1744, 1773), by the
Occupational Safety and Health Administration (OSHA) in
1994 (2825), and by Fowles and Bates in 2001 (1217). These
listings involved tobacco and tobacco smoke components
previously reported to be tumorigenic, carcinogenic, or bio-
logically active in various bioassays with individual compo-
nents. The components of tobacco smoke were particularly
emphasized (3265). Eventually, many of the listed MSS com-
ponents, because of their multiple listings by Hoffmann and
his colleagues, became defined as “Hoffmann analytes.”
Table XXVI-1 is a tabulation of toxicants in tobacco and
tobacco smoke from the IARC 1986 publication (1870) plus
the seven lengthy publications co-authored from 1986 through
2001 by Hoffmann and his colleagues at the American Health
Foundation (1727, 1740, 1741, 1743, 1744, 1773, 1808).
In their 1990 list, Hoffmann and Hecht (1727) classified
forty-three tobacco and/or tobacco smoke components as
“tumorigenic agents in tobacco smoke.” It is interesting to
note that they used the term “tumorigenic” rather than “carci-
nogenic” to define the components. A similar list was issued
by Hoffmann et al. (1773) in 1993. In 1994, OSHA (2825)*
tabulated forty-three tobacco smoke components for which it
claimed there was “sufficient evidence” of carcinogenicity in
humans or animals. For some unknown reason, the OSHA
list included only forty-two items. Obviously, polonium-210
was inadvertently omitted. OSHA listed many of the same
components as Hoffmann and Hecht but included several
components not listed by them (1727) and vice versa.
* OSHA [see pp 15979–15980 in (2825)] presented a table entitled Table
II-2. 43 chemical compounds identified in tobacco smoke for which
there is “Sufficient Evidence” of carcinogenicity in humans or animals.
However, Table II-2 lists only 42 items because 210Po, listed by many
investigators as a hazard, was inadvertently omitted by OSHA.
1173
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78836_C026.indd 1174

1174
Table XXVI-1
Tumorigens, Carcinogens, and Toxicants Listed by Hoffmann and Colleagues
1986 1986 1990 1993 1997 1998 2001 2001
Hoffmann and Hoffmann and Hoffmann Hoffmann and Hoffmann and Hoffmann and Hoffmann et al.
Component IARC (1870)a Wynder (1808) Hecht (1727) et al. (1773) Hoffmann (1740) Hoffmann (1741) Hoffmann (1743) (1744)

Number of tumorigens 52 35 43 43 60 70 68 69
and/or toxicants
Polycyclic Aromatic Hydrocarbons
Benz[a]anthracene 20–70 ng 40–70 ngg 20–70 ng 20–70 ng 20–70 ng 20–70 ng 20–70 ng 20–70 ng
40–70 ngb 40–60 ngj
4–76 ngc
Benzo[b]fluoranthene 4–22 ng 30 ngg 4–22 ng 4–22 ng 4–22 ng 4–22 ng 4–22 ng 4–22 ng
30 ngb
Benzo[j]fluoranthene 6–21 ng 60 ngg 6–21 ng 6–21 ng 6–21 ng 6–21 ng 6–21 ng 6–21 ng
60 ngb
Benzo[k]fluoranthene 6–12 ng NLe 6–12 ng 6–12 ng 6–12 ng 6–12 ng 6–12 ng 6–12 ng
Benzo[a]pyrene 20–40 ng 10–50 ng g 20–40 ng 20–40 ng 20–40 ng 20–40 ng 20–40 ng 20–40 ng
10–50 ngb 10–40 ngi
5–78 ngc
Chrysene 40–60 ngb 40–60 ng g 40–60 ng 40–60 ng NL NL NL NL
Chrysene, 5-methyl- 0.6 ng 0.6 ng 0.6 ng 0.6 ng 0.6 ng 0.6 ng 0.6 ng 0.6 ng
Dibenz[a,h]anthracene 4 ng 40 ng 4 ng 4 ng 4 ng 4 ng 4 ng 4 ng

The Chemical Components of Tobacco and Tobacco Smoke

Dibenzo[a,e]pyrene P d, NYLe NLe NL NL NL P, NYLf P, NYLf P, NYLf
Dibenzo[a,h]pyrene P d, NYLe NLe NL NL NL NL NL NL
Dibenzo[a,i]pyrene 1.7–3.2 ng NL 1.7–3.2 ng 1.7–3.2 ng 1.7–3.2 ng NLf NLf NL f
2–3 ngb
17–32 ngc
Dibenzo[a,l]pyreneg P, NYL P, NYL P, NYL P, NYL P, NYL 1.7–3.2 ngf 1.7–3.2 ngf 1.7–3.2 ngf
Indeno[1,2,3-cd]pyrene 4–20 ng 4 ng 4–20 ng 4–20 ng 4–20 ng 4–20 ng 4–20 ng 4–20 ng
Aza-arenes
Pyridine 16–40 mg NL NL NL 20–200 mgm 10–40 mg 20–200 mgp 20–200 mgs
16–40 mgr
Quinoline NLe NL 1–2 mg 0.2–1.3 mg 1–2 mg 2–180 ng 1–2 ngx 1–2 mg
Dibenz[a,h]acridineh 0.1 ng 0.1 ng g 0.1 ng 0.1 ng 0.1 ng 0.1 ng 0.1 ng 0.1 ng
Dibenz[a,j]acridine 2.7 ng 3–10 ngg 3–10 ng 3–10 ng 3–10 ng 3–10 ng 3–10 ng 3–10 ng
3–10 ngb
7H-Dibenzo[c,g]carbazole 0.7 ng 0.7 ng g 0.7 ng 0.7 ng 0.7 ng 0.9 ng 0.7 ng 0.7 ng
N-Nitrosamines
N-Nitrosodimethylamine 2–20 ng 1–180 ngh 0.1–180 ng 0.1–180 ng 0.1–180 ng 2–180 ng 2–180 ng 2–1000 ng
1–200 ngb 2–180 ngj
N-Nitrosoethylmethylamine 0–2.7 ng 1–40 ngh 3–13 ng 3–13 ng 3–13 ng 3–13 ng 3–13 ng 3–13 ng
0.1–10 ngb 0,1–40 ngj
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78836_C026.indd 1175

Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens

N-Nitrosodiethylamine 0–2.8 ng 0.1–28 ng 0–25 ng 0–25 ng 0–2.8 ng 0–2.8 ng 0–2.8 ng 0–2.8 ng
0–10 ngb
N-Nitrosodi-n-propylamine 0–1 ng 0–1 ng NL NL NL 0–1.0 ng 0–1.0 ng 0–1.0 ng
N-Nitrosodi-n-butylamine 0–3 ng 0–3 ng NL NL NL 0–30 ng 0–30 ng 0–30 ng
N-Nitrosopyrrolidine 0–110 ng 2–110 ngh 1.5–110 ng NL 3–60 ng 3–110 ng 3–110 ng 3–110 ng
2–42 ngb 2–42 ngj
N-Nitrosopiperidine 0–9 ng 0–9 ng NL NL NL 0–9 ng 0–9 ng 0–9 ng
N-Nitrosodiethanolamine 0–36 ng 0–40 ng 0–36 ng NL 0–68 ng 0–68 ng 0–68 ng 0–68 ng
0–90 ngb
N-Nitrososarcosine NL NL NL NL NYL ND e NL NL
N’-Nitrosonornicotine 0.2–3.0 mg 0.12–3.7 mg 0.12–3.7 mg 0.12–3.7 mg 0.12–3.7 mg 120–3.700 ngv 0.12–3.7 mgv 0.12–3.7 mgv
0.13–0.25 mgb
4-(N-Methylnitrosamino)-1- 0.08–0.77 mg 0.12–0.95 mg 0.08–0.77 mg 0.08–0.77 mg 0.08–0.77 mg 0.08–0.77 mg 0.08–0.77 mg 0.08–0.77 mg
(3-pyridyl)-1-butanone 0.08–0.7 mgb
N’-Nitrosoanabasine 0–150 ng 40–400 ngh 0.14–4.6 mg 0.14–4.6 mg 0.14–4.6 mg 0–150 ng NL NL
0–200 ngb 120 ngj
N’-Nitrosoanatabine NL NL NL NL NL NL NL NL
0–3.7 mgb
N-Nitrosomorpholine NL NL NDk in MSS ND in MSS ND in MSS ND in MSS NL NL
Aromatic Amines
Aniline NL 360 ng 360 ng NL NL 360–655 ng 360–655 ngr NL
2-Toluidine 32–160 ng 30–160 ng 30–200 ng 30–200 ng 30–200 ng 30–337 ng 30–337 ng 30–337 ng
30–200 ngb
Aniline, 2,6-dimethyl- NL NL NL NL NL NL 4–50 mgx 4–50 ngx
1-Naphthylamine NL NL NL NL NL NL NL NL
3–4 ngb
2-Naphthylamine 1.7–22 ng 4.3–27 ng 1–22 ng 1–22 ng 1–22 ng 1–334 ng 1–334 ng 1–334 ng
1–22 ngb
Biphenyl, 3-amino NL NL NL NL NL NL NL NL
Biphenyl, 4-amino- 2.4–4.6 ng 2.4–4.6 ng 2–5 ng 2–5 ng 2–5 ng 2–5.6 ng 2–5.6 ng 2–5.6 ng
2–5 ngb
N-Heterocyclic amines k
AaC NL NL NL NL 25–260 ng 25–260 ng 25–260 ng 25–260 ng
MeAaC NL NL NL NL 2–37 ng 2–37 ng NL 2–37 ng
Glu-P-1 NL NL NL NL 0.37–0.89 ng 6.37x–0.89 ng 0.37–0.89 ng 0.37–0.89 ng
Glu-P-2 NL NL NL NL 0.25–0.88 ng 0.25–0.88 ng 0.25–0.88 ng 0.25–0.88 ng
PhIP NL NL NL NL 11–23 ng 11–23 ng 11–23 ng 11–23 ng
IQ NL NL NL NL 0.26 ng 0.3 ng 0.3 ng 0.3 ng

MeIQ NL NL NL NL NL NL NL NL
Trp-P-1 NL NL NL NL 0.29-0.48 ng 0.3–0.5 ng 0.3–0.5 ng 0.3–0.5 ng
Trp-P-2 NL NL NL NL 0.82–1.1 ng 0.8–1.1 ng 0.8–1.1 ng 0.8–1.1 ng

1175
(Continued)
11/24/08 12:38:56 PM

© 2009 by Taylor & Francis Group, LLC

78836_C026.indd 1176

1176
Table XXVI–1 (continued)
Tumorigens, Carcinogens, and Toxicants Listed by Hoffmann and Colleagues
1986 1986 1990 1993 1997 1998 2001 2001
Hoffmann and Hoffmann and Hoffmann Hoffmann and Hoffmann and Hoffmann and Hoffmann et al.
Component IARC (1870)a Wynder (1808) Hecht (1727) et al. (1773) Hoffmann (1740) Hoffmann (1741) Hoffmann (1743) (1744)

Aldehydes and Ketones

Formaldehyde 70–100 mg 5–100 mg 70–100 mg 70–100 mg 70–100 mgl 70–100 mg 70–100 mg 70–100 mgl
20–88 mgb 20–100 mgm 20–100 mgp 20–100 mgs
Acetaldehyde 500–1200 mg 500–1200 mg 18–1400 mg 18–1400 mg 18–1400 mgl 500–1.400 mgu 500–1400 mgu 500–1400 mgu
18–1400 mgb 400–1400 mgm 400–1400 mgp 400–1400 mgs
Propionaldehyde NL NL NL NL NL NL NL NL
Butyraldehyde NL NL NL NL NL NL NL NL
Crotonaldehyde 10–20 mg NL 10–20 mg 10–20 mg NL 10–20 mg NL NL
Acrolein 60–100 mg 50–100 mg NL NL 60–140 mgm 60–140 mg 60–140 mgp 60–240 mgs
25–140 mgb
Acetone 100–250 mg 100–250 mg NL NL 100–650 mgm NL 100–650 mgp NL
2-Butanone NL NL NL NL NL NL NL NL
Volatile Hydrocarbons
1,3-Butadiene NL NL NL NL 20-75 mgl 20-75 mg 20-75 mg 20-75 mg
25-40 mgm 25-40 mgp 25-40 mgs

The Chemical Components of Tobacco and Tobacco Smoke

Isoprene NL NL NL NL 450-1000 mgl 450-1.00 mgu 450-1000 mgu 450-1000 mgu
200-400 mgm 200-400 mgp 200-400 mgs
Benzene 20-50 mg 20-50 mg 12-48 mg 12-48 mg 12–70 mgl 20–70 mg 20-70 mg 20–70 mg
6-70 mg m 12-50 mgp 6-70 mgs
Toluene NL NL NL NL 5-90 mg m NL 20-60 mg p 5-90 mg s
Styrene 10 mg NL NL NL 10 mg 10 mg 10 mg 10 mg
Miscellaneous Organic Compounds
Acetamide 38-56 mgb NL NL NL NL 38–56 mg 38–56 mg 38–56 mg
Acrylonitrile 3.2–15 mgb 3.2–15 mg 3.2–15 mg 3.2–15 mg 3.2–15 mg 3–15 mg 3–15 mg 3–15 mg
Acrylamide NL NL NL NL P, NYL P, NYL P, NYL P, NYL
Hydrazine, 1,1-dimethyl- P, NYL NL P, NYL P, NYL NYL P, NYL P, NYL P, NYL
Maleic hydrazide NL NL NL NL NL 1.16 mg 1.16 mgr
Methanol NL NL NL NL 80–180 mgm 100–250 mg 80–180 mgp 80–180 mgs
100–250 mgr
Methyl isocyanate NL NL NL NL NL 1.5–5 mg NL NL
Nitromethane NL NL NL NL NL NL 0.3–0.6 mg 0.5–0.6 mg
2–Nitropropane 0.2–2.2 mg 0.2–2.2 mg 0.73–1.21 mg 0.73–1.21 mg 0.73–1.21 mg 0.2–2.2 mg 0.7–1.2 mg 0.7–1.2 mg
0.73–1.21 mgb
Nitrobenzene NL NL NL NL NL 25 mg 25 mg 25 mg
Vinyl chloride 1.3–16 ng 1.3–16 ng 1–16 ng 1–16 ng 1–16 ng 11–15 ng 11–15 ng 11–15 ng
11/24/08 12:38:56 PM

1–16 ngb

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78836_C026.indd 1177

Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens

Ethyl carbamate 20–38 ng 20–38 ng 20–38 ng 20–38 ng 20–38 ng 20–38 ng 20–38 mg 20–38 mg
Ethylene oxide NL NL NL NL 7 mg 7 mg 7 mg 7 mg
Propylene oxide NL NL NL NL NL NL 12–100 ng 0–100 ng
Di(2-ethylhexyl) phthalate NL NL NL NL 20 mg 20 mg NL NL
Furan NL NL NL NL 18–30 mgl 18–30 ngu 18–37 ngu 18–37 mgu
20–40 mgm
Benzo[b]furan NL NL NL NL P, NYL P, NYL P, NYL P, NYL
Phenols
Phenol 60–140 mg 60–140 mg 80–60 NL NL 80–160 mg 80–160 mg r 60–180 mg t
o-Cresol 14–30 mg NL NL NL NL NL NL NL
m-Cresol NL NL NL NL NL NL NL NL
p-Cresol NL NL NL NL NL NL NL NL
Catechol 40–350 mg 25–360 mgg 200–400 mg NL NL 200–400 mg 100–360 mg 90–2000 mg
100–350 mgi 200–400 mgr 100–200 mgt
140–500 mgj
Resorcinol 8–80 mgb NL NL NL NL NL NL NL
Hydroquinone 88–155 mgb 110–300 mg NL NL NL NL NL NL
Methyleugenol NL NL NL NL NL 20 ng 20 ng 20 ng
Caffeic acid NL NL NL NL NL NL < 3 mg < 3 mg
Chloroaromatic Compounds
DDT NL NL NL NL 800–1200 ng 800–1.200 ngu 800–1200 mg 800–1200 mg
0.7–1.2 mg b

DDE NL NL NL NL 200–370 ng 200–370 ng 200–370 mg 200–370 mg

Polychlorodibenzo-p-dioxins NL NL NL NL NL NL NL NL
Polychlorodibenzofurans NL NL NL NL NL NL NL NL
Inorganic Components
Hydrazine 24–43 ng 24–43 ng 24–43 ng 24–43 ng 24–43 ng 24–34 mgx 24–43 ng 24–43 ng
Hydrogen sulfide NL NL NL NL 20–90 mg m 10–90 mg 20–90 mgp 20–90 mgs
Arsenic 1–25 mg NL 40–120 ng 40–120 ng 40–120 ng 40–120 ng 40–120 mg 40–120 mg
Beryllium NL NL NL NL NL 0.3 mg 0.5 ng 0.5 ng
Cadmium 9–70 ng NL 41–62 ng 41–62 ng 41–62 ng NL 7–350 ng 7–350 ng
Chromium (vi) 4–70 ng NL 4–70 ng 4–70 ng 4–70 ng 4–70 ng 4–70 ng 4–70 ng
Cobalt 0.2 ng NL NL NL NL 0.13–0.2 ng 0.13–0.2 ng 0.13–0.2 ng
Nickel 0–600 ngb 20–3000 ng 0–600 ng 0–600 ng 0–600 ng 0–600 ng 0–600 ng 0–600 ng
Mercury NL NL NL NL NL 4 ng NL
Lead Pc NL 35–85 ng 35–85 ng 35–85 ng 34–85 ng 34–85 ng 34–85 ng
Polonium-210 0.03 pCi 0.03–1.0 pCi 0.03–1.0 pCi 0.03–1.0 pCi 0.03–1.0 pCi 0.03–1.0 pCi 0.03–1.0 pCi 0.03–1.0 pCi
Selenium Pc NL NL NL NL NL NL NL

(Continued)

1177
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© 2009 by Taylor & Francis Group, LLC

78836_C026.indd 1178

1178
Table XXVI–1 (continued)
Tumorigens, Carcinogens, and Toxicants Listed by Hoffmann and Colleagues
1986 1986 1990 1993 1997 1998 2001 2001
Component IARC (1870)a Hoffmann and Hoffmann and Hoffmann Hoffmann and Hoffmann and Hoffmann and Hoffmann et al.
Wynder (1808) Hecht (1727) et al. (1773) Hoffmann (1740) Hoffmann (1741) Hoffmann (1743) (1744)

Additional Components
Nicotine 1.0–2.3 mg 1–2.5 mg 1.0–3.0 mg NL 0.1–3.0 mgn 1.0–3.0 mg 1.0–3.0 mgq 0.1–3.0 mgt
Carbon monoxide 10–23 mg 10–23 mg NL NL 14–23 mgm 10–23 mg 14–23 mgp 14–23 mgs
Ammonia 50–130 mg 50–170 mgi NL NL 10–130 mgm 10–130 mg 10–130 mgp 10–130 mgs
50–130 mgj
Nitrogen oxides 100–600 mg 50–600 mg NL NL 100–600 mgm 100–600 mg 100–600 mgp 100–600 mgs
Hydrogen cyanide 400–500 mg 400–500 mg NL NL 400–500 mgm 400–500 mg 400–500 mgp 400–500 mgs
a See Table 19 in (1870).
b See Appendix 2 in (1870).
c See Table 20 in (1870)

d P = present, as listed in Appendix 2 in (1870).

e NL= not listed; NYL = no per cigarette MSS yield listed; ND = not detected.

f The yield range listed for dibenz[a,l]pyrene is incorrect. It is the range usually listed for dibenzo[a,i]pyrene. The P,NYL designation should also apply to dibenzo[a,l]pyrene.

g See Table 5 in (1808).

h See Table 6 in (1808).

The Chemical Components of Tobacco and Tobacco Smoke

i See Table 11 in (1808).

j See Table 13 in (1808).

k AaC = 2-amino-9H-pyrido[2,3-b]indole; MeAaC = 2-amino-3-methyl-9H-pyrido[2,3-b]indole; Glu-P-1 = 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole; Glu-P-2 = 2-aminodipyrido[1,2-a:3’,2’-d]

imidazole; PhIP = 2-amino-1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridine; IQ = 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline; MeIQ = 2-amino-3,4-dimethyl-3H-imidazo[4,5-f]quinoline; Trp-P-1 = 3-amino-

1,4-dimethyl-5H-pyrido[4,3-b]indole; Trp-P-2 = 3-amino-1-methyl-5H-pyrido[4,3-b]indole
l See Table 3 in (1740).

m See Table 1 in (1740).

n See Table 2 in (1740).

p See Table 5-1 in (1743).

q See Table 5-2 in (1743).

r See Table 5-3 in (1743).

sSee Table 2 in (1744).

t See Table 3 in (1744).

u Compare yield listed in Table 1 in (1741), Table 5-4 in (1743), and Table 4 in (1744).

v Compare yield listed in Table 1 in (1741) with those listed in (1727, 1740, 1743, 1744).
11/24/08 12:38:57 PM

© 2009 by Taylor & Francis Group, LLC

 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1179
In 1997, Hoffmann and Hoffmann (1740) classified sixty
tobacco and/or tobacco smoke components as “carcinogens in
tobacco and cigarette smoke.” Several components listed by
Hoffmann and Hecht but omitted by OSHA were also omit-
ted by Hoffmann and Hoffmann. A major addition, account-
ing for much of the increase from forty-three to sixty was the
inclusion of the highly mutagenic N-heterocyclic amines.
EPA (1148) incorrectly assessed the health consequences
with regard to lung cancer of the components in the Hoffmann-
Hecht list by stating:
Of the 99 compounds in tobacco smoke that have been studied
in detail, at least 43 are complete carcinogens,* each able on its
own to cause the development of cancer in humans or animals.
The EPA erred in its assessment of the forty-three com-
ponents in the Hoffmann-Hecht list since most have been
shown not to be (1) tumorigenic to any human tissue or (2)
tumorigenic to lung tissue in laboratory animals. These facts
are addressed by comments from Hoffmann and Hecht in the
text accompanying their tabulation. In addition, the few com-
pounds that have been reported to produce tumors in labora-
tory animals have done so at dose levels far in excess of those
encountered in MSS, SSS, or ETS.
Careful examination of the Hoffmann-Hecht list reveals
significant flaws which, if they had been considered at all
by the EPA, would have profoundly affected its conclusions
concerning ETS. It has been known for over five decades that
classifying a substance as “tumorigenic” or “carcinogenic”
can be misleading. These terms should not be misinterpreted
or over-interpreted. Users of tables with headings “tumori-
genic” or “carcinogenic” must be aware of the meaning and
limitations of the terms “tumorigenicity” and “carcinogenic-
ity” when applied to specific compounds or elements.
The misunderstanding and misinterpretation of these
terms are not new. The term “carcinogenesis” and by exten-
sion derivative terms were defined precisely as early as 1923
and its original definition is still listed in various medical
dictionaries: Carcinogenesis is the process whereby a carci-
noma is generated. In the 27th edition (1051c) of Dorland’s
Medical Dictionary, this definition of carcinogenesis is the
same as that listed in the 13th edition (1051b). Some investiga-
tors incorrectly use the term “carcinogenesis” for the produc-
tion of any tumor type not just a carcinoma. The correct term,
if used in this manner, is “tumorigenesis.” The term “carcino-
gen” is often applied, again often incorrectly, to any factor
that induces any type of tumor. Common in the past, but sel-
dom used now, was the term “sarcogenesis” used to describe
sarcoma production, the end-point in studies in which a com-
pound injected subcutaneously induced a sarcoma.
Within twenty-five years of the first successful experi-
ments to produce tumors in animals by skin painting with
solutions of coal tar by Yamagiwa and Ichikawa (4361) and
* OSHA cited the U.S. Surgeon General’s 1989 report (4012) which, in turn,
reproduced the table subsequently presented in Hoffmann and Hecht
(1727).
© 2009 by Taylor & Francis Group, LLC
78836_C026.indd 1179
within a decade of the first successful skin tumor induc-
tions with pure compounds such as dibenz[a,h]anthracene
(DB[a,h]A) [Kennaway and Hieger (2078)] and benzo[a]
pyrene (B[a]P) [Cook et al. (796a, 797), Barry et al. (194)] the
misuse and misunderstanding of the term “carcinogenicity”
had reached such proportions that Shear, an outstanding and
highly regarded U.S. investigator of chemical carcinogenesis,
was invited to put the term in perspective. In 1941, Shear and
Leiter (3627) published an article in which their admonitions
regarding over-interpretation of these terms are as significant
today as they were then:
The term “carcinogenic potency”… is not to be considered as
an invariable property inherent in a compound but is merely
a summary of the results of particular experiments and is
valid only for animals of the species, strain, sex, age, diet,
etc. of the particular animal employed as well as the dose,
menstruum, mode and site of application, etc., of the com-
pound in question … Conclusions regarding the potency of
any given compounds should therefore be interpreted in the
light of the data upon which they are based.
In 1951, Hartwell compiled the second edition (1544) of
his survey on compounds tested for carcinogenicity since
the demonstrated carcinogenicity of DB[a,h]A and B[a]P
in mouse skin-painting experiments. To further the under-
standing of the terms “carcinogen” and “carcinogenicity”
and to minimize their future misuse, Hartwell quoted lib-
erally from the Shear-Leiter publication. He added several
important points, one of which was the following: There is
a tendency on the part of some to consider carcinogenic-
ity or lack of carcinogenicity as characteristic properties
of chemical compounds. In other words, some researchers
treat carcinogenicity as a fixed property of a compound.
This is not a valid approach to thinking about “carcinogens.”
Carcinogenicity is a variable property, depending on a num-
ber of factors. It differs from other properties of a compound
that are fixed, for example, melting point, boiling point,
refractive index, specific gravity, crystalline form. As noted
by Shear and Leiter (3627), by Hartwell (1544), and by many
others, a substance or factor can show a range from carci-
nogenicity to noncarcinogenicity to anticarcinogenicity and
the response will differ in the laboratory depending on the
animal used (species, strain, sex, age), route of administra-
tion (inhalation, ingestion, injection [subcutaneous, intra-
venous, intraperitoneal], skin painting, douching), mode of
administration (single vs. multiple doses, neat, in solution,
as an aerosol or as a vapor), diet supplied the animals, and
cage care.
Hartwell also cautioned:
Another pitfall is the attempt to carry over, without reserva-
tion, to man, conclusions based on animal experiments. We
do not know whether man is more or less susceptible than
mice to particular carcinogens. Some animal species, such
as the rat, rabbit, and dog are much more resistant than is
the mouse, and vice versa, while in the monkey none of the
powerful carcinogens has been shown to produce tumors.
11/24/08 12:38:57 PM
 1180 The Chemical Components of Tobacco and Tobacco Smoke
From an examination of Table XXVI-1, it is obvious that
several classes of components account for the greatest num-
ber of tumorigens classified as significant in tobacco smoke.
Further examination of the number of references cited for
each of them in the pertinent chapters of this book indicates
the magnitude of the research conducted on each class both
within and outside the tobacco industry since the early 1950s.
Sequentially, polycyclic aromatic hydrocarbons (PAHs), aza-
arenes, N-nitrosamines (NNAs), and N-heterocyclic amines
in tobacco smoke have attracted much attention on their iden-
tification, quantitation, precursors, and reduction or elimina-
tion. Tumorigenic components in these four class account for
nearly 60% of the total listed. The following pages contain
brief descriptions of the history and chronology of the four
classes of tobacco smoke components.
The components listed in Table XXVI-1 and by OSHA
(2825) and Fowles and Bates (1217) raise numerous questions
as to why many of them were included. First, attempts to
attribute the “carcinogenicity” of cigarette MSS to a particu-
lar component are questionable. Scores of citations over the
past five decades have been issued by eminent scientists and
health organizations in which it is stated that no single MSS
component or class of components acting either individually
or in concert can explain observations in human smokers or
in laboratory animals treated with heroic doses of MSS. For
example, comments on B[a]P in particular or other tumori-
genic PAHs in general include those by Cook (793) [see also
(796a, 797)], who wrote about B[a]P in cigarette smoke:
The tarry condensates of the smoke obtained by smok-
ing cigarettes in machines … have 3,4-benzpyrene, but the
amount is exceedingly small and there is considerable doubt
about whether the concentration is high enough to produce
carcinogenic action.
In 1981, the U.S. Surgeon General [see p. 36 in (4009)]
stated:
The contribution of BaP or PAH in general to mouse skin
carcinogenesis by cigarette smoke condensate cannot be fully
measured at this time … In the smoking and health program
of the National Cancer Institute … no significant dependence
of carcinogenic potency on BaP content was observed.
The American Association for Cancer Research (26A02)
in its 1984 position paper on smoking wrote:
Studies have presented the profile of the known carcinogens
in tobacco. At present, there is no direct method to assign
priority to any of these substances as putative causal agents
in human lung cancer.
That year, Peto and Doll (26A127) stated: “But 30 years of
laboratory research has yet to identify reliably the important
carcinogenic factors in cigarette smoke.”
The U.S. Surgeon General [see p. 200 in (4010)], on the
subject of N-nitrosamines in tobacco smoke, stated: “There
is lack of direct evidence that these compounds are also
human carcinogens.” This was also the view of Magee, who
first demonstrated the tumorigenicity of N-nitrosamines in
© 2009 by Taylor & Francis Group, LLC
78836_C026.indd 1180
laboratory animals. In 1983, Magee (26A89) noted, “a role
for nitrosamines in the causation of human cancer has not
been established.”
On the basis of the data available, the aromatic amines,
including b-naphthylamine, were discounted in the U.S.
Surgeon General’s 1981 and 1982 reports:
The presence of b-naphthylamine in cigarette smoke has
been demonstrated [Hoffmann et al. (1747)], along with other
carcinogenic aromatic amines [Patrianakos et al. (2900)].
The yield was so low that [the researchers] did not believe
these agents contributed significantly to the risk of bladder
cancer in smokers [see p. 41 in (4009)].
On the basis of quantitative data for aromatic amines in
cigarette smoke, an etiological significance of these traces of
carcinogenic amines in bladder cancer is questionable, even
if one were to consider the total of the aromatic amines and
their metabolites [see pp. 207–208 in (4010)].
Similar comments about other components on the various
lists have been published: arsenic (4010), nickel (4010), polo-
nium-210 (4009, 4010), and benzene (4005).
Many of these MSS and/or tobacco components should
be excluded from the lists on the basis of explicit comments
in the literature by numerous knowledgeable authorities on
their tumorigenicity to laboratory animals at levels deter-
mined in MSS, their lack of tumorigenicity in most instances
on inhalation, and the equivocal evidence showing their
tumorigenicity in humans at levels in MSS. All but four of
the forty-three components have never produced respiratory
tract tumors in laboratory animals exposed to the component
via inhalation. Many have never been tested in an inhala-
tion system, and one component of great interest (B[a]P) has
only produced lung carcinoma via inhalation in animals at an
extraordinarily massive dose.
The following situation should not be overlooked: the MSS
yield determined two, three, or four decades ago for a compo-
nent is not relevant to the MSS yield found by analysis for the
component from more recent or current cigarettes. For exam-
ple, MSS values for dibenz[a,h]acridine and 7H-dibenzo[c,g]
carbazole were obtained with 1959–1960 cigarettes, MSS
values for dibenz[a,j]acridine from 1959–1960 and from 1963
cigarettes, the MSS value for DB[a,h]A is from 1963 cigarettes,
the MSS value for 5-methylchrysene is from 1973 cigarettes,
and the MSS value for N-nitrosodiethanolamine (NDELA) is
from commercial cigarettes manufactured in or before 1981.
It is well recognized, as indicated in Figure XXVI-1, that the
variety of cigarette design technologies (efficient filtration,
filter-tip additives, processed tobacco materials [reconstituted
tobacco sheet, RTS, expanded tobaccos], air dilution [porous
paper, filter-tip perforations], and paper additives) has progres-
sively reduced the sales-weighted average MSS total particu-
late matter (TPM) by almost 70% from 40 mg/cigarette in the
early 1950s to less than 12 mg/cigarette in the late 1980s. These
eight cigarette design technologies have been defined, even by
various opponents of cigarette smoking, as significant in the
design of a “less hazardous” cigarette [Wynder and Hoffmann
(4319, 4332), USPHS (4005, 4009), Gori (1333), Hoffmann and
Hoffmann (1740, 1743, 1744)].
11/24/08 12:38:57 PM
 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1181

Replacement of all-flue-cured or all-Oriental

1913 tobaccos with a blend of flue-cured, burley,
and Oriental tobaccos

50.0 3.00
Filter tips
Reconstituted tobacco
2.50
40.0 Paper additives
Paper porosity
Expanded tobacco 2.00
Ventilation

NICOTINE, mg
30.0
‘TAR,’ mg

1.50

20.0
1.00

10.0
0.50

‘TAR’ NICOTINE
0.0 0.00
1954 1958 1962 1966 1970 1974 1978 1982 1986
Year

Figure XXVI-1  “Tar” and nicotine deliveries, sales weighted average basis.

At the same time that the reduction of delivery of MSS

TPM was accomplished, the composition of the MSS was Formaldehyde probable human carcinogen
N-Nitrosodimethylamine (NDMA) probable human carcinogen
altered. For example, for MSS TPM, the B[a]P content—
N-Nitrosodiethylamine (NDEA) probable human carcinogen
expressed as ng B[a]P/mg TPM—has decreased about 33%
N-Nitrosopyrrolidine (NPYR) probable human carcinogen
(from 1.2 ng/mg TPM to 0.8 ng/mg TPM) during the same 2-Toluidine listed only as an irritant,
time period. The U.S. Surgeon General in his 1979 report not as a carcinogen
(4005) summarized the B[a]P data for a commercial cigarette Benz[a]anthracene (B[a]A) listed only as an animal carcinogen
sold in the United States from 1954 to 1979. N’-Nitrosonornicotine (NNN) listed only as an animal carcinogen
As noted by Rodgman and Green (3300), Gold et al., col- 4-(N-Methylnitrosamino)-1- no relevant information available
leagues of Ames, as recently as 1998 questioned the extrapo- (3-pyridinyl)-1-butanone (NNK) re health effects
lation of laboratory animal tumorigenesis data generated by N-Nitrosodiethanolamine (NDELA) probable human carcinogen
the use of a maximum tolerated dose (MTD) to a human situ- Cadmium probable human carcinogen
ation. They stated (1318a):
Extrapolation of cancer potency results from MTD studies to Despite these and other equivocal statements, OSHA
real-life exposures is not scientifically supportable. stated with great certainty:
From these considerations and the information presented The corroborative evidence of the carcinogenic activity of
later, it is obvious that many of the components could and should tobacco smoke provided by animal bioassays and in vitro
be removed from the various Hoffmann-co-authored lists that studies and the chemical similarity between mainstream
smoke and ETS clearly establish the plausibility that ETS is …
subsequently led to the “Hoffmann analyte” phenomenon.
a human lung carcinogen.
In its 1994 report on indoor air quality, OSHA (2825)
dealt at some length with ETS. It presented a list of forty- Of the components in the various lists, the four classes
three tobacco smoke components for which it claimed “there of tobacco smoke components investigated in greatest detail
is sufficient evidence of carcinogenicity in humans or ani- during the past five decades were the PAHs, aza-arenes,
mals.” Comparison of the OSHA list with that of Hoffmann NNAs, and the N-heterocyclic amines. Because of the wealth
and Hecht (Table XXVI-1) reveals numerous similarities plus of background information available on PAHs demonstrated
some differences. OSHA (2825) described ten of its listed to be tumorigenic in laboratory animals, extensive research
tobacco smoke “carcinogens” in the following less-than-pos- (isolation, identification, quantitation, precursors, removal,
itive terms: prevention of formation, etc.) was conducted in the 1950s and

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78836_C026.indd 1181 11/24/08 12:38:58 PM

 1182 The Chemical Components of Tobacco and Tobacco Smoke
1960s on this compound class in tobacco smoke. The reason
for selection of this class of compounds was obvious.
It has been estimated that more research funds were
expended since the 1930s on the study of tumorigenic PAHs
in general (and B[a]P in particular) than on any other class
of compounds. The results of thousands of investigations on
PAHs (their synthesis, biological properties [tumorigenicity,
mutagenicity], metabolism, sources [air pollutants, industrial
oils and tars, tobacco smoke, foodstuffs, beverages, etc.],
isolation, quantitation, reduction, etc.) have been published.
Similar studies, but to a much lesser degree, have been con-
ducted on the aza-arenes. Since the early 1950s, over 500 PAHs
and slightly fewer than 300 aza-arenes have been reported as
tobacco smoke components. The per cigarette yields of most
of the PAHs and aza-arenes are in the subnanogram range.
In the early 1950s, the discovery of the tumorigenicity by
Barnes and Magee (192) of an NNA in laboratory animals ini-
tiated a flurry of research on the NNAs, initially in foodstuffs
and subsequently (mid-1960s) in tobacco smoke. In contrast
to the great number of PAHs and aza-arenes identified in
tobacco smoke, fewer than sixty NNAs have been identified
in tobacco and/or tobacco smoke to date. In the mid-1970s,
Japanese investigators in their investigations of various cooked
foodstuffs reported the isolation and identification of several
N-heterocyclic amines derived pyrogenetically from amino
acids and proteins [Sugimura et al. (3829, 3829a), Sugimura
(3828b, 3828c)]. Subsequently, several of the N-heterocyclic
amines were reported to possess inordinately high mutagenici-
ties in the Ames test with Salmonella typhimurium, be tumori-
genic in the mouse skin-painting bioassay, and to be present in
cigarette smoke condensate (CSC) at low nanogram or subnano-
gram levels [Sato et al. (3415a), Yamashita et al. (4367, 4368)].
Fewer than a dozen of the highly mutagenic N-heterocyclic
amines have been reported as CSC components.
XXVI.A.1 The Polycyclic Aromatic Hydrocarbons
In the case of the PAHs in general and the thirteen specific
PAHs listed in Table XXVI-1, many of the assertions about
them in tobacco smoke since the early 1950s have either
been shown to be incorrect or, in several instances, highly
equivocal.
Several sources of PAHs in cigarette MSS, originally con-
sidered to be the major sources of the PAHs, were shown to
be either incorrect (effluents from lighting source, such as
matches and butane- or hexane-fueled lighters) or insignifi-
cant (PAH-containing air pollutants deposited on the surface
of the tobacco leaf during growing, harvesting, and curing)
or primarily derived from cigarette paper combustion.
Long-chained saturated hydrocarbons were originally
defined as the major precursors in tobacco of PAHs in tobacco
smoke. Subsequently, it was shown that the contributions of
tobacco terpenes and phytosterols to the levels of MSS or
SSS PAHs exceeded those of the saturated hydrocarbons.
In the mid- to late 1950s, it was proposed (3241, 3242) that
the per cigarette yields of MSS PAHs would be diminished by
removal of saturated hydrocarbons, phytosterols, and terpenes
© 2009 by Taylor & Francis Group, LLC
78836_C026.indd 1182
from the tobacco by extraction with nonpolar solvents such as
hexane, a process dubbed the “dry cleaning” of tobacco.* It
was proposed that the reduced MSS PAH level in the CSC
from cigarettes fabricated with extracted tobacco would be
accompanied by reduced tumorigenicity to mouse skin of the
extracted tobacco CSC [Wynder and Wright (4354)]. In 1982,
Brunnemann and Hoffmann, members of a research group
that formerly proposed removal of wax-like compounds con-
sidered to be the precursors of the PAHs in smoke, advocated
addition of such compounds to tobacco (480).
Also in the late 1950s, it was proposed to use high-nitrate
tobacco in the tobacco blend or add nitrate to the blend to
modify the combustion process during smoking to decrease
the MSS PAH yields [Hoffmann and Wynder (1797, 1798)]. In
direct contrast was a 1982 proposal: Because of the involve-
ment of nitrate and nitrogen oxides generated from it in the
pyrogenesis of NNAs, use low-nitrate tobaccos in the blend
or remove the nitrate from tobacco as a means to control
NNAs in MSS (and SSS) (480).
The proposal that high molecular weight PAHs, includ-
ing B[a]P, could be removed from MSS by selective filtration
was shown to be incorrect. Selective filtration from MSS is
possible only with compounds that have an appreciable vapor
pressure, that is, they are found in both the particulate and
vapor phases of MSS. For example, the low molecular weight
phenols and the volatile NNAs are sufficiently volatile to be
selectively filtered from MSS, but the vapor pressures of most
PAHs of interest (B[a]P, DB[a,h]A, B[a]A) are too low for
selective filtration to be effective.
B[a]P in MSS was proposed as an “indicator” of (a) the
tumorigenicity of mainstream CSC to mouse skin, (b) the
levels of PAHs with four or more rings, and (c) the levels of
tumorigenic PAHs. In none of these cases is the level of B[a]P
a valid “indicator.” (Similarly, phenol, proposed as an “indi-
cator” of the level of low molecular weight promoting phenols
in cigarette MSS, was shown not to be a valid “indicator.”)
Assertions that the probability was extremely low that
alkylated PAHs (methyl- and dimethyl-PAHs) would occur in
tobacco smoke were demonstrated to be incorrect. Subsequently,
even polyalkylated PAHs such as pentamethyl- and hexamethyl
PAHs were identified in tobacco smoke, their major precur-
sor being the high molecular weight tobacco terpenes such as
solanesol [Snook et al. (3757)].
Assertions that cyclopentabenzanthracenes could not
occur in tobacco smoke were incorrect. Numerous cyclo-
pentabenzanthracenes were identified in MSS, their major
* The concept of extraction of tobacco with an organic solvent to remove
PAH precursors was not new. Roffo (3327) reported that extraction of
tobacco with organic solvents such as ethyl alcohol, chloroform, acetone,
petroleum ether, paraffin hydrocarbons, or benzene resulted in a reduc-
tion of the tumorigenicity of the tar generated by destructive distillation
of the extracted tobacco compared to the tar generated by destructive
distillation of the unextracted (control) tobacco. Roffo did not study the
smokes from cigarettes fabricated with the extracted and unextracted
tobaccos. He suggested that the extraction removed the phytosterols from
the tobacco, which he considered the major precursor of the PAHs in the
destructive distillate and in tobacco smoke.
11/24/08 12:38:58 PM
 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1183
N
Dibenz[a,h]acridine, I
Dibenz[a,h]anthracene, IV
Figure XXVI-2  Structural similarity of several polycyclic aromatic hydrocarbons and aza-arenes.
precursor being the phytosterols [Snook et al. (3736, 3756,
3758, 3759)].
PAHs in tobacco smoke are formed by either (a) a deg-
radation-combination mechanism or (b) an aromatization
mechanism involving a single molecule. Studies showed that
both mechanisms are operative.
To bolster several arguments concerning PAHs in MSS, it
was incorrectly asserted by some investigators that the fate of
an individual tobacco component during experimental pyrol-
ysis in an inert atmosphere and at a temperature approximat-
ing that of the cigarette coal was the same as its fate in the
tobacco matrix during the cigarette smoking process. This
assertion was shown to be incorrect by several investigators,
including Schmeltz et al. (3512), members of the same group
that originally proposed the equivalency of the fate of tobacco
components during pyrolysis and the smoking process.
The tumorigenicity of CSC to mouse skin is due to its con-
tent of PAHs with four or more fused rings. Even though it
was claimed that the PAHs are the only initiators in CSC, the
levels and tumorigenicities of the PAHs in CSC accounted
for no more than 2% to 2.5% of the observed tumorigenic
response in mouse or other rodent skin-painting bioassays.
With so many incorrect or equivocal assertions about the
MSS PAHs issued by anti-tobacco smoking investigators
over the last four decades (see Table XXVI-2), it was some-
what surprising that both OSHA and EPA were so willing to
accept the premise that the thirteen PAHs in the Hoffmann-
Hecht and/or the OSHA lists contributed significantly to the
alleged tumorigenic effects of MSS and ETS in the respira-
tory tract of active and passive smokers, respectively.
XXVI.A.2 Other Classes of Carcinogens,
Tumorigens, and Mutagens
XXVI.A.2.a Aza-Arenes
Within a few years of the discovery of the tumorigenicity to
mouse skin of the PAHs DB[a,h]A (2078) and B[a]P (194,
796a, 797), investigations on the tumorigenicity of aza-
arenes began. The aza-arenes selected for study were those
structurally related to the PAHs already demonstrated to be
© 2009 by Taylor & Francis Group, LLC
78836_C026.indd 1183
H
N
N
Dibenz[a,j]acridine, II 7H-Dibenzo[c,g]carbazole, III
Dibenz[a,j]anthracene, V
tumorigenic. The first aza-arenes studied were those corre-
sponding structurally to the dibenzanthracenes in which one
meso-carbon was replaced by a nitrogen atom. From a com-
parison of their tumorigenicities (mouse skin-painting exper-
iments), Barry et al. (194) reported that the tumorigenicity of
several dibenzacridines was much less than the correspond-
ing PAH, for example, dibenz[a,h]acridine {I} was reported
to be much less tumorigenic than DB[a,h]A {IV} under the
same experimental conditions.
For the PAHs, much of the early research on their synthe-
sis and tumorigenicity was conducted by the Kennaway group
(Barry, Cook, Hewett, Hieger, Lindsey, Schoental) in the
United Kingdom, by groups headed by Fieser and Newman
in the United States, and by the Clar group in Germany. For
the aza-arenes such as the benzacridines, much of the early
research was conducted by the Lacassagne group (Buu-Hoï,
Daudel, Lavit-Lamy, Zajdela) in France.
It has been known for nearly six decades [see the review
by Lacassagne et al. (2247a)] from the comparative tumori-
genicity studies involving structurally similar PAHs and aza-
arenes (see Figure xxvi-2) that the aza-arenes are much less
tumorigenic than the PAHs to mouse skin [compare DB[a,h]
A {IV} vs. dibenz[a,h]acridine {I} and DB[a,j]A {V} vs.
dibenz[a,j]acridine {I} or 7H-dibenzo[c,g]carbazole {III}].
These observations on tumorigenicity plus the reported
amounts of the three aza-arenes in cigarette MSS relative to
the amount of B[a]P certainly raises doubts as to the impor-
tance of the aza-arenes as significant tobacco smoke tum-
origens. In Table XXVI-1, B[a]P is listed as occurring in
cigarette MSS in yields ranging from 20 to 40 ng/cigarette,
whereas the yields of aza-arenes I, II, and III are listed at
0.1, 3 to 10, and 0.7 ng/cigarette, respectively. Even though a
more realistic range for B[a]P in the MSS of cigarettes mar-
keted over the past two decades would be 5 to 20 ng/cigarette
rather than 20 to 40 ng/cigarette, the ratios of B[a]P yield
to those of dibenz[a,h]acridine and 7H-dibenzo[c,g]carba-
zole are substantial. This of course assumes that the yields
for the three aza-arenes that were included in Table XXVI-1
are correct! It is obvious that the listed aza-arene yields are
not meaningful for recently manufactured cigarettes whose
design includes technologies not used in the late 1950s and
11/24/08 12:38:59 PM
 1184 The Chemical Components of Tobacco and Tobacco Smoke
Table XXVI-2
The Polycyclic Aromatic Hydrocarbon Paradoxes
Assertion
Major source of PAHs in cigarette MSS is the lighting source
(match, flammable fuel-charged lighter, gas burner in laboratory).
Because bulk pyrolysis of cigarette paper yielded PAHs, cigarette
paper (representing about 5% of the cigarette weight) was defined
as the major source of PAHs in cigarette MSS [Cooper et al. (817),
Cardon et al. (594)].
PAHs in cigarette MSS are the result of transfer of PAHs from the
surface of air pollutant-contaminated tobacco to MSS.
Since none of the factors noted above (means of cigarette lighting,
cigarette paper, air pollutant contamination) was the source of
PAHs in cigarette MSS, the source must be one or more of the
tobacco components. However, even in 1957, the presence of B[a]
P in tobacco smoke was questioned [cf. Fieser (1181)].
According to Wynder and Hoffmann, PAHs in cigarette smoke
were the only major tumor initiators in mouse skin carcinogenesis
(4332):
The many detailed data obtained in studies of tobacco
carcinogenesis on mouse skin exclude with some
certainty that major tumor initiators other than the PAH
type play a role in this assay system.
B[a]P, because of its potency in skin-tumor carcinogenesis and
level in MSS, was considered the major PAH of concern in
tobacco smoke. In the 1981 Surgeon General’s report (4009), it is
stated:
Benzo[a]pyrene appears to be the most important single
member of this class of compounds [the PAHs], taking
into consideration both its concentration and its relative
carcinogenic potency.
Initially, Fieser did not believe the evidence was sufficient to
demonstrate that B[a]P was present in tobacco smoke. He stated
that if B[a]P were present, its precursor would be tobacco
cellulose (1181).
Removal of lipophilic PAH precursors from tobacco by solvent
extraction reduced the MSS PAH levels and the tumorigenicity
(mouse skin-painting) of the CSC Wynder (4294), Wright (4282),
Wynder and Wright (4354)]. This led to recommendations to
remove the lipophilic tobacco components. Later, Wynder et al.
(4332) minimized the effectiveness of the removal of the lipophilic
tobacco components. Wynder and Hoffmann (4310) defined
tobacco extraction as “impractical both technically and
economically.” Wynder and Hecht (4306d) and the Surgeon
General (4005) described tobacco extraction as “of academic
interest.” Eventually, Wynder’s colleagues recommended addition
of lipophilic compounds, e.g., n-hentriacontane, to tobacco (480)
to offset effect of nitrate-derived NOx in NNA formation.
© 2009 by Taylor & Francis Group, LLC
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Contradiction
The PAH level in cigarette MSS was independent of lighting source: Cigarettes lit by
an electric lighter gave the same PAH levels as those lit by matches, fuel-charged
cigarette lighters, or a gas flame.
Comparison of PAH yields, including B[a]P, produced by bulk pyrolysis of cigarette
paper vs. pyrolysis of the paper in a cylindrical form approximating its configuration in
the cigarette revealed that the cylindrical configuration combustion produced very little
PAHs (or B[a]P) vs. bulk pyrolysis [Wright (4281)].
MSS PAH level was not due to transfer of contaminant PAHs transfer from the tobacco
rod to smoke: B[a]P injected into the tobacco rod produced very little increase in the
MSS B[a]P level. Most of the injected B[a]P was destroyed during smoking process.
Because the fragmentary evidence presented, the presence of PAHs, particularly B[a]P,
in tobacco smoke was questioned by such noted PAH experts as Fieser (1181) whose
colleagues identified B[a]P in roasted coffee beans but were unable to identify it in
tobacco smoke. Eventually, because of the isolation by Hoffmann of B[a]P in
crystalline form from cigarette MSS (4307), its presence in MSS became universally
accepted.
Mouse skin-painting studies with B[a]P solutions at concentrations much in excess of
that in CSC produced no skin carcinomas in rabbits or mice [Wynder et al. (4351),
Warshawsky et al. (26A180)]. Similarly, use of more reasonable doses of CSC in
skin-painting studies instead of the massive doses usually used resulted in neither
papilloma nor carcinoma formation [Wynder et al. (4351), Gori (1329, 1330, 1332,
1333), NCI (2683)].
Subsequent studies indicated the major precursors in tobacco of PAHs in its smoke
were not cellulose and lignin but were the lipophilic tobacco components. Rodgman
and Cook (3269, 3286, 3291) and Severson et al. (3616) reported that terpenoids,
phytosterols, and saturated hydrocarbons were PAH precursors
Biological activity of CSC from extracted tobacco was decreased but to a much lesser
extent than decrease in MSS PAH (and B[a]P) yields. This resulted from two
unanticipated effects of extraction on the tobacco and its smoke: Extracted lipophilic
compounds included various inhibitors (saturated hydrocarbons) and anticarcinogens
(a-tocopherol, b-sitosterol, cholesterol, D-limonene, duvanediols) which have been
reported to offset the tumorigenicity of PAHs.
• Residual tobacco after extraction contains higher levels of lignin, cellulose, and
pectins. All of these generate promoting/ cocarcinogenic phenols during the smoking
process: Levels of low molecular weight phenols in MSS were increased.
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 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1185
Table XXVI-2 (Continued)
The Polycyclic Aromatic Hydrocarbon Paradoxes
Assertion
PAHs in cigarette smoke are generated by one or other of the
following mechanism:
• Organic compounds in tobacco are degraded to simpler
molecules during the pyrolysis processes occurring in the
burning cigarette and these simpler molecules recombine to
PAHs (degradation-combination mechanism) [cf. Badger et al.
(142, 143) and earlier papers].
• During the pyrolysis processes occurring in the burning
cigarette, high molecular weight compounds in tobacco undergo
unimolecular cyclization, dehydration, aromatization, ring
expansion , etc. to form PAHs (aromatization reaction)
[Rodgman and Cook (3269, 3286)].
Inhaled cigarette smoke is the responsible agent for respiratory tract
cancer, particularly squamous cell carcinoma of the lung, in
smokers. It was implied in the late 1950s and in the 1960s that the
responsible agent in MSS may be the PAHs, particularly B[a]P.
Since B[a]P and other known tumorigenic PAHs account for so
little (< 2%) of the observed biological effect in mouse skin-
painting studies, two possibilities were proposed: A PAH whose
tumorigenicity was equivalent to that of B[a]P was present at a
substantially higher level (25 to 50 times) than B[a]P or there was
an unknown “supercarcinogenic” PAH in CSC, present at a level
similar to that of B[a]P but whose activity was 25 to 50 times that
of B[a]P [Wright (4282)].
Since B[a]P in CSC acting alone accounts for less than 2% and the
total PAH fraction accounts for less than 3% of the observed
biological response in mouse skin-painting studies and no
“supercarcinogenic” PAHs is present, additional mechanisms are
needed to explain the biological effect: The mechanisms of
promotion and cocarcinogenesis of tobacco smoke components
(phenols, etc.) may explain the observed effect in skin-painting
studies with CSC.
Wynder and Hoffmann (4317) reported that doubling the level of
tumorigenic 17 PAHs in CSC produces “a statistically significant
increase in tumor yield.”
© 2009 by Taylor & Francis Group, LLC
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Contradiction
The mechanism of PAH formation is not an either-or situation. Laboratory data
indicated that both mechanisms were operative in PAH formation in the burning
cigarette. Evidence for the unimolecular aromatization reaction was provided by
pyrolysis data and cigarette “spiking” data with phytosterols. In this instance, the
relatively high levels of chrysene and cyclopentaphenanthrene vs. B[a]P were more
readily explained by the unimolecular aromatization of the tetracyclic sterol.
Inhalation experiments with laboratory animals exposed for their lifetime to cigarette
MSS consistently failed to produce pulmonary squamous cell carcinoma [Essenberg
(1161-1163), Leuchtenberger et al. (26A81, 26A82, 26A83), Henry and Kouri (1621,
1622)], the lung tumor type reported to be associated with smoking in humans. Similar
exposures of laboratory animals to vehicular exhaust gases produced pulmonary
squamous cell carcinoma [Mauderly et al. (2505)].
Inhalation studies with B[a]P at levels comparable to those in cigarette MSS were
consistently negative. Tumor production at extremely high levels of inhalation exposure
to B[a]P were described as “equivocal” [RTECS (3085)].
From a study with roofers exposed via inhalation to levels of B[a]P equivalent to
the daily inhalation of MSS from over 700 cigarettes, Selikoff et al. (3584a) concluded:
If a high level of exposure to benzo[a]pyrene has any relation to lung cancer,
the effect must be small…If a high level of occupational exposure to benzo[a]
pyrene by way of inhalation results in little if any increase in the risk of lung
cancer — then it seems unlikely that the extremely small amount of benzo[a]
pyrene in cigarette smoke can account for the high degree of association
between cigarette smoking and lung cancer.
After a year and a half unsuccessful search, attempts to find either the highly
tumorigenic PAH present at a high level or the “supercarcinogenic” PAH were
discontinued [Wright (4282)]. Neither proposal has resurfaced since the late 1950s.
The promoting/cocarcinogenic effect of phenols on PAH tumorigenicity was offset by
the following:
• Removal of the low-molecular weight phenols by selective filtration of smoke “does
not change significantly the biological activity of the resulting condensate.” [Hecht
et al. (1582, 1583)].
• Phenol inhibited the tumorigenicity of PAHs such as B[a]P [Van Duuren et al. (4029,
4035)].
• Inclusion of known initiators, promoters, and cocarcinogens in tobacco smoke in the
calculation explained less than 5% of the observed biological effect in skin-painting
studies.
The following contradictory evidence was reported: Increasing the B[a]P level in CSC
by a factor of 10 produced no increase in the tumorigenicity of CSC [Roe (3310,
3311)]. Increasing the level of B[a]P by a factor of 30 produced no increase in the
tumorigenicity of the CSC in mouse skin-painting studies [Lazar et al. (2320)].
(Continued)
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 1186 The Chemical Components of Tobacco and Tobacco Smoke
Table XXVI-2 (Continued)
The Polycyclic Aromatic Hydrocarbon Paradoxes
Assertion
As proposed many times by Wynder, Hoffmann, and their
colleagues (1766, 4304, 4317, 4319, 4330, 4355), the B[a]P level in
CSC is an “indicator” (or “marker”) of the following:
• The levels of the tetracyclic and higher PAHs, particularly those
that are tumorigenic.
• The tumorigenicity of the cigarette smoke condensate in mouse
skin-painting studies.
Tumorigenicity of PAHs, e.g., B[a]P, is inhibited by representative
hydrocarbons (C31H64 and C35H72) in the saturated hydrocarbon
(SHC) fraction of CSC at SHC:B[a]P ratios much less than that
found in CSC [4314, see p. 370 in (4332)].
Reports of the presence of DMB[a]A in MSS CSC [Pietzsch
(2962), Kröller (2191)] were criticized because “the formation of a
dialkylated benz[a]anthracene during pyrolysis appears
questionable.” [Cook (796), Wynder and Hoffmann (4332)].
Report of presence of 1,2-dihydro-3-methylbenz[j]aceanthrylene
(3-methylcholanthrene) in CSC [Kröller (2191)] was criticized by
Wynder and Hoffmann (4332):
Since this carcinogenic hydrocarbon has not yet been
found in any other combustion product, it remains a
doubtful assumption that it is present in tobacco smoke.
Dibenzo[a,l]pyrene (dibenzo[def,p]chrysene) is present in CSC
and the pyrolysate from saturated tobacco hydrocarbons [Wynder
et al. (4355)]. It was identified on the basis of agreement between
spectral data for the isolate and those published for a synthetic
PAH [Lyons and Johnston (2430), Lyons (2427, 2428), Wynder
and Wright (4354), Rodgman and Cook (3273), Pyriki (3033),
Bonnet and Neukomm (398, 399)].
Addition of nitrate to the tobacco blend significantly reduced MSS
yields of “tar,” PAHs, and phenols. The odd-electron compound
NO generated during the smoking process interrupted the free
radical mechanism of formation of PAHs [Hoffmann and Wynder
(1797)]. The % tumor-bearing animals (%TBA) of the resulting
CSC was also reduced by about 80%. On the basis of these results,
nitrate addition or use of high-nitrate tobaccos was proposed.
© 2009 by Taylor & Francis Group, LLC
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Contradiction
Ample evidence indicated these premises are invalid:
• No significant correlation between levels of B[a]P and other PAHs in pyrolysates
from pyrolysis studies [Lam (2255, 2257)].
• Contradictory data provided from the studies of Wynder et al. (4355, 4356),
Campbell and Lindsey (583), and Severson et al. (3616).
• No significant correlation between levels of B[a]P and chrysene as reported by
Rodgman and Cook (3269) or B[a]P and B[a]A [Gori (1329, 1330, 1332, 1333) in
cigarette smoking studies.
• No significant correlation between tumorigenicity of over 130 test and reference
CSCs to mouse skin and their B[a]P and/or B[a]A content [Gori (1329, 1330, 1332,
1333), NCI (2683)].
• In non-CSC-related studies, Warshawsky et al. (26A180) found in their study of the
carcinogenic potential of mixtures that the carcinogenic “activity of a mixture cannot
be accounted for by the level of benzo[a]pyrene present.”
Inhibitors and anticarcinogens more potent in their effect against PAHs than the
saturated hydrocarbon fraction in mouse skin carcinogenesis were identified in CSC
(phytosterols, a-tocopherol, duvanediols, D-limonene): Their concentrations relative to
that of the PAHs are far in excess of that required to elicit anticarcinogenesis.
Snook et al. (3756, 3757) reported identification of numerous alkyl-, dialkyl-, and
multialkyl-B[a]As in CSC. Subsequent research indicated a host of mono- to
pentaalkyl-PAHs in the CSC. Their major precursors were tobacco terpenoid
compounds, e.g., solanesol, neophytadiene.
Several benzo[a]cyclopentanthracenes, structurally similar to 1,2-dihydro-3-
methylbenz[j]aceanthrylene (3-methylcholanthrene, a methylbenzo[a]cyclopent[fg]
anthracene) have been identified in CSC: These included an unmethylated
benzocyclopentanthracenes, originally reported erroneously as 1,2-dihydrobenz[j]
aceanthrylene (cholanthrene) by Rodgman and Cook (3273), 2,3-dihydro-1H-benzo[a]
cyclopent[h]anthracene and 9,10-dihydro-9H-benzo[a]cyclopent[j]anthracene [Bonnet
and Neukomm (394, 397-399), Ahlmann (39), Bonnet (392), Pyriki (3033), Rodgman
and Cook (3273)].
Lavit-Lamy and Buu-Hoï (2314) demonstrated that the synthetic PAH originally
defined as dibenzo[a,l]pyrene (dibenzo[def,p]chrysene) and spectrally identical with the
tobacco smoke isolate was actually dibenz[a,e]aceanthrylene (dibenzo[a,e]
fluoranthene), a fact accepted by Hoffmann and Wynder (1798). Dibenzo[def,p]
chrysene (dibenzo[a,l]pyrene) was subsequently identified in tobacco smoke by Snook
et al. (3756), but no quantitative data were reported. In citations of dibenzo[a,l]pyrene
as a “tumorigenic agents in tobacco smoke,” Hoffmann and his coauthors (1727, 1740,
1741, 1743, 1744, 1773), IARC (1869, 1870), and EPA (1148) indicated only that it
was “present.” Whether its “presence” was based on the erroneous dibenzo[a,l]pyrene
reports from the 1950s or the authentic dibenzo[a,l]pyrene report of Snook et al. (3756)
is unclear.
Reductions in these deliveries were confirmed (3246, 3286), but they were less than
those originally proposed. In fact, in the first NCI-TWG study (1329), doubling the
nitrate level produced the following changes: “Tar”, -7%; phenanthrene, -9%; B[a]P,
+23%; B[a]A, -17%; phenol, -10%; nitric oxide; +111%. Doubling the nitrate level
decreased the %TBA by about 20%. Later data showed that adding nitrate increased
volatile NNAs and tobacco-specific N-nitrosamines (TSNAs) in smoke. Nitrate removal
or use of low-nitrate tobaccos was proposed (Brunnemann and Hoffmann (480).
Hoffmann and colleagues included NNAs and TSNAs in their list of tumorigens or
carcinogens in tobacco smoke.
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 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1187
Table XXVI-2 (Continued)
The Polycyclic Aromatic Hydrocarbon Paradoxes
Assertion
According to Hoffmann and Wynder, increasing the number of
cuts/inch (decreasing the cut width) for the tobacco filler reduces
the delivery of CSC and B[a]P (1793).
PAHs are removed selectively by filters treated with reagents
(chloranil, picric acid, 2,4,7-trinitrofluorenone) that form stable
complexes with individual PAHs [Szent-Gyorgi (3847)].
Because of the nature of the cigarette smoke aerosol, Wynder
and Hoffmann (4311) considered selective filtration of a specific
smoke component or class of smoke components such to be an
“impossibility.” However, the next year, they reversed their view,
noting that selective filtration is not “impossible.” [Wynder and
Hoffmann (4314)].
Single compound pyrolysis at 800 °C in an inert atmosphere (N2
or He) is equivalent to the conditions existing in a smoked
cigarette [Wynder and Hoffmann (4319, 4332)]. This proposal was
an attempt to justify drawing conclusions on PAHs in MSS on the
basis of pyrolysis data.
Severson et al. (1979) describe “the pyrolytic conditions that
yielded [PAH] profiles of tobacco pyrolyzates that could be
correlated with [cigarette smoke condensate] profiles…”
Between the early 1950s and 1984, literally hundreds of articles
were published on PAHs in tobacco smoke with particular
emphasis on the tumorigenicity of many of them (3262, 3306a,
3306b, 3307, 3713, 3714).
© 2009 by Taylor & Francis Group, LLC
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Contradiction
The 1963 Hoffmann-Wynder findings were not confirmed either at RJRT or in the
NCI-TWG study on the first set of experimental cigarettes [Gori (1329)]. In the latter
study, the B[a]P and B[a]A yield for the normal filler cut (32 cpi) were less than those
for the coarse (20 cpi) and fine (60 cpi) cuts.
Complexing reagents such as chloranil or 2,4,7-trinitrofluorenone did not selectively
reduce MSS yields of individual PAHs [Rodgman and Cook, (3275)]. The complexing
agent is unable to react with the nonvolatile individual PAHs in the milieu of thousands
of compounds in the particles of the smoke aerosol.
Wynder and Hoffmann (4314) reversed their view on the impossibility of selective
filtration when they found that relatively volatile smoke components, e.g., low
molecular weight phenols, are selectively removed from the MSS by filters
incorporating certain plasticizers such as triacetin [cf. Laurene et al. (2312)]. Some
years later, the same phenomenon was observed with volatile NNAs [Fredrickson
(1236), Brunnemann et al. (514)].
On the basis of numerous laboratory data, this premise was criticized by several
investigators [Bell et al. (248), Benner et al. (276, 277), Schlotzhauer and Schmeltz
(3466, 3467), Chortyk and Schlotzhauer (722), Baker (163, 166, 167, 171a, 171b),
Baker and Robinson (174d)].
Proponents of the equivalence of inert-atmosphere pyrolysis of a tobacco
component and its behavior in a burning cigarette during the smoking process
misinterpreted one set of data and disregarded another:
The atmosphere immediately behind the burning coal is oxygen-deficient
compared to the oxygen level of the air entering the cigarette at the lit end and
the smoke exiting the cigarette at the mouthend but it is not oxygen-free.
The oxygen level in the tobacco rod a short distance (1-2 mm) behind the
tobacco rod-fire cone interface is influenced by diluting air entering the
tobacco rod through the cigarette paper and this diluting air increases as the
cigarette paper porosity increases.
The ultimate contradiction was provided from the laboratory of the original claimants.
Schmeltz et al. (3512) reported that the fate of radiolabeled nicotine on pyrolysis was
entirely different from its fate in the smoking process:
These results suggest to us that pyrolysis experiments may be of limited value
for establishing the fate of nicotine and possibly other tobacco components in
a burning cigarette.
The anticipated correlation was not attained: When the tobacco, a tobacco extract, and
the residual extracted tobacco were pyrolyzed, neither the amounts obtained for the
individual PAHs other than B[a]P, the phenols, nor the acids (volatile or nonvolatile) in
the tobacco pyrolysate matched the totals of the amounts in the extract pyrolysate plus
the amounts in the residual tobacco pyrolysate. For the individual PAHs (except for
B[a]P) and the acids, the totals of the amounts from the extract pyrolysate plus residue
pyrolysate were higher than the amounts from the tobacco pyrolysate. For the
individual phenols, the opposite was the case: The totals were less!
Despite the many published articles prior to 1984 on PAHs in tobacco smoke, none of
the authors contributing to the Searle-edited over 1400-page American Chemical
Society’s monograph on chemical carcinogens (3568) mentioned any of the
tumorigenic PAHs reported in cigarette smoke.
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 1188 The Chemical Components of Tobacco and Tobacco Smoke

early 1960s when Van Duuren et al. (4027) reported their
findings on aza-arenes in cigarette MSS.
The listing of single delivery values rather than a range for
dibenz[a,h]acridine (0.1 ng/cigarette) and 7H-dibenzo[c,g]
carbazole (0.7 ng/cigarette) indicates the MSS yields cited are
those reported from a single study, which appears to be that
of Van Duuren et al. (4027). Wynder and Hoffmann (4319,
4332) cited their own unpublished 1963 findings [Candeli
et al. (587)] that they could not detect dibenz[a,h]acridine
in cigarette MSS. Such findings were never published in a
peer-reviewed journal. Thus, the upper limit (10 ng/ciga-
rette) of the range for MSS yield of dibenz[a,j]acridine is that
reported by Hoffmann, co-author of all but one of the lists in
Table XXVI-1.
Single MSS yields for dibenz[a,h]acridine and 7H-
dibenzo[c,g]carbazole in MSS based on a cigarette manu-
factured in 1959–1960 or 1963 are hardly representative of
more recently manufactured cigarettes. It is well recognized
that a variety of cigarette design technologies has progres-
sively reduced the sales-weighted average mainstream TPM
by almost 70% from 40 mg/cigarette in the early 1950s to
less than 12 mg/cigarette currently. At the same time that the
reduction of delivery of mainstream TPM was accomplished,
the composition of the MSS was also altered. For example,
for mainstream TPM, the B[a]P content—expressed as ng
B[a]P/mg TPM—has decreased about 33% (from 1.2 ng/mg
TPM to 0.8 ng/mg TPM) during the same time period. The
1979 U.S. Surgeon General’s report (4005) summarized the
B[a]P data for a commercial cigarette sold in the United
States from 1954 to 1979. In addition to changes in the com-
position of mainstream TPM, changes in mainstream vapor-
phase composition also occurred.
Nicotine and the tobacco proteins and amino acids are
proposed as the major precursors of aza-arenes [Chortyk
and Schlotzhauer (722)]. Thus, the decrease in cigarette
nicotine content and delivery since 1960 should certainly
influence the pyrogenesis of the dibenzacridines and diben-
zocarbazole during the tobacco smoking process. The
levels of nicotine in U.S. cigarette tobacco blends (and
MSS) decreased on average more than 40% between 1960
and the late 1980s.
In addition, inconsistencies among numerous isolation
studies raise serious questions about the actual presence of
these three aza-arenes in the MSS (or SSS) from cigarettes
manufactured after the mid-1960s. Results from German,
Japanese, and American groups of investigators on their
search for dibenz[a,h]acridine {I}, dibenz[a,j]acridine {II},
and 7H-dibenzo[c,g]carbazole {III} in mainstream CSC and/
or nicotine pyrolysates are summarized in Table XXVI-3.
Only Van Duuren et al. (4027) in their published report and
Candeli et al. (587) in their unpublished report have detected
any of these three aza-arenes in cigarette MSS!

Table XXVI-3
Dibenz[a,h]Acridine {I}, Dibenz[a,j]Acridine {II}, and 7H-Dibenzo[c,g]Carbazole {III} in
Nicotine Pyrolysates (Pyr) and Mainstream Cigarette Smoke Condensate (CSC)
Dibenz[a,h]Acridine Dibenz[a,j]Acridine 7H-Dibenzo[c,g]Carbazole

Investigators Pyr CSC Pyr CSC Pyr CSC

Van Duuren et al. (4027) yes yes yes yes no yes

Candeli et al. (587), Wynder and NE no NE yes NE NE
Hoffmann (4319, 4332)
Kaburaki et al. (2006) no NE no NE NE NE
Schmeltz et al. (3499) no NE no NE no NE
Schmeltz et al. (3512) no no no no no no
Snook (3733) NE no NE no NE no
Snook et al. (3750) NE no NE no NE no
Grimmer et al. (1409) NE no NE no NE no
Kamata et al. (2021) NE no NE no NE NE
Sasaki and Moldoveanu (3414) NE no NE no NE NE
Rustemeier et al. (3370) NE no NE yes NE NE

yes = Compound identified.

no = Compound not found or identified.
NE = Substrate not examined for compound in question.

Examination of these results indicates that Van Duuren et al. (4027) reported the identification of the three N-heterocyclic
compounds {I, II, and III} in mainstream CSC and two of them {I and II} in a nicotine pyrolysate; whereas, Candeli et al.
(587) failed to identify {I} but did identify {II} in mainstream CSC. The 1963 Candeli et al. findings on {II} in mainstream
CSC were not confirmed in 1979 by investigators (3512) from the same laboratory: Hoffmann participated in both the
1963 and 1979 studies. Two studies (3499, 3512) confirmed the 1960 report by Van Duuren et al. that 7H-dibenzo[c,g]
carbazole {III} was not present in a nicotine pyrolysate.

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 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1189
Examination of the results summarized in Table XXVI-3
indicates that Van Duuren et al. (4027) reported the identifi-
cation of the three aza-arenes in mainstream CSC and two of
them, {I} and {II}, in a nicotine pyrolysate. However, Candeli
et al. (587) failed to identify {I} but did identify {II} in main-
stream CSC. The Candeli et al. findings reported in 1963
on {II} in mainstream CSC were not confirmed in 1979
by investigators from the same laboratory [Schmeltz et al.
(3512)]. Two later studies (3499, 3512) confirmed the 1960
finding by Van Duuren et al. that 7H-dibenzo[c,g]carbazole
was not present in a nicotine pyrolysate.
Examination of the detailed chromatograms presented in a
study on aza-arenes in MSS and SSS by Grimmer et al. (1409)
indicates the presence of several benzacridines (benz[a]acri-
dine, benz[c]acridine). However, no gas chromatographic
peaks corresponding to standard dibenz[a,h]acridine and
dibenz[a,j]acridine peaks are visible in the chromatograms
of the aza-arene fraction from either the MSS or SSS.
The failures by numerous talented research groups (Table
XXVI-3) to detect the two dibenzacridines, {I} and {II}, in
tobacco smoke cannot be attributed to difficulties or prob-
lems in the analytical procedures. Motohashi et al. (26A113)
reviewed the analytical procedures that enabled investigators
to identify several benzacridines and their homologs plus
dibenz[a,h]acridine and dibenz[a,j]acridine in a variety of
environmental samples (urban air, gasoline engine exhaust,
Diesel engine exhaust, street dust, and sediment from lake,
river, and salt-water sources). Motohashi et al. (26A113) also
reviewed in some detail the reports by Schmeltz et al. (3499),
Snook et al. (3750), Grimmer et al. (1409), and Kamata et al.
(2021) on the identification of various benzacridines in
tobacco smoke, but they did not mention the reported identifi-
cation of dibenz[a,h]acridine and dibenz[a,j]acridine in MSS
by Van Duuren et al. (4027).
In summary, the situation with regard to the four aza-
arenes considered to be significant “tumorigens” in tobacco
smoke by Hoffmann and his colleagues, OSHA (1994), and/
or EPA (which relied on the 1990 Hoffmann-Hecht list) is:
• OSHA did not list quinoline as a significant tum-
origen whereas EPA did.
• Only one laboratory, that of Van Duuren, reported
the presence of dibenz[a,h]acridine, dibenz[a,j]
acridine, 7H-dibenzo[c,g]carbazole, listed in Table
XXVI-1 as tumorigens in tobacco smoke.
• One other laboratory reported the presence of
dibenz[a,j]acridine in MSS but not the other two
aza-arenes [Candeli et al. (587), see Wynder and
Hoffmann (4319, 4332)]. Candeli et al. reported
the MSS yield for dibenz[a,j]acridine to be
roughly four times that reported by Van Duuren
et al. (4027). This disparity in per cigarette MSS
yield should have triggered additional research on
its presence and level in MSS. However, the 1963
finding by Candeli et al. has never appeared in a
peer-reviewed journal.
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78836_C026.indd 1189
• Failure to detect the three aza-arenes dibenz[a,h]
acridine, dibenz[a,j]acridine, and 7H-dibenzo[c,g]
carbazole in cigarette MSS and/or in nicotine
pyrolysates was reported in at least nine studies con-
ducted periodically between 1970 and 2002 (Table
XXVI-3).
• In comparable tumorigenicity studies, the aza-
arenes are much less tumorigenic to mouse skin
than their corresponding PAH analogs and much
less tumorigenic than B[a]P [Barry et al. (194)].
The MSS yields of the three aza-arenes listed by
OSHA and EPA, if they are present at all in MSS,
are much less than that of B[a]P.
Even when the repeated failure to confirm their presence
in tobacco smoke is ignored, the combination of their signifi-
cantly lower levels vs. that of B[a]P of the three aza-arenes in
cigarette MSS plus their significantly lower tumorigenicity
in the mouse skin-painting bioassay raises serious questions
about their inclusion in a table listing the “significant tumori-
gens in tobacco smoke.”
XXVI.A.2.b N-Nitrosamines
Hoffmann and Hecht (1727) did not acknowledge that
the MSS yields listed for both the volatile N-nitrosamines
(NNAs) and the tobacco-specific N-nitrosamines (TSNAs)
could be incorrect (and high) because of the artifactual for-
mation of both types of NNAs during MSS (and SSS) collec-
tion for analysis as reported by Caldwell and Conner (573).
EPA and OSHA accepted without question the mainstream
volatile NNA and TSNA yields tabulated by Hoffmann and
Hecht (1727) and cited by the U.S. Surgeon General in his
1989 report (4012).
The artifactual formation of NNAs during the collection
and analysis of MSS and SSS has been noted many times over
the years and it has not been limited to the determination
of NNAs in cigarette smoke. A similar problem was noted
with the determination of NNAs in foodstuffs. Neurath et
al. (2750) were one of the earliest groups of investigators
to discuss this problem in cigarette smoke. More recently,
Brunnemann et al. (457), from their study of the levels of
NNAs in MSS and SSS, reported lower levels than previously
reported for volatile NNAs in MSS, attributing the lower
levels to the avoidance of artifactual formation of N-nitro-
samines during smoke collection and analysis. They
wrote:
In fact, several of the cigarettes which were machine smoked
earlier and analyzed without precautions, when smoked by
us under the same conditions but with precautions, yielded
25 to 100% lower values for DMN [N-nitrosodimethylamine]
and NPY [N-nitrosopyrrolidine] for the mainstream smoke.
The nitrate content of the tobacco appears to be a determin-
ing factor for the concentration of volatile nitrosamines in the
smoke. Selective removal of these nitrosamines does occur with
cellulose acetate filter tips but not with charcoal filter tips.
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 1190 The Chemical Components of Tobacco and Tobacco Smoke

Guerin et al. [see p. 236 in (1445)], in their review of NNAs
in ETS commented on four ETS-related studies, those of
Brunnemann et al. (457), Stehlik et al. (3812), Matsushita
and Mori (2495), and Klus et al. (2134a). Guerin et al. sum-
marized the results on the determination of NNAs in natural
and artificial ETS environments:
The concentration of nitrosodimethylamine in commonly
encountered ETS-contaminated indoor air is likely to range
from <10–40 ng/m3. Nitrosodiethylamine and nitrosopyrro-
lidine are likely to be present at similar but lower concentra-
tions. Extrapolating from studies of artificial environments
suggest NNN and NNK concentrations in common environ-
ments will range from <1–3 ng/m3.
They also noted that occasionally, N-nitrosodimethylamine
(NDMA) concentrations may show excursions to 100 ng/m3
or more.
It was noted previously (Table XXVI-1) that many claims
about PAHs in tobacco smoke, particularly those demon-
strated to be tumorigenic to the skin of rodents, were sub-
sequently demonstrated to be either incorrect or equivocal.
However, the points of contention about NNAs in tobacco
smoke are fewer than the number listed for tobacco smoke
PAHs (see Table XXVI-4).
XXVI.A.2.c N-Heterocyclic Amines
While many of the N-heterocyclic amine mutagens are
present in tobacco smoke, the extensive research on this
class of compounds was initiated and extended because
of their presence in many foodstuffs consumed by many
people. Table XXVI-5 summarizes some details of these
N-heterocyclic amines in tobacco smoke.

Table XXVI-4
N-Nitrosamines in Tobacco Smoke
Assertion Contradiction

Druckrey and Preussmann (1057) proposed that conditions were appropriate

(presence of nitrogen oxides, water, and secondary amines, pH < 7.0) in a burning
cigarette for pyrogenesis of NNAs such as N-nitrosodimethylamine (NDMA).
Boyland et al. (422, 423) proposed that the presence in tobacco smoke of nornicotine
and anabasine, nitrogen oxides, and water made it highly likely that
N’-nitrosonornicotine (NNN) and N’-nitrosoanabasine (NAB) would be formed.
Serfontein and Hurter (3595, 3597) reported the identification of NNAs First claims by Serfontein and Hurter (3595, 3597) of identification of
in cigarette MSS. NNAs in cigarette MSS were challenged with counterclaims that
NNAs were artifactually produced during smoke generation,
collection, and analysis [cf. Neurath et al. (2751)]. Neurath et al.
(2751) reported the presence of an NNA but subsequently discovered
the identified compound was produced artifactually during the smoke
processing.
Since volatile NNAs and TSNAs occur in tobacco, a part of the NNAs in cigarette The premise of the pyrogenesis of NNN and NNK during the cigarette
MSS is a result of direct transfer of NNAs from tobacco to smoke, the remainder smoking process was challenged by Fischer et al. (1193, 1199) who
results from formation and transport during the smoking process [Adams et al. reported that these compounds occur in cigarette MSS only by
(29)]. For 4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone (NNK), the transfer transfer from the tobacco rod.
from tobacco to smoke ranges from 6.9 to 11.0% of the amount in the tobacco; this
represents about 30% of the 4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone
(NNK) in MSS. The remainder in MSS is formed during the smoking process
[Hoffmann et al. (1734), Hecht et al. (564)].
The problem of artifactual formation of NNAs has persisted from the mid-1960s to
the present [Neurath et al. (2751), Fredrickson (1236), Krull et al. (26A77),
Eisenbrand et al. (26A27), Caldwell and Conner (573)]. Continual improvement in
smoke collection and analytical procedures has progressively reduced the analytical
error.
TSNAs in CSC have little or no influence on the host response in skin-painting studies.
Little of the volatile NNAs remain in the CSC after collection and preparation for the
skin-painting bioassay. The only NNAs to consistently elicit a positive response at the
application site in skin-painting studies are the alkyl-N-nitrosourethanes, none of which
has been identified in tobacco or tobacco smoke to date.

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 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1191

Table XXVI-4 (continued)

N-Nitrosamines in Tobacco Smoke
Assertion Contradiction

Hundreds of rodent skin-painting studies with CSC and its fractions have been
conducted since the first successful production of carcinoma in mice painted with
CSC [see (4319, 4332 and references cited), Gori (1329, 1330, 1332, 1333), NCI
(2683)]. Even in the massive NCI decade-long study, no attempt was made to
correlate NNA content with bioassay results. It was assumed, from studies with
individual NNAs, that they had little if any influence on CSC tumorigenicity to
mouse skin. Millions of dollars and thousands of hours expended since 1953 in
conducting bioassays – particularly mouse skin-painting studies – did not
adequately define the total tumorigenicity of CSC in laboratory animals.
Precursors of NNAs in both tobacco and tobacco smoke are the proteins and amino acids
(plus nitrate) for the volatile NNAs [Brunnemann et al. (481, 482), Hoffmann et al.
(1694)] and nicotine and nicotine-related alkaloids (plus nitrate) for the TSNAs [Boyland
et al. (422, 423), Rathkamp et al. (3080), Hecht et al. (1563, 1565)]. The levels of NNAs
in tobacco and its smoke parallel the tobacco nitrate level [Morie and Sloan (2635), Hecht
et al. (1576, 1578), Tso et al. (3985)].
Removal of lipophilic PAH precursors from tobacco by solvent extraction reduces Personnel from Wynder’s laboratory subsequently recommended the
the PAH yield in MSS and the tumorigenicity (mouse skin-painting) of the CSC addition of lipophilic compounds, e.g., n-hentriacontane, to tobacco
[Wynder (4294), Wright (4281), Wynder et al. (4355, 4356)]. This led to their [Brunnemann and Hoffmann (480)] to reduce the generation during
recommendations to remove lipophilic components from tobacco. Confirmation of the smoking process of nitrate-derived nitrogen oxide which was
the reduced levels of PAHs in MSS from cigarettes fabricated with organic postulated as a reactant in the formation of NNAs.
solvent-extracted tobaccos was provided by Rodgman (3241, 3242, 3246) and
Rodgman and Cook (3286).

NNA formation in tobacco smoke involves the reaction of methyl nitrite and
secondary amines [Rodgman and Cook (3286), Wynder and Hoffmann (4332)].
NNA formation in tobacco smoke involves reaction among secondary amines,
nitrogen oxides, and water.
Despite the contradictory evidence that precludes the involvement of NNAs either
collectively or individually not only in various bioassays with laboratory animals
but also in respiratory tract cancer in cigarette smokers, some investigators still
maintain that the “tumorigenicity” of cigarette smoke in humans is due to its PAH
content and its content of the TSNA, NNK.
In 1991, Hecht and Hoffmann (1571a) wrote:
Polynuclear aromatic hydrocarbons and NNK [4-(N-methyl-nitrosamino)-
1-(3-pyridyl)-1-butanone] are the major carcinogens involved in lung
cancer induction by cigarette smoke…
Hoffmann and Hecht (1727) also noted that NNK had not been tested in laboratory
animals for tumorigenicity via inhalation.
On the basis of the following results, nitrate addition or use of high-nitrate tobaccos
was proposed: Addition of nitrate to the tobacco blend significantly reduced MSS
yields of “tar”, PAHs, and phenols. NO generated from nitrate during the smoking
process interrupted the free-radical mechanism of formation of PAHs [Hoffmann
and Wynder (1797, 1798)]. The tumorigenicity (% tumor-bearing animals) of the
resulting CSC is also reduced.
The proposal by Rodgman and by Wynder and Hoffmann (4332)
that NNAs arise by reaction of methyl nitrite with secondary amines
was shown to be invalid: Methyl nitrite in MSS is zero initially but
during the period of tobacco smoke generation, collection, and
analysis it is formed artifactually in tobacco smoke [Vilcins and
Lephardt (4058)].
Individual NNAs, particularly the TSNAs, have little or no influence
on CSC tumorigenicity in the skin-painting bioassay. Millions of
dollars and thousands of hours have been expended since 1953 in
conducting bioassays that do not adequately define the total
tumorigenicity of cigarette smoke condensate in laboratory animals.
Inhalation studies with NNAs at levels comparable to those in
cigarette MSS were consistently negative.
Lung tumor production by exposure to extremely high inhalation
levels of NNAs was classified as “equivocal”’ by the Registry of
Toxic Effects of Chemical Substances (RTECS) (3095).
Bioassay results in life-time inhalation studies with laboratory animals
exposed to various cigarette MSSs show no relationship between
tumor production and volatile NNAs and/or TSNA content.
Later, data showed that increasing the nitrate increases both the
volatile NNAs and TSNAs in MSS. Even though an increased level of
TSNAs in mainstream CSC was accompanied by decreased
tumorigenicity of the CSC to mouse skin, it was subsequently
proposed to remove nitrates from the tobacco or use low-nitrate
tobaccos [Brunnemann and Hoffmann (480)]. However, several of the
NNAs and TSNAs were included in the lists of “tumorigenic agents in
tobacco and tobacco smoke.”

(Continued)

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 1192 The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-4 (continued)

N-Nitrosamines in Tobacco Smoke
Assertion Contradiction

No volatile NNAs is considered a “marker” for other volatile NNAs in MSS; no As noted previously, as the level of nitrate in tobacco and
TSNA is considered a “marker” for other TSNAs, either individual or total, in MSS. subsequently the levels of the TSNAs in CSC increase, the
No NNAs – either a TSNA, a volatile NNA, or a nonvolatile NNA – is considered a tumorigenicity of cigarette smoke condensate to mouse skin decreases
“marker” for the tumorigenicity of CSC in the mouse skin-painting bioassay. [Wynder and Hoffmann (4332), Hoffmann and Wynder (1801, 1802)]
but its mutagenicity in the Ames system with Salmonella typhimurium
increases [Mizusaki et al. (2569)].
The tumorigenicity of NNAs is inhibited by a variety of tobacco smoke components.
For example, D-limonene is anticarcinogenic to NNK [Wattenberg and Coccia
(26A187)], ethanol, n-butanol, and tert-butanol are anticarcinogenic to NNN
[Waddell and Marlowe (26A178)], indole [Matsumoto et al. (26A97)], cholesterol
[Cohen et al. (26A12)], b-sitosterol [Wattenberg (4149b)], 3,4,5-trihydroxybenzoic
acid (gallic acid) [Mirvish et al. (2559c)] and its esters [Lo and Stich (26A87), Teel
and Castonguay (26A172)] are anticarcinogenic to several of the NNAs in tobacco
smoke [cf. Rodgman (3255, 3255a, 3257)]. Tobacco smoke not only contains other
compounds such as long-chained fatty acids [Takeda et al. (26A171)] reported to
diminish the tumorigenicity of various NNAs but also contains components
structurally similar to compounds [(+)-catechin, esculetin, esculin [Liu and
Castonguay (26A86), Teel and Castonguay (26A172)] that have been reported to act
as antitumorigens and/or antimutagens to NNAs
Various tobacco components and other compounds structurally similar to tobacco or
smoke components are known to inhibit the N-nitrosation of secondary and tertiary
amines to NNAs, a reaction known to occur among the nitrogen oxides, amino
compounds, and water during the tobacco smoking process. These inhibitors of
NNA formation include several primary amines, ascorbic acid and ascorbates
[Mirvish et al. (26A112), Mirvish and Shubik (26A111), Archer et al. (26A03a),
Mirvish (2559b, 26A104, 26A105)], indole, the tocopherols (particularly
a-tocopherol) [Mergens et al. (26A100), Mirvish, (2559b)], the carotenes, several
phenols, and polyphenolic compounds such as chlorogenic acid [cf. Brunnemann
and Hoffmann (484, 486)].
NOTE: The effect of these compounds on the N-nitrosation reaction should be
differentiated from the effect of some of the same compounds on the tumorigenicity
or mutagenicity of various NNAs, e.g., inclusion of ascorbic acid or ascorbate in the
reaction substantially reduces the yield of NNAs; administration of ascorbic acid
with a tumorigenic NNA such as NNK substantially reduces the tumorigenicity in
laboratory animals. Little study has been devoted to determining whether
compounds such as those noted above would exert a beneficial effect on MSS
properties if added to cigarette tobacco because of diminished N-nitrosation with
resulting lower NNA yield or because of the simultaneous delivery of the
antitumorigen or anti-mutagen together with the NNAs.
Because of the nature of cigarette smoke aerosol, Wynder and Hoffmann (4311) Selective filtration is not “impossible.” Wynder and Hoffmann (4314)
considered selective filtration of a specific smoke component or class of smoke reversed their view on the impossibility of selective filtration when
components such as the PAHs to be an “impossibility.” they found that relatively volatile smoke components, e.g., low
molecular weight phenols, are selectively removed from MSS by
filters incorporating certain plasticizers such as triacetin [cf. Laurene
et al. (3211, 2312)]. Some years later, the same phenomenon was
observed with volatile NNAs [Fredrickson (1236), Brunnemann et al.
(514), Hoffmann et al. (1711)].

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 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1193

Table XXVI-4 (continued)

N-Nitrosamines in Tobacco Smoke
Assertion Contradiction

Guerin et al. (1445) estimated the exposure to NNAs in ETS-filled rooms Consumers are exposed daily to NNAs from a variety of non-tobacco
to be low: sources. Many foodstuffs, beverages, and cosmetics contain
appreciable levels of some of the volatile NNAs also identified in
          NDMA    < 10-40 ng/m3
tobacco and/or tobacco smoke [Magee and Barnes (2442), Sebranek
          NDEA    3 ng/m3
and Cassens (26A142), Preussmann and Eisenbrand (2990), Maga
          NNN    < 1-3 ng/m3
(2438), Bailey and Williams (158a)]. Daily nontobacco exposure
          NNK  < 1-3 ng/m3
(primarily dietary) to NNAs is estimated to exceed 1800 ng/person;
daily nontobacco source exposure to NDMA is estimated to exceed
1100 ng/person [Preussmann and Eisenbrand (2990)].

NOTE: These estimates are based on analytical data that may have
included values for NNAs artifactually generated during the analytical
procedure.

As in the case of the tumorigens whose activity has been Table XXVI-6 summarizes the chronology of the stud-
shown to be substantially reduced by administration of ies dealing with the N-heterocyclic amines in tobacco smoke
anticarcinogens [see reviews (3255, 3257, 3300)], Lee et al. and in commonly consumed foodstuffs.
(2327c) reported that the mutagenicities (Ames test) of sev-
eral N-heterocyclic amine mutagens, each of which shows
XXVI.B Anticarcinogens, Inhibitors,
inordinately high mutagenicity, are substantially reduced by
CSC. The compounds studied by Lee et al. were 2-amino-6 and Antimutagens
-methyldipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1), 2-amino- In preceding publications and earlier chapters: (1) the listing
dipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2), 3-amino-1,4-dim- of numerous MSS components as significant toxicants was
ethyl-5H-pyrido[4,3-b]indole (Trp-P-1), and 3-amino-1-met- questioned [Rodgman and Green (3300)] and (2) the asser-
hyl-5H-pyrido[4,3-b]indole (Trp-P-2), 2-amino-3-methylimi- tions that ingredients added to cigarette tobacco adversely
dazo[4,5-f]quinoline (IQ), and 2-amino-3,4-dimethylimi- affect the chemical and biological properties of MSS were
dazo[4,5-f]quinoline (MeIQ). shown to be in error [Rodgman (3266)]. In this section, we
discuss the identified MSS components that have been shown
in bioassays to significantly diminish the adverse biological
effects of a number of the listed MSS toxicants.
Table XXVI-5 The toxicological properties of a MSS component asserted
Summary of Tumorigenic N-Heterocyclic Amines in to adversely affect the smoker have generally been defined in
Tobacco Smoke one or more bioassays devoted to the study of the effect of the
component administered individually to a host. In most cases
IARC Evaluation of Evidence
other than numerous studies of tumorigenesis, the effect on the
re Tumorigenicity in
toxicological property of a specific compound by other com-
MSS Level Laboratory pounds such as those in the complex MSS aerosol has not been
Component ng/ciga Animals Humans studied. The toxicological effect of a specific component in MSS
is usually derived by extrapolation from the effect observed in
AaC 25-260 sufficient —
one or more bioassays with the individual component.
MeAaC 2-37 sufficient —
It is known that the complex MSS aerosol has a significant
Glu-P-1 0.37-0.89 sufficient —
Glu-P-2 0.25-0.88 sufficient —
effect on the chemistry of components in it. For example, (1)
PhIP 11-23 sufficient possible the rate of conversion of NO to NO2 is significantly less in the
IQ 0.26 sufficient probable MSS aerosol than in a system comprising only NO and O2
MeIQ 0.28-0.75 b sufficient probable (816) and (2) methyl nitrite reported as an MSS component is
Trp-P-1 0.29-0.48 sufficient — not formed during the smoking process but is formed during
Trp-P-2 0.82-1.1 sufficient — ageing of the MSS during the analytical procedure (4058).
a See cigarette MSS yields listed in Table XXVI-1 (1740, 1741, 1743, 1744). If the chemistry of an MSS aerosol component is altered by
b  MeIQ was not listed in (1740, 1741, 1743, 1744) but was listed by Smith the presence of thousands of other aerosol components, then
et al. (3714) logic dictates that its toxicology will also be altered.

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 1194 The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-6
Chronology of N-Heterocyclic Amine Studies
Year Event

1959 Only one fused ring N-heterocyclic compound was listed by Johnstone and Plimmer (1971) as a tobacco smoke component: the
bicyclic compound, quinoline.
1960 Mold et al. (2592) isolated and identified the tricyclic N-heterocyclic 5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione
(pyrocoll) from CSC and defined its relationship to its precursor in tobacco, proline.
1961/ Poindexter and Carpenter (2972) reported the isolation and identification of 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9H-
1962 pyrido[3,4-b]indole (harman) from CSC. They reported that the yield of total harmans in burley and flue-cured MSSs was between
15 and 20 mg/g of tobacco smoked, values which were 40 to 50 times that of the harmans in the unsmoked tobacco. Since the
weight of tobacco in cigarettes sold at that time approximated 1 gram, the yield of these two compounds was about 15-20 mg/cig.
Poindexter and Carpenter concluded from experiments with radiolabeled tryptophan that the harmans (found to be radiolabeled in
the MSS) were generated pyrogenetically by a reaction between aldehydes (formaldehyde for norharman, acetaldehyde for
harman) and tryptophan in tobacco.
1962 Rodgman and Cook (3279) confirmed the presence in cigarette smoke condensate of 5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-
5,10-dione (pyrocoll) and also reported the identification of indole, carbazole, and several alkylated indoles and carbazoles.
Rodgman and Cook (3279) also reviewed the previously reported biological studies on indole, 3-methylindole (skatole), and
carbazole: None of the three was reported to be tumorigenic.
1964 Schmeltz et al. (3505) reported 5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll), 9H-pyrido[3,4-b]indole
(norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman) as tobacco smoke components. Testa and Testa (3886, 3887) also
identified 5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll) as components of CSC.
1964 The Advisory Committee to the U.S. Surgeon General (3999) briefly discussed only four fused-ring N-heterocyclic compounds in
tobacco smoke, quinoline and the two dibenzacridines (dibenz[a,h]acridine, dibenz[a,j]acridine) and the dibenzocarbazole
(7H-dibenzo[c,g]carbazole) reported by Van Duuren et al. (4027).
1968 In his review of tobacco smoke composition, Stedman (3797) discussed the identification of tumorigenic N-heterocyclic compounds
(dibenz[a,h]acridine, dibenz[a,j]acridine, 7H-dibenzo[c,g]carbazole) reported by Van Duuren et al. (4027) as well as 5H,10H-
dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll) reported by Mold et al. (2592) and 9H-pyrido[3,4-b]indole (norharman),
1-methyl-9H-pyrido[3,4-b]indole (harman), and 9H-pyrido[2,3-b]indole reported by Poindexter and Carpenter (2972).
1971/ Wakeham (4103) noted the reported presence of 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman) in
1972 cigarette MSS and discussed their formation from a reaction product of tryptophan and an aldehyde. As noted by Rodgman (3253a), the
structure of the aldehyde reacting with tryptophan ultimately dictated the structure of alkylated norharmans found in CSC.
1974 In addition to 5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll), Izard et al. (1899) reported the identification of
methyl-5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (methylpyrocoll) in CSC.
1974/ In a 1974 in-house RJRT report, a 1975 TCRC presentation, and a 1977 publication on their study of the water-soluble portion of
1975/ CSC, Schumacher et al. (3553) reported the identifications of 1-methyl-9H-pyrido[3,4-b]indole (harman), 5H,10H-dipyrrolo[1,
1977 2-a:1’,2’-d]pyrazine-5,10-dione (pyrocoll), octahydro-5H,10H-dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione (octahydropyrocoll),
and 2-ethyl-9H-pyrido[2,3-b]indole.
1977 Sugimura et al. (3829) reported the isolation and identification of the N-heterocyclic amines 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]
indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) from tryptophan pyrolysates.
1977 In separate studies, Levitt et al. (2355a) and Nagao et al. (2667b) demonstrated the mutagenicity of 9H-pyrido[3,4-b]indole
(norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman) in the Ames test.
1978 Yamamoto et al. (4365a) reported the isolation and identification of 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1)
and 2-aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2) from glutamic acid pyrolysates.
1978/ Heckman and Best (1587) reported the identification of nearly 270 previously unidentified and over 150 previously identified
1981 N-containing components in CSC. These included several components structurally similar to the mutagenic N-heterocyclic amine:
9H-pyrido[2,3-b]indole, 2-methyl-9H-pyrido[2,3-b]indole, 2-(2-methylpropyl)-9H-pyrido[2,3-b]indole, 2-pentyl-9H-pyrido[2,3-b]
indole, 1-butyl-9H-pyrido[3,4-b]indole, 9H-1-propenylpyrido[3,4-b]indole, and a partially characterized norharman isomer.
1979 In the 1979 U.S. Surgeon General’s report (4005), the aza-arenes dibenz[a,h]acridine, dibenz[a,j]acridine, 7H-dibenzo[c,g]
carbazole, quinoline, and alkylated quinolines in CSC were discussed but not the presence or properties of the mutagenic
N-heterocyclic amines identified in tobacco smoke.
1980/ Yoshida and Matsumoto (4388) and Matsumoto et al. (2492) reported the identification of 2-amino-9H-pyrido[2,3-b]indole (AaC)
1981 and 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAaC) in CSC.

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 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1195

Table XXVI-6 (continued)

Chronology of N-Heterocyclic Amine Studies

Year Event

1981 Matsukura et al. (2491a) demonstrated the tumorigenicity in mice of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and
3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2).
Hosaka et al. (1835a) demonstrated the tumorigenicity in rats of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and
3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2).
1982 In the 1982 Surgeon General report (4010), 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman)
were classified as “toxic and tumorigenic agents of cigarette smoke” in amounts of 3.2 to 8.1 mg/cig and 1.1 to 3.1 mg/cig,
respectively, in cigarette MSS. None of the other mutagenic N-heterocyclic amines in tobacco smoke was discussed.
1982/ Snook and Chortyk (3739, 3740) reported the MSS yield of 9H-pyrido[3,4-b]indole (norharman) to be 1.2 to 13.4 mg/cig; that for
1984 1-methyl-9H-pyrido[3,4-b]indole (harman) to be 0.3 to 3.8 mg/cig. They found a linear relationship between the yield of cigarette
MSS “tar” and the yields of 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9H-pyrido[3,4-b]indole (harman). In contrast to the
1962 findings of Poindexter and Carpenter (2972), Snook and Chortyk reported that the MSS yields of these two compounds were
not influenced by the tobacco type.
1983 Demarini (933) reviewed the studies on the mutagenicity of CSC. He discussed the studies of Yoshida and Matsumoto (4388) and
Matsumoto et al. (2492) on the mutagens 2-amino-9H-pyrido[2,3-b]indole (AaC) (80 ng/cig) and 2-amino-3-methyl-9H-
pyrido[2,3-b]indole (MeAaC) (7 ng/cig).
1984 None of the authors contributing to the Searle-edited 1400-page American Chemical Society’s monograph on chemical carcinogens
(3568) mentioned the tumorigenic and mutagenic N-heterocyclic amines reported in cigarette smoke and numerous cooked foods.
1984 Ohgaki et al. (2849b) demonstrated the tumorigenicity in mice and Takayama et al. (3862b) demonstrated the tumorigenicity in
rats of 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1) and 2-aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2).
Takayama et al. (3862c) demonstrated the tumorigenicity in rats of the tobacco smoke component 2-amino-3-methylimidazo[4,5-f]
quinoline (IQ).
1984/ Ohgaki et al. (2849, 2849a) demonstrated the tumorigenicity in mice of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and
1985 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), found in broiled fish, fried beef, beef extract, and CSC.
1985 Takayama et al. (3862d) demonstrated the tumorigenicity in rats of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and
3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2).
Tanaka et al. (3865c) demonstrated the tumorigenicity of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ).
1985/ The IARC (1870) listed several tryptophan-derived tobacco smoke isolates including 9H-pyrido[3,4-b]indole (norharman) and
1986 1-methyl-9H-pyrido[3,4-b]indole (harman). The levels in cigarette MSS of these two components were listed as 9.5 to 14.1 and 2.5
to 5.8 mg/cig, respectively. No mention was made of the mutagenic N-heterocyclic amines in CSC or the degree of evidence for
their carcinogenicity in animals and humans.
1985/ Yamashita et al. (4367, 4368) identified and quantitated the following mutagenic N-heterocyclic amines in CSC:
1986
2-amino-3-methylimidazo[4,5-f]quinoline (IQ)          0.3 ng/cig
3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1)      0.3 ng/cig
3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2)       0.2 ng/cig
2-amino-9H-pyrido[2,3-b]indole (AaC)            16.9 ng/cig
2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAaC)       1.6 ng/cig
1986 Sugimura (3828c) reviewed the isolation and identification of the mutagenic N-heterocyclic amines s, their high mutagenicity in the
Ames test (Salmonella typhimurium) of several of them, their tumorigenicity, and their various sources – including CSC for many.
However, Sugimura did write the following about the importance of the mutagenic N-heterocyclic amines as human carcinogens:
Taking various factors into consideration, it is probably impractical and not realistic to make risk estimations from the
carcinogenicity data on rodents given a single carcinogen. However, for a simple extrapolation of animal data for risk
estimation, TD50 values, which are the doses needed to develop cancers in 50% of animals fed on carcinogens [IQ, Trp-P-1,
Trp-P-2, Glu-P-1, Glu-P-2, AaC, and MeAaC] for their life time, have been calculated based on mouse experiments… If
we assume the average TD50 value of heterocyclic amines should be about 8mg/kg/day, we can roughly estimate the risk of
these carcinogenic heterocyclic amines for human beings. The intake of heterocyclic amines was calculated from available
data on their quantities in foods. Apparently the human intake is about 0.0002% times the TD50 obtained from animal data.
This means that heterocyclic amines may not be so serious for human cancer development… On the other hand, it is also
true that human beings are being exposed to many heterocyclic amines and many other carcinogens with tumor promoters
and/or suppressing factors for carcinogenesis. At this moment, it is honest to state that no solid information on the estimation
of risk of heterocyclic amines has been obtained in any direction, either positive or negative.
1990 Felton and Knize (1177d) reviewed the results of numerous studies on the mutagenicity and tumorigenicity of the mutagenic
N-heterocyclic amines.

(Continued)

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 1196 The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-6 (continued)

Chronology of N-Heterocyclic Amine Studies

Year Event

1994 Lee et al. (2327c) reported that the condensate from cigarette MSS significantly inhibited the mutagenicity of several
N-heterocyclic aromatic amines as measured in the Ames assay with Salmonella typhimurium, strain TA 98 in presence of S-9 mix.
The mutagenic N-heterocyclic amines tested included:
2-amino-3-methylimidazo[4,5-f]quinoline (IQ)
2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ)
2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1)
2-aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2)
3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1)
3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2)
The mutagenic activities of these mutagens were suppressed as much as 80% by addition of 50 to 100 mg of CSC per plate.
1997 Hoffmann and Hoffmann (1740) issued a revised list of tumorigenic components in tobacco and tobacco smoke. Their revision of
the Hoffmann-Hecht (1727) list included, in addition to several vapor-phase components, eight of the mutagenic N-heterocyclic
amines:
2-amino-3-methylimidazo[4,5-f]quinoline (IQ)
2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ)
2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-1)
2-aminodipyrido[1,2-a:3’,2’-d]imidazole (Glu-P-2)
3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1)
3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2)
2-amino-9H-pyrido[2,3-b]indole (AaC)
2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAaC)

Except for tumorigenic effects, little has been reported on
the effect of other components in the complex MSS aerosol on
the toxicological properties of an individual component. The
tumorigenicity of many MSS components has been discussed
frequently and in great detail but little has been written about
the biological activity of nontumorigenic MSS components
reported to counteract the tumorigenicity in laboratory ani-
mals of the various tumorigens.
Inhibitors of carcinogens or anticarcinogens are com-
pounds that prevent tumor development. Wattenberg (26A186)
divided them into three categories based on the time in the
carcinogenic process when they are effective. The first cate-
gory consists of compounds that prevent the formation of car-
cinogens from precursor substances, for example, ascorbic
acid [Mirvish (26A103, 26A104)], tocopherols [Newmark
and Mergens (26A116)], and phenols [Newmark and Mergens
(26A116), Kuenzi et al. (2216)] which inhibit the formation
of nitroso tumorigens from precursor amine and nitrite both
in vivo and in vitro. The second category includes “blocking
agents,” which inhibit carcinogenesis by preventing carcino-
genic compounds from reaching or reacting with critical tar-
get sites in the tissues, for example, disulfiram [Wattenberg
(26A183)], which inhibits the metabolism of symmetrical
dimethylhydrazine to its carcinogenic metabolites [Fiala et
al. (26A34)]. The last category of inhibitors, the “suppress-
ing agents,” works by suppressing the expression of neopla-
sia in cells exposed to a carcinogenic agent. Retinoids are an
example of this category.
In 1941, Shear and Leiter (3627) described in detail the
many factors affecting tumorigenicity of a chemical. In the
mid-1940s, several nontumorigenic aromatic hydrocarbons
(benzene, naphthalene, anthracene) administered with B[a]
P or dibenz[a,h]anthracene (DB[a,h]A) significantly dimin-
ished the B[a]P and DB[a,h]A tumorigenicity (843, 844,
26A17). In recent lists of MSS toxicants, benzene, B[a]P,
and DB[a,h]A are listed as significant tumorigens. Reported
many times, however, is the noncarcinogenicity of benzene
in the solvent-control group when it was used as the solvent
for known or suspect tumorigens in skin-painting bioassays
(1544, 3665).
Steiner and Falk (3814) reported that benz[a]anthracene
(B[a]A), categorized as either an extremely weak or an inac-
tive mouse-skin tumorigen (983), significantly diminishes
DB[a,h]A tumorigenicity when both DB[a,h]A and B[a]A
are administered simultaneously by subcutaneous injection.
Despite this and similar bioassay results plus the presence of
B[a]A and DB[a,h]A in MSS, both are repeatedly categorized
as significant tumorigens in cigarette MSS! Similar inhibi-
tion was reported with mixtures of 7,12-dimethylbenz[a]
anthracene (DMB[a]A) and several inactive PAHs (1654).
In subsequent studies, other nontumorigenic PAHs
(phenanthrene, fluoranthene, pyrene) were reported to be
effective antitumorigens against B[a]P and DMB[a]A (976,
3686). The nontumorigenic hydrocarbons — benzene, naph-
thalene, anthracene, phenanthrene, fluoranthene, pyrene —
are MSS components, present at per cigarette delivery levels

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 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1197
far in excess of those of B[a]P, DB[a,h]A, or any of the other
PAHs classified as tobacco smoke toxicants.
Much evidence collected since 1932 on the tumorigenic-
ity of PAHs indicates their tumorigenicity is not inherent but
depends on specific metabolites that comprise one or more
epoxides, dihydroxy compounds, and dihydroxy epoxides.
For B[a]P, more than a dozen metabolites are known and they
show a range of tumorigenicities (983).
Conversion of B[a]P in an inhaled MSS particle to a par-
ticular metabolite cannot be a simple process. The more than
500 PAHs in cigarette MSS range from bicyclic to decacyclic
structures. In a variety of chemical reactions, the rate of reac-
tion decreases as the molecular weight (number of rings) of
the PAH increases. That is, with stoichiometric levels of the
PAH and the reactant, bicyclic PAHs react faster than tricyclic
PAHs, which in turn react faster than tetracyclic PAHs, etc.
Diol, epoxide, and/or diol-epoxide metabolites structurally
similar to those described for B[a]P have been reported for
many PAHs, for example, naphthalene, anthracene, phenan-
threne, B[a]A, benzo[c]phenanthrene, pyrene, chrysene,
DB[a,h]A, benzo[b]triphenylene, and DMB[a]A (983). All of
these and structurally similar PAHs have been reported by
Snook et al. as cigarette MSS components (3756).
In a situation, such as the formation of metabolites, where
an equimolar mixture of bicyclic through hexacyclic PAHs is
present, a pentacyclic aromatic hydrocarbon such as B[a]P will
form little of its metabolite(s) compared to the levels formed
by a more reactive bicyclic or tricyclic aromatic hydrocarbon.
Numerous in vitro studies have demonstrated that inclusion
of equimolar quantities of lower molecular weight PAHs,
such as phenanthrene or anthracene, inhibits the hydroxyla-
tion-epoxidation of B[a]P in hepatic microsomes (26A192).
However, PAH data from Hoffmann and Wynder (1798) and
Rodgman and Cook (3273) indicate the PAH classes (bicy-
clic, tricyclic, etc.) in MSS are present at significantly higher
molar levels than the pentacyclic PAHs, which include B[a]
P and DB[a,h]A.
In an in vitro study, the nontumorigenic PAHs pyrene and
fluoranthene significantly inhibited the binding of a tumori-
genic PAH to calf thymus DNA (enzyme source = mouse
skin homogenate) [Slaga and Boutwell (3683), Slaga et al.
(3688)]. The in vitro inhibition of the hydroxylation reaction
is paralleled by a reduction of in vivo tumorigenicity.
Because of their vapor pressure properties, tumorigenic
PAHs (B[a]P, DB[a,h]A, etc.) and aza-arenes are present
primarily in the MSS particulate phase. Similarly, many of
the reported anticarcinogens or inhibitors occur in the MSS
particulate phase (3255, 3255a, 3257), for example, high
molecular weight alkanes (1099), b-sitosterol and choles-
terol (1099), a-tocopherol (3271, 3347), indole (3279), indole-
3-acetonitrile (1898), duvatrienediols (3361), and PAHs
(anthracene, phenanthrene, pyrene, fluoranthene, B[e]P) [see
(3255a)].
Despite the fact that the anticarcinogenicity of certain
components of tobacco (1171) and tobacco smoke (1824,
1672a) and of tobacco smoke itself (1824) has been known
for over four decades, most discussions are directed at them
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78836_C026.indd 1197
as toxicants. Seldom is any significant discussion directed at
smoke components known to possess anticarcinogenic prop-
erties. In a brief 1964 review of the possibility of anticarcino-
genic agents in tobacco smoke, Wynder and Hoffmann [see
296, 330 in (4319)] discussed the findings of Steiner and Falk
(3814) and Kotin and Falk [see 489–490 in (26A76)] in their
studies with potent and weakly tumorigenic PAHs in the sub-
cutaneous injection bioassay as well as their own findings in
the mouse skin-painting bioassay (4314, 4316). Ignored was
the discussion by Kotin and Falk (26A76) on the anticarcino-
genicity vs. B[a]P or vs. DB[a,h]A of nine PAHs (anthracene,
benzo[a]fluorene, B[a]A, chrysene, pyrene, B[e]P, benzo[k]flu-
oranthene, benzo[ghi]fluoranthene, perylene), two aza-arenes
(benzo[a]carbazole, benz[c]acridine), and 2-naphthol. All but
the two aza-arenes had been identified in cigarette MSS prior
to their 1964 review. Subsequently, the aza-arenes noted were
identified as MSS components (3339, 3750).
Earlier, Wynder and Hoffmann (4311) had reported on
MSS components that inhibited the action of a “tumorigen”
invariably listed as significant. The finding was an outgrowth
of their investigation of the effect of organic solvent extraction
of tobacco on the PAH content of MSS. Cigarettes fabricated
from the extracted tobacco yielded lower quantities of B[a]
P and DB[a,h]A in MSS (3240, 3242, 3262). Skin-painting
bioassays with MSS CSCs from the control and extracted
tobaccos gave a lower percentage of tumor-bearing animals
(% TBA) in the group treated with the extracted tobacco
CSC. However, the decrease in % TBA was considerably less
than the percent decrease in the level of tumorigenic PAHs in
the CSC (4307). One explanation for the difference was that
the solvent extracted almost all the alkanes from the tobacco.
Thus, the alkanes were absent from the MSS from extracted-
tobacco cigarettes. This fraction (constituting about 3% of
MSS CSC) was reported to significantly inhibit the tumori-
genicity of B[a]P (4311, 4314, 26A59).
Mouse skin-painting studies with B[a]P and the alkanes
n-hentriacontane and n-pentatriacontane at ratios of alkane:
B[a]P of 20:1 and 100:1 for each alkane showed they signifi-
cantly inhibited B[a]P tumorigenicity (4311, 4314, 26A59).
The MSS of a cigarette delivering 20 mg of CSC contains
about 0.6 mg (600000 ng) of the alkane fraction and 10 ng
of B[a]P, an alkane fraction: B[a]P ratio of 60000:1, far in
excess of the ratios that produced significant inhibition of
B[a]P tumorigenicity [Wynder and Hoffmann (4311, 4319, see
pp. 370–371 in (4332)]. Increasing the long-chained alkane
level in CSC by 1% from ~3% (C12 to C30) to 4% by addition of
crystalline alkanes isolated from CSC resulted in reduction of
the tumorigenicity of the CSC from 40% TBA to 24% TBA.
This result was dismissed as “not statistically significant.”
Wynder and Hoffmann [see 245–247, 628 in (4332)] again
discussed anticarcinogenic components of tobacco smoke:
Any discussion of as complex a carcinogen as tobacco smoke
should at least mention the existence of anticarcinogens.
These are substances that reduce or “neutralize” the effect
of a carcinogen by reacting with the carcinogen or a carci-
nogenic metabolite, thereby deactivating it, or by competing
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 1198 The Chemical Components of Tobacco and Tobacco Smoke
for reaction with cell constituents, or by interfering with the
resorption of a carcinogen … The existence of anticarcino-
gens, however, must be considered in evaluating any complex
mixture such as tobacco smoke condensate … An explana-
tion of the tumorigenic activity of tobacco smoke condensate
in terms of single constituents is made more difficult by the
presence of substances that may act as anticarcinogens and/
or absorption retarders, especially for tumorigenic agents. It
is known that structurally related noncarcinogenic hydrocar-
bons can inhibit the effect of carcinogenic hydrocarbons …
Several investigators have noticed some inhibition of
tumor growth by tobacco smoke condensate … [including]
Hoffman and Griffin [1672a] … Falk et al. [1174] … [and]
Homburger and Treger [1823b] … it should not come as a
surprise that a material which has been proved to be carcino-
genic may also interfere with tumor development, if not with
tumor initiation.
They also noted [see pp. 370–371, 628–629 in (4332)]:
An explanation of the tumorigenic activity of tobacco
smoke condensate in terms of single constituents is made
more difficult by the presence of substances that may act as
anticarcinogens and/or absorption retarders, especially for
tumorigenic agents. It is known that structurally related non-
carcinogenic hydrocarbons can inhibit the effect of carcino-
genic hydrocarbons. The same interrelationship may apply
to tumor-promoting and nontumor-promoting phenols.
Numerous compounds demonstrated in various bioassays
to be highly effective anticarcinogens against many MSS toxi-
cants have been identified in tobacco smoke at per cigarette
delivery levels far in excess of those of the alleged tumorigens.
Seldom have these anticarcinogenic MSS components been
discussed in the numerous reviews of the biological properties
of MSS. Even though some of the earliest data on MSS com-
ponents, for example, the alkanes, that inhibit B[a]P tumorige-
nicity in the skin-painting bioassay were provided by Wynder
and Hoffmann [4314, see 370–371, 628–629 in (4332)], they
more often preferred to discuss alkanes as major precursors
of tumorigenic PAHs in MSS [see 496–501 in (4332), 1798,
4314, 4342] rather than inhibitors of B[a]P tumorigenicity.
MSS components reported to possess significant inhibitory or
anticarcinogenic action against various tumorigenic PAHs and
NNAs in MSS have been cataloged (3255, 3255a, 3257).
Those opposed to cigarette smoking view the complex
mixture MSS differently from other complex mixtures such
as raw or cooked foods, gasoline and Diesel engine exhausts,
factory effluents, etc. [see (1345, 3685)]. Most are reluctant
to accept the premise that a nontumorigenic component will
offset the tumorigenicity of a tumorigen in animals treated
with the complex mixtures CSC, MSS, SSS, or environmen-
tal tobacco smoke (ETS) containing the two (1773).
Other MSS components may have also influenced the
mouse skin-painting results obtained with control tobacco
and extracted tobacco CSCs. Hexane extraction of tobacco
not only removes alkane inhibitors, thus making impossible
their transfer to MSS, but also removes substantial amounts
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78836_C026.indd 1198
of b-sitosterol (4356), a-tocopherol (3271, 3347), indole
(3279), duvatrienediols (3361, 3389), and D-limonene (765,
2174), thus eliminating or drastically reducing their transfer
to MSS during smoking. Subsequently, it was demonstrated
that: (1) these smoke components are present by transfer from
tobacco to MSS during smoking and to SSS during smol-
der between puffs or they are generated during smoking; (2)
the compounds listed are anticarcinogenic vs. several of the
listed tumorigens, for example, PAHs, NNAs, and ethyl car-
bamate. However, in the 1950s, neither the identity of several
of these tobacco or smoke components nor their anticarcino-
genicity was known.
Comparison of identified MSS components (1373) with
lists of compounds (1177a, 3685) that possess inhibitory or
anticarcinogenic action in tumorigenesis studies reveals not
only that MSS contains many anticarcinogens but also that
their MSS levels often exceed those of the components listed
as significant tumorigens. Previously, we discussed a few
inhibitory and anticarcinogenic MSS components, but they
represent a small sample of the MSS components reported
to exhibit such properties. From the review by Slaga and
DiGiovanni (3685) and other reports (1177a), we compiled a
list of MSS (and tobacco) components reported to counteract
the tumorigenicity of MSS toxicants (Table XXVI-7A).
From the per cigarette MSS deliveries (Table XXVI-7A), it
may be calculated that the tumorigenic PAHs listed contrib-
ute from 4 to 10 mg/g of mainstream CSC. Nontumorigenic
PAHs (naphthalene, anthracene, pyrene, phenanthrene, fluo-
ranthene, benzo[e]pyrene, and benzo[b]triphenylene) total 90
to 180 mg/g of CSC. The anticarcinogenic effect of nontum-
origenic PAHs and weakly tumorigenic or nontumorigenic
aza-arenes vs. carcinogenic PAHs has been known since the
1940s (3685, 3814).
An interesting aspect of Table XXVI-7A is that it includes
the dioxins as antitumorigens. Slaga and DiGiovanni (3685)
summarized the studies in which dioxins were shown to
interfere with the enzyme pathways responsible for tumori-
genesis of several of the most potent PAHs. The dioxins were
not listed as MSS toxicants in previous tabulations similar to
Table XXVI-7A (3255, 3255a, 3257). In fact, only the 2001
Fowles-Bates toxicant list issued since 1990 (1217) included
the dioxins even though their presence in MSS was known
in 1980 (854). Is the omission of such MSS toxicants related
in any way to the fact that dioxins are significant antitum-
origens vs. some of the most potent mouse-skin tumorigenic
PAHs present in MSS? The 1964 Advisory Committee, in
Chapter 6 of its 1964 Report, mentions that twenty-seven
nontumorigenic PAHs had been identified in MSS, but none
by name [see Chapter 6, p. 55 in (3999)]. Was the omission of
their identities related to the fact that several were known to
be antitumorigenic to several potent mouse-skin tumorigens
such as B[a]P?
In Table XXVI-7A are listed only the two n-alkanes (C31
and C35) shown experimentally by Wynder and Hoffmann to
reduce the tumorigenicity of B[a]P to mouse skin. However,
the alkane listing in Table XXVI-7A could logically be
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 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1199

Table XXVI-7A
Anticarcinogens, Inhibitors, and Antimutagens in Tobacco and Tobacco Smoke
Approximate Representative References to
Delivery, mg/g AT, Anticarcinogenicity, Inhibition,
CAS No. Component MSS CSC Effective Against AMa and/or Antimutagenicitye

Hydrocarbons, Aliphatic
Saturated aliphatic hydrocarbons b 30000 B[a]P AT Wynder and Hoffmann (4314)
630-04-6 Hentriacontane C31H64
630-07-9 Pentatriacontane C35H72
7235-40-7 b,b-Carotene DMB[a]A AT Mathews-Roth (2486a)
5989-27-5 D-Limonene 15–50 NNK AT Wattenberg and Coccia (26A187)
Hydrocarbons, Aromatic
DB[a,i]P AT Homburger et al. (26A61)
71-43-2 Benzene 480–1900 B[a]P, DB[a,h]A AT Crabtree (843, 844, 26A17)
91-20-3 Naphthalene 80–160 B[a]P, DB[a,h]A AT Crabtree (843, 844, 26A17)
120-12-7 Anthracene 4–7 B[a]P, DB[a,h]A AT Crabtree (843, 844, 26A17)
85-01-8 Phenanthrene 2–4 DMB[a]A AT DiGiovanni et al. (976)
206-44-0 Fluoranthene 3–4 DMB[a]A AT DiGiovanni et al. (976)
Slaga et al. (3686)
129-00-0 Pyrene 3–4 DMB[a]A AT DiGiovanni et al. (976)
Slaga et al. (3686)
56-55-3 Benz[a]anthracene 0.8–2.8 DB[a,h]A AT Steiner and Falk (3814)
B[a]P Hoffmann and Wynder
[unpublished data cited on pp.
246, 292 in (4332)]
192-97-2 Benzo[e]pyrene 0.2 DMB[a]A AT DiGiovanni et al. (976)
Slaga et al. (3686)
215-58-7 Benzo[b]triphenylenec 0.05 MC, DB[a,h]A, AT Slaga and Boutwell (3683)
DMB[a]A Slaga et al. (3686)
Alcohols
64-17-5 Ethanol NNN AT Waddell and Marlowe (26A178)
NNN AM Farinati et al. (26A32)
71-36-3 1-Butanol NNN AT Waddell and Marlowe (26A178)
75-65-0 2-Propanol, 2-methyl- {tert-butanol} NNN AT Waddell and Marlowe (26A178)
57605-80-8 a-4,8,13-Cyclodecatriene-1,3-diol, 1,5,9- 8–20 DMB[a]A AT Saito et al. (3389)
trimethyl-12-(1-methylethyl)- {a-4,8,13-duvane-
1,3-diol}
57605-81-9 b-4,8,13-Cyclodecatriene-1,3-diol, 1,5,9- 12–25 DMB[a]A AT Saito et al. (3389)
trimethyl-12-(1-methylethyl)-{b-4,8,13-duvane-
1,3-diol}
68-26-8 2,4,6,8-Nonatetraen-1-ol, 3,7-dimethyl-9-(2,6,6- DMB[a]A AT Shamberger (26A158)
trimethyl-1-cyclohexen-1-yl)-, (all-E)- {retinol}
83-46-5 b-Sitosterol 400–550 NNA AT Wattenberg (4149b
PAH Yasukawa et al. (26A196)
57-88-5 Cholesterol 120–240 NNA AT Cohen et al. (26A12)
Acids
Acids, long-chained aliphatic NNA AM Takeda et al. (26A171)
57-10-3 Palmitic acid C16H32O2
57-11-4 Stearic acid C18H36O2
149-91-7 Benzoic acid, 3,4,5-trihydroxy- {gallic acid} NNA AT Mirvish et al. (2559c)
499-12-7 1-Propene-1,2,3-tricarboxylic acid {aconitic acid} B[a]P AT Kallistratos (26A68)
Kallistratos and Fasske (26A17)
331-39-5 2-Propenoic acid, 3-(3,4-dihydroxyphenyl)- B[a]P AT Wattenberg et al. (4149c)
{cinnamic acid, 3,4-dihydroxy-} {caffeic acid}
1135-24-6 2-Propenoic acid, 3-(3-hydroxy-4- B[a]P AT Wattenberg (4149b)
methoxyphenyl)- {cinnamic acid, 3-hydroxy-4-
methoxy-} {ferulic acid}

(Continued)

© 2009 by Taylor & Francis Group, LLC

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 1200 The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-7A (continued)

Anticarcinogens, Inhibitors, and Antimutagens in Tobacco and Tobacco Smoke
Approximate Representative References to
Delivery, mg/g AT, Anticarcinogenicity, Inhibition,
CAS No. Component MSS CSC Effective Against AMa and/or Antimutagenicitye

614-60-8 2-Propenoic acid, 3-(2-hydroxyphenyl)- B[a]P AT Wattenberg et al. (4149c)

{o-coumaric acid
621-82-9 2-Propenoic acid, 3-phenyl- {cinnamic acid} NPYR, NNN AT Chung et al. (26A07, 26A08)
Lactones
50-81-7 Ascorbic acid DMB[a]A AT DiGiovanni et al. (976)
Slaga and Bracken (3684)
91-64-5 2H-Benzopyran-2-one {coumarin} B[a]P, DMB[a]A AT Wattenberg et al. (26A189)
108-29-2 3H-2-Furanone, dihydro-5-methyl- {a-angelica B[a]P AT Wattenberg et al. (26A189)
lactone}
Phenols
117-39-5 4H-1-Benzopyran-4-one, 2-(3,4- DMB[a]A AT Kato et al. (2046a)
dihydroxyphenyl)-3,5,7-trihydroxy-{quercitin}
327-97-9 Cyclohexanecarboxylic acid, 3-[[3-(3,4- B[a]P AT Lesca (2351a)
93451-46-8 dihydroxyphenyl)-1-oxo-2-propenyl]oxy]-1,4,5-
trihydroxy-, [1S-(1a,3b,4a,5a)]- {chlorogenic
acid; 3-O-caffeoylquinic acid}
108-95-2 Phenol 1000–7000 B[a]P AT Van Duuren et al. (4035)
NNN. NPYR Chung et al. (26A07, 26A08)
88-18-6 Phenol, 2-(1,1-dimethylethyl)- B[a]P AT Lam et al. (26A79)
128-37-0 Phenol, 2,6-bis(1,1-dimethylethyl)-4-methyl- B[a]P, DMB[a]A AT Slaga and Bracken (3684)
Slaga et al. (3687)
Wattenberg (26A182)
NDEA Clapp et al. (26A11)
1,2-DMH Clapp et al. (26A10)
150-76-5 Phenol, 4-methoxy- B[a]P AT Wattenberg et al. (4149c)
DMB[a]A Slaga et al. (3687)
59-02-9 a-Tocopherol {vitamin E} 400–600 MC, DMB[a]A AT Shklar (3655a)
DB[a,i]P Slaga and Bracken (3684)
1,2-DMH Viaje et al. (4049a)
Weerapradist and Shklar (4159c)
NNA AT Thompson (26A175)
CSC AM Rosin (26A136)
305-01-1 2H-1-Benzopyran-2-one, 6,7- NNK AT Teel and Castonguay (26A172)
dihydroxy- {esculetin}
520-18-3 4H-1-Benzopyran-4-one, 3,5,7-trihydroxy-2- AHR AT Puppala et al. (26A132)
(4-hydroxyphenyl)- {kaempferol}
N-Containing Components
120-72-9 Indole 400–600 NNA AT Matsumoto et al. (26A97)
NNN, NPYR Chung et al. (26A07, 26A08)
NNK Chung et al. (26A09)
771-51-7 Indole-3-acetonitrile B[a]P AT Wattenberg and Loub (26A190)
83-67-0 1H-Purine-2,6-dione, 3,7-dihydro-3,7-dimethyl- EC AT Nomura (26A119)
{theobromine}
58-08-2 1H-Purine-2,6-dione, 3,7-dihydro-1,3,7- EC AT Nomura (26A119)
trimethyl- {caffeine} DMB[a]A Perchellet and Boutwell (26A126)
NNA, NMOR Mirvish et al. (2559c)
54-11-5 Nicotine NNK AT Schüller et al. (26A141)
NDMA AM Lee et al. (2327b)
NNAL AM Brown et al. (437)
494-97-3 Nornicotine NDMA AM Lee et al. (2327b)
NNAL AM Brown et al. (437)

© 2009 by Taylor & Francis Group, LLC

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 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1201

Table XXVI-7A (Continued)

Anticarcinogens, Inhibitors, and Antimutagens in Tobacco and Tobacco Smoke
Approximate Representative References to
Delivery, mg/g AT, Anticarcinogenicity, Inhibition,
CAS No. Component MSS CSC Effective Against AMa and/or Antimutagenicitye

486-56-6 Cotinine NDMA AM Lee et al. (2327b)

NNAL AM Brown et al. (437)
Miscellaneous Components
622-78-6 Benzene, (isothiocyanatomethyl)- DMB[a]A AT Wattenberg (26A184, 26A185)
121-79-4 Benzoic acid, 3,4,5-trihydroxy-, propyl ester NNK AT Lo and Stich (26A87)
{propyl gallate} Teel and Castonguay (26A172)
75-15-0 Carbon disulfide 1,2-DMH AT Wattenberg and Fiala (26A188)
52-90-4 Cysteine NDMA AT Lo and Stich (26A87)
Dioxin DMB[a]A, MC, AT Berry et al. (26A06)
B[a]P, 7-MB[a]A, Cohen et al. (26A13)
12-MB[a]A, 5-MeC, DiGiovanni et al. (26A23)
DB[a,h]A
108-31-6 Maleic anhydride PAH, DMB[a]A AT Klein (26A74)
7439-96-5 Manganese B[a]P AT Sunderman et al. (3836a)
7782-49-2 Selenium DMB[a]A AT Shamberger (26A157)
NNA AT Thompson (26A175)
Cigarette smoke condensate Glu-P-1, Glu-P-2, AM Lee et al. (2327c)
Trp-P-1, Trp-P-2, IQ,
MeIQd
Abbreviations
B[a]P = benzo[a]pyrene MC = 3-methylcholanthrene
DB[a,h]A = dibenz[a,h]anthracene = 1,2-dihydro-3-methylbenz[j]aceanthrylene
DB[a,i]P = dibenzo[a,i]pyrene = benzo[rst]pentaphene NDMA = N-nitrosodimethylamine
DMB[a]A = 7,12-dimethylbenz[a]anthracene NNA = N-nitrosamine
1,2-DMH = 1,2-dimethylhydrazine NNAL = 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol
7-MB[a]A = 7-methylbenz[a]anthracene NNN = N’-nitrosonornicotine
12-MB[a]A = 12-methylbenz[a]anthracene NNK = 4-(N-methylnitrosamino)-1-(3-pyridinyl)-1-butanone
5-MeC = 5-methylchrysene NPYR = N-nitrosopyrrolidine
EC = ethyl carbamate PAH = polycyclic aromatic hydrocarbon
Glu-P-1 = 2-amino-6-methyldipyrido[1,2-a:3’,2’-d]imidazole AHR = aryl hydrocarbon receptor
Glu-P-2 = 2-aminodipyrido[1,2-a:3’,2’-d]imidazole MeIQ = 2-amino-3,4-dimethyl-3H-imidazo[4,5-f]quinoline
PhIP = 2-amino-1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridine Trp-P-1 = 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole
IQ = 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline Trp-P-2 = 3-amino-1-methyl-5H-pyrido[4,3-b]indole
a AT = test for antitumorigenicity; AM = test for antimutagenicity.
b This fraction consists primarily of the n-, iso- (2-methyl-), and anteiso- (3-methyl-) alkanes from C15 to C40.
c Benzo[b]triphenylene was formerly known as dibenz[a,c]anthracene.

d Several of the highly mutagenic N-heterocyclic amines identified in cigarette smoke (and foods) by Sugimura and his colleagues (see Chapter XVII.F).

increased because the total alkane fraction consisting of n-,
iso-, and anteiso-alkanes reduced the tumorigenicity of B[a]
P and presumably all of the alkanes could be involved in the
tumorigenicity reduction. The number of identified compo-
nents in the alkane fraction in tobacco smoke approximates
seventy. The complete list of the identified tobacco smoke
alkanes appears in Table I.A-10 in Chapter 1.
The antitumorigens and antimutagens in Table XXVI-7A
are presented in a slightly different way in Table XXVI-7B.
Several of the significant PAH, NNA, and N-heterocyclic
amine tumorigens or mutagens are listed in the same sequence
as in Table XXVI-1 and the tobacco smoke components that
reduce or nullify their tumorigenicity or mutagenicity are
listed for each. It is interesting to see how many tobacco
smoke components have been reported to inhibit or reduce
the potent tumorigenicity of B[a]P (eighteen in all) or DB[a,h]
A or DMB[a]A (twenty in all). Here again, only two of the
seventy alkanes examined for their inhibition of B[a]P tum-
origenicity are included.
In Table XXVI-7C, references are listed on various
aspects (identification, quantitation, tobacco precursors,
biological results, etc.) of the tobacco and tobacco smoke

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 1202 The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-7B
Anticarcinogens, Inhibitors, and Antimutagens in Tobacco and Tobacco Smoke
Component Affected Anticarcinogen, Inhibitor, Antimutagen Reference

Polycyclic aromatic hydrocarbons maleic anhydride Klein (26A74)

b-sitosterol Wattenberg (4149b)
Yasukawa et al. (26A196)
Benz[j]aceanthrylene, 1,2-dihydro-3-methyl-a dioxin Berry et al. (26A06)
Cohen et al. (26A13)
DiGiovanni et al. (26A23)
a-tocopherol {vitamin E} Shklar (3655a)
Slaga and Bracken (3684)
Viaje et al. (4049a)
Weerapradist and Shklar (4159c)
Benz[a]anthracene, 7,12-dimethyl- b ascorbic acid DiGiovanni et al. (976)
Slaga and Bracken (3684)
benzene, (isothiocyanatomethyl)- Wattenberg (26A184, 26A185)
benzo[e]pyrene DiGiovanni et al. (976)
Slaga et al. (3686)
2H-benzopyran-2-one {coumarin} Wattenberg et al. (26A189)
4H-1-benzopyran-4-one, 2-(3,4-dihydroxyphenyl)-3,5,7- Kato et al. (2046a)
trihydroxy- {quercitin}
benzo[b]triphenylene Slaga and Boutwell (3683)
Slaga et al. (3686)
b,b-carotene Mathews-Roth (2486a)
a-4,8,13-cyclodecatriene-1,3-diol, 1,5,9-trimethyl-12-(1- Saito et al. (3389)
methylethyl) {a-4,8,13-duvane-1,3-diol}
b-4,8,13-cyclodecatriene-1,3-diol, 1,5,9-trimethyl-12-(1- Saito et al. (3389)
methylethyl) {b-4,8,13-duvane-1,3-diol}
dioxin Berry et al. (26A06)
Cohen et al. (26A13)
DiGiovanni et al. (26A23)
fluoranthene DiGiovanni et al. (976)
Slaga et al. (3686)
maleic anhydride Klein (26A74)
2,4,6,8-nonatetraen-1-ol, 3,7-dimethyl-9-(2,6,6-trimethyl-1- Shamberger (26A158)
cyclohexen-1-yl)-, (all-E)- {retinol}
phenanthrene
phenol, 2,6-bis(1,1-dimethylethyl)-4-methyl- Slaga and Bracken (3684)
Slaga et al. (3687)
Wattenberg (26A182)
phenol, 4-methoxy- Wattenberg et al. (4149c)
Slaga et al. (3687)
1H-purine-2,6-dione, 3,7-dihydro-1,3,7-trimethyl- {caffeine} Nomura (26A119)
Perchellet and Boutwell (26A126)
Mirvish et al. (2559c)
pyrene DiGiovanni et al. (976)
Slaga et al. (3686)
selenium Shamberger (26A157)
a-tocopherol {vitamin E} Shklar (3655a)
Slaga and Bracken (3684)
Viaje et al. (4049a)
Weerapradist and Shklar (4159c)
Benzo[rst]pentaphene {dibenzo[a,i]pyrene} D-limonene Homburger et al. (26A61)
Benzo[a]pyrene anthracene Crabtree (843, 844, 26A17)
benz[a]anthracene Hoffmann and Wynder [unpublished
data cited on pp. 246, 292 in (4332)]
benzene Crabtree (843, 844, 26A17)
2H-benzopyran-2-one {coumarin} Wattenberg et al. (26A189)

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 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1203
Table XXVI-7B (Continued)
Anticarcinogens, Inhibitors, and Antimutagens in Tobacco and Tobacco Smoke
Component Affected
Benzo[a]pyrene (cont.)
Dibenz[a,h]anthracene
N-Nitrosamines
N-Nitrosodimethylamine
N-Nitrosodiethylamine
N-Nitrosopyrrolidine
© 2009 by Taylor & Francis Group, LLC
78836_C026.indd 1203
Anticarcinogen, Inhibitor, Antimutagen Reference
cyclohexanecarboxylic acid, 3-[[3-(3,4-dihydroxyphenyl)-1- Lesca (2351a)
oxo-2-propenyl]oxy]-1,4,5-trihydroxy-,
[1S-(1a,3b,4a,5a)]- {chlorogenic acid, 3-O-caffeoylquinic
acid}
dioxin Berry et al. (26A06)
Cohen et al. (26A13)
DiGiovanni et al. (26A23)
3H-2-furanone, dihydro-5-methyl- {a-angelica lactone} Wattenberg et al. (26A189)
hentriacontane C31H64 Wynder and Hoffmann (4314)
manganese Sunderman et al. (3836a)
naphthalene Crabtree (843, 844, 26A17)
pentatriacontane C35H72 Wynder and Hoffmann (4314)
phenol Van Duuren et al. (4035)
phenol, 2-(1,1-dimethylethyl)- Lam et al. (26A79)
phenol, 2,6-bis(1,1-dimethylethyl)-4-methyl- Slaga and Bracken (3684)
Slaga et al. (3687)
Wattenberg (26A182)
1-propene-1,2,3-tricarboxylic acid {aconitic acid} Kallistratos (26A68)
Kallistratos and Fasske (26A69)
2-propenoic acid, 3-(3,4-dihydroxyphenyl)- {cinnamic acid, Wattenberg et al. (4149c)
3,4-dihydroxy-, caffeic acid}
2-propenoic acid, 3-(3-hydroxy-4-methoxyphenyl)- Wattenberg (4149b)
{cinnamic acid, 3-hydroxy-4-methoxy-, ferulic acid}
2-propenoic acid, 3-(2-hydroxyphenyl)- {o-coumaric acid} Wattenberg et al. (4149c)
anthracene Crabtree (843, 844, 26A17)
benz[a]anthracene Steiner and Falk (3814)
benzene Crabtree (843, 844, 26A17)
benzo[b]triphenylene Slaga and Boutwell (3683)
Slaga et al. (3686)
dioxin Berry et al. (26A06)
Cohen et al. (26A13)
DiGiovanni et al. (26A23)
naphthalene Crabtree (843, 844, 26A17)
phenol, 4-methoxy- Wattenberg et al. (4149c)
Slaga et al. (3687)
benzoic acid, 3,4,5-trihydroxy- {gallic acid} Mirvish et al. (2559c)
cholesterol Cohen et al. (26A12)
indole Matsumoto et al. (26A97)
palmitic acid C16H32O2 Takeda et al. (26A171)
1H-purine-2,6-dione, 3,7-dihydro-1,3,7-trimethyl- {caffeine} Nomura (26A119)
Perchellet and Boutwell (26A126)
Mirvish et al. (2559c)
stearic acid C18H36O2 Takeda et al. (26A171)
selenium Thompson (26A175)
b-sitosterol Wattenberg (4149b)
Yasukawa et al. (26A196)
cotinine Lee et al. (2327b)
cysteine Lo and Stich (26A87)
nicotine Schüller et al. (26A141)
nornicotine Lee et al. (2327b)
phenol, 2,6-bis(1,1-dimethylethyl)-4-methyl- Clapp et al. (26A11)
2-propenoic, 3-phenyl- {cinnamic acid} Chung et al. (26A07, 26A08)
phenol Chung et al. (26A07, 26A08)
indole Chung et al. (26A07, 26A08)
(Continued)
11/24/08 12:39:03 PM
 1204 The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-7B (Continued)

Anticarcinogens, Inhibitors, and Antimutagens in Tobacco and Tobacco Smoke
Component Affected Anticarcinogen, Inhibitor, Antimutagen Reference

N’-Nitrosonornicotine 1-butanol Waddell and Marlowe (26A178)

ethanol Waddell and Marlowe (26A178)
Farinati et al. (26A32)
indole Chung et al. (26A07, 26A08)
phenol Chung et al. (26A07, 26A08)
2-propanol, 2-methyl- {tert-butanol} Waddell and Marlowe (26A178)
2-propenoic, 3-phenyl- {cinnamic acid} Chung et al. (26A07, 26A08)
4-(N-Methylnitrosamino)-1-(3-pyridyl)-1-butanone benzoic acid, 3,4,5-trihydroxy-, propyl ester {propyl gallate} Lo and Stich (26A87)
Teel and Castonguay (26A172)
2H-1-benzopyran-2-one, 6,7-dihydroxy- {esculetin} Teel and Castonguay (26A172)
indole Chung et al. (26A09)
D-limonene Wattenberg and Coccia (26A187)
nicotine Schüller et al. (26A141)
N-Nitrosomorpholine 1H-purine-2,6-dione, 3,7-dihydro-1,3,7-trimethyl- {caffeine} Mirvish et al. (2559c)
N-Heterocyclic Amines
Glu-P-1 cigarette smoke condensate Lee et al. (2327c)
Glu-P-2 cigarette smoke condensate Lee et al. (2327c)
IQ cigarette smoke condensate Lee et al. (2327c)
MeIQ cigarette smoke condensate Lee et al. (2327c)
Trp-P-1 cigarette smoke condensate Lee et al. (2327c)
Trp-P-2 cigarette smoke condensate Lee et al. (2327c)

1,2-Dihydro-3-methylbenz[j]aceanthrylene = 3-methylcholanthrene, regarded as one of the most potent tumorigens to mouse skin known. Although it does
a 

not appear in any of the lists in Table XXVI-1 by Hoffmann and his colleagues, it is a tobacco smoke component.
b 7,12-Dimethylbenz[a]anthracene
 is regarded as one of the most potent tumorigens to mouse skin known. Although it does not appear in any of the lists in
Table XXVI-1 by Hoffmann and his colleagues, it is a tobacco smoke component.

components listed in Table XXVI-7A as known inhibitors,
anticarcinogens, and antimutagens. For the reader’s benefit,
the sequence of components in Table XXVI-7C is identical
with that in Table XXVI-7A and the CAS nomenclature has
been included in each case.
In a review of antimutagens and inhibitors of mutagenesis,
Ramel et al. (26A133) discussed the many antimutagens found
naturally occurring in plants. They did not discuss tobacco
specifically but did discuss the natural occurrence of the fol-
lowing antimutagens: a-tocopherol, 2H-1-benzopyran-2-one,
7-hydroxy-2H-1-benzopyran-2-one, and 3-phenyl-2-prope-
nal. All four have been identified as tobacco components; all
but 7-hydroxy-2H-1-benzopyran-2-one have been identified
in MSS.
Lee and Reed (2327d) investigated the antimutagenicity
of nicotine vs. N-nitrosodimethylamine (NDMA) and nico-
tine vs. B[a]P in the Ames test (Salmonella typhimurium TA
100). They observed that nicotine inhibits the mutagenicity
of NDMA but not that of B[a]P. Although the mechanism
of this antimutagenicity was not elucidated, the report by
Murphy and Heilbrun (26A115) on the inhibition of NNN
metabolism by nicotine suggests nicotine inhibition of NNA
activation may be involved. Lee et al. (2327b) repeated their
earlier experiment and not only confirmed the antimutagenic
effect of nicotine on NDMA but also demonstrated the simi-
lar activity of nornicotine and cotinine. Brown et al. (437)
reported the antimutagenicity of nicotine and cotinine vs.
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL).
Lee et al. (2327c) reported that CSC inhibits the muta-
genic activity of several N-heterocyclic amines when tested
in the Ames assay with Salmonella typhimurium TA 98 in
the presence of the S-9 activation system. The mutagenic
N-heterocyclic amines tested included Glu-P-1, Glu-P-2, Trp-
P-1, Trp-P-2, IQ, and MeIQ. These compounds are among
the most potent mutagens known (3828c, 3829, 3829a, 4365a,
4357, 4368). Several have also been reported to be tumorigenic
in mammalian bioassays (1177d). In one of the first demon-
strations of antimutagens in tobacco smoke, Lee et al. (2327c)
reported that 50 to 100 mg of CSC per plate suppresses the
mutagenic activity of these compounds by as much as 80%.
Enzymatic studies indicate that CSC is a potent inhibitor of
cytochrome P-450 dependent monooxygenase. Therefore, it
appears that CSC exerts its antimutagenicity by inhibiting the
P-450 system. Lee et al. (2327c) subsequently reported that
fractionation of CSC gave fractions that showed low muta-
genicity themselves but were significantly antimutagenic.
Only a few of the listed MSS tumorigens have ever been
tested for tumorigenicity to lung tissue by exposure of animals

© 2009 by Taylor & Francis Group, LLC

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 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1205

Table XXVI-7C
Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco
Substitute Smoke
Note: The symbol (0) indicates the component identified in tobacco substitute smoke was not detected in tobacco smoke or vice versa.

(Continued )

© 2009 by Taylor & Francis Group, LLC

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 1206 The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-7C (Continued)

Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco
Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

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 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1207

Table XXVI-7C (Continued)

Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco
Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

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 1208 The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-7C (Continued)

Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco
Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

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 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1209

Table XXVI-7C (Continued)

Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco
Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

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 1210 The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-7C (Continued)

Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco
Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

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 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1211

Table XXVI-7C (Continued)

Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco
Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C026.indd 1211 11/24/08 12:39:10 PM

 1212 The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-7C (Continued)

Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco
Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C026.indd 1212 11/24/08 12:39:11 PM

 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1213

Table XXVI-7C (Continued)

Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco
Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C026.indd 1213 11/24/08 12:39:12 PM

 1214 The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-7C (Continued)

Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco
Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C026.indd 1214 11/24/08 12:39:13 PM

 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1215

Table XXVI-7C (Continued)

Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco
Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C026.indd 1215 11/24/08 12:39:14 PM

 1216 The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-7C (Continued)

Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco
Substitute Smoke

© 2009 by Taylor & Francis Group, LLC

78836_C026.indd 1216 11/24/08 12:39:15 PM

 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1217

Table XXVI-7C (Continued)

Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco
Substitute Smoke

(Continued )

© 2009 by Taylor & Francis Group, LLC

78836_C026.indd 1217 11/24/08 12:39:16 PM

 1218 The Chemical Components of Tobacco and Tobacco Smoke
Table XXVI-7C (Continued)
Anticarcinogens, Antitumorigens, Inhibitors, and Antimutagens in Tobacco, Tobacco Smoke, and Tobacco
Substitute Smoke
via inhalation. The results with all but one of the four MSS
components (B[a]P, NDMA, NDEA, 210Po), tested via inhala-
tion at dose levels substantially exceeding those in MSS, were
rated “equivocal” (3095). Only 210Po, administered via inha-
lation at massive dose levels to rats, produced squamous cell
carcinoma, the lung tumor type similar to that associated sta-
tistically with cigarette smoking. However, the U.S. Surgeon
General (4005, 4010) and Hoffmann and Hecht (1727) dis-
counted the effect of 210Po in MSS in lung cancer causation in
active smokers. From the type of evidence available presently,
it is doubtful that many of the toxicants should be included
in the various lists. Examination of data and reports on the
tobacco smoke components present in one or more of the
many lists sustains the premise that it is inappropriate to use
such lists as evidence of any relationship between exposure
to MSS and lung cancer induction in smokers or exposure to
ETS and lung cancer induction in nonsmokers.
Several specific components could and should be excluded
from the toxicant lists for reasons other than the failure to
induce lung tumors via inhalation.
1. By the early 1960s, dibenzo[a,l]pyrene had been
reported in MSS by several groups [see account
in (3262)]. For its identification, the investigators
© 2009 by Taylor & Francis Group, LLC
78836_C026.indd 1218
relied on a published UV spectrum purportedly
that of synthetic dibenzo[a,l]pyrene (dibenzo[def,p]
chrysene). However, in 1966 it was demonstrated
that the published spectrum was that of an isomer,
dibenz[a,e]aceanthrylene (dibenzo[a,e]fluoran-
thene) (2314).
2. Previously noted was the failure by many research
groups between 1963 and 2000 to confirm the
presence in MSS of the tumorigenic aza-arenes
reported by Van Duuren et al. (4027). Dibenz[a,j]
acridine was reported recently by Rustemeier et al.
(3370).
3. The precursors of arsenic and NDELA in MSS
have been banned from U.S. tobacco agronomy
since 1952 and 1981, respectively.
XXVI.B.1 Alternate Exposures to Carcinogens,
Tumorigens, and Mutagens
Examination of the tumorigens listed in Table XXVI-1 logi-
cally leads to the questions: What, if any, are the human expo-
sures to the listed tumorigens other than MSS and/or ETS?
11/24/08 12:39:17 PM
 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1219

Is the exposure to a given tumorigen less, more, or equal to

that from cigarette smoke? A detailed account of such alter- Table XXVII-8
nate exposures requires many pages and tables. Most tum- Exposures to Tumorigens and Mutagens from Sources
origens in Table XXVI-1 have many alternate sources. The Other than Mainstream and Environmental Tobacco
one obvious exception is the tobacco-specific N-nitrosamines Smoke
(TSNAs) which, by definition, being tobacco specific, have
Alternate Exposure References
no alternate.
Table XXVI-8 is a brief list, with references, of alternate Polycyclic Aromatic Hydrocarbons
exposures to the major classes of tumorigens in tobacco Foodstuffs Bailey and Williams (158a)
smoke. The cited references provide tabulated details of Grasso (1345)
human exposures to them. Subsequent to Table XXVI-8 are Lijinsky and Shubik (2364a, 2364b)
discussions and tables in which the alternate exposures to the Maga (2438)
four major tumorigen classes in tobacco smoke are presented Neukomm and Bonnet (2715)
Vaessen et al. (4014)
in more detail.
Waldman et al. (4106)
Beverages (coffee, tea, cocoa, etc.) Kuratsune (2237)
Kuratsune and Hueper (2238)
XXVI.B.1.a Alternate Exposures to Polycyclic Maga (2438)
Aromatic Hydrocarbons Vehicle engine exhaust Grimmer (1399-1402, 1405, 1406a,
1406b)
Despite the ubiquity of PAHs in modern society, their pres- Lyons (2428)
ence in and their contribution to the alleged hazard of tobacco Mauderly et al. (2505)
smoke have been repeatedly emphasized for nearly half a Strach (3821)
century but seldom are the other many sources and/or levels Sawicki et al. (3419b, 3419c)
of exposure to PAHs currently acknowledged as they were in Williams et al. (4247a)
Wynder and Hoffmann (4315, 4316)
the 1930–1950 period. Daily exposure to PAHs by inhalation
Furnace effluents Mumford et al. (26A114)
(MSS, ETS, air pollutants) may represent only a small part of
the total daily exposure; other exposures to PAHs often sub- Aza-arenes
stantially exceed exposure via inhalation. Exposures to vari- Vehicle engine exhaust Grimmer (1407a)
Furnace effluents Grimmer (1407b)
ous PAHs are summarized in two different forms in Tables
XXVI-9 and XXVI-10. N-Nitrosamines
Results from many studies have been reported on the types Foodstuffs Bailey and Williams (158a)
and levels of PAHs, with particular emphasis on B[a]P, B[a]A, Grasso (1345)
chrysene, benz[e]acephenanthrylene (benzo[b]fluoranthene), Kröller (2205, 2206)
Preussmann and Eisenbrand (2990)
benzo[k]fluoranthene, indeno[1,2,3-cd]pyrene, DB[a,h]A, and
Beverages (coffee, tea, cocoa, Preussmann and Eisenbrand (2990)
benzo[ghi]perylene. As noted by Menzie et al. (2533), all of
water, etc.)
these PAHs have been identified in exhausts or effluents from Mitch et al. (26A112a)
fossil fuel combustion sources, in soils, sediments, and water, Cosmetics Preussmann and Eisenbrand (2990)
and in a variety of commonly used foodstuffs. Industrial exposure (rubber, leather, Preussmann and Eisenbrand (2990)
Although concern about PAHs in foodstuffs, particularly metal, and pharmaceutical
those arising pyrogenetically during cooking (grilling, broil- industries)
ing, roasting, etc.) predates the major concern over their pres- N-Heterocyclic Amines
ence in tobacco smoke, efforts to identify them in foodstuffs Foodstuffs Bailey and Williams (158a)
have been much less than for tobacco smoke. The number Jägerstad et al. (1916b)
of PAHs identified in tobacco smoke exceeds 500, including Matsumoto et al. (2492)
several hundred derivatives where the positions of the alkyl Nagao et al. (2667f)
groups have not been precisely defined (3757, 3758). PAHs Sugimura (3828b, 3828c, 3828e,
identified in foodstuffs, both cooked and uncooked, number 3828f)
fewer than 150. Whether one considers the overall composi- Sugimura and Nagao (3829b)
tion in general or the PAH fraction in particular, no other Sugimura et al. (3829a)
Tanaka et al. 3865c)
commercial product has been examined as extensively as
Yasuda et al. (4382a)
tobacco or tobacco smoke.
Beverages (coffee, tea, cocoa, etc.) Aeschbacher and Würzner (38a)
Many PAHs are components of foodstuffs in the average Kosugi et al. (2178b)
diet (see Tables XXVI-9 and XXVI-10). Except for 5-methyl- Nagao et al. (2667d, 2667e)
chrysene, PAHs listed in the many reports by Hoffmann and
Metals
his colleagues (1727, 1740, 1741, 1743, 1744, 1773, 1808) and
Foodstuffs Grasso (1345)
OSHA (2825) as tobacco and tobacco smoke “tumorigens”
have been identified in many foodstuffs. Grasso discussed

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 1220 The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-9
Personal Exposure to Tobacco Smoke Polycyclic Aromatic Hydrocarbons Listed as Tumorigens
Exposure Source B[a]Aa B[e]A B[j]F B[k]F B[a]P Chr Chr, me DB[a,h]A NC DB[b]C B[rst]P DB[d]P IP

Fish
-Raw × × — × × — — — — — — — —
-Cooked × × — × × — — — — — — — —
-Smoked — — — — × — — — — — — — —
Oysters × — — — × — — — — — — — —
Mussels — — — — × — — — — — — — —
Meat
-Frankfurters — — — — × — — — — — — — —
-Hamburgers × × — × × — — × × × — — ×
-Bacon — — — — × — — — — — — — —
-Ham, smoked — — — — × — — — — — — — —
-Bologna — — — — × — — — — — — — —
-Sausage × — — — × — — — — — — — —
-Beef, broiled × — — — × — — — — — — — —
-Beef, roasted × — — — × — — — — — — — —
-Beef, barbecued — — — — × — — — — — — — —
-Poultry — — — — × — — — — — — — —
-Cholesterol, heated — — — — — × — — — — — — —
Dairy Products
-Milk — — — — × — — — — — — — —
-Cheese — — — — × — — — — — — — —

Cereals
-Puffed corn — × — × × — — — — — — — —
-Puffed oats × × — — — — — — — — — — —
-Puffed wheat × — × × — — — — — — — —
-Barley malt × × — — × — — × — — — — ×
-Bran × × — × × — — — — — — — —
Bread
-Untoasted — — — — × — — — — — — — —
-Toasted — — — — × — — — — — — — —
Beverages
-Tea — — — — × — — — — — — — —
-Coffee, regular — — — — × — — — — — — — —
-Coffee, instant — — — — × — — — — — — — —
-Water — × — — × — — — — — — — —
-Bourbon — — — — × — — — — — — — —
-Scotch — — — — × — — — — — — — —

Fruits, Vegetables
-Fresh × — — — × — — — — — — — —
-Potatoes, cooked — — — — × — — — — — — — —
-Potatoes, French fried — — — — × — — — — — — — —
-Endive — — — — × — — — — — — — —
-Spinach — — — — × — — — — — — — —
-Soybeans — — — — × — — — — — — — —
-Kale — — — — × — — — — — — — —
-Tomatoes — — — — × — — — — — — — —
-Apples — — — — × — — — — — — — —
-Prunes — — — — × — — — — — — — —

Oils, cooking
Coconut oil × — — — × — — — — — — — —
-Vegetable oil × — — — × — — — — — — — —
Mayonnaise × — — — × — — — — — — — —

© 2009 by Taylor & Francis Group, LLC

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 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1221

Table XXVI-9 (continued)

Personal Exposure to Tobacco Smoke Polycyclic Aromatic Hydrocarbons Listed as Tumorigens
Exposure Source B[a]Aa B[e]A B[j]F B[k]F B[a]P Chr Chr, me DB[a,h]A NC DB[b]C B[rst]P DB[d]P IP

Margarine × — — — × — — — — — — — —

MSS, SSS, ETS × × × × × × × × × × × × ×

Engine exhausts b, c, d × × × × × × × × — — — — ×
Tars, soots, oils, × × — × × × — × — — — — ×
excluding ETS c
Oils, catalytically — — — — × × × — — — — — —
cracked
Vehicle tire carbon × — — — × × — — — — — — —
blacks
Open-fire, coal × × × × × × — × × — × × ×
combustion e
Urban atmospheres × — — — × × × — — — — — —

B[a]A = benz[a]anthracene DB[a,h]A = dibenz[a,h]anthracene

B[e]A = benz[e]acephenanthrylene = benzo[b]fluoranthene NC = naphtho[1,2,3,4-def]chrysene = dibenzo[a,e]pyrene
B[j]F = benzo[j]fluoranthene DB[b]C = dibenzo[b,def]chrysene = dibenzo[a,h]pyrene
B[k]F = benzo[k]fluoranthene B[rst]P = benzo[rst]pentaphene = dibenzo[a,i]pyrene
B[a]P = benzo[a]pyrene DB[d]P = dibenzo[def,p]chrysene = dibenzo[a,l]pyrene
Chr = chrysene IP = indeno[1,2,3-cd]pyrene]
Chr, me = chrysene, 5-methyl-
a The PAHs listed also occur in MSS, SSS, and ETS.
b Wynder and Hoffmann (4315)
c Williams et al. (4247a)

d Grimmer et al. (1405)

e Mumford et al. (26A114)

the PAHs in foods and their significance [see p. 1213 in
(1345)]:
The significance of these low levels of PAH carcinogens
in food is difficult to assess. Undoubtedly, they are among
the most potent carcinogens known, and every effort should
be made to reduce their concentration in food. There are
no clear indications, however, that they cause human can-
cer … Furthermore, there are indications that low levels of
[benzo[a]pyrene], probably one of the most potent of the
PAH found in food, do not produce tumors in experimental
animals. The repeated application of 1.25 mg of [benzo[a]
pyrene] in acetone to the skin of mice for 68 weeks failed
to produce tumors [Roe (3310, 3311)]; dietary intake of 100
ppm of [benzo[a]pyrene] or less also had no effect in mice
[Neal and Rigdon (2687].
His comments on the carcinogenicity to humans of PAHs
in ingested foods are equally applicable to the carcinogenic-
ity to humans of the PAHs in inhaled cigarette MSS or ETS.
Grasso noted that the following five PAHs were commonly
found in foods: B[a]A, B[a]P, DB[a,h]A, benz[e]acephenan-
thrylene (benzo[b]fluoranthene), and benzo[k]fluoranthene;
all listed by Hoffmann and his colleagues (1727, 1740,
1741, 1743, 1744, 1773, 1808) and OSHA (2825) as “tobacco
smoke tumorigens.” Grasso also listed the ranges of B[a]A
and B[a]P levels found in a variety of commonly consumed
foodstuffs.
Maga (2438) listed sixty-five common foodstuffs contain-
ing PAHs. As did the list compiled by Grasso, Maga’s list
included fruits and vegetables, dairy products, cereal prod-
ucts, legumes, beverages (including water), cooking oils,
meat products, seafood products, and miscellaneous food-
stuffs such as eggs, sugar, and olives. When many foodstuffs
are heated during preparation, their PAH content increases
dramatically, for example, a single serving of charcoal-
broiled meat contains more than 600 times the B[a]P level
in the MSS from one cigarette [Lijinsky and Shubik (2364a,
2364b)].
Estimates such as this one are usually based on the Federal
Trade Commission’s (FTC) listing of total particulate matter
(TPM), “tar,” nicotine, and CO deliveries plus an average
value for the level of the B[a]P in the MSS TPM. Such com-
parisons between cigarettes and foodstuffs may yield esti-
mates that are actually too low. For a given cigarette brand,
the FTC numbers are obtained via precisely defined smoking
regimen and analytical methods (preconditioned cigarettes:
25°C; relative humidity, 60%; conditioning time, 24 hr; and
smoking parameters: 35-ml puff volume, 2-sec puff duration,
1 puff/min; 25°C, 60% relative humidity, cigarette smoked to
a defined butt length). On the other hand:

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 1222 The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-10
Polycyclic Aromatic Hydrocarbon Sources
Tobacco Gasoline Engine Broiled Barley Puffed Common
Polycyclic Aromatic Hydrocarbon Smoke Exhausta Cooked Fishb Hamburgerb Maltbh Cerealsb Foodsb

Benz[j]aceanthrylene, 1,2-dihydro-c × — — — — — ×
Benz[j]aceanthrylene, 1,2-dihydro-3-methyl-d × — — — — — ×
Benz[e]acephenanthrylenee × × × — × ×
Benz[a]anthracene × × × × × × ×
Benz[a]anthracene, 7,12-dimethyl- × — — — — × ×
Benzo[j]fluoranthene × × — — — — ×
Benzo[k]fluoranthene × × × × — × ×
11H-Benzo[b]fluorene × × — — — ×
Benzo[rst]pentaphenef × — — — — — ×
Benzo[ghi]perylene × × × — — — ×
Benzo[c]phenanthrene × — — — — — ×
Benzo[a]pyrene × × × × × ×
Benzo[e]pyrene × × × — — — ×
Benzo[b]triphenyleneg × — — × × — ×
Chrysene × × — × — ×
Dibenz[a,h]anthracene × × — × × — ×
Dibenz[a,j]anthracene × × — — — — ×
Dibenzo[e,l]pyrenei × — — × — ×
Indeno[1,2,3-cd]fluoranthene × × — — — — ×
Indeno[1,2,3-cd]pyrene × × — — — — ×
a Wynder and Hoffmann (4315)
b Maga (2438)
c Previously known as cholanthrene

d Previously known as 3-methylcholanthrene

e Previously known as benzo[b]fluoranthene

f Previously known as dibenzo[a,i]pyrene

g Previously known as dibenz[a,c]anthracene

h Also contains a high level of N-nitrosodimethylamine

i Also known as dibenzo[fg,op]naphthacene

• Few smokers, if any, in the smoking of a ciga-
rette take in the TPM amount found in the FTC
determination.
• Few smokers smoke their cigarettes to as short a
butt length as in the FTC procedure.
• Because of involvement in other tasks, smokers
often place their cigarette in an ash tray for a brief
time, thus missing one or more puffs on the cigarette.
Few smokers take the number of puffs obtained for
a given cigarette brand in the FTC procedure. The
smoking machine used in the method never misses
a puff on the cigarette under test!
• The smoking machine used in the FTC procedure does
not “exhale” as do smokers. It has been determined
in numerous studies that cigarette smokers exhale
between 10% and 50% of the TPM inspired during the
puffs needed to consume the cigarette, thus retaining
between 50% and 90% of the inspired TPM.
All of these factors, if taken into account for a foodstuff-
cigarette comparison such as the one noted previously, will
increase the calculated number of cigarettes in the B[a]P
comparison.
Analysis of a foodstuff as elementary as bread reveals a
B[a]P level of 0.23 ng/g (mainly in the crust); light toasting
raised the B[a]P level to 0.39 ng/g; darker toasting raised it to
0.56 ng/g. For an average slice of bread (weight one ounce or
approximately 30 g), these values would be about 7, 12, and
17 ng/slice. Maga also reported the dietary intake of B[a]P
(charcoal-broiled meat excluded) averaged about 500 ng/day.
From their analysis of human exposure to B[a]P, Waldman
et al. (4106) reported in 1991 that “the range and magnitude
of dietary exposures to benzo[a]pyrene” ranged from 2 to
500 ng/day and “were much greater than for inhalation (10
to 50 ng/[day]).” For some subjects, however, they found a
dietary maximum of 1149 ng/day, despite omission of the
contribution of B[a]P-containing beverages such as coffee.
These B[a]P-intake estimates [Maga (2438), Waldman et al.
(4106)] were lower than that reported by Hattemeyer-Frey and
Travis (1551): 2200 ng/day (97% from diet; 3% from inhala-
tion and water contamination). If B[a]P were tumorigenic in
man and its threshold limit value were “zero,” the incidence

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 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1223

ETS in such environments reach approximately 2.5 ng/m3 …

Table XXVI-11 The magnitude of ETS-contribution [to PAH and BaP con-
Levels of Benzo[a]pyrene and Benz[a]anthracene in centration] is generally small and is often difficult to consis-
Common Foodstuffs tently detect in most environments.

Benzo[a]pyrene, Benz[a]anthracene, The daily intake of B[a]P from ETS may be estimated if
Foodstuff ng/g ng/g the following assumptions are made:
Fresh vegetables 2.85-24.5 0.3-43.6
Vegetable oils 0.4-1.4 0.8-1.1
• The average hourly intake of air is independent of
Coconut oil 43.7 98.0 whether the host is awake or asleep and is 1 m3.
Margarine 0.4-0.5 1.4-3.0 • The B[a]P level due to ETS is at the high end of
Mayonnaise 0.4 2.2 the range estimated by Guerin et al. (1992) to be
Coffee 0.3-1.3 1.3-3.0 0.5 to 1 ng/m3.
Tea 3.9 2.9-4.6 • None of the daily intake of B[a]P, whether from
Grain 0.19-4.13 0.40-6.85 diet, ETS, and the like, is eliminated by exhala-
Oysters and mussels 1.5-9.0 … tion, etc.
Smoked ham 3.2 2.8
Smoked fish 0.83 1.9
Table XXVI-13 shows a comparison of the intake of B[a]
Smoked bonito 37 189
P from ETS vs. the other B[a]P intakes discussed previously.
Cooked sausage 12.5-18.8 17.5-26.2
Singed meat 35-99 28-79
Broiled meat 0.17-0.63 0.2-0.4 XXVI.B.1.b Alternate Exposures to Aza-Arenes
Charcoal-broiled steak 8.0 4.5
Broiled mackerel 0.9 2.9
Even though, as indicated in Table XXVI-3 and the text
Barbecued beef 3.3 13.2 accompanying it, the presence of the three pentacyclic
Barbecued ribs 10.5 3.6 N-heterocyclic compounds in tobacco smoke is equivocal,
Cigarette mainstream 20-25 20-35 the alternate exposure to them and similar components is
smoke a discussed below.
In their 1956 review of angular benzacridines and diben-
a The total mainstream smoke (particulate phase plus vapor phase) from an
zacridines and their tumorigenicity, Lacassagne et al. (2247a)
85-mm filtered cigarette smoked under FTC conditions approximates 0.5 g.
made the following interesting observation, pertinent to the
alleged “carcinogenicity” of benzene, frequently used as a sol-
vent in tumorigenicity studies in the 1930s, 1940s, and 1950s:
These molecules [the angular benzacridines] are very soluble
of digestive tract cancer would be substantially higher than in benzene and acetone (two solvents currently used for the
it is. investigations of carcinogenic activity).
The data tabulated in Table XXVI-11 on B[a]P and B[a]
A from Maga, Grasso, and other investigators of the PAHs In addition to the exposure to acridines and benzacridines
in frequently consumed foodstuffs have been expanded in in tobacco smoke, other exposures to various acridines and
Table XXVI-12 to include the cigarette equivalents of vari- benzacridines have been cataloged in the scientific literature.
ous dietary items consumed at estimated per meal levels. The Many of the sources (Table XXVI-14) comprise environmen-
inhaled cigarette MSS particulate phase from one cigarette tal pollutants.
is assumed to deliver 10 ng of B[a]P and 12.5 ng of B[a]A to Unlike the PAHs and the NNAs, nontobacco smoke expo-
the smoker. The following situation, known to be contrary sure to the acridines and benzacridines does not include
to experimentally determined fact, is also assumed: None of foods. However, exposures other than tobacco smoke to poly-
the MSS particulate phase, nor its B[a]P content, nor its B[a] cyclic nitrogen compounds include exposures to the muta-
A content is exhaled by the smoker. genic N-heterocyclic amines in a variety of foods.
How do these exposures to B[a]P in the diet, etc., compare
to the exposure to B[a]P in ETS? It is obvious that dietary XXVI.B.1.c Alternate Exposures to N-Nitrosamines
intake of B[a]P far outweighs the intake of B[a]P via inhala-
Among several groups who have been involved in research
tion, including that inhaled in ETS. Guerin et al. (1445) of the
on NNAs since soon after their tumorigenicity in laboratory
Oak Ridge National Laboratory discussed the contribution
animals was first reported by Magee and Barnes (2441a)
of ETS to indoor air PAH concentrations and tabulated their
are Barnes, Magee, and Schoental in the United Kingdom
assessments of the situation. They noted:
and Dontenwill, Druckrey, Preussmann, and Schmähl in
The data suggest that ETS contributes between 0.5 and 1 ng/m3
Germany. From the German group, Preussmann has been a
of BaP to indoor environments containing measurable ETS- key contributor to our knowledge of N-nitrosamines. He has
contamination … Excursions in BaP concentrations due to authored or co-authored research results and review articles
continuously on NNAs since 1959. Initially, Preussmann was

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 1224 The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-12
Cigarette Equivalents of Benzo[a]pyrene (B[a]P) and Benz[a]anthracene (B[a]A) in Common Foodstuffs
B[a]P B[a]A

Foodstuff ng/g ng/Servinga Cigarette Equivalentb ng/g ng/Servinga Cigarette Equivalentb

Fresh vegetables 2.85-24.5 325-2800 (4) 32-280 0.3-43.6 34-4970 (4) 3-400
Vegetable oils 0.4-1.4 46-160 (4) 5-16 0.8-1.1 91-125 (40 7-10
Coconut oil 43.7 1245 (1) 125 98.0 2800 (1) 225
Margarine 0.4-0.5 11-14 (1) 1 1.4-3.0 40-85 (1) 3-7
Mayonnaise 0.4 23 (2) 2 2.2 125 (2) 10
Coffee 0.3-1.3 17-74 (2) 2-7 1.3-3.0 74-171 (2) 6-14
Tea 3.9 222 (2) 22 2.9-4.6 165-262 (2) 13-21
Grain 0.19-4.13 22-471 (4) 2-47 0.40-6.85 46-780 (4) 4-62
Bread, untoasted 0.23 20 (3) 2 — — —
Bread, light toast (3 min) 0.39 33 (3) 3 — — —
Bread, dark toast (5 min) 0.56 48 (3) 5 — — —
Oysters and mussels 1.5-9.0 171-1026 (4) 17-103 — — —
Smoked fish 0.83 95 (4) 10 1.9 217 (4) 17
Smoked bonito 37 4218 (4) 422 189 21500 (4) 1720
Smoked whiting 6.9 787 (4) 79 — — —
Broiled mackerel 0.9 103 (4) 10 2.9 330 (4) 26
Smoked ham 3.2 370 (4) 37 2.8 319 (4) 25
Cooked sausage 12.5-18.8 1425-2143 (4) 143-214 17.5-26.2 2000-2900 (4) 160-232
Singed meat 35-99 3990-11290 (4) 400-1130 28-79 3200-9000 (4) 256-720
Broiled meat 0.17-0.63 19-72 (4) 2-7 0.2-0.4 23-46 (4) 2-4
Broiled hamburger, fatty 2.6 296 (4) 30 — — —
Broiled hamburger, lean 0 0 (4) 0 — — —
Charcoal-broiled steak 8.0 912 (4) 9(4) 4.5 513 (4) 41
1824 (8) 182 (8) 1026 (8) 1026 (8) 82
Charcoal-broiled T-bone 50 5700 (4) 570 — — —
11400 (8) 1140

Barbecued beef 3.3 376 (4) 38 13.2 1500 (4) 120

Barbecued pork 4.5 513 (4) 51 … … …
Barbecued ribs 10.5 1197 (4) 120 3.6 410 (4) 33
Cigarette mainstream smokec 20-25 20-35
a Number in parentheses indicate number of ounces consumed. B[a]P and B[a]A content calculated at level per ounce (28.5 g) consumed.
Inhaled cigarette MSS particulate phase from one cigarette is assumed to deliver 10 ng of B[a]P and 12.5 ng of B[a]A to the smoker. The following, contrary
b 

to experimental fact, is also assumed: None of the MSS particulate phase, nor its B[a]P content, nor its B[a]A content is exhaled by the smoker.
c The weight of the total MSS (vapor phase + particulate phase) from an 85-mm filtered cigarette smoked under FTC conditions approximates 0.5 g.

Table XXVI-13
Comparison of Daily Dietary and Inhalation Intake of Benzo[a]pyrenea
Study Type B[a]P from Diet B[a]P via Inhalation Total B[a]P Intake

Maga (2438) estimated — — 500 ng/day

Hattemeyer-Frey and Travis (1551) measured 2130 ng/day 70 ng/day 2200 ng/day
Waldman et al. (4106) measured 2-500 ng/day b 10-50 ng/day 12-550 ng/day b
From inhaled ETS estimated — 24 ng/day c
a Based on assumptions listed above.
b Dietary intakes as high as 1149 ng/day were noted.
c Even if intake were at the excursion value of 2.5 ng/m3, the daily intake from ETS would be 60 ng.

© 2009 by Taylor & Francis Group, LLC

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 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1225
Table XXVI-14
Aza-Arenes Sources Other Than Tobacco Smoke
Acridine/Benzacridine Source Reference
Automobile exhaust Sawicki et al. (3419b),
Williams et al. (4247a)
Coal-fired residential furnace Grimmer et al. (1407b)
emission
Coal distillate Graebe and Caro (1334f),
Kruber (2210a)
Coal tar Lang and Eigen (2261a),
Merli et al. (2534a)
Crude oil Schmitter et al. (3519b),
Grimmer et al. (1407a)
High boiling petroleum distillate McKay et al. (2519a),
Later et al. (26A80)
Industrial stack effluent Sawicki et al. (3419a)
Urban suspended particulate matter Sawicki et al. (3419c), Cautreels and
van Cauwenberghe (636a), Dong
et al. (1040a), Adams et al. (35)
involved with the investigation of the relationship between
the structure of a NNA and its tumorigenicity [Druckrey et
al. (1059)]. In 1962, Druckrey and Preussmann (1057) pro-
posed the possibility of the formation of NNAs in tobacco
smoke from the secondary amines, nitrogen oxides, and
water present. For the next two decades, Preussmann
investigated methods of NNA analysis [Preussmann et al.
(26A129), Egan et al. (1112a)], tumorigenicity of various
NNAs [Druckrey et al. (1056a, 1058), Habs et al. (1469a),
Magee et al. (2443), Janzowski et al. (1921a, 1921b), Ketkar et
al. (2086c, 2086d), Zerban et al. (26A197)], the involvement
of nitrate and nitrite in NNA formation [Spiegelhalder et al.
(26A165)], NNAs in foods [Spiegelhalder et al. (26A167)],
beverages [Spiegelhalder et al. (26A166, 26A168)], and toi-
letries [Spiegelhalder and Preussmann (26A169)].
In the late 1980s, Preussmann returned to the study of
NNAs in tobacco and tobacco smoke and the question of the
possible endogenous formation of tobacco-specific NNAs
in smokers [Tricker et al. (3944, 3945, 3953, 3954), Tricker
and Preussmann (3946–3951), Fischer et al. (1191–1200);
Spiegelhalder et al. (3773, 3774), Kumar et al. (2235)].
Discussing the escalation in publications on N-nitroso
compounds, Preussmann (2989a) wrote:
At present (1981), more than 1400 papers are published annu-
ally on the analysis, formation, chemistry, biochemistry,
metabolism and biological effects of N-nitroso compounds.
There is no equivocal and convincing evidence of carcino-
genicity in humans of N-nitroso compounds. Therefore, an
answer is needed to the question whether exposure to traces
of these compounds from the general environment … poses
a risk to human health. In this situation animal data must be
extrapolated to man, with all the inherent uncertainties.
Preussmann and Stewart (2991) noted the exponential
increase in publications on NNAs between 1972 and 1984 and
© 2009 by Taylor & Francis Group, LLC
78836_C026.indd 1225
estimated that about three papers were published daily on this
topic in the scientific literature in 1983. They also cautioned:
Patterns of investigations established with nitroso com-
pounds are being extended to more structurally complex car-
cinogens. Yet the contribution of nitroso compounds to the
burden of environmentally determined neoplasia in humans
remains to be determined … The priority that might reason-
ably be placed on reducing human exposure to nitroso com-
pounds could be better judged if the number of cancers likely
to be affected by such measures were known.
Discussions in this chapter are limited primarily to the
NNAs common to tobacco and tobacco smoke and the other
exposures (foodstuffs, beverages, cosmetics, drugs, etc.). As
described by Preussmann and Stewart (2991), various bio-
assays on laboratory animals have been conducted on over
220 different NNAs and 110 N-nitrosamides, over 330 in all.
Fewer than sixty of these N-nitroso compounds have been
identified in tobacco and/or tobacco smoke.
Historically, the search for tumorigenic compounds in
foodstuffs and beverages began in the early 1930s, shortly
after the demonstration that the synthetic PAH DB[a,h]A
[Kennaway and Hieger (2078)] and the coal tar isolate B[a]P
[Cook et al. (796a, 797), Barry et al. (194)] were carcinogenic
when painted on mouse skin and sarcogenic when injected
subcutaneously. The initial investigations were limited to
attempts to demonstrate the presence of these and similar
PAHs in heated foodstuffs (meat, fish, etc.), particularly those
containing cholesterol and its derivatives.
Subsequent to the demonstration of the tumorigenicity in
laboratory animals of NNAs such as N-nitrosodimethylamine
(NDMA) [Barnes and Magee (192), Magee and Barnes
(2441a)], the search for NNAs in commonly used foods and
beverages began. Despite nearly half a century of study of
food components tumorigenic to laboratory animals, caution
was recommended as recently as 1984 in the interpretation
of the laboratory findings, for example, Grasso (1345) in his
review of carcinogens in food noted:
Carcinogens occur at very low concentrations in food so that
if any type of tumors result at all, the number is expected to
be very low indeed. At present much thought is being given
to the relative hazards of these levels and how they can be
assessed. Certainly no firm association has been established
between any human cancer and the low levels of carcinogens
in food, but this problem may only reflect the imperfect state
of current epidemiological investigations.
Despite hundreds of publications on the presence of
NNAs in foods and beverages and the results of bioassays
with NNAs in laboratory animals, Grasso also wrote:
Despite intensive experimental investigations, however, the
hazard to humans from small doses of nitrosamines present
in our food and water are difficult to assess, and until fur-
ther experimental evidence is available, no firm opinion can
be given.
11/24/08 12:39:19 PM
 1226 The Chemical Components of Tobacco and Tobacco Smoke

This opinion is almost identical with that of Preussmann and

Stewart (2991), who reviewed not only the human exposure Table XXVI-15
to NNAs in foods, beverages, water, drugs, cosmetics, etc., N-Nitrosamines in Foods and Beverages (ng/g)
but also exposure to the NNAs (volatile, nonvolatile, and
Food or Beverage NDMAa NDEA NPYR NPIP
tobacco specific) in tobacco products:
Meat
Although estimates of the total human burden caused by Bacon, uncooked 1–9.5 1–4 ≤17 0
exposure to nitroso carcinogens have been attempted …, we Bacon, fried 0.1–28 ≤ 40 3–44 1
do not think that sufficient data exist for meaningful evalu-
Cured meats 1–80 10–105d ≤60d
ation; therefore, estimation of nitrosamine contribution to
human cancer risk is largely speculative. Premature calcula- Fish
tions are liable to be misinterpreted by those who are not Fresh or frozen 3–18 1–2 … …
thoroughly familiar with the multitude of uncertainties and Salted or pickled 1–35 50–108 0–37 …
difficulties inherent in such calculations, especially when Smoked, baked, or processed 6–177 ≤147 … …
estimates of lifetime risks are based on such figures.
Vegetables/vegetable oils
Table XXVI-15 lists the levels (ng/g) of several NNAs iden- Beans 0 0–0.2 … …
Vegetablesb 0 0 … …
tified in commonly used foods and beverages. Table XXVI-16
Soybean oilc 0–20 0–4 … …
summarizes the studies in which various NNAs were identi-
fied in foods and beverages. One of the earliest investigators Cheeses 0.1-68 … … 2–11
of NNAs in foodstuffs was Kröller (2205), who identified Beverages
N-nitrosodimethylamine (NDMA) in cheese. Kröller’s studies Water 0.8–3.3 0.1–1.83 … …
were not limited to possible tumorigens in foodstuffs. From Alcohol beverages ≤10 ≤0.1
1963 through 1966, he also investigated the pyrosynthesis of
Cigarette Mainstream Smoke 0.1–180 ND–25 30–60 ND–9
PAHs, particularly B[a]P, in cigarette smoke and from various
(ng/cig) e
materials used in cigarette fabrication, for example, cigarette
paper, adhesives, humectants, dyes, inks, flavorants, tobaccos a NDMA = N-nitrosodimethylamine; NDEA = N-nitrosodiethylamine;
[see summary in Wynder and Hoffmann (4332)]. NPYR = N-nitrosopyrrolidine; NPIP = N-nitrosopiperidine
b 16 different vegetable species tested
Also included in Table XXVI-15 are data for the per
c Freshly refined
cigarette deliveries of several NNAs identified in foods and
d Levels in sausage
beverages. From these data, comparisons of the relative e See Table XXVI-1
exposures from foods, etc., and cigarette smoke are possible,
for example, the per cigarette MSS range for NDMA has
been reported as 0.1 to 180 ng (see Table XXVI-1). Since one
ounce is approximately 30 g, a person eating 1 oz of fried was demonstrated to be an effective inhibitor of N-nitrosation
bacon would be exposed to 3 to 840 ng of NDMA that is, 30 during the analytical procedure.
times 0.1 to 28 ng of NDMA. Similarly for cured meat, the A variety of investigations has been conducted during the
per cigarette exposure of 0.1 to 180 ng should be compared past decade on exposures to NNAs, and a few will be cited
to the dietary exposure of 30 to 2400 ng from eating 1 oz here. Okieimen et al. (26A120) reported on the total NNAs
of cured meat. Also, compare the exposure to 30 to 60 ng/ content of beer, dairy products, bouillon cubes, and tobacco
cigarette of N-nitrosopyrrolidine (NPYR) vs. 300 to 3150 ng products. They reported that dairy products showed the
NPYR from eating 1 oz of sausage! lowest total value; bouillon cubes, the highest. Mandagere
Over the years, numerous reports [see Neurath et al. (2450a) reported on the high NNA levels in a variety of meats
(2751), Fredrickson (1236), Krull et al. (26A77), Eisenbrand cured via a smoking process.
et al. (26A27), Caldwell and Conner (573)] on the artifac- Coker et al. (26A16) tested some 200 commercial food-
tual formation of NNAs during the collection and analy- stuffs for NNAs and noted the values for beverages were
sis of tobacco smoke and the various remedial procedures high, those for dairy products low. Craddock (26A18) and
taken to minimize this problem have been published. Similar Sen (26A143) found NNA levels in Canadian foodstuffs and
problems were noted by Wolff and Wasserman (26A195) on beverages to be similar to those for U.S. products. Since the
inflated levels of NNAs reported in foodstuffs and beverages. review by Preussmann and Stewart (2991) on the tumori-
They expressed reservations about the validity of pre-1972 genicity of NNAs and that by Preussmann and Eisenbrand
analytical methodology since later studies demonstrated that (2990) on exposure to NNA tumorigens in the environment,
the earlier procedures introduced both artifact and error. numerous detailed reviews of NNA exposures (alcoholic
Thus, the levels of NNAs reported in foodstuffs were actu- beverages, meats, seafood, cosmetics, tobacco, rubber goods,
ally lower than those reported prior to 1972. In 1986, Sen metal cutting oils, pharmaceuticals, environment, and water)
et al. (26A150) proposed improvements in analytical meth- have been presented by Mejstrik et al. (26A99), Tricker and
odology to prevent artifactual formation and subsequent Preussmann (3946), Tricker et al. (3954), Ellen (26A30), and
inflated levels of NNAs in rubber products; propyl gallate Matsui and Kaya (26A95).

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 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1227

Table XXVI-16
Volatile and Nonvolatile N-Nitrosamines in Foodstuffs and Beverages
N-Nitrosamine:
Foodstuff/Beverage Reference

Acetic acid, 2-methylnitrosamino)- [N-nitrososarcosine (NSAR)]

Meat Hamburg and Kann (26A49)
Beer (and malt) Pollock, (26A128), Sen et al. (26A156)
1-Butanamine, N-butyl-N-nitroso- [N-nitrosodibutylamine (NDBA)]
Fish Huang et al. (26A63)
Ethanamine, N-ethyl-N-nitroso- [N-nitrosodiethylamine (NDEA)]
Bacon Crosby et al. (26A19), Wasserman et al. (26A181)
Fish Sen et al. (26A155), Crosby et al. (26A19), Wasserman et al. (26A181), Fong and Chan (26A39, 26A40), Huang et al. (26A63)
Cheese Crosby et al. (26A19), Wasserman et al. (26A181)
Powdered milk Maduagwu and Bassir (26A88)
Beer (and malt) Spiegelhalder et al. (26A166), Scanlan et al. (26A139), Kawabata et al. (2058)
Gastric juices + nitrite Sen et al. (26A154)

Methanamine, N-methyl-N-nitroso- [N-nitrosodimethylamine (NDMA)]

Meat, cured meat Wasserman et al. (26A181), Panalaks et al. (26A121, 26A122), Sen (26A142a), Spiegelhalder et al. (26A167), Eisenbrand
(26A26), Helgason et al. (26A58)
Bacon Crosby et al. (26A19), Wasserman et al. (26A181), Vecchio et al. (26A177), Sen et al. (26A152)
Fish Sen et al. (26A155), Crosby et al. (26A19), Wasserman et al. (26A181), Fong and Chan (26A39, 26A40), Iyengar et al. (26A64),
Havery and Fazio (26A51), Kawabata et al. (26A71), Maki et al. (26A90), Josefsson and Nygren (26A67), Matsui et al. (26A96),
Huang et al. (26A63), Pedersen and Meyland (26A123) Nieper and Etzel (26A117), Röper (26A134), Röper et al. (26A135),
Squid Kawabata et al. (26A71), Matsui et al. (26A96)
Cheese Kröller (2205), Crosby et al. (26A19), Wasserman et al. (26A181), Goodhead et al. (26A42), Havery et al., (26A55), Gough
et al. (26A44), Eisenbrand et al. (26B16), Elgersma et al. (26A29); Danish Institute of Protein Chemistry (26A21),
Spiegelhalder et al. (26A167), Eisenbrand (26A26)
Powdered milk Maduagwu and Bassir (26A88), Libbey et al. (26A84), Lakritz and Pensabene (26A78), Havery et al. (26A52) , Sen and
Seaman (26A147)
Wheat flour Hedler and Marquardt (26A57)
Beer (and malt) Sen and Dalpe (26A144), Goff and Fine (26A41), Spiegelhalder et al. (26A166, 26A167), Walker et al. (26A109), USFDA
(26A176), Maki et al. (26A91, 26A92), Preussmann et al. (26A130, 26A131), Scanlan et al. (26A138, 26A139), Sen et al.
(26A151), Stephany and Schüller (26A170), Eisenbrand (26A26), Havery et al. (26A54), Hotchkiss et al. (26A62), Sen and
Seaman (26A146, 26A148), Slack and Wainwright (26A160), Kann et al. (26A70), Kawabata et al. (2058), Mangino et al.
(26A93), Spiegelhalder (26A162), Jasinski (26A66), Scanlan et al. (26A139), Scanlan and Barbour (26A138)
Scotch whiskey Goff and Fine (26A41)
Brandy (French) Walker et al. (26A179)
Other alcohol beverages Sen and Dalpe (26A144), Gough (26A43), Bassir and Maduagwu (26A05)
Water Fine et al. (26A37, 26A38), Kimoto et al. (26A72), Mitch et al. (26A112a)
Morpholine, 4-nitroso- [N-nitrosomorpholine (NMOR)]
Fish Fong and Chan (26A39, 26A40)
Piperidine, 1-nitroso- [N-nitrosopiperidine (NPIP)]
Meat, cured meat Spiegelhalder et al. (26A167), Eisenbrand (26A26)
Bacon Crosby et al. (26A19), Wasserman et al. (26A181), Vecchio et al. (26A177)
Fish Crosby et al. (26A19), Wasserman et al. (26A181)
Squid Kawabata et al. (26A71), Matsui et al. (26A96)
Cheese Crosby et al. (26A19), Wasserman et al. (26A181)
1-Propanamine, N-nitroso-N-propyl- [N-nitrosodipropylamine (NDPA)]
Fish Sen et al. (26A155), Huang et al. (26A63)
Pyrrolidine, N-nitroso- [N-nitrosopyrrolidine (NPYR)]
Meat, cured meat Pensabene et al. (26A124), Spiegelhalder et al. (26A167), Eisenbrand (26A26), Theiler et al. (26A173), Alldrick et al. (26A01)
Bacon Hansen et al. (26A50), Sen et al. (26A145, 26A153), Gough et al. (26A45), Havery et al. (26A53), Janzowski et al. (26A65),
Cross and Bharucha (26A20), Gray and Randall (26A47), American Meat Institute (26A03), Nitrite Safety Council (26A118),
Webb and Gough (26A191), Josefsson and Nygren (26A67), Fazio et al. (26A33), Gray (26A46), Pensabene et al. (26A125),
Alldrick et al. (26A01), Vecchio et al. (26A177)

(Continued)

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 1228 The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-16 (continued)

Volatile and Nonvolatile N-Nitrosamines in Foodstuffs and Beverages
N-Nitrosamine:
Foodstuff/Beverage Reference

Fish Crosby et al. (26A19), Wasserman et al. (26A181), Kawabata et al. (26A71), Matsui et al. (26A96)
Cheese Crosby et al. (26A19), Wasserman et al. (26A181)
Beer (and malt) Spiegelhalder et al. (26A166), Scanlan et al. (26A139), Kawabata et al. (2058), Jasinski (26A66)
2-Pyrrolidinecarboxylic acid, 1-nitroso-[N-nitrosoproline (NPRO)]
Meat Pensabene et al. (26A124), Hamburg and Hamburg (26A48), Dennis et al. (26A22), Dunn and Stich (26A25), Helgason et al.
(26A58), Sen and Seaman (26A148)
Bacon Hansen et al. (26A50), Brunnemann et al. (509), Sen and Seaman (26A148), Massey et al. (26A94)
Chicken Brunnemann et al. (509)
Ham Brunnemann et al. (509)
Toast Brunnemann et al. (509)
Biscuits Brunnemann et al. (509)
Cornflakes Brunnemann et al. (509)
Beer (and malt) Pollock (26A128), Sen et al. (26A156), Brunnemann et al. (509)
Diethanolamine, N-nitroso- [N-nitrosodiethanolamine (NDELA)]
Meat, cured Coker et al. (26A15)

The daily intake of NNAs from ETS may be estimated
with these assumptions:
• The average hourly intake of air is independent of
whether the host is awake or asleep and is 1 m3.
• The NNA level due to ETS is at the high end
of the range estimated by Guerin et al. (1445)
for the various NNAs, that is, 40 ng/m3 for
N-nitrosodimethylamine (NDMA), 3 ng/m3 for
N-nitrosodiethylamine (NDEA), N-nitrosopyrrolidine
(NPYR), N’-nitrosonornicotine (NNN), and 4-(N-
methyl-nitrosamino)-1-(3-pyridinyl)-1-butanone
(NNK).
• None of the daily intake of the NNAs, whether
from diet, ETS, and the like, is eliminated by
exhalation, etc.
• The measured values reported for NNAs in diet,
ETS, etc.
From the dietary NNA data of Preussmann and Eisenbrand
(2990), Preussmann et al. (26A130), and Spiegelhalder et al.
(26A167) and environmental tobacco smoke NNA data sum-
marized by Guerin et al. (1445), the comparison in Table
XXVI-17 was developed.
It is obvious that the estimated exposure to the NNAs in
diet vs. ETS differs from the B[a]P exposure case. Whereas the
dietary exposure to B[a]P was between twenty and ninety times
the exposure to B[a]P in ETS, the dietary exposure to NNAs is
essentially the same as the exposure to NNAs in ETS.
Previously, the review by Holcomb (26A60), his propor-
tioning of male and female respiration rates during the day,
his use of 11% particle retention, and his comments on the
contribution of ETS to PAH exposure, were discussed. His
summary of the NNA situation was:
Two studies [Stehlik et al. (3812), Hoffmann et al. (1678)]
have reported the presence of … (NDEA) and … (NDMA)
in smoke-filled rooms … These are not tobacco-specific nit-
rosamines. The lack of reported background levels and the
unusually high level of smoking prevents the evaluation of
ETS contribution of these substances. Other nitrosamines
reported to be found in tobacco smoke have either not been
monitored or not been reported in ambient air where ETS is
present.
Unlike the volatile NNAs, which are found primarily in
the vapor phase, TSNAs are predominantly particulate-phase
components.* Thus, their intake and retention should be
proportional to the intake and retention of ETS particles. If
Holcomb’s assigned values for respiration rates during the day
and his use of 11% retention are applied to the TSNA values
in the above summary, the intake of NNN plus NNK will be
much less than the 144 ng/day indicated. It probably would be
less than 10 ng/day. If the more recent data of McAughey et al.
(26A98) for the percent retention of particulates from aged and
diluted SSS is used in the calculations (17% to 41%, depending
on analytical procedure and subjects’ gender), the estimated
exposure to NNN plus NNK will not be as low as if the 11%
retention from the Hiller et al. (1654a, 1654b) study is used.
Brunnemann et al. (460) determined the levels of several
TSNAs in bars (3), restaurants (2), a car, trains (2), an office,
and a smoker’s private residence. The values reported and
the subsequent descriptions of the values found are shown in
Table xxvi-18.
In their discussion of exposure to TSNAs in ETS at vari-
ous sites, Hoffmann et al. (1702)—perhaps to embellish the
situation—apparently disregarded the fact that no NNN nor
* Although data are sparse, there is some evidence to indicate that TSNAs
in ETS may be distributed between the vapor and particulate phases.

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 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1229

Table XXVI-17
Comparison of Dietary and Environmental Tobacco Smoke
Dietary Intake, ng/Day

Country NDMA NDEA NPYR NPIP Total

Federal Republic of Germany 1100a 100–150 10 1210–1260

United Kingdom 530
Japan 1780
The Netherlands 1100
Intake from ETSb, ng/day

NDMA NDEA NPYR NPIP NNN + NNK Total

Estimated from German, Japanese, 960 72 72 144 1248

and American ETS studiesc
a Because of the reduction in N-nitrosodimethylamine (NDMA) level in beer after 1979, this number is now probably closer to 700 ng/day.
b On basis of the assumptions listed previously.
c Brunnemann et al. (457), Stehlik et al. (3812), Matsushita and Mori (2495), Klus et al. (26A75); unfortunately, the tobacco-specific N-nitrosamine

results from a more recent study on ETS by Brunnemann et al. (1992) were not included in the assessment by Guerin et al. (1445) or Holcomb
(26A60).

N’-anatabine was detected in half the test sites! Hoffmann and Eisenbrand (2990), Mejstrik et al. (26A99), Lijinsky
et al. (1702) list total TSNAs in the MSS from two differ- (26A85), Ellen (26A30), and Matsui and Kaya (26A95) have
ent U.S. cigarettes at 979 and 670 ng/cigarette. Thus, at an reviewed the studies on the detection of NNAs in pharma-
exposure level of 62 ng/m3 and a respiration rate of 1 m3/hr, ceuticals as well as in other consumer products.
it would require a nonsmoker to remain for nearly 16 and 11 Examination by Fan et al. (26A31) of a series of cosmetics
hours in such an atmosphere to be exposed to similar levels widely used in the United States revealed that twenty-seven of
of TSNAs as a smoker who inhales MSS from the two ciga- twenty-nine samples contained NDELA at levels varying from
rettes, respectively. Such a period surely exceeds the “several 1 to 48000 ppb. From a similar study conducted several years
hours” noted by Hoffmann et al. (1702). later, Klein et al. (26A73) reported that five of ten cosmetic
Analysis of sixty-eight commercially available drug prep- samples contained NDELA at levels ranging from 20 to 4113
arations containing aminopyrine indicated that all contained ppb. Despite the concern about the possible tumorigenicity of
NDMA [Schoenhard et al. (26A140)]. The following ranges NDELA, its use in cosmetics has continued since its ban as
for the NDMA levels were reported: thirty-five samples, 1 to an agricultural chemical in the United States in 1981 (1147).
10 ppb; twenty-seven samples, 11 to 50 ppb; five samples, 51 Although none of the three has been identified in tobacco or
to 100 ppb; one sample, 370 ppb. More recently, Preussmann tobacco smoke to date, N-nitrosomethyldodecylamine (in six
of seven products tested), N-nitrosomethyloctadecylamine,
and N-nitrosobenzylmethylamine were identified in 1981 by
Table XXVI-18
Hecht (26A56) in various commonly used cosmetics. Fan
Tobacco-Specific N-Nitrosamines in Indoor Air
et al. (26A31) described an analytical method to determine
TSNAs in indoor air, ng/m3 NDELA in various cosmetics and shampoos; this procedure
was updated by Fine (26A36). Erickson et al. (1159) reported
Total of 3 the presence of NDELA and similar compounds in cosmet-
Reference NNN NAT NNK TSNAs
ics. Preussmann and Eisenbrand (2990) commented on the
Brunnemann NDa b–22.8 NDb–9.5 1.4–29.3 1.4–61.6 rapid absorption of NDELA in rats when administered by a
et al. (460) variety of routes (subcutaneous, oral, and intratracheal).
Hoffmann 1.8–23 1.5–10 1–29 4.3–62 Preussmann and Eisenbrand (2990), Mejstrik et al.
et al. (1702) (26A99), Ellen (26A30), Lijinsky (26A85), and Matsui and
Kaya (26A95) have reviewed the findings on the detection of
a ND = not detected
b Not detected in 5 of the 10 sites monitored (a restaurant, both trains, the
NNAs in cosmetics. Spiegelhalder and Preussmann (26A169)
office, smoker’s residence) described the volatile and nonvolatile NNAs found in many

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 1230 The Chemical Components of Tobacco and Tobacco Smoke

samples of toiletries and cosmetics. Eisenbrand et al. (26B15)
reported a series of N-nitrosodialkylamines in cosmetics.
Investigations [Spiegelhalder and Eisenbrand (26A164),
Spiegelhalder (26A163)] of various rubber products that come
in frequent contact with human tissue revealed the presence
of several NNAs. Baby-bottle nipples and pacifiers contained
appreciable levels of NDMA, NDEA, N-nitrosodibutylamine
(NDBA) [Thompson et al. (26A174)], and NPIP. NDMA and
NDEA were found in various rubber toys. These two NNAs
plus NPIP were also found in rubber gloves. In their study of
NNAs in rubber products, Sen et al. (26A149), in their analy-
sis of thirty samples, reported the detection of NMOR in var-
ious rubber products in addition to NDMA, NDEA, NDBA,
and NPIP. Solenova et al. (26A161) reported the presence of
NDMA and NDEA.
Several NNAs have been identified in pesticides used on vari-
ous vegetable crops, for example, NDMA [Ross et al. (26A137)]
and N-nitrosodipropylamine (NDPA) [Zweig et al. (26A198)].
Most water supplies show little evidence of volatile or non-
volatile NNAs. However, water deionized by passage through
various anion-exchange resins containing trialkylammonium
compounds were reported to show NDMA levels ranging
from 0.03 to 0.34 mg/liter [Fiddler et al. (26A35), Fine et al.
(26A37, 26A38), Gough et al. (26A44), Cohen and Bachman
(26A14), Kimoto et al. (26A72), Mitch et al. (26A112a)].
On the subject of industrial and occupational exposures to
NNAs, Preussmann and Eisenbrand (2990) wrote:
Data on occupational exposure to different nitrosamines are
recent and not yet representative or complete. Nevertheless,
the data indicate that certain industries have a serious
nitrosamine problem and that the highest known concentra-
tions of preformed N-nitrosamines occur in the workplace,
especially in the rubber and leather industries … Exposures
have been shown to vary considerably in regard to amount
and type of nitrosamine found in different working places in
several industries and occupations.
Preussmann and Eisenbrand (2990) summarized the
following situations: In the rubber industry, workers were
exposed to NDMA, NDEA, NMOR, and NPIP. In their
study of the atmospheres in 132 sites in twelve rubber-
processing plants in France, Ducos and Gaudin (26A24)
reported the detection of NDMA, NDEA, and NMOR in
93%, 27%, and 13% of the sites surveyed, respectively. In
the leather-tanning industry, exposures to NDMA [Bailey
et al. (26A04), Skrabs (26A159), Wolf et al. (26A194)] and
to NDEA [Skrabs (26A159), Wolf (26A193)], and NMOR
[Wolf (26A193)] occur. Exposures to NDELA [Erickson et
al. (1159)] in the cutting oils used in machine shops and to
NDMA and NDEA [Wolf et al. (26A194), Wolf (26A193)]
in foundries have been reported. In a plant producing
rocket fuels, including 1,1-dimethylhydrazine by reduction
of NDMA, workers were exposed to extremely high levels
of NDMA. Shortly after this high exposure was recorded,
the factory ceased manufacture of 1,1-dimethylhydrazine.
Exposures to NDMA and NDEA have been reported in
chemical and pharmaceutical factories where amines are
used in production.
In Table XXVI-19 is presented a simplified summary of the
possible exposures to non-tobacco-specific N-nitrosamines
that are known components of tobacco smoke. All ten NNAs

Table XXVI-19
Non-Tobacco Exposures to Tobacco/Tobacco Smoke N-Nitrosamines
N-Nitrosaminea

Consumer Good or Environment NDMA NDEA NDPA NDBA NDELA NPIP NPYR NPRO NMOR NSAR

Tobacco and/or tobacco smokeb × × × × × × × × × ×

Food, beverages × × × × × × × × × ×
Rubber goods × × — × × — — × —
Cosmetics — — — — × — — — — —
Pharmaceuticalsc × — — — — — — — — —
Pesticidesc × — × — — — — — — —
Water × — — — — — — — — —
Industrial environments — — — — — — — — — —
  Rubber processing plants × × — — — × — — — ×
  Leather tanneries × × — — — — — — — ×
  Foundries × × — — — — — — — —
  Machine shops — — — — × — — — — —

NDMA = N-nitrosodimethylamine; NDEA = N-nitrosodiethylamine; NDPA = N-nitrosodipropylamine; NDBA = N-nitrosodibutylamine; NDELA =

a 

N-nitrosodiethanolamine; NPIP = N-nitrosopiperidine; NPYR = N-nitrosopyrrolidine; NPRO = N-nitrosoproline; NMOR = N-nitrosomorpholine; NSAR =
N-nitrososarcosine
b In addition to the NNAs listed, tobacco and tobacco smoke contain a variety of TSNAs and N-nitrosamino acids other than N-nitrososarcosine.

c N-Nitrosamines other than those determined in tobacco and/or tobacco smoke have also been detected in various consumer goods

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 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1231
listed are found not only in tobacco smoke but also in a great
variety of commonly consumed foodstuffs and beverages.
XXVI.B.1.d Alternate Exposures to N-Heterocyclic
Amines
Because of their concerns about the mutagenicity of com-
monly consumed heated foods, many of the studies of the
isolation, identification, and estimation of N-heterocyclic
amines in heated foodstuffs or heated food components,
particularly amine-containing components such as amino
acids, proteins, and peptides, were conducted by Japanese
investigators. This becomes obvious from examination
of the authors and co-authors of the references listed in
Table XXVI-20.
With the advent of the Ames mutagenicity test with
Salmonella typhimurium in the mid-1970s and the dem-
onstration of its utility, the number of studies on potential
mutagenic systems and the mutagenicity-tumorigenicity
relationship virtually exploded. By highly competent appli-
cation of up-to-date isolation and characterization tech-
niques plus utilization of the Ames test, Sugimura and his
staff at the Japanese National Cancer Research Institute
contributed significantly to our knowledge of the struc-
tures, properties, and precursors in foods of the mutagenic
N-heterocyclic amines. Although the methodologies dif-
fered, the 1977 isolation and identification of the mutagenic
N-heterocyclic amines (Trp-P-1, Trp-P-2) from a tryptophan
pyrolysate paralleled the historic 1932 isolation and identi-
fication of polycyclic aromatic hydrocarbons (B[a]P, B[e]P,
B[a]A, perylene) from coal tar. In the 1930s, the Kennaway
group in the United Kingdom used ultraviolet spectropho-
tometry [Hieger (1631)] to monitor coal-tar PAHs during
their concentration and purification by repeated precipita-
tions and recrystallizations of PAH-picric acid complexes
[Cook et al. (796a, 797)]. In the mid-1970s, Sugimura et al.
(3829) used the Ames test (Salmonella typhimurium, TA 98
strain/S-9) to monitor tryptophan pyrolysate mutagens (Trp-
P-1, Trp-P-2) during their concentration and purification by
sequential chromatography on silicic acid, alumina, and
CM-Sephadex® columns.
References to several early studies on the identification
of biologically active compounds in heated foodstuffs are
included in Table XXVI-20, for example, the 1956 study of
PAHs such as B[a]P in roasted coffee [Kuratsune, (2237)]
and the similar mid-1960s studies of PAHs in broiled meat
[Lijinsky and Shubik (2364a, 2364b)]. PAHs such as B[a]
P were identified in both studies. The major concern of the
early investigators was the possible presence of tumorigenic
PAHs, particularly B[a]P, in the heated foodstuff. Another
PAH of concern was the potent tumorigen 3-methylcholan-
threne because of its possible pyrosynthesis during cooking
from cholesterol, a component of many meats. Of course, it
was subsequently demonstrated that B[a]P, in addition to its
tumorigenicity to mouse skin, is also mutagenic in the Ames
test. However, its specific mutagenicity is insignificant com-
pared to that of many N-heterocyclic amines.
© 2009 by Taylor & Francis Group, LLC
78836_C026.indd 1231
From their studies of heated foods or food pyrolysates
(thirty different foods, including rice, flour, soy beans, fish,
meat, and eggs), Sugimura and Nagao (3828b) reported:
• Mutagenicity was proportional to the protein
content.
• Mutagenicity was proportional to the levels of spe-
cific amino acids (tryptophan, glutamic acid, etc.)
in the constituent protein.
• Mutagenicity was dependent on water content and
heating temperature, for example, for foods with
low water content, the mutagens appear at 300°C;
for those with high water content, the mutagens
appear at 400°C.
As noted in the sections on PAHs and NNAs in foods,
estimates of daily exposures to these classes of compounds
in foods, beverages, and other factors have been made by
numerous investigators. Estimates of exposures to mutagenic
N-heterocyclic amines are limited. Part of the reason is the dif-
ference in time span since the particular class of compounds
was found to be tumorigenic and/or mutagenic. Exposures to
PAHs tumorigenic in laboratory animal bioassays have been
studied for more than seven decades [since the early 1930s and
the identification of B[a]P in coal tar by Cook et al. (796a, 797)].
Exposures to NNAs tumorigenic in laboratory animal bioas-
says have been studied [Magee and Barnes (2441a)] since the
mid-1950s. In contrast, exposures to mutagenic N-heterocyclic
amines reported to be tumorigenic in laboratory animal bioas-
says have only been studied for about thirty years (since the
mid-1970s and the availability of the Ames test).
In his mid-1980s review, Sugimura (3828c) attempted to
estimate the exposure of humans to mutagenic N-heterocyclic
amines with the limited data at his disposal. He wrote:
Taking various factors into consideration, it is probably
impractical and not realistic to make risk estimations from
the carcinogenicity data on rodents given a single carcino-
gen. However, for a simple extrapolation of animal data for
risk estimation, TD50 values, which are the doses needed to
develop cancers in 50% of animals fed on carcinogens [IQ,
Trp-P-1, Trp-P-2, Glu-P-1, Glu-P-2, AaC, and MeAaC] for
their life time, have been calculated based on mouse experi-
ments … If we assume the average TD50 value of heterocyclic
amines should be about 8mg/kg/day, we can roughly estimate
the risk of these carcinogenic heterocyclic amines for human
beings. The intake of heterocyclic amines was calculated
from available data on their quantities in foods. Apparently
the human intake is about 0.0002% times the TD50 obtained
from animal data. This means that heterocyclic amines may
not be so serious for human cancer development.
Sugimura added:
On the other hand, it is also true that human beings are being
exposed to many heterocyclic amines and many other carcino-
gens with tumor promoters and/or suppressing factors for car-
cinogenesis. At this moment, it is honest to state that no solid
information on the estimation of risk of heterocyclic amines
has been obtained in any direction, either positive or negative.
11/24/08 12:39:20 PM
 1232 The Chemical Components of Tobacco and Tobacco Smoke

Table XXVI-20
Mutagenicity of Beverages, Heated Foods, and Heated Food Components
Food or Food Component References

Foods, heated (grilled, broiled, etc.) Sugimura et al. (3829a), Sugimura and Nagao (3829b), Matsumoto et al. (2492), Sugimura (3828a, 3828c, 3828f),
Nagao et al (2667a), Tanaka et al. (2667a), Felton and Knize (1177d)
Beef, extract Commoner et al (790a), Hargraves and Pariza (1501a), Hayatsu et al. (1555b), Turesky et al. (3988b), Ohgaki et al.
(2849a), Takayama et al. (3862c)
Beef, broiled, fried, and/or charred Lijinsky and Shubika (2364a, 2364b), Nagao et al. (2667c), Commoner et al. (790a), Yasuda et al. (4382a), Hayatsu
et al. (1555a, 1555b), Kasai et al. (2037a), Jägerstad et al. (1916b), Felton et al. (1177d), Ohgaki et al. (2849a),
Takayama et al. (3862c)
Cuttlefish, broiled Yamaguchi et al. (4361a), Ohgaki et al. (2849a)
Eggs; fish; meat 
Flour; rice  Sugimura and Nagao (3829b)
Soy beans 
Fish, broiled, charred Nagao et al. (2667c), Yasuda et al. (4382a),
Kasai et al. (2037c, 2037d), Yamaizumi et al. (4361b)
Herring, broiled 
Mackerel, broiled  Nagao et al. (2667c, 2667f)
Pike, broiled 
Sardine, broiled 
Sardine, broiled Ohgaki et al. (2949a), Takayama et al. (3862c)
Protein pyrolysates Nagao et al. (2667f), Yoshida and Matsumoto (4387b), Nebert et al. (2688a), Yoshida et al. (4390)
Albumin Yasuda et al. (4382a)
Soybean globulin Yoshida et al. (4389a, Ohgaki et al. (2849b)
Calf thymus 
Egg white  Nagao et al. (2667b)
Serum albumin 
Casein; collagen; 
Gluten; histone; 
Insulin; lysozyme;  Matsumoto et al. (2491c)
Ovalbumin; zein; 
Tobacco protein 
Peptide pyrolysates
Polypeptides Johnson et al. (1968)
Carnosine 
Glycyl glycineb 
Glycyl glutamic acid 
Glycyl proline 
Glycyl tryptophan 
Leucyl glycyl phenylalanine  Matsumoto et al. (2491c)
Tryptophanyl alanine 
Tryptophanyl glycine 
Tryptophanyl tryptophan 
Tryptophanyl tyrosine 
Amino acid pyrolysates Masuda et al. (2486), Kato et al. (2048, 2049), Kosuge et al. (2178a), Nebert et al. (2688a)
Phenylalanine Sugimura et al. (3829)
Lysine Wakabayashi et al. (4102a)
Tryptophan Sugimura et al. (3829), Yoshida and Matsumoto (4387a), Negishi and Hayatsu (2689a), Yamazoe et al. (4379a),
Hosaka et al. (1835a), Matsukura et al. (2491a), Takayama et al. (3862d)
Glutamic acid Sugimura (3828a, 4365a), Takeda et al. (3863a), Yamamoto et al. (4365a), Ohgaki et al. (2849b), Takayama et al.
(3862b)
Histidine Smith et al. (3722a)
3-Methylhistidine

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 Carcinogens, Tumorigens, and Mutagens vs. Anticarcinogens, Inhibitors, and Antimutagens 1233

Table XXVI-20 (continued)

Mutagenicity of Beverages, Heated Foods, and Heated Food Components
Food or Food Component References

Alaninec; arginine; 
Asparagine; citrulline; 
Cysteine; cystine; 
Glutamic acid; 
Glutamine; histidine;  Matsumoto et al. (2491b)
Lysine; methionine; 
Ornithine; 
Phenylalanine; serine; 
Threonine; tryptophan; 
Tyrosine; valine 
Beverages
Coffee, roasted Kuratsune b (2237), Nagao et al. (2667d, 2667e), Sugimura (3828b), Aeschbacher and Würzner (38a)
Coffee, instant Aeschbacher and Würzner (38a), Kosugi et al. (2178b)
Tea Nagao et al. (2667e), Sugimura (3828d)
Brandy Sugimura (3828d)
Sake Takase and Murakami (3862a)
Cigarette smoke condensate Sugimura (3828d), Yoshida and Matsumoto (4388), Matsumoto et al. (2492), DeMarini (930, 9329, 933)
a This was a PAH study, with emphasis on the generation of B[a]P.
b No mutagens detected in glycylglycine pyrolysate.
c The pyrolysates from the various amino acids studied showed mutagenicities (Ames test) in the following sequence (revertant/mg of pyrolysate), the amino

acid yielding the highest mutagenic pyrolysate listed first: Tryptophan, serine, glutamic acid, ornithine, lysine, arginine, citrulline, threonine, alanine, cys-
tine, glutamine, methionine, cysteine, tyrosine, phenylalanine, histidine, asparagine, valine.

Sugimura (3828d) reported comparisons of the mutagen-

icities (Ames test) of various beverages (coffee, brandy, and
Table XXVI-21 tea) and CSC. His data are summarized in Table XXVI-21.
Mutagenicity of Common Beverages vs. Cigarette In another comparison of mutagenicities toward
Smoke Condensate Salmonella typhimurium TA 98, Nagao et al. (2667c) calcu-
lated the B[a]P equivalency of extracts of charred fish and
Agent Exposure Level ST Straina S-9 mix Revertants
meat. Their data, with additions (charred food weight in
Cigarette one, inhaled TA 98 yes 4000 ounces, cigarette equivalents based on B[a]P), are shown in
Coffee 200 ml TA 100 no 180000 Table XXVI-22.
Teab 200 ml TA 100 no mutagenic
Brandy 50 ml TA 100 no 10500
XXVI.C Summary
a ST = Salmonella typhimurium
b Japanese green tea
It is obvious from the numerous Hoffmann co-authored
lists (1727, 1740, 1741, 1743, 1744, 1773, 1808) summarized
in Table XXVI-1 plus many other listings (1217, 2825) and
articles that some seventy tobacco smoke components are
Table XXVI-22 defined as significant toxicants, with most of the seventy
Benzo[a]Pyrene Equivalency of Extracts of Charred Fish being defined as significant tumorigens. Forty or so have
and Meat recently been defined as “Hoffmann analytes” and their ciga-
rette MSS yield reductions are used to define a “potentially
Sample B[a]P Cigarette Equivalency
reduced exposure product” (PREP). It should be noted that
Analyte wt., g Equivalency, ng Based on B[a]Pa
the various bioassays that generated the data used to define
Sardine 100 (3.5)b 35800 2983 the tumorigenicity of the various cigarette smoke compo-
Mackerel 60 (2.1) 68200 5683 nents are similar to or identical with the various bioassays
Beefsteak 190 (6.7) 85500 7125 that generated the data to define the antitumorigenicity of
a Calculation based on assumption of MSS yield of 12 ng/cig of B[a]P
various compounds to several known potent tumorigens such
b Number in parentheses is weight in ounces as B[a]P or DB[a,h]A. Many of the compounds with demon-
strated antitumorigenicity have been identified in CSC and

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 1234 The Chemical Components of Tobacco and Tobacco Smoke
are present in it at much higher levels than such potent tum-
origens as B[a]P, DB[a,h]A, and DMB[a]A.
Why do so many of the proponents of the hazards of cig-
arette MSS seldom discuss in detail the many anticarcino-
gens, antitumorigens, or antimutagens present in MSS or the
many alternate exposures to the various compound classes,
the PAHs, aza-arenes, NNAs, and N-heterocyclic amines,
defined as significant cigarette MSS problems?
At the 1962 American Association for Cancer Research
conference (4314), in their 1964 review [see pp. 330–331 in
(4319)], and in their 1967 book, Wynder and Hoffmann [see
pp. 370–371 in (4332)] also described the results of their
experiments on the antitumorigenicity of two tobacco smoke
paraffinic hydrocarbons, n-hentriacontane (C31H64) and
n-pentatriacontane (C35H72), co-administered separately at
two different levels with B[a]P. Subsequently, they noted [see
pp. 628–629 in (4332)]:
An explanation of the tumorigenic activity of tobacco smoke
condensate in terms of single constituents is made more diffi-
cult by the presence of substances that may act as anticarcino-
gens and/or absorption retarders, especially for tumorigenic
agents. It is known that noncarcinogenic hydrocarbons can
inhibit the effect of carcinogenica hydrocarbons … The pres-
ence of substances such as long-chain paraffinic hydrocarbons
may interfere with absorption of tumorigenica components.
a It is interesting to note the authors’ interchange of these
two terms.
In their book, Wynder and Hoffmann described not only
the 1951 results reported by Steiner and Falk (3814) on the
antitumorigenicity of B[a]A to B[a]P when co-administered
subcutaneously but also their own 1963 results of the antitu-
morigenicity of B[a]A to B[a]P when administered in a skin-
painting bioassay [see pp. 246–247 in (4332)]. They noted:
The existence of anticarcinogens, however, must be con-
sidered in evaluating any complex mixture such as tobacco
smoke condensate.
© 2009 by Taylor & Francis Group, LLC
78836_C026.indd 1234
Despite such a statement, neither Wynder and Hoffmann
nor any of the proponents of the hazards of cigarette smok-
ing discussed in any detail the presence of antitumorigens in
cigarette MSS.
The same proponents usually disregard alternate expo-
sures to various tumorigens despite the many pre-mid-1950s
articles by Kennaway and Hueper on respiratory effect of air
pollutants. Because of the chronology of the discovery of the
tumorigenicity of NNAs in the mid-1950s and N-heterocyclic
amines in the late 1970s, it is obvious that neither Kennaway nor
Hueper could discuss alternate exposures to them. Examples
of more recent research are the many publications by Grimmer
et al. on exposure to PAHs (1397–1402, 1405, 1406a, 1406b,
1407b) and aza-arenes (1407a) as air pollutants.
In the monograph edited by Searle, comprising over 1400
pages on chemical carcinogens (3568), only one of the major
classes (PAHs, aza-arenes, N-heterocyclic amines) of tum-
origenic components in MSS was mentioned. The exception,
the presence of NNAs in tobacco and smoke, was described
briefly by Preussmann and Eisenbrand [see pp. 839–842 in
(2990)]. The bulk of the material they cited on NNAs in
tobacco and/or smoke included tabulated results by Hoffmann
and his colleagues on NNAs and TSNAs in tobacco smoke
(514, 1680) and tobacco [including snuff (1675, 1677, 1685)].
However, Preussmann and Eisenbrand cited many pre-1984
publications in which much data were presented on exposure
to NNAs from many alternate sources such as food [see pp.
832–834 in (2990)], beverages [see pp. 834–839 in (2990)],
cosmetics [see pp. 842–844 in (2990)], prescriptions [see pp.
844–845 in (2990)], pesticides [see pp. 845–846 in (2990)],
rubber products [see pp. 846–848 in (2990)], water [see
pp. 848–849 in (2990)], and occupations [see pp. 851–857
in (2990)]. In his chapter in Searle (3568), Grasso (1345)
described the results of much research on PAHs and NNAs in
foods but none on N-heterocyclic amines in food. Many ref-
erences to alternate exposures to NNAs are presented herein
but a great many more may be obtained by a search of the
Internet.
11/24/08 12:39:21 PM
 27 Free Radicals
XXVII.A Introduction
Free radicals and reactive oxygen species are common to all
living animals and plants, including tobacco. Reactive oxygen
species in plants include hydrogen peroxide (H2O2) and sin-
glet oxygen (1O2), as well as several free radicals and radical
anions, such as nitric oxide (NO), superoxide anion radical
(O2ˉ˙), hydroxyl radical (HO˙), and perhydroxyl radical (HO2˙),
[Bartosz (27A06), Dat et al. (27A23), Halliwell (27A40)]. These
highly reactive oxidation by-products are created by normal
cell metabolism and environmental factors such as pollution
and are continuously produced by living organism.
Free radicals play an important role in the life processes
of plants. Free radicals and reactive oxygen species are pro-
duced predominantly in plant cells during photosynthesis
and photorespiration, and to a lesser extent, in respiration
processes. Free radicals and reactive oxygen species play
crucial roles as signaling molecules in various physiologi-
cal processes. For example, during periods of environmen-
tal stress intra- and intercellular levels of H2O2 and NO tend
to increase. Additionally, specific types of free radicals and
reactive oxygen species interact with thiol-containing pro-
teins and activate different signaling pathways as well as
transcription factors, which in turn regulate gene expres-
sion and cell-cycle processes. Therefore, free radicals and
reactive oxygen species control numerous types of cellular
redox reactions (homeostasis), signaling processes (photo-
synthetic and respiratory metabolism), and processes that
regulate plant growth, development, acclimatory and defense
responses [S ´ lesak et al. (27A105)].
The role of free radicals and reactive oxygen species in
plant biochemistry and physiology have been described in
many review papers [Kuz  ´niak and Urbanek (27A63), Neill
et al. (27A80, 27A81), Apel and Hirt (27A02), Hung et al.
(27A47)]. There are no free radicals or reactive oxygen spe-
cies that are unique to tobacco. As a result there will not be
an in-depth discussion of free radicals or reactive oxygen
species specifically found in tobacco. In most cases the free
radicals in biological systems are highly reactive and have
half-lives of 10 -6 to 10 -3 seconds. Nonetheless, free radical
activity has been observed in tobacco. Analytical methodolo-
gies rapid and specific enough to monitor and identify these
free radicals are just emerging.
It is believed that the presence of oxygen (O2) in the
Earth’s atmosphere originated from photosynthetic activity.
However, oxygen is involved in two very different roles in
biological systems. It is a prerequisite for aerobic metabolism
and consequent normal growth and development, but at the
same time a reduction or an increase of molecular oxygen in
biological systems very often results in the formation of reac-
tive oxygen species that can cause deregulation of normal
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78836_C027.indd 1235
cellular processes and eventually cause cell death. Therefore,
in plants and in other aerobic organisms antioxidant systems
have evolved.
The balance of oxidants and antioxidants in plants and
animals is critical for survival. The production of reactive
oxygen species is normally carefully controlled by living
organisms. A dynamic equilibrium exists between the forma-
tion of reactive oxygen species and the activity of the antioxi-
dant scavenging systems [Hancock et al. (27A45), Irshad and
Chaudhuri (27A49), Mittler et al. (27A74), Mittler (27A73),
Vranova et al. (27A119)]. To protect themselves from reac-
tive oxygen species, plants possess a number of free-radical
scavenging enzymes, such as ascorbate peroxidase, catalase,
and superoxide dismutase, and low molecular weight anti-
oxidants, like ascorbate and tocopherols [Hancock et al.
(27A45), Vranova et al. (27A119)]. Antioxidants in tobacco
and tobacco smoke are discussed in Chapter 26.
At the senescence stage in tobacco growth, enzyme activities
(especially hydrolytic and other degradative enzyme systems)
are intensified. These systems are responsible for breakdown
of functional and structural components of the cell, such as
proteins, nucleic acids, carbohydrates, and lipids. The latter
stage of senescence resembles the early stage of leaf curing
[Tso (27A114)]. During each of these processes, free radical
reactions are occurring in tobacco leaf. In 1955, Frankenburg
et al. reported that free radical reactions were occurring in
cured tobacco leaves to form a nicotine dimer (1224, 1226).
After tobacco is grown, cured, and aged there are free
radicals still found in the lamina. It is believed that free radi-
cals are present on the polyphenols, carbohydrates, and lignin
present in tobacco. This is supported by evidence for the gen-
eration of free radicals in cellulose by irradiation with ultra-
violet light [Kleinert (27A61)]. The existence of stable free
radicals in lignin has also been demonstrated [Rex (27A98),
Steelink (27A107), Steelink et al. (27A108)]. The formation of
free radicals in wood by ionizing radiation has been shown,
as well as the generation of free radicals in wood resulting
from exposure to light [Kalnins et al. (27A57)].
Free radicals are ubiquitous. They are found in living
plants and for practical purposes are essential to all life. They
also exist in plant material that is dried. These types of free
radicals are called persistent free radicals and are normally
associated with free radicals present in the structural bio-
mass of the plant (polyphenols, carbohydrates, and lignin).
The tobacco precursors of free radicals found in the partic-
ulate phase of cigarette mainstream smoke (MSS) are also
long-lived, persistent free radicals but arise from the thermo-
lysis of the tobacco biomass to form numerous types of phe-
nolic and quinoidal free radicals [Wooten et al. (27A120)].
Short-lived free radicals are also present in the vapor phase
1235
11/24/08 2:38:14 PM
 1236 The Chemical Components of Tobacco and Tobacco Smoke
of MSS. Although the types of free radical in tobacco may be
similar in form to those in tobacco smoke, in some cases, for
example, NO, they are generated in very different ways.
Free radicals can participate in a wide variety of reactions,
such as additions, substitutions, eliminations, rearrangements,
reductions, electron transfers, and oxidations (27A01). From
the beginning of the twentieth century, free radical chem-
istry has spread its influence over a wide range of research
areas that impact our progress and well-being. Apart from
polymer chemistry, synthetic organic chemistry, and environ-
mental chemistry, much effort in recent times is expended on
research in health and nutrition [Nagendrappa (27A78)].
There are some general features of a free radical reaction.
Free radical reactions take three distinct, identifiable steps.
The first is formation of the free radical that can happen by
enzyme catalysis, homolysis, thermolysis, radiation, light
induction, combustion and pyrolysis, or other means. The
second step, called propagation, is the heart of a free radical
reaction. In this step, free radicals are repeatedly regener-
ated and can react with neutral molecules to produce new
free radicals. If there is no intervention, two free radicals can
react to form a neutral molecule and the reaction is termi-
nated, which represents the third step in the general reaction
scheme. Because of this repetitive nature of the reaction, free
radical reactions are called “chain reactions” and are often
represented as a cyclic process [Nagendrappa (27A78)].
XXVII.B Analytical Methods for
Determination of Free Radicals
The instrumental method historically used for the detection
of free radicals is electron spin resonance (ESR) (sometimes
called electron paramagnetic resonance, ERP). ESR is a spec-
troscopic technique that detects species that have unpaired
electrons. Free radicals can be organic compounds that have
a free electron on carbon, oxygen, or nitrogen, or inorganic
compounds or complexes that have a free electron, usually
residing on a metal (27A31). ESR spectroscopy is the preferred
and major analytical technique for the detection and quantifi-
cation of free radicals [Demopoulos (27A28)]. ESR has been
used in many fields of science to explore the presence and
effects of free radicals in chemistry, physics, and biology.
Free radicals can be gases, liquids, or solids and generally
exist in very low, and in some cases, steady-state concentra-
tions. ESR can be used to make direct measurements of free
radicals that exist in steady-state concentrations [Demopoulos
et al. (27A29)]. For short-lived, highly reactive free radicals,
regardless of their physical and chemical form, numerous
methodologies are now available to convert these free radicals
into longer-lived species for analysis. Short-lived free radicals
are first treated with another reagent called a spin trap. The
resultant product, the spin adduct, is a more stable free radical
species that can then be measured by ESR. Concentrations
of free radicals are determined by measuring the spin-trap
adducts. A wide variety of spin-trapping reagents have been
used. Figure XXVII-1 shows the chemical structures for a
© 2009 by Taylor & Francis Group, LLC
78836_C027.indd 1236
selection of these spin traps. Techniques that use ESR alone
or ESR with spin-trapping methodologies have advanced
tremendously over the last forty years [Janzen and Gerlock
(27A54), Janzen (27A52, 27A53), Janzen et al. (27A55)].
Unlike other typical analytical techniques, such as infra-
red spectroscopy, ESR measurements require a high level
of technical skill and expertise. ESR sample measurements
are highly dependent on sample collection, sample prepa-
ration, types of solvents, temperature, choice of spin trap,
and instrument calibration of electrical and magnetic fields,
among other things.
ESR, by itself, is considered a very specific, yet semiquan-
tifiable, technique for the measurement of free radicals. It can
be used in conjunction with other analytical techniques, such
as gas chromatography, mass spectroscopy, and high perfor-
mance liquid chromatography (HPLC) for the study of free
radicals [Cranton and Frackelton (27A20)]. ESR used in con-
junction with other analytical techniques is an emerging field.
Free radicals can also be measured in biological samples.
In a recent review by Sanchez-Moreno (27A103), several ESR
techniques were described for the collection and determina-
tion of free radicals (superoxide, hydroxyl, and peroxyl) that
occur in biological systems. These techniques include the
total radical-trapping antioxidant parameter method (TRAP),
the oxygen-radical absorbance capacity method (ORAC), and
the Trolox equivalent antioxidant capacity method (TEAC).
McAnalley et al. (27A70) have provided descriptions and
applications of these (and other) methodologies for the
determination of free radicals in biological media. Sanchez-
Moreno (27A103) concludes that “in spite of the diversity of
biological methods, there is a great need to standardize mea-
surements of antioxidant activity.”
Sophisticated ESR instrumentation is now becoming
available that allows for the direct study of free radicals and
free radical damage in living systems. In 2006, Hirata and
Fujii (27A46) reviewed newly developed technologies in
ESR spectroscopy and imaging equipment that are useful for
the analysis of free radicals in living (biological) systems.
Automatic control techniques used for a continuous-wave ESR
spectrometer were discussed. Recent developments in time-
domain ESR spectroscopy were also reported. Time-domain
ESR spectroscopy is a technically challenging method, but
can be very useful for the detection of free radicals with very
short relaxation times in biological tissues. ESR imaging
techniques were also reviewed which are able to visualize
free radicals in animal subjects noninvasively. Applications
of in vivo ESR spectroscopy and imaging for the detection
of free radicals generated in biological specimens is another
emerging field especially designed for the noninvasive direct
detection of free radicals in biomedical applications. Shulaev
and Oliver (27A104) and Tarpey et al. (27A113) have also
recently written reviews on ESR methods for the detection of
reactive oxygen- and nitrogen-centered free radical metabo-
lites in in vitro and in vivo systems employing metabolic and
proteomic markers for oxidative stress.
Additional articles, reviews, and books on ESR and meth-
odologies to detect and measure reactive free radicals in vitro
11/24/08 2:38:15 PM
 Free Radicals 1237
O O
CH3
HC=N CH3 HC=N
CH3
4-PBNO
N
CH3
N N
PNO
O O
Figure XXVII-1  Chemical structures of 4-POBN, PBN, MNP, PNO, 4-methyl-PNO, and DMPO spin traps. (From McCormick, M.L.,
G.R. Buettner, and B.E. Britigan; J. Biol. Chem. 270 (1995) 29265-29269. With permission.)
and in vivo in plants and animals have been written by Khan
and Swartz (27A58), Khan et al. (27A59), Bacic and Mojovic
(27A03), Muckenschnabel et al. (27A75), Halliwell and
Whiteman (27A43), Utsumi and Yamada (27A116), Utsumi
et al. (27A117), and Halliwell and Poulsen (27A42).
The newest methodologies for the detection, quantifica-
tion, and identification of free radicals in cigarette smoke
employ HPLC and high-resolution mass spectrometry (MS)
analysis of stable radical adducts [Bartalis et al. (27A05)],
hyphenated LC-MS/MS techniques with a C18 reverse phase
column fitted to a triple quadrupole instrument for analysis of
stable radical adducts [Rolando et al. (27A99, 27A100)], and
electrospray ionization (ESI)-HPLC/MS analysis of stable
radical adducts [Masselot et al. (27A68, 27A69)].
XXVII.C Free Radicals in Tobacco Smoke
Tobacco smoke contains free radicals. As presented in pre-
vious chapters, tobacco smoke is a highly complex aero-
sol composed of more than 5000 components distributed
between the vapor and the particulate phases. The enor-
mous complexity of cigarette smoke is the result of multiple
thermolytic processes that occur in heated tobacco within
the confines of the burning cigarette rod. These processes
involve distillation, pyrolysis, and combustion and are influ-
enced by several factors, including the design of the cigarette
[Norman (27A82)] and the composition of the tobacco blend
[Bokelman and Ryan (385), Leffingwell (2338)]. As indi-
cated in Chapters 1 through 21, numerous classes of organic
compounds are represented in cigarette smoke, including
saturated, unsaturated, and polycyclic aromatic hydrocar-
bons, alcohols, aldehydes, ketones, carboxylic acids, esters,
phenols, nitriles, N-nitrosamines, terpenoids, and alkaloids
[see also Baker (172), Dube and Green (1067), Hoffmann
et al. (1744)]. Invariably, the combustion of tobacco, like
© 2009 by Taylor & Francis Group, LLC
78836_C027.indd 1237
CH3
CH3 CH3
CH3 O=N CH3
CH3
PBN MPN
CH3
N
CH3
4-methyl-PNO O DMPO
that of any organic matter, also produces free radicals via
oxidative processes involving homolytic reactions. The high
temperatures produced during the smoking process are eas-
ily capable of causing bond scissions that lead to free radical
production [Badger et al. (141), Brown (27A14)].
An elaborate description of the fluctuating thermal gradi-
ents and vapor environment inside a cigarette during smok-
ing has been given by Baker (172). The chemical complexity
of cigarette smoke is strongly dependent on the heating con-
ditions inside the lit cigarette. To summarize briefly, when a
smoker lights and draws on a cigarette, the temperature of
the ignited tobacco rises rapidly, and a hot coal forms at the
lit end of the cigarette (the combustion zone and pyrolysis
zone). Peak temperatures inside the coal can exceed 900°C.
The high temperature inside the coal during a puff causes an
increase in the viscosity of the air flowing through the coal
and a concomitant increase in the resistance to the draw of
air through the cigarette. This effect forces air to be drawn
primarily into the periphery of the coal at the paper burn
line rather than through the center of the coal. The deple-
tion of oxygen due to combustion inside the coal and the flux
of air around the coal results in the formation of a region
immediately behind the coal that is depleted of oxygen, but
where the temperatures remain high enough to promote the
thermal decomposition of the unburned tobacco. This area
behind the coal is known as the pyrolysis/distillation zone.
Large amounts of volatile and semivolatile smoke constitu-
ents evolve from this zone. These constituents result, in part,
from the pyrolysis of tobacco, and in part, from the distil-
lation of volatile constituents native to tobacco because of
the heat of the encroaching coal. Numerous types of MSS
free radicals are formed in this pyrolysis/distillation zone
[Wooten et al. (27A120)].
Cigarette smoke can be divided into two phases, particu-
late- and vapor-phase smoke, by the use of a Cambridge filter
11/24/08 2:38:16 PM
 1238 The Chemical Components of Tobacco and Tobacco Smoke
[Dube and Green (1067)]. The radicals in these two fractions
differ greatly. The MSS particulate phase contains more than
1017 stable, long-lived radicals per gram of total particulate
matter (TPM). The vapor phase of smoke contains more than
1015 short-lived radicals per puff [Baker (27A04), Wooten et
al. (27A120)]. Free radicals in tobacco smoke were initially
detected in whole smoke by Lyons et al. (2429). After some
years, scientists became interested in examining the popula-
tion of free radicals in the particulate and vapor phases of
MSS. This trend has continued for nearly forty-five years.
It was not until recently that it was proposed that artifacts
may be forming during the separation of the whole smoke
[Culcasi et al. (27A22), Bartalis et al. (27A05)].
XXVII.D Historical Review of Free
Radical Research on
Cigarette Smoke
The following paragraphs chronologically summarize
research reported on free radicals in MSS [Prier (27A84)]
and important discoveries that shaped the mechanisms pro-
posed to explain the generation of free radicals in MSS and
their possible biological impact. This historical review of free
radicals in cigarette smoke is not exhaustive, but attempts to
capture much of the fundamental research that has shaped
this field of science and gives the researcher ready sources
for further examination.
In 1958, Lyons et al. (2429) first observed free radicals by
electron spin resonance (ESR) in whole cigarette smoke that
was condensed at liquid oxygen temperature. These workers
reported that whole cigarette smoke contains two popula-
tions of free radicals, an unstable population that can only
be observed at -183°C and that vanishes when the condensate
is warmed to 60°C, and a persistent, stable population that
exists for “several days” at room temperature. They reported
that the unstable population accounts for about one-sixth of
the total free radical population determined at -183°C and
consists of about 1015 free electrons per gram of tar. This
work was repeated by Forbes et al. (1211) in 1967 with very
similar results.
In a second set of experiments Lyons and Spence in 1958
studied the effect of extracting benzene solutions of the
stable free radicals with water, 2 N sodium hydroxide, and
2 N sulfuric acid. They reported that the ESR signal of the
stable free radicals was reduced in intensity following each
extraction by 20, 50, and 57%, respectively. They concluded
that whole cigarette smoke contains several different types of
free radicals, some of which are very stable while others exist
only fleetingly. They also suggested for the first time that free
radicals might be involved in the carcinogenicity of cigarette
smoke (2432).
In a follow-up study, Lyons and Spence in 1960 reported the
detection of free radicals in sidestream smoke (SSS) as well
as in MSS. They reported that dried SSS condensate contains
5 × 1014 spins per gram of tar, while MSS condensate contains
6 × 1015 spins per gram of tar. These results were compared
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78836_C027.indd 1238
to chimney soot and to the condensed exhaust material from
Diesel-powered automobiles that contain 5 × 1018 and 2 × 1019
spins per gram of material, respectively (2435).
Ingram and Allen in 1959 (1862) and Ingram in 1961 (1861)
published two further extensions of earlier work in which the
pyrolysis of organic material was related to the production
of free radicals detected by ESR. They demonstrated that
free radical production by pyrolysis is a general phenomenon
that occurs with various types of hydrocarbons and that the
concentration of free radicals produced is proportional to the
percent of carbon in the pyrolyzed material. A maximum
free radical concentration was detected at about 90% carbon.
They concluded that such a high percentage of carbon is con-
sistent with a polycyclic aromatic hydrocarbon (PAH) and
that free electrons must reside within such a structure. Ingram
(1861) postulated that the stable free radicals generated from
the pyrolysis of tobacco could be benzosemiquinone radicals.
He also postulated that PAH free radicals would be present in
tobacco smoke condensate.
In 1963, Marsden and Collins (2466) reported on their
results from measurements of α-activity in leaf tobacco used
for cigarettes marketed in the United Kingdom, and in specially
made, standard-size unblended cigarettes made from tobaccos
originating from widely separated geographical locations. The
origin of free radicals in tobacco smoke was discussed. They
speculated on contributions of α-radiation and free radicals in
cigarette smoke in the induction of lung cancer.
In that same year, Westermark (4220a) suggested that free
radicals generated during smoking could lead to a free radi-
cal chain reaction, which could possibly generate enough free
radicals to be carcinogenic.
Wynder and Hoffmann in their lengthy 1964 review of
tobacco carcinogenesis (4319) discussed tobacco smoke as a
“complete carcinogen” and in their evaluation of the role of
tobacco smoke components in experimental carcinogenesis
listed radicals with the comment that radicals are “suggested
as possible carcinogens in disagreement with the experi-
ments” [see p. 391, Table XXII in (4319)].
Takeshita and Ohe in 1964 published a paper on the
effects of aging of cigarette smoke and its relation to radi-
cal concentration (3864). In their study they used the radical
scavenger α,α’-diphenyl-β-picrylhydrazyl (DPPH) and were
able to detect free radicals in condensed whole smoke from
flue-cured tobacco after 300 hr, employing a colorimetric
method. DPPH is a fluorescent stable free radical and will
react with other radicals to form a neutral, nonfluorescent
hydrazine species. DPPH is not considered a spin trap, which
generally involves free radical addition to a nitroso function.
The reaction produces stable nitroxides which build up to
readily detectable concentrations in the presence of a free
radical source. The usefulness of radical addition reactions
with nitrones has been found to exceed that of the nitroso
compound because of their greater stability in a variety of
reaction conditions. Much work has been done with phenyl
N-tert-butylnitrone (PBN) in solution, although many new
spin adducts are now available. The free radical addition reac-
tion is called a spin-trapping reaction. The nitrone or nitroso
11/24/08 2:38:17 PM
 Free Radicals 1239
compound is called a spin trap and the radical addition prod-
uct is called a spin adduct [Janzen and Gerlock (27A54)].
In 1965, Boenig (369) reported on the pyrolytic products
of cigarettes irradiated with 60Co γ-radiation. ESR experi-
ments were not conducted on the tobacco to determine the
presence or extent of free radicals, although a reduction in
concentration of free radicals in smoke condensate (as mea-
sured by ESR) was noted along with reductions in MSS tars
and tar-like components. Later in 1975, Severson et al. (3610)
conducted studies on γ irradiation of cigarettes and concluded
that γ irradiation had no major effects on smoke composition.
Their study negated the possibility of decreased formation of
PAHs as a result of fewer free radicals and other suggested
changes in smoke chemistry.
Boenig reviewed the literature on free radicals and health
in 1966 (370, 371). In his reports, he considered the funda-
mental processes involved in the pyrolysis of tobacco dur-
ing smoking, that is, distillation, steam distillation, thermal
oxidation, decomposition, and thermal cracking (thermal
cracking apparently playing a major role in this combus-
tion). He emphasized that thermal cracking probably is the
most important step, during which free radicals are formed.
Interaction of a considerable proportion of these free radi-
cals then leads to the formation of various types of molecules
including the PAHs. He proposed a mechanism that would
explain the formation of PAHs from various tobacco constitu-
ents and a variety of small reactive free radicals, for example,
NO, hydroxyl, and alkyl. Later that year, he authored a paper
in which he proposed a unifying concept that free radical
exposure and health are intimately linked (372).
Browning and Patton presented a paper at the 20th Tobacco
Chemists’ Research Conference in 1966 on a quantitative ana-
lytical procedure to determine stable free radicals in tobacco
smoke condensate by ESR (448). Their analytical method for
the determination of stable free radicals in tobacco smoke
condensate was generally applicable to all types of tobacco
tars. Accuracy for the method was based upon standard coal
reference samples that yielded 7.52 × 1016 spins/g of tar. The
experimental precision was 10%. They discussed the limi-
tations (heating effects, sample isolation and concentration,
and solvent effects) and utility of the method.
In 1966, Forbes reported on the role of free radicals in
tobacco smoke carcinogenesis (1210). In that publication, he
concluded that tobacco smoke condensates contained a vari-
ety of free radical species that had a broad range of stability.
Some of the free radicals had life-times of only a few seconds,
while others are stable over long periods of time. The chemical
nature of the radicals formed in tobacco smoke was not fully
identified. Forbes postulated that some of the free radicals
formed resembled radicals obtained from benzo[a]pyrene.
In 1967, Forbes et al. further examined free radicals
present in tobacco smoke condensates by ESR (1211). They
prepared and examined sulfuric acid solutions of smoke con-
densates. They reported that the free radical species present
in sulfuric acid solutions of smoke condensates corresponded
to a modified benzopyrene-type cation radical and to the
spectrum of a modified anthracene cation radical, with the
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78836_C027.indd 1239
latter decaying fairly rapidly. No definitive proof was given
for these two cation radicals.
Rowlands et al. (27A101) studied the effect of MSS free
radicals on the tissue of perfused rabbit lungs in 1967. The
lungs were removed from the animals and attached to bell
jars that were used to simulate the breathing operation. The
animal blood was circulated through the veins and arteries
attached to the lung while smoke were periodically drawn
into the lung. The blood was then sampled and studied by
ESR. They found a three-line ESR spectrum superimposed
on a second broad singlet. They theorized that a covalent,
hexa-coordinated ferric hemoglobin complex explained the
ESR spectra.
In 1968, Rowlands et al. (27A102) published an exten-
sion of their previous work in which the reaction of ciga-
rette smoke condensate (CSC) with hemoglobin was studied
in more detail. In addition, the electron transfer properties
of the smoke condensate were studied. The involvement of
the oxides of nitrogen in the free radical properties of the
smoke was suggested by a selective condensation experiment
in which the smoke was fractionated at various temperatures
and the various condensates reacted with hemoglobin.
Cooper et al. published a paper (814) in the 1968 National
Cancer Institute monograph Toward a Less Harmful Cigarette
(4343) in which they suggested that free radicals in MSS
were possible contributors to tobacco smoke carcinogenesis.
They summarized research from the previous decade on free
radicals in tobacco smoke and discussed the possible role of
free radicals as a cause of cancer (814). It should be noted that
as early as 1954, Dorn reviewed the published experimental
evidence that indicated that the products formed by the com-
bustion of tobacco may cause skin cancer in mice. He stated
that compared to other known carcinogens, the combustion
products of tobacco smoke are relatively weak. (27A30).
In their 1967 book, Wynder and Hoffmann [see pp.
461–463 in (4332)] briefly described the studies on cigarette
smoke free radicals conducted up to that time. Summing up
the available evidence, they wrote:
Several facts seem to exclude an importance of radicals in
tobacco smoke condensate carcinogenesis. Even though
sidestream smoke condensate contains only about one tenth
the amount of free radicals found in the mainstream smoke
condensate, the tumor response of both sidestream and
mainstream “tar” on mouse skin is not different statistically
… Since both types of radicals are present mainly in the par-
ticulate matter, it remains questionable whether in freshly
generated tobacco smoke organic radicals participate in the
carcinogenic effect.
During 1968, Stedman wrote his review on the chemical
composition of tobacco and smoke (3797). In his review he
summarized much of the prior work on free radicals in MSS.
At that time, no free radicals in tobacco or tobacco smoke
had been identified. As free radicals were considered to be
playing some role in the induction of cancer, efforts were
concentrated on determining the quantity of free radicals in
smoke and their stability.
11/24/08 2:38:17 PM
 1240 The Chemical Components of Tobacco and Tobacco Smoke
In 1961, Larson et al. (2264) published their book on
experimental and clinical studies on tobacco. Free radicals
in smoke were not mentioned. However, in Supplements I, II,
and III, issued successively in 1968, 1971, and 1975, respec-
tively, Larson and Silvette (2266) summarized reported
research on free radicals in tobacco smoke. In the nearly
800-page 1968 Supplement I, they reviewed the free-radical
findings of Lyons and Spence (2432), Ingram (1861), Ingram
and Allen (1862), and Westermark (4220a) in a few para-
graphs. In the over 500-page 1971 Supplement II, Larson and
Silvette summarized the findings on free radicals in tobacco
smoke by Boenig (370, 371), Peacock and Spence (27A82b),
and Cooper et al. (814) in less than a page. In the nearly 800-
page 1975 Supplement III, their only reference to radicals in
tobacco smoke was in two separate paragraphs on a study
by Dontenwill et al. (1046a) in which the specific tumorige-
nicities of the CSCs from control and tobacco treated with
n-propyl gallate were compared. The n-propyl gallate was a
known scavenger of free radicals. No tumorigenic difference
was observed.
During 1969, Rathkamp and Hoffmann (3086) reported on
the inhibition of the pyrosynthesis of several selective smoke
components. They suggested from the results of their pyroly-
sis studies on tobacco containing KNO3 or I2 that PAHs are at
least partially formed via C and H free radicals.
In 1969, Tully et al. (27A115) were the first authors to pub-
lish a study of the free radicals in the vapor phase of MSS
cigarette smoke that was condensed at liquid oxygen tempera-
ture. The condensed vapor phase of MSS produced no ESR
signal until the temperature of the ESR cavity holding the
sample was raised to -100°C. At this temperature, a three-
line ESR spectrum was obtained that had nitrogen splitting
[a(N)] of 1.26 mT. For cigarettes made with tobacco that con-
tained 3.4% copper nitrate by weight, a complex ESR spec-
trum consisting of at least seventeen lines was observed. The
three-line spectrum from the untreated tobacco increased to a
maximum intensity after 1.5 hr at -100°C. When warmed to
room temperature, the ESR signals observed at -100°C van-
ished irreversibly. These authors concluded that the observed
free radicals may have formed as a result of some unspecified
participation by nitrogen oxides (NOx) in free radical reac-
tions within the smoke. Interestingly, nitrogen dioxide (NO2),
itself a free radical, adds to olefinic double bonds to produce
carbon-centered free radicals [Estefan et al. (27A35)]. ESR
spectra taken on solutions of NO2 mixed with different olefins
show three-line spectra that are very much like those observed
by Tully et al. (27A115). In each case, a three-line spectrum
with a(N) = 1.22 to 1.33 mT is obtained [Estefan et al. (27A35),
Bielski and Gebicki (27A09), Pryor et al. (27A91)].
Short-lived particulate- and vapor-phase free radicals that
cannot be measured directly by ESR can be measured with
the aid of spin traps. The first application of spin trapping to
the study of free radicals in tobacco smoke was reported in
1971 by Bluhm et a1. (349). MSS from commercial cigarettes,
pipes, and cigars was bubbled through solutions of α-phenyl-
N-tert-butylnitrone (PBN) in benzene (a spin trap). In each
case, a doublet of triplets with a(N) = 1.376 and a(H) = 0.199
© 2009 by Taylor & Francis Group, LLC
78836_C027.indd 1240
mT was obtained along with a triplet with a(N) = 0.801 mT.
The former splittings were assigned to an alkoxyl free radical
adduct of PBN, while the latter signal was assigned to ben-
zoyl tert-butylnitroxide (PBNOx). The intensity of the spin-
adduct signal from cigarette smoke was the weakest, while
that from cigars was the strongest. The identity of the specific
alkoxyl radical was not determined.
Bilimoria et al. investigated the inhibition of radical ini-
tiated polymerization of vinyl acetate by tobacco smoke
and some PAHs in 1973 (329). Their results indicated that
vapor phase of smoke is an efficient inhibitor of vinyl acetate
polymerization and that conjugated dienes like isoprene are
responsible for the inhibition. There were no free radicals
from tobacco smoke specifically identified in this research.
Nisbet and Schmeller presented the results of this research
at the 27th Tobacco Chemists’ Research Conference (TCRC)
in 1973 (2789a).
At that same TCRC in 1973, Johnson (1956) presented a
paper on the antioxidant activity of tobacco smoke. The inves-
tigation was undertaken to determine whether or not smoke
initiates or promotes the formation of radical peroxides which
would in turn lead to lipid peroxidation. He found that both
the vapor phase and particulate phase of smoke behaved as
an antioxidant. Fractionation of the total smoke condensate
showed antioxidant activity in the neutral and water-insol-
uble acidic fractions, with virtually no activity in the basic
fractions. The mode of antioxidant action of tobacco smoke
was discussed in terms of free radical mechanisms involving
atom transfer, addition, substitution, and coupling.
De Hys et al. in 1973 (27A25) studied the spin trapping of
free radicals in the filtered MSS of 1R1 research cigarettes.
They obtained spin-adduct spectra that did not exhibit hydro-
gen splitting, although the three-line spectra were very broad
(the hydrogen splitting was not resolved). They reported that
smoke held in the syringe for 15 sec before being bubbled
through the PBN solution showed no change in spectral fea-
tures, while smoke held in the syringe for 30 sec resulted
in a 50% decrease in the spin-adduct spectral intensity.
These authors also found that spin trapping unfiltered smoke
resulted in no spin-adduct spectra. Experiments were also
performed using 2-nitrosotoluene and 5-nitroso-8-quino-
linol as spin traps. In the first case, a three-line spectrum
was obtained with a(N) = 1.56 mT, while the second spin
trap gave no spin adduct. No attempt was made to identify
the free radical trapped with 2-nitrosotoluene. These results
indicate that time and smoke filtration impact free radical
collection and measurement.
NO2 was bubbled through a solution of PBN in benzene
and the resulting solution studied by ESR. A strong three-line
ESR spectrum with a(N) = 1.0 mT was observed. Smoke bub-
bled through cyclohexene produced no ESR signal, although
NO2 can react with olefins to give the three-line spectrum
described above (27A35, 27A09, 27A91). These authors con-
cluded that the free radicals in the vapor phase of cigarette
MSS have half-lives of about 30 sec and that NO2 is not the
dominant free radical species responsible for production of
spin-adducts from cigarette smoke.
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 Free Radicals 1241
In 1974, Morie evaluated the effectiveness of free radical
traps in cellulose acetate filters for the removal of nitrogen
oxides from cigarette smoke (2625). Four free radical spin
traps were tested as cigarette filter additives for the removal
of nitrogen oxides from tobacco smoke. A filter consisting of
cellulose acetate fibers containing 20 mg of 4-(3,5-di-tert-bu-
tyl-4-hydroxybenzylidene)-tert-butylamine N-oxide removed
42% of the nitrogen oxides from cigarette smoke. Three other
free radical traps when placed on cellulose acetate fibers or
activated carbon within cigarette filters reduced the concen-
tration of nitrogen oxides in the smoke to a lesser extent. The
mechanism proposed by Morie for the removal of nitrogen
oxides was that the free radical spin trap reacted with a free
radical in the tobacco smoke to yield a long-lived nitrox-
ide radical, which in turn reacts with nitrogen oxides in the
smoke.
A spin-trapping study of the free radicals in the MSS from
1R1 research cigarettes was performed by Menzel et al. in
1976 (27A72). These authors used spin-adduct spectral line
broadening to determine that the MSS vapor phase results in
1 × 1018 spin-trapped free radicals per cigarette puff (about
1019 spins/g of tar produced). Using spin-trap solutions in
series, they estimated the efficiency of spin trapping of the
tobacco smoke free radicals with PBN to be about 47%. They
obtained extremely broad spectral lines (by ESR) showing
no hydrogen splitting. Their results were somewhat suspect
as the spin-adduct concentration that they obtained (2 × 1019
spins/g) was much larger than any other free radical concen-
tration reported before or since (2429, 2435, 27A95).
During 1976, Pryor edited and contributed to a book on
free radicals in biology (2998a). In that book, he discussed
free radicals in cigarette smoke and the possible action of
free radicals in smokers.
A comprehensive study of free radicals in the vapor
phase of MSS produced by 1R1 research cigarettes was
reported in 1976 by Pryor et al. (27A95). Using three dif-
ferent spin traps, PBN, 5,5-dimethyl-1-pyrroline-N-oxide
(DMPO), and 3,5-(di-tert-butyl-4-hydroxyphenyl)-N-tert-
butylnitrone (OHPBN), they found that MSS produces three
types of spin adducts: an alkoxyl or aroyloxyl spin-adduct,
PBNOx, and an unknown adduct with a(N) = 1.00 mT.
They reported that the intensity of the alkoxyl adduct
increases with the distance that the smoke must travel from
the cigarette to the spin-trap solution and then decreased
thereafter. They called this phenomenon the path length
effect. The concentration of spin-trapped free radicals was
found to be about 1 × 1015 spins/g of tar. In addition, the
effect of aging on the absolute and relative concentrations
of the spin adducts was studied. The conditions of collec-
tion also had an impact on free radical measurement. Their
data did not allow them to specify the identity of either the
aromatic group in the aroyloxy (ArCO2˙) radical or the
alkyl group in the alkoxy (RO˙) radicals.
Ishiguro and Sugawara published their review on chemis-
try of tobacco smoke in 1980 (1884). This was the last major
review of compounds identified in tobacco smoke. In their
massive report they reviewed the literature on free radicals in
© 2009 by Taylor & Francis Group, LLC
78836_C027.indd 1241
tobacco smoke. There were no identified free radicals specifi-
cally mentioned in their review. They stated that:
The study of radicals in smoke has not advanced very far
because of the difficulty of identifying the radicals. It is hoped
that further progress will be made in this field so that the for-
mation routes of many components can be understood and the
composition of smoke components can be better controlled.
In a paper written in 1982 entitled “Free Radical Biology:
Xenobiotics, Cancer, and Aging,” Pryor suggested that free
radicals in cigarette MSS could pose a significant health risk
to smokers (2998b). In that paper he proposed several com-
plicated interactions between MSS components, for example,
NO, dienes, phenols, and free radicals that he believed were
operative means leading to carcinogenesis.
In 1983, Slaga et al. suggested that free radicals may be
involved not only in initiation but also in the promotion of
carcinogenesis (3687).
In 1983, using ESR spin-trapping techniques with PBN as
the spin trap, Pryor et al. (2999a) observed free radicals in
the vapor phase of both cigarette MSS and SSS. The princi-
pal vapor-phase free radicals appeared to be alkoxyl radicals
(RO˙). Pryor et al. determined that each of the vapor phases
of cigarette MSS and SSS has about the same concentration
of radicals, about 1 × 1016 radicals per cigarette (or 5 × 1014
per puff) (2999a).
In that same year, Pryor et al. (2999) examined and found
that the particulate matter from both MSS and SSS con-
tained persistent free radicals. The ESR signal was obtained
when the particulate matter collected on Cambridge pads
was measured directly and when the particulate matter was
extracted from the Cambridge pad with various solvents.
Pryor et al. listed the occurrence of four paramagnetic radi-
cal species in CSC. Three of these radicals, an inorganic
phosphorus radical, a graphitic carbon associated radical,
and a radical that appeared associated with an odd elec-
tron delocalized over an aromatic ring system, appeared to
have relatively short half-lives. However, the fourth type of
free radical had an unusually long half-life of several days.
It was speculated that the dominant ESR signal from this
fourth type was from free radicals generated from catechol
and hydroquinone. Neither of these free radicals was identi-
fied unequivocally (2999). Treatment of alcoholic solutions
of particulate matter with base generated a new group of
radicals that appeared to be semiquinone radicals derived
from the oxidation of phenolic and polyphenolic species in
the particulate matter. Pryor et al. suggested this latter radi-
cal was associated with a quinone/hydroquinone acceptor/
donor chain (2999). Again, the identification of the specific
free radicals was not obtained.
In these two papers and again in 1984 (3001), Pryor et al.
suggested the possible involvement of particulate-phase MSS
free radicals in smoking-related diseases (2999, 2999a). In vitro
assays were performed that suggested that cigarette smoke
may cause oxidative stress or oxidative damage to essential
biological molecules (3000, 27A120). Specifically in 1984,
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 1242 The Chemical Components of Tobacco and Tobacco Smoke
ESR evidence of the binding of the particulate-phase MSS free
radicals to DNA and polynucleotides was shown (3001).
In the 1984 American Chemical Society monograph on
chemical carcinogenesis, edited by Searle (3568) and with
contributions from experts in carcinogenesis, there was no
mention of the carcinogenicity of free radicals, nor any tum-
origenic PAH or aza-arene in tobacco smoke, despite the
reports by Snook et al. (3756–3759, 3750, 3752, 1544, 3664,
3665, 3908).
In 1985, Nakayama et al. published a report that described
the generation and identification of H2O2 and superoxide
anion radical from cigarette smoke (2677). H2O2 and super-
oxide anion radical were generated in a neutral buffer solution
through which cigarette smoke was bubbled. They speculated
that the H2O2 may have been formed by the autooxidation of
polyphenols such as catechol and hydroquinone in the ciga-
rette smoke.
During 1985, Halpern and Knieper isolated and tenta-
tively identified the tert-butoxy radical by the spin trapping
of radicals in the vapor phase of cigarette smoke (27A44).
Cosgrove et al. in 1985 (828a) showed that it was possible to
detect hydroxyl radicals in an aqueous extract of the particulate
phase of cigarette MSS under metal-mediated conditions. An
unidentified alkyl radical and the carbon dioxide anion radical
were also observed under their experimental conditions. They
concluded that the results of their experiment indicated that
the major particulate-phase free radical was a quinone/hydro-
quinone redox system in a polymeric matrix and that the radi-
cal signal could become associated with DNA. Unequivocal
proof was not provided for these claims.
Church and Pryor in a 1985 publication (746) summa-
rized their work (to that point) on the free radical chem-
istry of cigarette smoke and its toxicological implications.
They stated that cigarette smoke contains two very different
populations of free radicals, one in the particulate phase
and one in the vapor phase. The particulate phase contains
several relatively stable free radicals. Church and Pryor
stated that they had “identified” the principal radical as a
quinone/hydroquinone complex (QH/QH 2) held in the tarry
matrix. However, no unequivocal identification was ever
made. They suggested that this QH/QH 2 complex was an
active redox system that is capable of reducing molecular
oxygen to produce superoxide, eventually leading to H2O2
and hydroxyl radicals.
In that same publication, Church and Pryor (746) stated
that the vapor phase of cigarette smoke contains small oxygen-
and carbon-centered radicals that are much more reactive
than the particulate-phase radicals. Although no vapor-phase
radicals were specifically identified, they stated that the
vapor-phase radicals do not arise from the initial combustion
of the tobacco, but are rather produced in a steady state by
the oxidation of NO to NO2, which then reacts with reactive
species already present in smoke, such as isoprene. They sug-
gested that these reactive vapor-phase free radicals and the
metastable products derived from the radical reactions may
be responsible for the inactivation of α1-proteinase inhibitor
by fresh smoke.
© 2009 by Taylor & Francis Group, LLC
78836_C027.indd 1242
Church and Pryor (746) proposed that the excess super-
oxide that is expected to form in lung tissue exposed to ciga-
rette smoke is one possible means of inactivating α1-protease
inhibitor, a protein associated with the onset of emphysema
in deficient individuals. In the same report, the authors noted
that after particulate-phase MSS was incubated with deoxy-
ribonucleic acid (DNA), an ESR signal was observed in the
recovered DNA. Later, it was suggested that hydroxyl free
radicals generated from the particulate-phase MSS free radi-
cals may cause DNA damage [Kiyosawa et al. (27A60), Pryor
(27A85), Pryor et al. (27A93)]. Later in 1992, Pryor (27A85)
noted that such molecular damage is not unique to tobacco
smoke, but also occurs with smoke from other sources, such
as Diesel fuel and wood.
In 1986, Pryor wrote a paper on the formation, lifetimes,
and reactions of oxy-radicals and related species (2998c). In
his overview, he discussed some of the ways in which free
radicals and other highly reactive species are produced in
biological systems. He discussed the reactivity and lifetimes
of these species and listed some pathological conditions and
chronic diseases in which these species may be involved. He
discussed that cigarette smoking is a rich source of free radi-
cals and that much of the toxicity associated with cigarette
smoking may be due to the presence of free radicals in MSS.
In 1986, the International Agency for Research on Cancer
(IARC) issued its monograph on tobacco smoking (1870).
Free radicals in tobacco smoke were discussed:
Smoke can be a major indirect or direct source of chemical
oxidants and radicals, and also causes a rapid influx of pul-
monary alveolar macrophages and polymorphonuclear neu-
traphils in the lung. These actively phagocytic cells release
a variety of oxidative intermediates when exposed to par-
ticulates such as those in cigarette smoke. The intermedi-
ates found in cigarette smoke and/or released by activated
macrophages include superoxide anion, hydrogen peroxide
and hydroxyl radical.
Other than referring to the article on free radicals in ciga-
rette smoke by Church and Pryor (746), IARC cited none of
the many other pre-1986 references to free radicals in tobacco,
for example, Bilimoria et al. (329), Bluhm et al. (349), Boenig
(370–372), Browning and Patton (448), Cooper et al. (814),
Cosgrove et al. (828a), Forbes (1210), Forbes et al. (1211),
Ingram (1861), Ingram and Allen (1862), Lyons et al. (2429),
Lyons and Spence (2432, 2435), Marsden and Collins (2466),
Morie (2625), Nakayama et al. (2677), Nisbet and Schmeller
(2789a), Pryor (2998a, 2998b), Pryor et al. (2999, 2999a,
3001), Slaga et al. (3687), and Takeshita and Ohe (3864).
During the 1980s, R.J. Reynolds Tobacco Company
(RJRT) developed a new cigarette product called Premier
that heated rather than burned tobacco. A tremendous
amount of research was conducted on that product prior to
introduction. The research on Premier was summarized in a
monograph by RJRT (3190). Free radical analyses comparing
the Premier product and University of Kentucky 1R4F refer-
ence cigarette were conducted by Rice and Hayes in 1989
(1555c, 3129). In two studies, they reported that Premier had
11/24/08 2:38:18 PM
 Free Radicals 1243
a 99% reduction in vapor- and particulate-phase free radicals
compared to the 1R4F reference cigarette. Similar ESR spec-
tra were obtained but the yields of radicals in both phases
were decreased. In the 1R4F cigarette, the particulate-matter
free radicals appeared to be from species with an odd elec-
tron delocalized over an aromatic ring system, for example,
a PAH. The second source of particulate-matter free radicals
appeared to come from what Church and Pryor (746) sug-
gested was a donor/acceptor chain involving hydroquinone as
the donor and quinone as the acceptor. ESR analysis of 1R4F
vapor phase indicated the presence of radical species similar
to those previously reported for tobacco-burning cigarettes.
No identification of specific free radicals was conducted in
these studies.
In 1988, O’Brien (27A82a) discussed the fate of free radi-
cals and their effect on chemical carcinogenesis. Only one
comment was included on cigarette smoke and it involved
the PAH B[a]P in MSS and the assertion of its involvement in
lung cancer induction. O’Brien stated that PAHs like B[a]P
donate a single electron to an enzyme which may be involved
in the generation of tumorigenic diol-epoxides of the PAH.
In 1989, Nakayama et al. (27A79) reported on a reliable
method for the detection and quantitation of H2O2 generated in
aqueous extracts of cigarette smoke tar. Aqueous tar extracts
(ACT) were passed through a short reverse-phase column
and the H2O2 concentration was determined by differential
pulse polarography using an automatic reference subtraction
system. The H2O2 concentration in the ACT increased with
aging, pH, and temperature; the presence of superoxide dis-
mutase led to lower H2O2 concentrations. Their method was
applied to several types of research and commercial ciga-
rettes. They reported that, with few exceptions, the amount
of H2O2 formed after a fixed time from each cigarette smoke
was proportional to its tar yield.
Brunmark and Cadenas (27A15) reviewed the major
mechanisms that are involved in quinone-induced cytotoxic-
ity in 1989. The redox chemistry of quinoid compounds was
surveyed in terms of (1) reactions involving only electron
transfers, such as those accomplished during the enzymatic
reduction of quinones and nonenzymatic interaction with
redox couples generating semiquinones, and (2) nucleophilic
addition reactions. In their explanation of the mechanisms
involved, quinone is reduced to the hydroquinone or semiqui-
none radical by cellular reductase. The semiquinone radical
then undergoes rapid autooxidation with the generation of
the parent quinone and concomitant formation of superox-
ide. The hydroquinone reacts rapidly with superoxide to form
H2O2 and the semiquinone.
In 1992, Pryor (27A85) reviewed, compared, and con-
trasted the chemistry of cigarette smoke, wood smoke, and
the smoke from plastics and building materials that was
inhaled by persons trapped in fires. He contended that ciga-
rette smoke produced cancer, emphysema, and other dis-
eases after a delay of years. He discussed that acute exposure
to smoke from a fire could produce a loss of lung function
and lead to death after a delay of days or weeks. Tobacco
smoke and the smoke inhaled in a burning building have
© 2009 by Taylor & Francis Group, LLC
78836_C027.indd 1243
some similarities from a chemical viewpoint, for example,
both contain high concentrations of CO and other combus-
tion products. In addition, both contain varied concentrations
of free radicals, which if inhaled could lead to biological
harm (27A65). At this time, personnel in Pryor’s laboratory
had studied these free radicals, largely by ESR methods, for
about 15 years. The article reviewed what was known about
the radicals present in these different types of smokes, soots,
and tars. His article summarized the evidence that suggested
that free radicals could be involved in cigarette-induced
pathology and smoke-inhalation deaths.
In 1993, Diana and Pryor edited a book entitled Tobacco
Smoking and Nutrition: Influence of Nutrition on Tobacco-
Associated Health Risks (960c). In that book, Pryor and
Stone wrote a chapter on oxidants (free radicals, H2O2, per-
oxynitrate, and peroxynitrite) in cigarette smoke (3000).
They reported that methyl nitrite (CH3ONO), NO, and NO2
were primary oxidants in the vapor phase of MSS and that
the proposed quinone/semiquinone/hydroquinone equilib-
rium complex was the primary oxidant in particulate-phase
MSS. They postulated that peroxynitrite (HOO-N=O) and/
or peroxynitrate (HOO-NO2) or their esters (RO-ONO and
RO-ONO2) were present in the vapor phase of MSS. They
argued that hydroxyl radicals were generated from H2O2 via
the Fenton reaction (27A36), that carbon-centered radicals
were generated from dienes in MSS, and that peroxyl radicals
(ROO˙), alkoxyl radicals (RO˙), and superoxide radicals (O˙-)
were present in the vapor phase of MSS. In that same book,
Niki et al. reviewed information on membrane damage from
lipid oxidation by free radicals in cigarette smoke (2786a).
Cigarette smoke contains metals and metal ions (see
Chapter 20). Certain metal ions are important in free radical
reactions, for example, Fenton-type metal catalyzed free rad-
ical reactions. In 1993, Li and Trush (27A67) reported on the
oxidation of hydroquinone by copper and provided chemical
mechanisms for the generation of quinone species and their
biological effects. Since the interaction of several xenobiotics
with copper had been shown to result in their metabolism, Li
and Trush investigated the role of copper in the oxidation of
hydroquinone (HQ) and HQ-induced toxicity to mice bone
marrow stromal cells, target cells of HQ in the bone marrow.
In phosphate-buffered saline, HQ underwent autooxidation
slowly to benzoquinone (BQ), while the presence of Cu2+
ions (1 to 50 µM) strongly accelerated the oxidation of HQ
to BQ in a concentration-dependent manner. Reaction of HQ
with Cu2+ was also accompanied by the reduction of Cu2+ to
Cu1+, the utilization of O2, and the concomitant generation
of H2O2. Their results indicate that Cu2+ strongly induced
the oxidation of HQ and as such may be a factor involved in
the oxidative activation and toxicity of HQ in target cells. As
copper, HQ and BQ are known components of MSS, the rel-
evance of the work of Li and Trush became important in light
of the postulated mechanism of Pryor and Stone (3000).
Cueto and Pryor in 1994 (27A21), following up on the
report by Pryor and Stone in 1993 (3000), reported their work
on the conversion of NO to NO2 by Fourier Transform IR.
They also reported their results on the reactions of olefins
11/24/08 2:38:18 PM
 1244 The Chemical Components of Tobacco and Tobacco Smoke
with nitrogen oxides. In order to explain the apparent lon-
gevity of the presumably short-lived free radicals in aging
filtered smoke, a steady-state production mechanism was
proposed involving oxygen, nitrogen oxides, and vapor-phase
olefins. No specific reaction products were discussed.
Tanigawa et al. (27A112) published a paper on the spin
trapping of superoxide in aqueous solutions of fresh and aged
cigarette smoke in 1994. Superoxide generation was deter-
mined as a function of the age of the smoke using spin trap-
ping. 5,5-Dimethylpyrroline-N-oxide (DMPO) was used as
the spin trap. The superoxide adduct of DMPO was detected
in a solution of fresh MSS for over 1 hr. The superoxide-
generating potential of smoke was rapidly lost as the smoke
was kept in a plastic syringe. Smoke aged for 3 min did not
generate superoxide. Additional evidence of superoxide gen-
eration in aqueous solutions of cigarette smoke was obtained
by the chemiluminescence method.
Church in 1994 (27A19) published an article on the spin
trapping of organic radicals. In that article, he postulated a
steady-state mechanism that he believed explained the for-
mation of longer-lived vapor-phase free radicals in cigarette
MSS. The proposed mechanism was based on the observa-
tion that NO2 concentration in MSS followed the concentra-
tion of the free radicals in the vapor phase of MSS.
In 1995, Stone et al. (27A111) reviewed the previous work
conducted in the laboratories of Pryor, which showed that
extracts from MSS or SSS nicked DNA. These solutions
were believed to contain the semiquinone free radical. Aged
solutions of catechol containing a semiquinone species that
had ESR properties similar to those of the radical in cigarette
tar extracts were used as a model for the MSS particulate-
phase radical. Both the radical in aged catechol solutions and
the cigarette tar radical become associated with the DNA
in mammalian cells and nicked DNA. The nicking of DNA
caused by both the MSS particulate-phase radical and aged
catechol solutions followed saturation kinetics. The authors
believed that aged catechol solutions could be used as a
model for the MSS particulate-phase radical. Unfortunately,
their model did not take into account the fact that MSS is a
complex mixture and that other constituents in MSS could
have altered their finding.
In 1995 Stohs and Bagchi (27A109) reviewed the role of
reactive oxygen species, with the subsequent oxidative deterio-
ration of biological macromolecules in the toxicities asso-
ciated with transition metal ions. Studies have shown that
metals, including iron, copper, chromium, and vanadium
undergo redox cycling, and that this cycling can result in the
production of reactive oxygen species such as superoxide ion,
H2O2, and hydroxyl radical. As a consequence, lipid peroxida-
tion can be enhanced, DNA can be damaged, and calcium and
sulfhydryl homeostasis can be altered. Various studies have
suggested that the ability to generate reactive oxygen spe-
cies by redox cycling quinones and related compounds may
require metal ions. Cigarette MSS contains metal ions. Some
mechanisms associated with the toxicities of metal ions are
very similar to the effects produced by many organic xenobi-
otics. Specific differences in the toxicities of metal ions may be
© 2009 by Taylor & Francis Group, LLC
78836_C027.indd 1244
related to differences in solubility, the complex mixture con-
taining the metal, absorbability, transport, chemical reactiv-
ity, and the complexes that are formed within the body. Their
review summarized studies (through 1995) that had been con-
ducted with transition metal ions, regarding the production of
reactive oxygen species and oxidative tissue damage.
In 1995, Li et al. (27A66) reported on ESR evidence for
the generation of reactive oxygen species from the copper-
mediated oxidation of the benzene metabolite hydroquinone
and its possible role in DNA damage. Prior to this study, Li
and Trush (27A67) had observed that Cu2+ strongly induces
the oxidation of hydroquinone (HQ), producing benzoqui-
none and H2O2 through a Cu2+/Cu1+ redox cycle mechanism.
The oxidation of HQ by Cu2+ also resulted in plasmid DNA
cleavage. In this study, using ESR spectroscopy, they investi-
gated whether this chemical-metal redox system could gener-
ate reactive oxygen species that induce DNA damage. Studies
were not performed with cigarette MSS but were conducted
on solutions of HQ. Results indicated that both H2O2 and
Cu1+ are critical for the formation of reactive oxygen from the
HQ/Cu2+ systems. Aerobic conditions were necessary for the
redox system to function. Reactive oxygen scavengers sig-
nificantly inhibited the redox mechanism. Overall, the results
indicated that it is possible through a copper-redox cycling
mechanism, to generate a reactive oxygen species of HQ
that may participate in DNA damage. The conditions of the
experiments were not those that a smoker would experience.
Zang et al. investigated the presence of free radicals in
aqueous extracts of cigarette tar by ESR (27A122) in 1995.
They demonstrated that aqueous extracts of cigarette tar
(ACT) autooxidized to produce semiquinone, hydroxyl, and
superoxide radicals in air-saturated, buffered aqueous solu-
tions. Semiquinone species were detected by direct ESR
measurements and were tentatively identified as o- and
p-benzosemiquinone radicals by comparison with the ESR
signals of catechol and hydroquinone radicals under simi-
lar conditions. The rate of formation of these radicals was
dependent on pH. Hydroxyl and superoxide radicals were
detected as 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) spin
adducts by ESR spin trapping. Superoxide dismutase (SOD)
(20 units/mL) inhibited the formation of the superoxide spin
adduct of DMPO completely. Addition of Fe2+ to this system
increased the ESR signal intensity of hydroxyl radical spin
adduct of DMPO. Their results indicated that superoxide and
hydroxyl radicals are produced during the autooxidation of
hydroquinone- and catechol-related species in ACT under
the specific conditions of their experiments.
Borgerding et al. (27A13) presented a paper at the 1995
TCRC on a method for the quantitative determination of free
radicals in the vapor phase of cigarette MSS. The method
was based on trapping free radicals in a α-phenyl-N-tert-
butylnitrone (PBN)/benzene solution to form a stable radi-
cal species, that is, spin trapping, followed by detection with
an ESR spectrometer. Two smoke collection techniques were
discussed which differed in the extent of smoke aging prior
to spin trapping. Both techniques were found to be accept-
able for the comparison of cigarette smoke yields. Free
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 Free Radicals 1245
radical analysis of the vapor phase of MSS from cigarettes
that contained a novel carbon filter and experimental low
N-containing tobacco blend demonstrated that vapor-phase
free radical reductions on the order of 80% were possible
when compared to other equivalent “tar” cigarettes.
At the same conference in 1995, Blakley et al. (27A10)
reported the results of their studies on MSS vapor-phase radi-
cal formation and possible formation mechanisms. Church
and Pryor (746) had previously suggested a mechanism for
formation of mainstream vapor-phase radicals that involved a
reaction between NO2 and reactive dienes, such as isoprene.
Experiments were conducted to systematically explore the
proposed mechanism. Included in the experiments were ciga-
rettes from different “tar” categories, cigarettes comprising a
new type of carbon filter [Blakley et al. (27A12)] and blends,
and cigarettes that primarily heated, rather than burned,
tobacco. Some results indicated that the suggested NO2/diene
mechanism was viable, while other results did not support the
Church-Pryor mechanism. For many of the cigarettes stud-
ied, vapor-phase radical yields increased as either isoprene or
NOx smoke yields increased. [It should be noted that in 1978,
Cooper and Hege (816) reported that there is very little NO2 in
cigarette smoke, most of the NOx is NO.] However, in a series
of experimental cigarettes where isoprene yield was held con-
stant and NOx levels substantially increased, vapor-phase free
radicals were dramatically reduced. In addition, preliminary
research suggested that some processed tobaccos yielded
diminished radicals as compared to unprocessed tobaccos,
while NOx smoke concentrations remained constant. Data
were also presented on a cigarette constructed from wood
shavings that produced a substantial free-radical response
with virtually no isoprene or NOx present in the smoke.
In 1996 Rahman and MacNee (27A96, 27A97) reviewed
the literature on the imbalance between oxidants and anti-
oxidants concerning the pathogenesis of smoking-induced
lung diseases, such as chronic obstructive pulmonary disease
(COPD), particularly emphysema. There was evidence that
indicated that increased neutrophil sequestration and activa-
tion occurred in the pulmonary microvasculature in smok-
ers and in patients with COPD, with the potential to release
reactive oxygen species. Reactive oxygen species generated
by airspace phagocytes or inhaled directly from the environ-
ment can increase the oxidant burden and may contribute to
the epithelial damage. Although much research has focused
on the protease/antiprotease theory of the pathogenesis of
emphysema, less attention had been paid to the role of reac-
tive oxygen species in this condition. The possible effects of
the increased oxidant burden in smokers and in patients with
COPD are opposed by the lung antioxidant defenses. In their
article, they reviewed the evidence for the presence of an oxi-
dant/antioxidant imbalance in smoking-induced lung disease
and its relevance to therapy in these conditions. They noted
that the involvement of MSS vapor-phase free radicals in
oxidative damage was unclear because generally the reactive
vapor-phase free radicals in MSS are quenched immediately
on contact with the moist surfaces of the respiratory tract.
© 2009 by Taylor & Francis Group, LLC
78836_C027.indd 1245
In 1997, Kodama et al. (27A62) analyzed multiple com-
ponents in cigarette smoke for their ability to form active
oxygen species using a spin-trapping agent, 5, 5-dimethyl-1-
pyrroline-N-oxide (DMPO). The main source of O2 and H2O2
was ascribed to polyphenols in a particulate phase of MSS.
Hydroxyl free radicals (OH˙) were identified in the vapor
phase of MSS. Carbonyl sulfide in the vapor phase was shown
to be a source of DMPO-OH adduct. NO in the vapor phase
of MSS did not show appreciable reactivity. They added that
the quantification and identification of active oxygen species
in cigarette smoke could provide important information for
elucidating the mechanism of tobacco carcinogenesis, as
certain types and concentrations of free radicals have shown
genotoxic effects to induce DNA strand breaks, as well as
epigenetic effects, to act as cell proliferation signals.
In 1997, Pryor summarized the free radical mechanisms
developed in his laboratory over the previous twenty-one
years (27A86). He stated:
Cigarette smoke is a rich source of free radicals, as well
as other oxidants and puts an oxidative burden on the
entire organism. Smoke contains two phases, operationally
defined as gas-phase smoke, which passes through a glass-
fiber Cambridge filter and particulate matter, or tar, which
is retained on the filter. Gas-phase smoke contains reactive,
short-lived radicals that can be detected and quantified using
electron spin resonance (ESR) spin trap methods. The radi-
cals in gas-phase smoke do not result from the flame directly,
but rather are continuously generated by the oxidation of NO
to NOx, which then adds to reactive species in the smoke
(primarily isoprene) to give R˙ radicals, which react with O2,
to give RO- and ROO˙ radicals. Gas-phase smoke, with up to
500 ppm NO as well as oxy-radicals, also produces a vari-
ety of reactive nitrogen species (RNS), including HOONO,
NOONO˙, ROONO˙, and ROONO˙. Gas-phase smoke oxi-
dizes α-I-antiproteinase by a process involving H2O2 and
RNS. Cigarette tar contains a stable semiquinone radical Q -˙,
that can be observed by direct ESR; the tar radical reduces
O, and thus aqueous cigarette tar (ACT) extracts contain O2-˙,
H2O2 and ˙OH. The tar radical binds to and associates with
DNA (both by ESR and by 14C). ACT extracts nick DNA,
and ˙OH or a species like it are responsible for the damage.
Fractionation of ACT shows that the fractions that contain
the tar radical O2-˙ are responsible for >85% of the nicks.
In 1997, Stohs et al. (27A110) reviewed the potential of
metal ions reacting in conjunction with other constituents
of tobacco smoke to cause cellular damage by free radical
reactions. Various studies had demonstrated the role of reac-
tive oxygen species in the toxicity of transition metals. They
concluded that the presence of several reactive metal ions in
tobacco smoke indicates that there may be a role for metal
ions in the subsequent toxicity and carcinogenicity of tobacco
smoke. They described the metal-catalyzed mechanisms that
might be involved.
By the early 1990s, free radicals generated from MSS
were considered a significant health risk because of their
potential involvement in oxidative stress. Müller et al.
(27A77) reported that NO in cigarette smoke could react with
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 1246 The Chemical Components of Tobacco and Tobacco Smoke
superoxide derived from the reducing constituents in the
particulate phase of cigarette smoke to form peroxynitrite
(ONOO-). NO may also be converted to a number of more
reactive nitrogen derivatives, such as NO2, dinitrogen trioxide
(N2O3), and dinitrogen tetraoxide (N2O4). Their results were
consistent with a rapid NO-consuming reaction coupled with
superoxide-generating properties of the particulate phase of
MSS.
The roles of superoxide (O2˙-), peroxynitrite, and carbon
dioxide (CO2) in the oxidative chemistry of NO was reviewed
by Squadrito and Pryor (27A106) in 1998. Each of these
reactive oxygen species can cause biological damage at high
concentrations. They contended that NO and superoxide are
produced by several cell types and can rapidly combine to
form peroxynitrite. Peroxynitrite is a potent and versatile oxi-
dant that can attack a wide range of biological targets, if not
held in check. In previous publications, Pryor implied that
NO and superoxide (both known MSS components) could
be linked to numerous diseases associated with smoking.
Of course, CO2 is also present in MSS. Peroxynitrite is nor-
mally scavenged by antioxidants, but CO2 can also compete
with certain antioxidants. Squadrito and Pryor proposed a
mechanism for the reaction of CO2 with OONO˙ that pro-
duced metastable nitrating, nitrosating, and oxidizing species
as intermediates. An analysis of the lifetimes of the possible
intermediates and of the catalysis of peroxynitrite decompo-
sition suggested that the reactive intermediates responsible
for reactions with a variety of substrates may be the free radi-
cals NO2 and CO3˙-. In closing, Squadrito and Pryor noted
that increased formation of peroxynitrite has been linked to
Alzheimer disease, rheumatoid arthritis, atherosclerosis, lung
injury, amyotrophic lateral sclerosis, and other diseases.
Flicker and Green (27A38) developed a new HPLC
method for the detection of free radicals in cigarette smoke
and diesel exhaust in 1998. Carbon-centered radicals were
trapped from the vapor phase of cigarette smoke and diesel
engine exhaust by reaction with a nitroxide, 3-amino-2,2,5,5-
tetramethyl-1-pyrrolidinyloxy (3AP). The resulting mixture
of stable, diamagnetic adducts was derivatized with naph-
thalenedicarboxaldehyde (NDA) to produce highly fluores-
cent products. Derivatives were separated by HPLC, which
revealed distinctly different sets of radicals present in the two
systems. Integration of HPLC peaks gave approximately 22
± 7 nmol of radicals per cigarette and 3 ± 1 nmol of radicals
per liter of diesel engine exhaust. An estimated eight to ten
different carbon-centered radical species are present in each
system. No identification of the free radicals was made.
In 1999, Halliwell and Gutteridge (27A41) published a
second edition of their book Free Radicals in Biology and
Medicine. It has become a classic text in the field of free radi-
cal and antioxidant research. In their book, they reviewed the
role of free radicals in the life and biomedical sciences and
provided methods available to measure reactive species and
oxidative damage (and their potential pitfalls), as well as the
importance of antioxidants in the human diet. It is important
to note that free radicals in cigarettes were not discussed,
although, their text has often been cited concerning oxidizing
© 2009 by Taylor & Francis Group, LLC
78836_C027.indd 1246
species/free radicals found in MSS that are known to cause
oxidative damage in essential biomolecules.
In 1999, a World Patent was granted to Emami on a
cigarette filter additive to capture and remove free radicals
from cigarette MSS (27A34). The filter additives described
in the patent were based on natural polyphenols which effi-
ciently scavenge free radicals in cigarette smoke. Among the
various polyphenols tested, oils of rosemary extracts from
Rosemarinus officinialis L. proved to be the most active in
reducing the yields of both vapor- and particulate-phase free
radicals. The additive-containing filters were stable at high
temperature, had a twelve-month shelf-life, were not air sen-
sitive, and had normal pressure drop characteristics.
Emami et al. reported on the free radical scavenging effi-
ciency of the cigarette filters containing rosemary extract in
2000 (1143). Employing ESR, Emami et al. were only able to ten-
tatively identify the presence of hydroxyl, methoxyl, and cyano
free radicals in MSS. Unfortunately, ESR techniques alone give
poor structural information on the nature of free radicals.
In 2000, Liu et al. (2380a) presented their research on
the design of a unique low-“tar” cigarette designed to yield
approximately 40% less particulate-phase free radicals. The
cigarette employed a special filter, casing additives to reduce
free radicals (vitamin E, vitamin A, cysteine, and selenic
compounds of mannitol), a specially formulated casing with
burn control agents, expanded tobacco, and tobacco filler rich
in selenium. Although it was not possible to determine the
interactive effects of all the changes in the uniquely designed
cigarette, ESR results confirmed a reduction in particulate-
phase free radicals.
Blakley et al. (27A11) published a paper in 2001 that
questioned published reports postulating that the particulate-
phase free radicals of cigarette MSS consisted of a hydroqui-
none/semiquinone/quinone shuttle. Their results showed that
there was no positive correlation between the smoke yield
of hydroquinone and the presence of particulate-phase free
radicals. When a tenfold reduction in MSS hydroquinone
yield was obtained when KNO3 was applied to the surface
of tobacco of an American blended cigarette, there was no
significant corresponding change in the yield of particu-
late-phase free radicals. In experiments testing MSS from
low- and high-hydroquinone-yielding tobaccos there was no
consistent corresponding relationship between hydroquinone
and particulate-phase radical yields. In one series of blends
there was at best an inverse relationship between hydroqui-
none and particulate-phase radical yields. In contrast with
the published literature, Blakley et al. concluded that the par-
ticular compound or compounds driving particulate-phase
free radical formation are currently unknown.
Flicker and Green (27A37) published an improved method
for trapping carbon-centered free radicals (R˙) from the vapor
phase of the MSSs from cigarettes and cigars in 2001. They
compared free radical concentrations trapped from various
cigarettes and model smoke systems. Using a nitroxide trap,
3-amino-2,2,5,5-tetramethyl-1-pyrrolidinyloxy (3AP), on solid
support, they trapped radicals directly from the vapor phase,
washed them off the support, and analyzed them with HPLC.
11/24/08 2:38:19 PM
 Free Radicals 1247
Separation of the trapped radicals showed that the vapor phase
of smoke from each cigarette type produced a unique set of
free radicals (four to ten distinct peaks). Vapor mixtures used
to model tobacco smoke consisted of NO, air, isoprene, and
methanol. The model systems produced a set of free radicals
that consisted of four major and several minor peaks, two
of which matched peaks in tobacco smoke chromatograms.
Quantities of free radicals trapped from cigarettes tested var-
ied from 54 ± 2 nmol to 66 ± 9 nmol. The cigar tested pro-
duced 185 ± 9 nmol of free radicals. In their experiments,
oxygen competed with the nitroxide trap for MSS vapor-phase
radicals. A kinetic analysis of the O2 competition shows that
actual radical concentrations in the smoke were approximately
100-fold higher than measured.
Valavanidis and Haralambous reported in 2001 (27A118)
on the free radical populations in the MSS and SSS of ciga-
rettes with conventional acetate filters compared to biofil-
ters (BF) that claimed reductions in yields of certain toxic
substances and oxidants in the vapor phase of the MSS
(Deliconstantinos et al. 27A26) They found that BF cigarette
smoke had similar tar radical species with the same intensity
ESR signals to those of the other cigarettes containing cel-
lulose acetate filters. The ability of the aqueous cigarette tar
extracts to produce hydroxyl radicals in the cigarettes with
the BF filter was very similar to, or even higher than, the
other three brands tested. The vapor phase of the MSS of
the BF cigarette showed a 30% to 35% reduction in the pro-
duction of oxygen-centered radicals. In the case of the SSS,
BF cigarettes produced substantially higher concentrations
of vapor-phase free radicals, compared to the other brands.
Their results suggested that cigarettes with the BF were par-
tially effective at removing some of the vapor-phase oxidants
but not effective in the reduction of tar and its radical species
in the MSS and SSS.
In their paper at the 55th Tobacco Science Research
Conference (TSRC) in 2001, Wooten et al. reviewed free
radicals and proposed mechanisms for their generation in
tobacco smoke (4277). Their review was mainly a synopsis
of work published by Pryor and his colleagues over the pre-
vious twenty years. No specifically identified free radicals
were presented.
The free radical NO is both found in all living organisms
and is required for many physiological functions. NO is also
an important regulatory molecule for immune response and
cytotoxicity. It is naturally produced from l-arginine by NO
synthases (NOS). As a free radical, it produces many reactive
intermediates that account for its bioactivity. NO is also a
component of MSS. One mechanism for NO-induced cyto-
toxicity was through its interaction with superoxide to pro-
duce peroxynitrite, which can cause DNA damage. Müller
et al. (27A76) and Squadrito and Pryor (27A106) previously
suggested that this same mechanism may be operative for
free radicals in MSS. In 2001, Lala and Chakraborty pub-
lished a paper on the role of NO in carcinogenesis and tumor
progression (27A64). However, they also suggested that selec-
tive inhibitors of NOS may have a therapeutic role in certain
cancers associated with free radicals.
© 2009 by Taylor & Francis Group, LLC
78836_C027.indd 1247
In 2002, Takanami et al. reviewed their research on the
detection of free radicals in vapor phase of cigarette smoke
by ESR at the 56th TSRC (3862).
Usually, highly reactive free radicals are detected by ESR
techniques once stable spin adducts are formed but this may
lead to many pitfalls. In 2002, Masselot et al. (27A68) reported
a new methodology to study free radicals based on electrospray
ionization (ESI) and MS. The concentration of free radicals
in MSS smoke is too low, compared to the total concentra-
tion of MSS, to allow for their identification by molecular ion
identification alone. Stable spin adducts of free radicals from
samples of MSS were analyzed by ESI-MS/MS and the result-
ing fragmentation spectra were used to determine the nature
of the free radicals trapped in MSS. With this methodology,
Masselot et al. successfully identified two free radicals in the
cigarette smoke, the OH˙ and the CH3˙ radicals, and were able
to tentatively identify the O2˙- radical. When coupled to LC
techniques, the ESI-MS/MS analyses allowed not only for rad-
ical identification, but also for their quantification. Masselot et
al. applied their new method to characterize and optimize a
new filter, based on rosemary extracts, which efficiently scav-
enged free radicals in cigarette smoke and had been patented
by Emami in 1999. The relative efficiency in the removal of the
various free radicals present in cigarette smoke (C-centered,
O-centered) were discussed.
In 2002, Anderson et al. presented a review on the impor-
tance of previous work conducted on free radicals in ciga-
rette smoke at the 56th TSRC (74).
Ingebrethsen and Lyman (27A48) examined the mecha-
nism proposed by Cueto and Pryor (27A21) and Pryor and
Stone (27A93a) for the formation of reactive free-radical spe-
cies from NO and NO2 in the vapor phase of cigarette MSS
in 2002. Inspection of the generic reaction scheme proposed
by Cueto and Pryor (27A21) and Pryor and Stone (27A93a)
suggested that some condensable materials were likely
to result. The possibility of particle formation and growth
due to this condensable material suggested only one route
for phase transformation in filtered smoke. From a practical
perspective, those working with cigarette smoke have long
been aware that totally filtered smoke can yield condensable
deposits in smoking machine plumbing even in the absence
of temperature gradients. Ingebrethsen and Lyman reported
that aerosol particle formation and growth were observed in
aging, initially particle-free vapors obtained from filtered cig-
arette MSS. The time scale of particle formation and growth
was on the order of minutes and was highly dependent on
cigarette tobacco type. Measurements by both ensemble and
single particle light-scattering methods were consistent with
scattering from an aerosol with a fixed number of particles
that grew into the tenth micron range. The rate of particle
size increase agreed best with that predicted for growth con-
trolled by condensable species formation by vapor-phase reac-
tion slower than the diffusion rate of the reaction products.
A simple reaction scheme involving NO oxidation and reac-
tion with isoprene reproduced the observed form of the par-
ticle growth curves but did not yield a consistent reaction
rate constant for the various cigarette tobacco types. Their
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 1248 The Chemical Components of Tobacco and Tobacco Smoke
results were inconsistent with the proposed mechanisms of
Cueto and Pryor (27A21) and Pryor and Stone (3000) and
suggested that additional reactants are involved in the par-
ticle formation.
Müeller and Intorp reported on the longer-lived par-
ticulate-phase free radicals (quinone, hydroquinone, and
semiquinone species) they detected in MSS by ESR directly
after extraction of Cambridge filter pads in 2003 (27A76).
They also reported on their study of short-lived vapor-phase
free radicals (alkoxy and alkyl species) in MSS. These radi-
cals were spin trapped with α-phenyl-N-tert-butylnitrone
(PBN) and detected by ESR. No specific identification of the
free radicals was reported.
In 2003, Baum et al. (27A08) reported on a rigorous set
of experimental protocols they believed were necessary to
conduct ESR experiments on particulate- and vapor-phase
free radicals in MSS. In their paper, they discuss experiments
that were conducted in order to determine the optimal condi-
tions for maximum signal intensities and reproducibility of
results. Their results showed that radical concentrations in
smoke vary among cigarettes in both the vapor phase and
particulate phase of MSS. By use of a series of commercial
cigarettes, where many parameters change from cigarette to
cigarette, no statistically significant correlations were found
between radical levels and total particulate matter in smoke.
However, a weak correlation was found between the vapor-
phase free radical levels and total particulate matter levels in
smoke. They also reported that there may also be a complex
effect of tobacco type on radical levels in smoke.
Emami et al. presented a paper at the 2003 CORESTA
meeting in Freiburg, Germany, on an improved method for
the detection, quantification, and identification of vapor-
phase free radicals in MSS (27A32). They commented that
the detection and quantification of vapor-phase free radicals
by ESR has two main limitations: (1) free radical/spin-trap
adducts are readily oxidized to give nonradical species,
which cannot be detected by ESR; and (2) ESR techniques
have a low capability to give structural information in the
case of mixtures. Consequently, the unequivocal identifica-
tion of many free radicals in cigarette smoke is still to be
determined and in addition, quantitative results for com-
parison studies are difficult to obtain (27A08). Masselot et
al. (27A68, 27A69) had previously reported on use of 4,5,5-
trimethylpyrroline-N-oxide for characterizing O-centered
radicals and of 3-amino-2,2,5,5 tetramethyl-1-pyrrolidiny-
loxy for C-centered radicals. These two free radical trapping
agents were used to identify the hydroxyl (OH˙) and methoxyl
(CH3O˙) radicals and cyano (CN˙) radical, respectively. In
this report, they described the quantitation of these radicals
employing a hyphenated LC-MS/MS technique with a C18
reverse-phase column fitted to a triple quadrupole MS instru-
ment. The addition of a stable free radical as internal standard
(TEMPO, 2,2,6,6-tetramethyl-1-piperinodyloxy) allowed
them to cleanly quantify the detected free radicals by the so-
called MRM (multi-reaction monitoring) mode. The absolute
quantification they obtained (ca. 1016 radicals per cigarette)
was in good agreement with previous experiments based on
© 2009 by Taylor & Francis Group, LLC
78836_C027.indd 1248
ESR techniques. They applied their improved free-radical
method to characterize a new filter, patented by Emami in
1999, containing rosemary extracts, which scavenge free
radicals in cigarette smoke (27A34). The relative efficiency
in the removal of the various free radicals present in cigarette
smoke (C-centered, O-centered) was 50% for filters contain-
ing 50 mg of formulated rosemary extract.
Numerous presentations on free radicals were made in
2004 at the 58th TSRC and at the CORESTA Congress in
Kyoto, Japan.
In 2004, Zhou et al. (27A123) presented a systematic
approach to the study of these free radicals in the particulate
phase of MSS at both the CORESTA Congress and at the
58th TSRC (4415). They reviewed much of the prior research
on detection methods for free radicals, discussed means to
reduce free radical in MSS, and the need for more biomedi-
cal evaluation.
In 2004, Rolando et al. (27A100) reported on the iden-
tification and quantitation of the hydroxyl (OH˙), methoxyl
(CH3O˙), cyano (CN˙), formyl (HC(O)O˙), peroxyl (˙OOH),
and nitrite (NO2˙) free radicals employing their previously
reported hyphenated LC-MS/MS technique that used a C18
reverse-phase column fitted to a triple quadrupole instrument
at the CORESTA Congress in Kyoto.
Little et al. presented results of their investigation of phe-
nolic particulate-phase free radicals (e.g., benzoquinone-
hydroquinone radical) in MSS measured by direct ESR
measurements at low temperatures (2379) at the 58th TSRC.
Variable temperature ESR studies were performed on the
particulate-phase free radicals in MSS. Different particulate-
phase free radicals showed temperature dependence. Isolated
particulate-phase free radicals began to form at about 450°C.
It should be noted that stable benzoquinone-hydroquinone
complexes (CAS No. 106-34-3) had been identified in tobacco
smoke and Cytrel® smoke in 1969 by Green et al. (1378) and
by Newell et al. (2767) in 1974. In neither study was any spe-
cial procedure used to deal with free radicals.
At the 58th TSRC, Rickert et al. reported on an ESR method
used at LabStat for the determination of the yields of vapor-
phase and particulate-phase free radicals generated in MSS
(3134). No specific identified free radicals were discussed.
In 2004 at the 58th TSRC, Johnson and Chapman pre-
sented a general review on the identification of free radicals
in whole smoke (1957). Again, no specifically identified free
radicals were discussed.
Johnson reported at the 59th TSRC, in 2005, on the results
of the identification of spin-trapped vapor-phase free radi-
cals in MSS via an ESI-triple quadrupole tandem mass spec-
trometry analysis method. Four alkoxyl free radicals were
unequivocally identified (˙OC2H5, ˙OC3H7, ˙OC4H9, and
˙OC5H11). The superoxide free radical was also tentatively
identified (27A56).
Employing an Amplex Red assay, Yan et al. (27A121)
were able to detect, quantify, and positively identify H2O2
in whole cigarette smoke. Although not a free radical,
H2O2 has been proposed as an intermediate in certain free
radical reactions. Church and Pryor (746) proposed that
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 Free Radicals 1249
hydroquinones present in the particulate phase of MSS
can reduce dioxygen (O2) to produce superoxide (O2 –˙) and
semiquinone (Q –˙) radical anions. The superoxide radical
anion was thought to be the immediate precursor to H2O2,
which could then be reduced to the hydroxyl radical by
metals such as iron. Church and Pryor (746) suggested that
the resulting HO˙ radical can then damage DNA. Yan et
al. found that there was a time dependency of H2O2 pro-
duction in whole cigarette smoke in their experiments. The
Amplex Red assay showed an increase in the production of
H2O2 of up to 120 min and then reached a plateau there-
after; suggesting H2O2 was formed over this time period
by some reaction(s) involving the highly complex mixture
of chemical constituents present in whole cigarette smoke.
In the work of Yan et al., concentrations of 3 to 8 µM H2O2
were found in aqueous solutions of whole-smoke bubbled
samples, while there was negligible H2O2 formation from
vapor-phase bubbled samples. The data in this work suggest
that the major constituents responsible for H2O2 formation
are in the particulate phase. Aqueous solutions of hydroqui-
none and catechol, both of which are particulate-phase con-
stituents of cigarette smoke, generated no H2O2 even though
they are free radical precursors involved in the production
of reactive oxygen species in the smoke matrix.
In 2005, Chouchane et al. (27A18) studied cigarettes
that had varied levels of polyphenols in the tobacco filler
(flue-cured, burley, Oriental tobacco, and blends of these
tobaccos). They found that the yield of particulate-phase
free radicals generated in the MSS from these cigarettes
was not directly related to the total amount of polypheno-
lic compounds in the tobacco leaf filler. For example, ciga-
rettes prepared from flue-cured tobacco, which contains a
significantly higher amount of polyphenols in comparison
to burley tobacco, did not generate a higher yield of par-
ticulate-phase free radicals in MSS compared to cigarettes
prepared with burley tobacco.
Halliwell and Poulson recently published a book on ciga-
rette smoke and oxidative stress (27A42). The currently pro-
posed mechanisms for free radical production in cigarette
smoke were discussed. They concluded that the proposed
mechanisms by which cigarette smoke causes or contributes
to inflammatory diseases like COPD, cardiovascular disease,
and cancer remain unclear. In several chapters in their book,
they discussed recent developments in cellular signaling and
suggested that cigarette smoke may cause oxidative stress in
cellular systems. The assessment, consequences, and pos-
sible modulation of biological effects from oxidative stress
were discussed. Analytical methods for the determination of
isolated free radicals and biological assays for free radicals
were also discussed.
In 2006, Rolando et al. (27A99) developed a new meth-
odology based on liquid chromatography (LC), mass spec-
trometry (LC-MS and LC-MS/MS) for the identification
and quantification of free-radical–spin-trap adducts. The
improved method involved the use of a nano-LC fitted
with a 75-µmcolumn for separation that allowed for shorter
analysis time and higher sensitivity. The main advantage of
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78836_C027.indd 1249
their improved method was its ability to detect and identify
certain free radical adducts (so-called ESR silent adducts)
which had been oxidized or reduced after the trapping. By
using spin traps that were specific for the trapping of C- or
O-centered free radicals, they unambiguously identified the
OH˙ and CH3˙ radicals. Using this new methodology, they
were able to ascertain the presence and identification of
the cyanide radical (CN˙) and nitrite (ONO˙) radical. They
stated that they were continuing their work on the structure
of more complex free radicals at higher molecular mass by
comparing spectra from chemically generated free radicals
to those present in MSS.
Free radicals in cigarette smoke have attracted a great deal
of attention because they are hypothesized to be responsi-
ble in part for several of the pathologies related to smoking.
Hydroquinone, catechol, and their methyl-substituted deriva-
tives are abundant in the particulate phase of cigarette smoke,
and they are known precursors of semiquinone radicals. In
the study by Chouchane et al. (27A17) in 2006, the in vitro
cytotoxicity of these dihydroxybenzenes was determined
with the neutral red uptake (NRU) assay, and their radical-
forming capacity was determined by ESR. All of the dihy-
droxybenzenes studied were found to generate appreciable
amounts of semiquinone radicals when dissolved in the cell
culture medium employed in the NRU assay. Hydroquinone
exhibited by far the highest capacity to form semiquinone
radicals at physiological pH, even though it was not the most
cytotoxic dihydroxybenzene. Methyl-substituted dihydroxy-
benzenes were found to be more cytotoxic than either hydro-
quinone or catechol. The formation of semiquinone radicals
via autooxidation of the dihydroxybenzenes was found to be
dependent on the reduction potential of the corresponding
quinone/semiquinone radical redox couple. The capacity to
generate semiquinone radicals was found to be insufficient
to explain the variance in the cytotoxicity among the dihy-
droxybenzenes in their study; consequently, other possible
mechanisms of toxicity must also be involved. The observed
interactions between 2,6-dimethylhydroquinone and hydro-
quinone in the cytotoxicity assay and ESR analysis suggested
that care needs to be taken when studying the bioactivity of
cigarette smoke constituents, that is, the effect of the whole
cigarette smoke complex matrix on the activity of the sin-
gle constituent studied must be taken into consideration.
Biological studies of the separated particulate and vapor
phases of MSS may provide results that are different from
those of studies of whole MSS.
In 2006, Culcasi et al. (27A22) also reported on the free
radical-related cytotoxicity of the vapor phase of MSS and
the paradoxical temporary inhibition of cytotoxicity of
vapor-phase free radicals by the MSS particulate phase. In
their ESR studies, the spin trap 5-(diethoxyphosphoryl)-5-
methyl-1-pyrroline-N-oxide (DEPMPO) was employed. They
experimented with cigarettes made with cellulose acetate fil-
ters, empty cavity filters, and cavity filters containing car-
bon (charcoal). In their study, filters containing carbon were
effective in reducing vapor-phase free radical formation,
cytotoxicity, and lipid peroxidation in three cell lines. The
11/24/08 2:38:19 PM
 1250 The Chemical Components of Tobacco and Tobacco Smoke
results of their experiments also showed that NO and NO2
are more important than hydroxide free radicals in generat-
ing the cytotoxicity of vapor-phase MSS free radicals gen-
erated from MSS constituents. Culcasi et al. also suggested
that something in the MSS TPM reduced the cytotoxicity of
vapor-phase free radicals in MSS as there was an unexpected
protective effect of TPM on the cytotoxicity of whole smoke
compared to that of vapor phase of MSS alone. They con-
cluded that the conventional smoke collection method (sepa-
ration of the smoke into vapor and particulate phases) distorts
the true picture of free radical activity. In other words, free
radical activity in cigarette smoke should only be evaluated
on a “whole smoke” basis.
In 2007, Dellinger et al. (27A27) conducted and reported
on the formation and stability of resonance stabilized free
radicals of the type hypothesized by Pryor and his associ-
ates in the particulate phase of MSS. They concluded that
the commonly observed free radicals in the particulate phase
of MSS were not a surface associated semiquinone and were
more likely an intrinsic, polymeric radical with a delocal-
ized electron. The EPR signal observed by Pryor in the alco-
hol extract of the particulate phase of MSS may be from an
extracted and autooxidized hydroquinone, not a particulate-
phase-associated semiquinone radical. The semiquinone
radical was observed in the particulate-phase MSS collected
below 400°C and has a five-line spectrum with g ~ 2.006.
Semiquinone radicals were formed in the particulate phase
of MSS only after aging.
Ghosh et al. in 2007 (27A39) presented their research
results on the ESR study of free radicals in the vapor phase
of the MSS from 2R4F reference cigarettes. The vapor phase
of MSS trapped with DMPO contained a mixture of three
free radical species that correspond to two oxygen-centered
radicals (90%), and an unidentified radical (10%) resulting
from the decomposition of the spin adducts. They were able
to identify the methoxy free radical in the vapor phase of
MSS via computer simulation. The oxygen-centered free rad-
ical concentration in the vapor phase of MSS was in the range
of 1014 to 1015 spins per cigarette smoked under ISO standard
smoking conditions.
In 2007, Bartalis et al. (27A05) identified seven acyl and
eleven alkylaminocarbonyl radicals in whole MSS employ-
ing HPLC and high-resolution mass spectrometry analysis
of stable radical adducts. The combined abundance of these
free radicals measured in fresh whole smoke from a single
2R4F cigarette was approximately 225 nmol (1.4 × 1017 radi-
cals). The fiberglass Cambridge filter pad conventionally
employed to separate the vapor phase from the particulate
phase of MSS was found to reduce the apparent yield of these
radicals, introducing artifacts of measurement. They stated
that the long-accepted steady-state mechanism for the for-
mation of C-centered radicals in cigarette smoke involving
NO2 chemistry cannot account for these newly identified
radicals, and does not in general appear to be a major source
of C-centered radicals in fresh cigarette MSS. Consequently,
they suggested that the precise nature of radicals in cigarette
smoke warrants reexamination.
© 2009 by Taylor & Francis Group, LLC
78836_C027.indd 1250
XXVII.E Proposed Mechanisms
for the Generation of
Free Radicals in MSS
Smoking has been implicated in numerous diseases (4012,
27A50, 27A51, 27A83, 27A87). Over the last fifty to sixty
years, extensive research has been conducted to understand
relationships between individual smoke constituents and
smoking-related diseases. Because cigarette smoke is a com-
plex mixture and a great number of complex biological pro-
cesses are involved in each disease, no simple correlations
have been found between smoking and disease. This is not to
say that we have not progressed in our understanding of the
biological effects of smoking and disease but causal relation-
ships are still largely unknown (27A17).
Numerous constituents of cigarette smoke have been
identified as potential agents of biological damage, includ-
ing tobacco-specific N-nitrosamines, PAHs, phenolic com-
pounds, and free radicals (746, 1727, 2999, 3712).
Free radicals in tobacco smoke have attracted much atten-
tion during the last thirty years. Free radicals in biological
systems can cause DNA damage, lipid peroxidation, and
protein oxidation [Baskin and Salem (27A07), Halliwell and
Gutteridge (27A41)] if not moderated by the body’s oxidative
stress defenses. Cigarette smoke and other environmental
pollutants contain free radicals (2999, 2999a). Although free
radicals in tobacco smoke have been implicated in human
disease, no unequivocal proof of their harm has been estab-
lished. Tobacco smoke is a complex mixture containing
thousands of chemical constituents that can readily produce
free radicals in aqueous media (828a, 2999). Tobacco smoke
also contains an even greater concentration of antioxidants,
antimutagens, and anticancer agents that have been shown
to effectively inhibit several biological processes that could
lead to disease. In Chapter 26 on carcinogens, cocarcinogens,
anticarcinogens, and antimutagens, this subject is reviewed.
Nevertheless, there are still many unanswered questions con-
cerning the involvement of free radicals in the toxicology of
tobacco smoke. In-depth studies are needed to delineate their
precise effects (27A17).
In 1958, Lyons et al. (2429) first observed free radicals by
electron spin resonance (ESR) in whole cigarette smoke that
was condensed at liquid oxygen temperature. These workers
reported that whole cigarette smoke contains two popula-
tions of free radicals, an unstable population that can only be
observed at -183°C and that vanishes when the condensate
is warmed to 60°C, and a persistent, stable population that
exists for “several days” at room temperature. The unstable
population of free radicals included those in the vapor phase
of whole cigarette smoke and the more stable population of
free radicals included those found in the particulate phase of
whole smoke. As a result, the early examination of the chem-
ical and physical characteristics of free radicals in tobacco
smoke was conducted mainly on free radicals in the particu-
late phase. In 1969, Tully et al. (27A115) were the first to
publish a study of the free radicals in the vapor phase of ciga-
rette MSS that was condensed at liquid oxygen temperature.
11/24/08 2:38:20 PM
 Free Radicals 1251
By passing whole cigarette smoke through a fiberglass filter,
called a Cambridge pad, the particulate phase of cigarette
smoke can be efficiently separated from the vapor-phase
constituents (172, 1067). The use of Cambridge pads allowed
investigators to separate and independently investigate the
free radicals in both phases of whole smoke. The chemical
behaviors of the vapor- and particulate-phase free radicals of
MSS smoke were found to be quite distinct. The vapor-phase
radicals have been shown to be unstable and very reactive,
whereas the radicals in the particulate phase are much longer
lived (2999, 2999a, 27A95). Derivative methods or spin-trap-
ping techniques were developed to stabilize the vapor-phase
free radicals for quantitation. From about the mid-1960s,
chemical and biological research on free radicals in tobacco
smoke involved separation of the smoke stream into vapor
and particulate phases.
From 1976 through 2006, Pryor and his associates stud-
ied both vapor- and particulate-phase free radicals in tobacco
smoke (746, 828a, 2999, 2999a, 3000, 3001, 27A19, 27A21,
27A24, 27A84-27A95, 27A106, 27A111, 27A122). They gen-
erated experimental evidence that suggested possible mecha-
nisms for the initiation, propagation, and termination of free
radicals in tobacco smoke. They also alleged that free radicals
in MSS were important to numerous smoking-related diseases.
They hypothesized that vapor-phase free radicals in tobacco
smoke were formed by a continuous mechanism, whereby NO
reacted with molecular oxygen in air to form NO2, and sub-
sequent reactions between NO2 and unsaturated molecules in
cigarette smoke, for example, isoprene and butadiene, yielded
alkyl, peroxyl, and alkoxy radicals. They contended that the
reaction of peroxyl radicals with NO generated additional
NO2, creating a steady-state cycle (2999a, 27A94).
Pryor and his associates also postulated a mechanism
for the generation and reaction of free radicals in the par-
ticulate phase of tobacco smoke. In that mechanism, par-
ticulate-phase free radicals in MSS were postulated to be
semiquinone radicals in a polymeric matrix (2999). They
stated that the particulate phase of MSS contained numer-
ous dihydroxybenzenes, which could generate semiquinone
radicals (27A122). They supported their hypothesis by show-
ing that hydroquinone and catechol can undergo oxidation
in air to form semiquinone radicals and ultimately quinones.
They further showed under laboratory conditions that reac-
tions between the semiquinone free radicals and molecular
oxygen, either in aqueous extracts of cigarette tar (ACT) or in
living cells, could lead to the creation of reactive oxygen spe-
cies (ROS) such as superoxide radical, H2O2, and hydroxyl
radical (27A122). It is important to note that the measure-
ments of Pryor et al. (27A93) and others performing research
on free radicals in tobacco smoke are not representative of
free radical formation under physiological conditions or in
biological systems (27A17). The free radical mechanisms
proposed by Pryor and his associates were very convincing
but, like all mechanisms, as scientific curiosity is piqued,
they were vigorously tested by others.
In 2001, Blakley et al. (27A11) showed that the yield of par-
ticulate-phase free radicals was not correlated with the yield
© 2009 by Taylor & Francis Group, LLC
78836_C027.indd 1251
of hydroquinone in MSS. For a series of cigarettes containing
different tobacco blends with variable yields of MSS hydroqui-
none, the amount of free radicals in the particulate phase of MSS
remained unchanged. In their experiments, methylene chloride
was used to extract the particulate matter from Cambridge pads,
the solvent evaporated, and the residue redissolved in benzene
for EPR measurements. Under these experimental conditions,
hydroquinone would be less likely to undergo autooxidation,
which is less favorable in organic solvents. Nevertheless, sig-
nificant levels of particulate-phase free radicals were observed,
which calls into question the exact nature of the radicals that
could be involved in biological damage.
Ingebrethsen and Lyman in 2002 conducted experiments
on particle formation and growth in vapors from totally fil-
tered cigarette MSS (27A48). In their experiments, they tested
a simple reaction scheme involving nitrogen oxide oxidation
and its reaction with isoprene. Their experiments reproduced
the expected and observed form of the particle growth curves
and did not yield a consistent reaction rate constant for the
various cigarette tobacco types. Their results were inconsis-
tent with the proposed vapor-phase free radical mechanisms
of Cueto and Pryor (27A21) and Pryor and Stone (3000) and
suggested that additional reactants are involved in the par-
ticle formation.
Cytotoxicity is regarded as a potential step in several
chronic disease processes, including carcinogenesis and
emphysema [Butterworth et al. (27A16)]. The cytotoxic con-
stituents of cigarette smoke and their mechanisms of action
are poorly understood [Chouchane et al. (27A17)]. Thus far,
most research has focused either on the chemistry of ciga-
rette smoke or on the in vitro and in vivo effects of cigarette
smoke on biological systems. The lack of a bridge between
these two approaches has made it difficult to assess the
relationship between cigarette smoke constituents and their
effects in biological systems. It is known, for example, that
cigarette smoke contains a substantial amount of dihydroxy-
benzenes in the particulate phase of MSS (2681, 3175, 3743).
In vitro assays have demonstrated that ACT, which contains
significant amounts of hydroquinone, catechol, and other
mono- and dihydroxybenzenes, can damage DNA [Pryor et
al. (27A93)]. However, there is no direct evidence to suggest
that pure hydroquinone or catechol can induce the same level
of free-radical formation and DNA damage as any isolated
fraction of ACT [Chouchane et al. (27A17)]. Again, it must be
repeated that the experimental conditions employed by Pryor
and others for measurement of free radical activity in tobacco
smoke are not representative of free radical formation under
physiological conditions or in biological systems (27A17).
In 2006, Culcasi et al. (27A22) suggested that something
in the MSS particulate phase reduced the cytotoxicity of MSS
vapor-phase free radicals as there was an unexpected protec-
tive effect of particulate phase on the cytotoxicity of whole
smoke compared to that of vapor phase of MSS alone. They
concluded that the conventional smoke collection method,
that is, separation of the smoke into vapor and particulate
phases, distorted the true picture of free radical activity. In
other words, free radical activity in cigarette smoke should
11/24/08 2:38:20 PM
 1252 The Chemical Components of Tobacco and Tobacco Smoke
only be evaluated on a “whole smoke” basis, unlike much of
the research that had been conducted previously. Therefore, a
reexamination of some of the toxicological data on free radi-
cals would be prudent.
Chouchane et al. (27A17) recently studied the involvement
of semiquinone radicals in the in vitro cytotoxicity of cigarette
MSS. Prior to their study it was known that dihydroxyben-
zenes can generate semiquinone radicals, quinones, and reac-
tive oxygen species (ROS) in oxygenated physiological media
in vitro, for example, in the growth media used in cytotoxicity
assays. It was believed that certain dihydroxybenzenes could
possibly generate similar semiquinone radicals, quinones,
and ROS in vivo in the epithelial lining fluid of the lungs of
smokers. Brunmark and Cadenas (27A15) suggested that the
cytotoxicity of quinols and quinones may be due to the con-
certed action of several processes that include redox cycling,
alteration of thiols balance through oxidation or arylation,
inhibition of cellular functions, alteration of Ca2+ homeostasis,
and covalent binding to nucleic acids, proteins, and lipids. It is
difficult to extrapolate in vitro data analysis to an in vivo sys-
tem, especially if the in vitro experiments were not conducted
under conditions close to physiological conditions. Moreover,
few data are available on the cytotoxicity of pure dihydroxy-
benzenes to compare with the toxicity of a complex mixture
containing dihydroxybenzenes, such as cigarette smoke. The
dihydroxybenzenes in their study were constituents of the
particulate phase of MSS and were found to exhibit signifi-
cant cytotoxicity. The methyl-substituted dihydroxybenzenes
were shown to have higher cytotoxicity than the unsubstituted
compounds. The dihydroxybenzenes were shown to generate
semiquinone radicals in the medium used in the NRU cytotox-
icity assay. Nevertheless, a correlation between the abundance
of semiquinone radicals formed and their cytotoxicity was not
found. The observed interaction between 2,6-dimethylhydro-
quinone and hydroquinone in the cytotoxicity assay and EPR
analysis demonstrates that the EC50 values in binary mixtures
of the dihydroxybenzenes cannot, in general, be assumed to
be additive. Consequently, the interpretation of the bioactivity
of cigarette smoke evaluated by similar methods should con-
sider the possible effects of the complex mixture of MSS on
the activities of the individual constituents.
The most recent study of free radicals in tobacco smoke,
published by Bartalis et al. (27A05), indicated that the analy-
sis of whole smoke vs. vapor-phase and/or particulate-phase
samples is not only important but absolutely necessary in eval-
uating the true chemistry of free radicals in tobacco smoke.
Bartalis et al. measured and identified seven acyl and eleven
alkylaminocarbonyl radicals in fresh whole smoke from a
single 2R4F cigarette. These eighteen free radicals had a spin
concentration of 1.4 × 1017 radicals/cigarette and accounted
for nearly the entire ESR signal. They showed that the long-
accepted steady-state mechanism for the formation of carbon-
centered radicals in cigarette smoke involving NO2 chemistry
cannot account for these newly identified radicals, and that it
does not in general appear to be a major source of carbon-
centered radicals in fresh cigarette MSS. The fiberglass
© 2009 by Taylor & Francis Group, LLC
78836_C027.indd 1252
Cambridge filter pad conventionally employed to separate the
vapor phase from MSS was found to reduce the yield of these
radicals, introduced artifacts of measurement. The introduc-
tion of a Cambridge pad reduced the yield of the eighteen free
radicals measured and identified by 96%. In their experimen-
tal procedure that did not use Cambridge pads or any spin
traps, no NO2 was detected in the smoke. [This finding paral-
lels that of Cooper and Hege (816), who reported that, even
under unfavorable conditions, the nitrogen oxides in cigarette
MSS are predominantly NO]. NO2 formation was shown to
be an artifact of the smoke separation procedure. Bartalis et
al. found no evidence of any type of free radicals containing
a NO2 group as previously proposed by Pryor and his associ-
ates (746, 2999, 27A88, 27A89) and Flicker and Green (27A37,
27A38). The proposed mechanism of the addition of NO2 to
dienes in cigarette smoke, cigarette pyrolysates, or model gas
mixtures of NO, air, and isoprene was found to have no merit.
The long-accepted steady-state mechanism for the formation
of carbon-centered radicals in cigarette smoke involving NO2
chemistry cannot account for these newly identified radicals;
consequently, they suggested that the precise nature of radicals
in cigarette smoke warrants a total reexamination.
Bartalis et al. stated:
The widely accepted mechanism for the formation of both
alkyl and alkoxyl radicals in cigarette was proposed by Pryor
and co-workers and supported by persuasive, but primarily
indirect, evidence was based on comparisons of gas-phase
cigarette smoke and model gas mixtures.
Based on the work of Blakley et al. (27A11), Ingebrethsen
and Lyman (27A48), Chouchane et al. (27A17, 27A18),
Culcasi et al. (27A22), and Bartalis et al. (27A05), the pro-
posed mechanisms of Pryor and his associates certainly need
to be reexamined. Additionally, the previously made biologi-
cal assertions need to be reevaluated since the free radicals
presumably present in MSS may not actually exist. The
clear evidence of artifacts formed by the separation of whole
smoke into particulate and vapor phases supports the total
reexamination of the chemistry and biology of free radicals
in tobacco smoke proposed by Bartalis et al. (27A05).
In summary, it would appear that we have come full circle
over the last fifty years. Lyons et al. (2429) initially examined
free radicals in whole smoke without the use of Cambridge pads
and today this appears to be the collection method of choice.
Tremendous analytical advancements have occurred over the
last fifty years and now the identification and quantification
of free radicals in whole tobacco smoke are finally possible.
Artifact formation is always possible in research and is not a
weakness of the experimenter. As additional research continues
on free radicals in tobacco smoke, we express the same con-
cerns and hopes of Ishiguru and Sugawara (1884) in 1980:
It is hoped that further progress will be made in this field
so that the formation routes of many smoke components can
be understood and the composition of smoke components can
be better controlled.
Table XXVII-1 is a catalog of free radicals identified to
date in tobacco and tobacco smoke. The catalog contains
11/24/08 2:38:20 PM
 Free Radicals 1253


Table XXVII-1

Free Radicals in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke
7DEOH;;9,,)UHHUDGLFDOVLQWREDFFRWREDFFRVPRNHDQGWREDFFRVXEVWLWXWHVPRNH
  5HIHUHQFHV
    7REDFFR
&$61R 1DPHSHU&$&ROOHFWLYH,QGH[ 7REDFFRVPRNH

7REDFFR VXEVWLWXWH
VPRNH

   
 5DGLFDOVIUHH>*(1(5$/',6&866,21@   
DF
F
ED
DD
DEFD

D
$$$$
$$$$
$$$$
 $F\OUDGLFDOEXW\O^LVRPHUV` $  $
&2&+&+&+&+
 $F\OUDGLFDOHWK\O $  $
&2&+&+
 $F\OUDGLFDOPHWK\O $  $
&2&+
 $F\OUDGLFDOSURS\O^LVRPHUV` $  $
&2&+&+&+
 $ON\ODPLQRFDUERQ\OUDGLFDOEXW\O^LVRPHUV` $  $
&21+&+&+&+&+
 $ON\ODPLQRFDUERQ\OUDGLFDOHWK\O $  $
&21+&+&+
 $ON\ODPLQRFDUERQ\OUDGLFDOPHWK\O $  $
&21+&+
 $ON\ODPLQRFDUERQ\OUDGLFDOSHQW\O^LVRPHUV` $  $
&21+&+&+&+&+&+
 $ON\ODPLQRFDUERQ\OUDGLFDOSURS\O^LVRPHUV` $  $
&21+&+&+&+
 $ON\ODPLQRFDUERQ\OUDGLFDOXQVDWXUDWHG $  $
&+12
 $ON\ODPLQRFDUERQ\OUDGLFDOXQVDWXUDWHG $  $
&+12
 R%HQ]RVHPLTXLQRQHUDGLFDO $  
 S%HQ]RVHPLTXLQRQHUDGLFDO $  
 %XWDGLHQHUDGLFDO $  
 %XWDGLHQHPHWK\OUDGLFDO $  
^LVRSUHQHUDGLFDO`
 %XWR[\OUDGLFDO $  
2&+
 WHUW%XWR[\OUDGLFDO $  
 &\DQLGHUDGLFDO $$$  
&1

(Continued )

 

© 2009 by Taylor & Francis Group, LLC

78836_C027.indd 1253 11/24/08 2:38:21 PM

 1254 The Chemical Components of Tobacco and Tobacco Smoke

Table XXVII-1 (continued)

Free Radicals in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke

  5HIHUHQFHV
    7REDFFR
&$61R 1DPHSHU&$&ROOHFWLYH,QGH[ 7REDFFRVPRNH

7REDFFR VXEVWLWXWH
VPRNH

   
 &\DQLGHUDGLFDO^DFU\ORQLWULOHUDGLFDO` $  
&+1
 &\DQLGHUDGLFDO $  
&+1
 (WKR[\OUDGLFDO $  
2&+&+
 )RUP\OUDGLFDO $  
+&22
 +\GURJHQSHUR[LGH   
 +\GURJHQSHUR[\OUDGLFDO $  
22+
 +\GURTXLQRQHVHPLTXLQRQHTXLQRQHIUHH $  
UDGLFDO
 +\GUR[LGHIUHHUDGLFDO D$$$$  
 0HWKR[\UDGLFDO $  
&+2
 0HWK\OUDGLFDO $$$$  
&+
 1LWULWHUDGLFDO $$  
21 2
 1LWURJHQR[LGH ^QLWULFR[LGH` D D D
12  
 
ED
DE





D
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 2[\JHQGLUDGLFDO  D D
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$
 3HQWR[\OUDGLFDO2&&+ $  
 3URSR[\OUDGLFDO2&+ $  
 6XSHUR[LGHDQLRQUDGLFDO $  

 

© 2009 by Taylor & Francis Group, LLC

78836_C027.indd 1254 11/24/08 2:38:22 PM

 Free Radicals 1255

only thirty-five entries, including a general entry labeled
Radicals, free. The vast majority of the entries in the table
are tobacco smoke components, except for NO and oxygen
that are also found in tobacco. Hydrogen peroxide was added
for completeness since it was discussed several times in the
chapter. It is anticipated that with the new analytical methods
recently demonstrated by Bartalis et al. (27A05), Masselot et
al. (27A68), and Rolando et al. (27A99, 27A100) that many
additional free radicals in tobacco smoke will soon be iden-
tified. It should be kept in mind that, in light of the recent
discovery by Bartalis et al. (27A05), some of the previously
identified free radicals in tobacco smoke may be artifacts.

© 2009 by Taylor & Francis Group, LLC

78836_C027.indd 1255 11/24/08 2:38:22 PM

 28 Summary
The following initial comments were presented in greater
detail in the Foreword. Since the mid-1950s, the combined
referenced cataloging of the chemical components of tobacco
and tobacco smoke may have been conducted in-house at var-
ious U.S. and foreign tobacco companies, as well as by vari-
ous governmental agencies, but none has been published since
the 1968 review by R.L. Stedman of the U.S. Department of
Agriculture (3797). Prior to that, there were only a few such
publications, one in 1959 [Johnstone and Plimmer (1971)] and
one in 1963 [Philip Morris, Inc. (2939)]. In subsequent years,
several tobacco and tobacco smoke publications dealt with
specific types of components, for example, the 1977 review
by Schmeltz and Hoffmann on the nitrogen-containing
components in tobacco and tobacco smoke (3491). Several
catalogs of the chemical components of only tobacco smoke
have been published, but the most recent one was that of
Ishiguro and Sugawara (1884) in 1980. Since the 1968 article
by Stedman, the number of identified tobacco and tobacco
smoke components has increased sevenfold to almost 8600.
No other commercial product has been so completely defined.
This catalog is our attempt to categorize with references the
identified and reported components in tobacco and tobacco
smoke as of 2007.
Hundreds of scientific articles (many of them referenced
in this text) have stated that tobacco and tobacco smoke are
complex mixtures. This is an accurate statement. But some
have alluded to or emphasized that they are primarily com-
plex, that is, these mixtures of chemicals are just too multifari-
ous, too difficult to completely understand, or so complicated
and/or convoluted that the normal individual could not pos-
sible comprehend the totality of the concept or composition
of the mixture. This was never the intent of the definition of
a complex mixture, but nevertheless, some have implied that
this multifaceted conglomeration of chemical components
in tobacco and tobacco smoke is too difficult to explain and
understand. The tobacco industry has often stated that tobacco
and tobacco smoke are complex mixtures, without providing
a basis for the statement. This text illustrates the complexity
of tobacco and tobacco smoke. It provides the reader with
an historical perspective on the identification of thousands of
chemical components in tobacco and tobacco smoke, it con-
tains reviews of all known and identified classes of chemical
components in tobacco and tobacco smoke, and it provides
thousands of accessible references on identified chemical
components in tobacco and tobacco smoke. Also provided
in the preceding pages are references and discussions of one
of the major problems with a complex mixture, that is, the
extrapolation of a biological property found in experimental
studies with an individual compound in the mixture to the
property of that component in a mixture which may contain
© 2009 by Taylor & Francis Group, LLC
78836_C028.indd 1257
components that either enhance or offset the experimentally
observed biological property of the component. Even though
tobacco and tobacco smoke are complex mixtures, they are
not incomprehensible.
Tobacco and tobacco smoke are among the most extensively
studied complex mixtures. There are literally millions of pro-
tein fragments being cataloged as part of the tobacco genome
projects. Over 30,000 enzymes are known to participate in
plant growth and regulation. Oxidation, reduction, additions,
hydrogenation, pyrolysis, decarboxylation, and dehydration
are but a few of the many chemical reactions known to be
involved in tobacco pyrolysis and combustion. These reac-
tions are capable of producing hundreds of thousands of
reaction products. The limiting factor in the discovery and
identification of additional chemical components in tobacco
and tobacco smoke was the early analytical technology but
this was changed significantly over the years by the develop-
ment of new and ever-improved analytical technologies.
Since the 1954 listing of fewer than a hundred tobacco
smoke components by Kosak (2170), various investigators
have estimated from gas chromatographic scans that for
each component identified in tobacco smoke there are five
to twenty components present at extremely low per cigarette
yields that have not yet been identified. Thus, as noted by
Wakeham (4103) in 1971 when the identified tobacco smoke
components numbered about 1350:
Gas chromatographic scans indicate there are many more,
probably over ten thousand, possibly even a hundred thou-
sand [tobacco smoke components].
Grob (1422), one of the pioneers of the use of glass capil-
lary gas chromatography in tobacco smoke composition stud-
ies, as well as other tobacco smoke investigators, also noted
that the number of peaks, each of which represented at least
one component, in the chromatographic scans far exceeded
the number of identified components.
If it were not for scientists’ curiosity and the tremendous
advances in analytical chemistry over the last fifty to sixty
years, the need for this up-to-date catalog of compounds in
tobacco and tobacco smoke would not be critical. As analyti-
cal technology advances, surely thousands of new chemical
components in tobacco and tobacco smoke will be added to
the listings found in this text.
In each chapter of this text, one or more tabulations were
made that contained the distribution of the components (by
chemical class) that were identified in tobacco, tobacco smoke,
or in both tobacco and tobacco smoke. Table XXVIII-1 illus-
trates the total distribution of chemical components distrib-
uted between tobacco and tobacco smoke.
1257
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 1258 The Chemical Components of Tobacco and Tobacco Smoke

Table XXVIII-1
Distribution of Chemical Components between Tobacco and Tobacco Smoke
Component Table Totala Smoke Tobacco Smoke and Tobacco
Hydrocarbons
Alkanes Table I.A-10 132 111 96 75
Alkenes and alkynes Table I.B-1 363 347 42 25
Alicyclics Table I.C-1 142 95 61 16
Monocyclic aromatic Table I.D-1 98 89 39 30
Polycyclic aromatic Table I.E-6 586a 575a 86 74
Sub-Totals 1321 1217 324 220
Oxygen-Containing Components b

Alcohols Table II.A-5 1462 531 1152 221

Phytosterols and derivatives Table II.B-2 111 44 102 35
Aldehydes Table III-12 263 143 199 79
Ketones Table III-13 1090 656 647 213
Carboxylic acids Table IV.A-3 745 354 614 223
Amino acids Table IV.B-7 103 30 102 29
Esters Table V-3 1030 617 924 511
Lactones Table VI-2 304 162 201 59
Anhydrides Table VII-1 20 13 13 6
Carbohydrates Table VIII-3 279 35 271 27
Phenols Table IX.A-22 558 444 244 130
Quinones Table IX.B-2 48 33 21 6
Ethers Table X-2 992 506 659 173
Sub-Totals 7005 3568 5149 1712
Nitrogen-Containing Components b

Nitriles Table XI-2 141 131 23 13

Amines Table XII-2 469 259 316 106
Amides Table XIII-1 212 118 127 33
Imides Table XIV-1 79 59 39 19
N-Nitrosamines Table XV-8 67 53 51 37
Nitroalkanes, nitroarenes, and nitrophenols Table XVI-1 73 55 19 1
Sub-Totals 1041 675 575 209
Nitrogen Heterocyclic Components
Monocyclic 4-membered N-containing ring Table XVII.A-1 5 1 5 1
compounds
Monocyclic 5-membered N-containing ring Table XVII.A-3 321 256 117 52
compounds
Compounds with multiple monocyclic Table XVII.A-5 14 1 14 1
5-membered N-containing ring
Monocyclic 6-membered N-containing ring Table XVII.B-1 538 440 221 123
compounds
Compounds with a 6-membered N-containing Table XVII.B-3 95 54 62 21
ring and a second 5-membered N-containing ring
Compounds with two or more 6-membered Table XVII.B-5 76 64 31 19
N-containing rings
Lactams Table XVII.C-1 118 97 35 14
Oxazoles Table XVII.D-1 56 14 44 2
Aza-arenes Table XVII.E-6 294 286 23 15
Aza-arene derivatives c Table XVII.E-8 76 24 55 3
N-Heterocyclic amines Table XVII.F-8 9 9 0 0
Sub-Totals 1602 1246 607 251
Miscellaneous Components
Sulfur-containing Table XVIII.A-1 260 119 178 37
Halogen-containing Table XVIII.B-3 242 169 131 58
Fixed gases Table XIX-5 35 33 22 20
Metal, nonmetals Table XX-5 146 116 142 112
Ions, etc. Table XX-6 125 22 112 9

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 Summary 1259

Table XXVIII-1 (Continued)

Distribution of Chemical Components between Tobacco and Tobacco Smoke
Component Table Total a Smoke Tobacco Smoke and Tobacco

Pesticides Table XXI-3 303 102 299 98

Enzymes Table XXII-2 499 1 499 1
Anticarcinogens Table XXVI-7C 56 55 49 48
Free radicals Table XXVII-1 34 34 2 2
Sub-Totals 1700 651 1434 385
Grand Total 12669 7357 8089 2777

a This number includes the various isomers of alkyl-PAHs reported in which the position of the alkyl group or groups has not been precisely defined.
b Polyfunctional O-containing compounds are counted in each functional group, e.g., propanoic acid, 2-hydroxy- {lactic acid} appears in the alcohol
catalog and the acid catalog; benzoic acid, 4-hydroxy-3-methoxy- {vanillic acid} appears in the acid catalog, the phenol catalog, and the ether
catalog.
c The number of aza-arene derivatives does not include the nine N-heterocyclic amines.

There are twenty-seven chapters in the book (excluding
this Summary). Table XXVIII-1 contains summary data
on the distribution of chemicals discussed in all but three
chapters (Chapter 23, on “Hoffmann Analytes,” Chapter
24, on Tobacco and/or Tobacco Smoke Components Used
as Tobacco Ingredients, and Chapter 25, on Pyrolysis).
The tobacco and tobacco smoke components discussed in
Chapters 23, 24, and 25 are all previously covered in the
remaining chapters of the book. Table XXVIII-1 is divided
into five sections: Hydrocarbons (Tables in Chapter 1),
Oxygen-containing components (Tables in Chapters 2 to 10),
Nitrogen-containing components (Tables in Chapters 11 to 16),
Nitrogen Heterocyclic components (Tables in Chapter 17),
and Miscellaneous components (Tables in Chapters 18, 19 to
22, 26, and 27). Below each section in Table XXVIII-1 is a
subtotal of the total of identified chemical components found
in tobacco, tobacco smoke, or both tobacco and tobacco
smoke.
As previously mentioned throughout the text, a great
number of the individual identified components found in
tobacco and/or tobacco smoke are multifunctional. Many
contain two or more functionalities and for that reason they
are located in multiple chapters. The Alphabetical Index to
Components Identified in Tobacco, Tobacco Smoke, and
Tobacco Substitute Smoke that follows the Reference sec-
tion contains 8590 components. The Index contains 8398
individually identified components and several isomers.
Each component is tabulated to indicate its identification in
smoke, tobacco, or both. The total number of isomers noted
in the Index is 292, but 100 of them are accounted for in
the 8398 listed components. Thus, the number of identified
or partially identified components in tobacco and tobacco
smoke listed in the Index totals 8590 (8398 + 292 - 100).
The total number of chemical components listed in Table
XXVIII-1 is 12669. There are 8089 found in tobacco, 7357
found in tobacco smoke, and 2777 found in both tobacco and
smoke. The difference between 12669 and 8590 indicates
that indeed many of the chemical components of tobacco
and smoke are multifunctional and as such are listed in sev-
eral chapters. The oxygen-containing components (Tables
in Chapters 2 to 10) account for the largest number of com-
pounds found in tobacco and tobacco smoke, that is, 7005.
These components are distributed: 5149 in tobacco and
3568 in tobacco smoke, with 1712 found in both tobacco
and tobacco smoke. The compounds in Chapters 18 to 22,
26, and 27, listed under miscellaneous components, number
1700. There are 1434 components identified in tobacco, 651
components identified in tobacco smoke, and 385 found in
both tobacco and tobacco smoke. The nitrogen heterocyclic
components (Tables in Chapter 17) represent the next larg-
est class of compounds, with 1602 components identified
in tobacco and tobacco smoke. In this section there are 607
components identified in tobacco, 1246 components identi-
fied in tobacco smoke, and 251 found in both tobacco and
tobacco smoke. The hydrocarbons (Tables in Chapter 1)
represent the next class of compounds identified in tobacco
and tobacco smoke. This section of Table XXVIII-1 con-
tains 1321 compounds. There are 324 hydrocarbons iden-
tified in tobacco, 1217 hydrocarbons identified in tobacco
smoke, and 220 found in both tobacco and tobacco smoke.
The nitrogen-containing components (Tables in Chapters
11 to 16) are the smallest and last group of compounds iden-
tified in tobacco and tobacco smoke. This group of com-
pounds numbers 1041. There are 575 nitrogen-containing

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 1260 The Chemical Components of Tobacco and Tobacco Smoke
components identified in tobacco, 675 identified in tobacco
smoke, and 209 found in both tobacco and tobacco smoke.
In closing, the authors hope that this text will serve a useful
purpose. The content of the book represents over fifty years
of effort by the researchers attempting to build a framework
about our understanding of the complex mixtures of tobacco
and tobacco smoke. Much progress has been made during
the last fifty years in terms of understanding of tobacco and
tobacco smoke. During that time, the number of identified
components in tobacco and tobacco smoke has increased
nearly sevenfold. This progress has been due, in large part,
to the great strides that have been made in analytical technol-
ogy, but more than that, these scientists have shown great
© 2009 by Taylor & Francis Group, LLC
78836_C028.indd 1260
perseverance in the face of uncertainty and controversy sur-
rounding the roles of tobacco and tobacco smoke and health.
Great works are performed, not by strength, but by persever-
ance. (Samuel Johnson, ca. 1740)
We hope that present and future scientists will persevere
and use the information contained herein to answer new
questions by looking back to history.
If you want to understand today, you have to search yester-
day. (Pearl Buck, 1892–1973)
11/24/08 1:40:12 PM
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Weigert, F. and J.C. Mottram: Intermediate stages in
the metabolic conversion of benzopyrene to 8-hydroxy-
benzopyrene in mice; Biochem. J. 37 (1943) 497–501;
The biochemistry of benzopyrene. I. A survey, and new
methods of analysis; Cancer Res. 6 (1946) 97–108;
The biochemistry of benzopyrene. II. The course of its
metabolism and the chemical nature of the metabolites;
Cancer Res. 6 (1946) 109–120.
423b. Bradford, J.A., W.R. Harlan, and H.R. Hanmer: Nature
of cigaret smoke: Technic of experimental smoking; Ind.
Eng. Chem. 28 (1936) 836–839.
424. Bradford, J.A., E.S. Harlow, W.R. Harlan, and H.R.
Hanmer: Nature of cigaret smoke: Volatile bases and
acids; Ind. Eng. Chem. 29 (1937) 45–50.
424a. Brandle, J.D. and D. Bai: Biotechnology: Uses and
applications in tobacco improvement; Chapter 3 in:
Tobacco: Production, chemistry and technology, edited
by D.L. Davis and M.T. Nielsen, Blackwell Science,
Oxford, UK (1999) 49–65.
425. Brandt, W.: Tabak und Tabakrauch. Teil. I [Tobacco and
tobacco smoke. Part I]; Chem. Zeit. 62 (1938) 841–843.
426. Brandt, W.: Tabak und Tabakrauch. Teil. II [Tobacco
and tobacco smoke. Part II]; Chem. Zeit. 62 (1938)
851–852.
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427. Braun, K.: Zur Gehaltsbestimmung von Nikotin im Tabak
und im Tabakrauch [Determination of nicotine content
in tobacco and in tobacco smoke]; Chem. Ztg. 55 (1930)
354–355.
428. Braun, K.: Erfahrung bei der Nikotinbestimmung im
Tabak und im Tabakrauch [Knowledge of the estima-
tion of nicotine in tobacco and tobacco smoke]; Pharm.
Zentralhalle 71 (1930) 209–213.
429. VOID.
429a. Bregeon, B., M. Coupe, and B. Gonny; HCN and tobacco
precursors; 60th Tobacco Science Research Conference,
Program Booklet and Abstracts, Vol. 60, Paper No. 35, 2006,
p. 37.
429b. BRENDA: The comprehensive enzyme informa-
tion system; see www.genome.jp/dbget-bin/show_
pathway?map00500+2.4.1.35; see also Kanehisa, M.
and S. Goto: KEGG: Kyoto Encyclopedia of Genes
and Genomes (KEGG); Nucleic Acids Res. 28 (2000)
27–30; Enzymes, glycolysis, arginine and proline
metabolism, fructose and mannose metabolism, path-
ways of Nicotiana); also Lyon, G.D.: Host pathogen
interactions and crop protection: Metabolic pathways
of the diseased potato; see www.scri.sari.ac.uk/publica-
tions/annualreports/98Indiv/21Metabo.pdf.
429c. BRENDA: The comprehensive enzyme information
system, Entry of hydroxymethylglutaryl-CoA reductase
(NADPH) (EC-Number 1.1.1.34), Nicotiana, KEGG
Link 00100 Steroid Biosynthesis, see: www.genome.jp/
dbget-bin/show_pathway?map00100+1.1.1.34
429d. BRENDA: The Comprehensive Enzyme Information
System Entry of histidinol-phosphate transaminase (EC-
Number 2.6.1.9), Histidine metabolism pathway: http://www.
genome.jp/dbget-bin/show_pathway?map00340+2.6.1.9.
429e. Brice, B.A.: Ultraviolet absorption spectra of nicotine,
nornicotine, and some of their derivatives; 2nd Tobacco
Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 2, Paper No. 4, 1948.
430. Briggs, C.D. and S.J.A. Hawthorne: Determination of
polycyclic aromatic hydrocarbons in tobacco smoke
condensate; Proc. Anal. Div., Chem. Soc. 15 (1978)
181–184.
431. Bright, M.N., T.M. Larson, and C.I. Lewis: Analytical
method for determination of pyrazine and alkylpyrazines
in shredded tobacco; 29th Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 29,
Paper No. 27, 1975, p. 22.
432. British Empire Cancer Campaign: Aromatic polycyclic
hydrocarbons in cigarette smoke; Brit. Emp. Cancer
Camp., Ann. Rpt. 35 (1958) 303–305.
433. Britt, P.F., A.C. Buchanan iii, and C.V. Owens Jr:
Formation of polycyclic aromatic hydrocarbons from
the gas-phase pyrolysis of terpenes and steryl esters at
short residence times; 55th Tobacco Science Research
Conference, Program Booklet and Abstracts, Vol. 55,
Paper No. 20, 2001, p. 32.
434. Britt, P.F., A.C. Buchanan iii, and C.V. Owens Jr:
Formation of nitrogen containing polycyclic aromatic
hydrocarbons (aza-arenes) from the pyrolysis of Amadori
compounds; 55th Tobacco Science Research Conference,
Program Booklet and Abstracts, Vol. 55, Paper No. 46,
2001, p. 48.
435. Britt, P.F., A.C. Buchanan iii, C.V. Owens Jr, and T. Skeen:
Formation of polycyclic aromatic hydrocarbons from the
gas phase pyrolysis of sterols: The role of residence time;
11/24/08 2:39:30 PM
 1278
54th Tobacco Science Research Conference, Program
Booklet and Abstracts, Vol. 54, Paper No. 29, 2000, p. 35.
436. Brosch, A.: Theoretische und experimentelle
Untersuchungen zur Pathogenesis und Histogenesis der
malignen Geschwülste [Theoretical and experimental
investigation of the pathogenesis and histogenesis of
malignant tumors]; Virchows Arch. Pathol. Anat. Physiol.
162 (1900) 32–84.
437. Brown, B.G., J.T. Avalos, C.K. Lee, and D.J Doolittle:
The effect of tobacco smoke, nicotine, and cotinine on
the mutagenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-
1-butanol (NNAL); 55th Tobacco Science Research
Conference, Program Booklet and Abstracts, Vol. 55,
Paper No. 10, 2001, p. 26.
437a. Brown, E.G. and F.M. Diffin: Biosynthesis and metabo-
lism of pyrazole by Cucumis sativus: Enzymatic cycl-
ization and dehydrogenation of 1,3-diaminopropane;
Phytochemistry 29 (1990) 469–478.
438. Brown, E.V.: Analysis of basic constituents of tobacco
smoke; Proc. University of Kentucky Tobacco Hlth.
Workshop 1 (1969) 79.
439. Brown, E.V.: The question of nitrosamines in cigarette
smoke tar; Proc. University of Kentucky Tobacco Hlth.
Workshop 1 (1969) 80.
440. Brown, E.V. and I. Ahmad: Investigations of the isolation
and identification of the higher boiling heterocyclic nitro-
gen compounds in cigarette smoke; Proc. University of
Kentucky Tobacco Hlth. Workshop 2 (1970) 124.
441. Brown, E.V. and I. Ahmad: Alkaloids of ciga-
rette smoke condensate; Phytochemistry 11 (1972)
3485–3490.
442. Brown, E.V., I. Ahmad, and A.J. Poole: Investigations of the
identification and quantitative estimation of N-heterocyclic
hydrocarbons in tobacco smoke; Proc. University of
Kentucky Tobacco Hlth. Workshop 2 (1970) 124.
443. Brown, E.V. and K.W. Yang: Investigations on detection,
identification and quantitative determination of nitro-
samines in cigarette smoke; Proc. University of Kentucky
Tobacco Hlth. Workshop 2 (1970) 124.
444. Brown, J.R. and A.A. Jarvis: The strontium-90 content
of Canadian tobacco samples; Med. Serv. J. Canada 20
(1965) 613–615.
445. Browne, C.L., C.H. Keith, and R.E. Allen: The effect of fil-
ter ventilation on the yield and composition of mainstream
and sidestream smoke; 32nd Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 32, Paper
No. 16, 1978, p. 8; CORESTA 1978 Symp., Sofia, Bulgaria,
CORESTA Inf. Bull., Spec. Edition 1978: Paper ST-01,
124; Beitr. Tabakforsch. Int. 10 (1980) 81–90.
446. Browne, C.L. and S.M. Serad: The effect of the level of
clove addition on the composition of smoke from kretek
cigarettes; 9th Internat. Tob. Sci. Cong., Guangzhou,
China, 1988, CORESTA Inf. Bull., Spec. Edition 1988:
Paper ST-3, 79.
447. Browner, R.F., G.K.E. Copeland, P.B. Stockwell, and I.
Bergman: Determination of carbon monoxide in ciga-
rette smoke using an electro-chemical transducer; Beitr.
Tabakforsch. Int. 9 (1977) 38–44.
448. Browning, H.L. Jr and H.W. Patton: Determination of
the stable free radicals in tobacco smoke condensate by
electron magnetic resonance; 20th Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 20, Paper No. 24, 1966, p. 31; Manuscript
(1967).
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449. Brozinski, M., U. Dölberg, and G. Lipp: Untersuchungen
über die Verteimung des Menthols auf Tabak, Filter und
Rauch von Mentholcigaretten [The determination of men-
thol in tobacco, in filters, and in the smoke of mentholated
cigarettes]; Beitr. Tabakforsch. 6 (1972) 124–130.
450. Brückner, H.: Die Biochemie des Tabaks [The biochem-
istry of tobaccos]; Paul Parey Publisher, Berlin (1936) pp.
235–236, 444.
451. Brückner, H.: Die Biochemie des Tabaks [The biochemis-
try of tobaccos]; Paul Parey, Berlin (1936).
452. Brugidou, C., I. Marty, Y. Chartier, and Y. Meyer: The
Nicotiana tabacum genome encodes two cytoplasmic
thioredoxin genes which are differently expressed;
Molecular Gen. Genetics 238 (1993) 285–293.
453. Brümmer, U., C. Paulsen, G. Spremberg, F. Seehofer, V.
Heemann, and V. Sinnwell: New cembranoids from bur-
ley tobacco; Z. Naturforsch. 36c (1981) 1077–1080.
454. Brunnemann, K.D.: Routine HPLC method for assessing
sorbate in reconstituted tobacco; 33rd Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 33, Paper No. 61, 1979, p. 33.
455. Brunnemann, K.D.: Volatile N-nitrosamines in side-
stream smoke and indoor air; in: Environmental carcino-
gens: Methods of analysis and exposure measurement.
Vol. 9: Passive smoking, edited by I.K. O’Neill, K.D.
Brunnemann, B. Dodet, and D. Hoffmann, IARC, Lyon,
France, IARC Sci. Publ. No. 81 (1988) 221–230.
456. Brunnemann, K.D. and J.D. Adams: Nicotine and
minor alkaloids in sidestream smoke and indoor air; in:
Environmental carcinogens: Methods of analysis and
exposure measurement. Vol. 9: Passive smoking, edited
by I.K. O’Neill, K.D. Brunnemann, B. Dodet, and D.
Hoffmann, IARC, Lyon, France, IARC Sci. Publ. No. 81
(1988) 239–246.
457. Brunnemann, K.D., J.D. Adams, D.P.S. Ho, and D.
Hoffmann: The influence of tobacco smoke on indoor
atmospheres. II. Volatile and tobacco-specific nitro-
samines in mainstream and sidestream smoke and their
contribution to indoor pollution; Proc. 4th Joint Conf. on
Sensing of Environmental Pollutants, New Orleans, LA,
Am. Chem. Soc. (1977) 876–880.
458. Brunnemann, K.D., J.D. Adams, and D. Hoffmann:
Nonvolatile N-nitrosamines: Analysis in tobacco and
tobacco smoke by HPLC-TEA; 31st Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 31, Paper No. 52, 1977, p. 27.
459. Brunnemann, K.D., J.E. Cox, and D. Hoffmann: Methods
of analysis for tobacco-specific N-nitrosamines in indoor
air; 45th Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 45, Paper No. 50,
1991, p. 40.
460. Brunnemann, K.D., J.E. Cox, and D. Hoffmann: [Chemical
studies on tobacco smoke. XCVII.] Analysis of tobacco-
specific N-nitrosamines in indoor air; Carcinogenesis 13
(1992) 2415–2418.
461. Brunnemann, K.D., J.E. Cox, and D. Hoffmann:
Determination of cadmium in cigarette smoke and its
possible role as a biomarker; 47th Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 47, Paper No. 20, 1993, p. 30 .
462. Brunnemann, K.D., J.E. Cox, R. Kagan, and D. Hoffmann:
Analysis of selected environmental tobacco smoke com-
ponents in indoor air by thermal desorption-GC-MS;
CORESTA 1990 Symp., Halithea, Greece, CORESTA Inf.
11/24/08 2:39:30 PM
 Bibliography
Bull., Spec. Edition, 1990: Paper S10, 216; Application
of thermal desorption for the analysis of environmental
tobacco smoke (ETS); 44th Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 44,
Paper No. 27, 1990, p. 24.
463. Brunnemann, K.D., J.E. Cox, Y. Liu, and D. Hoffmann:
Analysis of volatile and tobacco-specific N-nitrosamines
in tobacco smoke by conventional method and by super-
critical fluid extraction; 46th Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 46,
Paper No. 22, 1992, pp. 33–34.
464. Brunnemann, K.D., M.V. Djordjevic, R. Feng, and D.
Hoffmann: Analysis and pyrolysis of some N-nitrosamino
acids in tobacco and tobacco smoke; in: Relevance to
human cancer of N-nitroso compounds, tobacco and myc-
otoxins, edited by I.K. O’Neill, J. Chen, and H. Bartsch,
IARC, Lyon, France, IARC Sci. Publ. No. 105 (1991)
477–481.
465. Brunnemann, K.D. and H. Enzmann: Application of the in
ovo bioassay to tobacco research; 53rd Tobacco Science
Research Conference, Program Booklet and Abstracts,
Vol. 53, Paper No. 26, 1999, pp. 33–34.
466. Brunnemann, K.D., R. Feng, and D. Hoffmann: Pyrolysis
studies of selected nitrosamino acids in cigarettes; 43rd
Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 43, Paper No. 44, 1989,
p. 36.
467. Brunnemann, K.D., W. Fink, and F. Moser: Analysis of
volatile N-nitrosamines in mainstream and sidestream
smoke by GLC-TEA; in: Risk assessment of N-nitroso
compounds for human health, Symp. Proc., German
Cancer Res. Center, Heidelberg (1979); Oncology 37
(1980) 217–222.
468. Brunnemann, K.D., L. Genoble, and D. Hoffmann:
N-Nitrosamines in chewing tobacco: An international
comparison; J. Agr. Food Chem. 33 (1985) 1178–1181.
469. Brunnemann, K.D., L. Genoble, and D. Hoffmann:
Identification and analysis of a new tobacco-specific nit-
rosamine 4-methylnitrosamino-4-(3-pyridyl)-1-butanol;
Carcinogenesis 8 (1987) 465–469.
469a. Brunnemann, K.D., N.J. Haley, J.D. Adams, D.W.
Sepkovic, and D. Hoffmann: Model studies on the uptake
of nicotine after exposure to environmental tobacco smoke
(ETS); 41st Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 41, Paper No. 31,
1987, p. 28.
470. Brunnemann K.D., S.S. Hecht, and D. Hoffmann:
Analysis of N-nitrosamines in tobacco and tobacco smoke
with the aid of the thermal energy analyzer; 30th Tobacco
Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 30, Paper No. 38, 1976, p. 28.
471. Brunnemann K.D., S.S. Hecht, and D. Hoffmann:
N-Nitrosamines: Environmental occurrence, in vivo for-
mation, and metabolism; 184th Natl. Mtg., Am. Chem.
Soc., Paper No. 34 (1982); J. Toxicol. Clin. Toxicol. 19
(1982) 661–668.
472. Brunnemann K.D. and D. Hoffmann: Gas chromato-
graphic determination of ammonia in cigarette and cigar
smoke; 28th Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 28, Paper No. 53,
1974, p. 34.
473. Brunnemann, K.D. and D. Hoffmann: On the pH of
tobacco smoke; 26th Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 26,
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Paper No. 11, 1972, pp. 16–17; The pH of tobacco smoke;
Food Cosmet. Toxicol. 12 (1974) 115–124.
474. Brunnemann K.D. and D. Hoffmann: Chemical studies
on tobacco smoke. XXIV. A quantitative method for car-
bon monoxide and carbon dioxide in cigarette and cigar
smoke; J. Chromat. Sci. 12 (1974) 70–75.
475. Brunnemann K.D. and D. Hoffmann: Chemical studies
on tobacco smoke. XXXIV. Gas chromatographic deter-
mination of ammonia in cigarette and cigar smoke; J.
Chromat. Sci. 13 (1975) 159–163.
476. Brunnemann K.D. and D. Hoffmann: Analysis of poly-
nuclear aromatic hydrocarbons in the respiratory environ-
ment; Carc. Comp. Serv. 1 (1976) 283–297.
477. Brunnemann K.D. and D. Hoffmann: Chemical studies
on tobacco smoke. LIX. Analysis of volatile nitrosamines
in tobacco smoke and polluted indoor environments; in:
Environmental aspects of N-nitroso compounds, edited by
E.A. Walker, M. Castegnaro, L. Griciute, and R.E. Lyle,
IARC, Lyon, France, IARC Sci. Publ. No. 19 (1978)
343–356.
478. Brunnemann K.D. and D. Hoffmann: Concurrent gas
chromatographic determination of volatile, nonvola-
tile, and tobacco-specific N-nitrosamines; 35th Tobacco
Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 35, Paper No. 33, 1981, p. 17.
479. Brunnemann K.D. and D. Hoffmann: Assessment of
the carcinogenic N-nitrosodiethanolamine in tobacco
products and tobacco smoke; Carcinogenesis 2 (1981)
1123–1127.
480. Brunnemann K.D. and D. Hoffmann: [Chemical studies
on tobacco smoke, LXXIV.] Pyrolytic origins of major
gas phase constituents of cigarette smoke; Recent Adv.
Tob. Sci. 8 (1982) 103–140.
481. Brunnemann K.D. and D. Hoffmann:
N-Nitrosodiethanolamine in tobacco and mainstream
and sidestream smoke; in: Environmental carcinogens.
Selected methods of analysis. Vol. 6. N-Nitroso com-
pounds, edited by H. Egan, R. Preussmann, G. Eisenbrand,
T. Spiegelhalder, I.K. O’Neill, and H. Bartsch, IARC,
Lyon, France, IARC Sci. Publ. No. 45 (1983) 85–92.
482. Brunnemann K.D. and D. Hoffmann: GC-TEA of
N-nitrosodiethanolamine (NDELA) from tobacco prod-
ucts; in: Environmental carcinogens. Selected methods
of analysis. Vol. 6. N-Nitroso compounds, edited by H.
Egan, R. Preussmann, G. Eisenbrand, T. Spiegelhalder,
I.K. O’Neill, and H. Bartsch, IARC, Lyon, France, IARC
Sci. Publ. No. 45 (1983) 399–402.
483. Brunnemann K.D. and D. Hoffmann: Analytical stud-
ies on tobacco-specific N-nitrosamines in tobacco and
tobacco smoke; J. Cancer Res. Clin. Oncol. 116 (Suppl.
Pt. 2) (1990) 1087.
484. Brunnemann K.D. and D. Hoffmann: [Chemical studies
on tobacco smoke. XCIII.] Analytical studies on tobacco-
specific N-nitrosamines in tobacco and tobacco smoke;
Crit. Rev. Toxicol. 21 (1991) 235–240.
485. Brunnemann K.D. and D. Hoffmann: [Chemical stud-
ies on tobacco smoke. XC.] Decreased concentrations
of N-nitrosodiethanolamine and N-nitrosomorpholine
in commercial tobacco products; J. Agr. Food Chem. 39
(1991) 207–208.
486. Brunnemann K.D. and D. Hoffmann: [Chemical stud-
ies on tobacco smoke. XCVII.] Analytical studies on
N-nitrosamines in tobacco and tobacco smoke; Recent
Adv. Tob. Sci. 17 (1991) 71–112.
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487. Brunnemann K.D. and D. Hoffmann: Analysis of
tobacco-specific N-nitrosamines in tobacco and tobacco
smoke; 204th Natl. Mtg., Am. Chem. Soc., Washington,
DC: Paper No. 161 (1992).
488. Brunnemann, K.D., D. Hoffmann, C.G. Gairola, and B.C.
Lee: Analysis of selected mainstream smoke compo-
nents of low ignition propensity cigarettes; 48th Tobacco
Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 48, Paper No. 54, 1994, p. 58.
489. Brunnemann, K.D., D. Hoffmann, C.G. Gairola, and B.C.
Lee: Low ignition propensity cigarettes: Smoke analysis
for carcinogens and testing for mutagenic activity of the
smoke particulate matter; Food Chem. Toxicol. 10 (1994)
917–922.
490. Brunnemann, K.D., D. Hoffmann, and T.C. Tso: The
fate of diethanolamine in tobacco and cigarette smoke;
34th Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 34, Paper No. 51, 1980, p. 26.
491. Brunnemann, K.D., D. Hoffmann, and E.L. Wynder:
Studies on the inhalability of cigarette and cigar smoke;
27th Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 27, Paper No. 27, 1973, p.
21.
492. Brunnemann, K.D., D. Hoffmann, E.L. Wynder, and G.B.
Gori: Determination of tar, nicotine, and carbon monoxide
in cigarette smoke. A comparison of international smok-
ing conditions; in: Modifying the risk for the smoker.
Proc. 3rd World Conf. on Smoking and Health, edited by
E.L. Wynder, D. Hoffmann, and G.B. Gori, 1975, DHEW
Publ. No. (NIH) 76–1221 (1976) 441–449.
493. Brunnemann, K.D., M.R. Kagan, J.E. Cox, and D.
Hoffmann: Determination of benzene, toluene, and 1,3-
butadiene in cigarette smoke by GC-MSD; Exp. Pathol.
37 (1989) 108–113.
494. Brunnemann, K.D., M.R. Kagan, J.E. Cox, and D.
Hoffmann: Analysis of 1,3-butadiene and other selected
gas-phase components in cigarette mainstream and side-
stream smoke by gas chromatography-mass selective
detection; Carcinogenesis 11 (1990) 1863–1868.
495 Brunnemann, K.D., M.R. Kagan, and D. Hoffmann:
Analysis of selected gas phase components by GC-MSD;
42nd Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 42, Paper No. 18. 1988, p.
25.
496. Brunnemann, K.D., H.-C. Lee, and D. Hoffmann: A
study of the precursors and on the quantitative analysis
of catechols in cigarette smoke; 29th Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 29, Paper No. 46, 1975, p. 31.
497. Brunnemann, K.D., H.C. Lee, and D. Hoffmann:
Chemical studies on tobacco smoke. XLVII. On the quan-
titative analysis of catechols and their reduction; Anal.
Lett. 9 (1976) 939–955.
498. Brunnemann, K.D., S.J. Lee, S. Adams, and D.
Hoffmann: Occurrence of N-nitrosamines in chewing
tobacco: A closer look; 38th Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 38,
Paper No. 26, 1984, p. 14.
499. Brunnemann, K.D., J. Masaryk, and D. Hoffmann: The
role of tobacco stems on the formation of N-nitrosamines
in tobacco and cigarette mainstream and sidestream
smoke; 37th Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 37, Paper No. 6,
1983, p. 4; Role of tobacco stems on the formation of
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N-nitrosamines in tobacco and cigarette mainstream
and sidestream smoke: J. Agr. Food Chem. 31 (1983)
1221–1224.
500. Brunnemann, K.D., R. Onrust, and D. Hoffmann:
Determination of volatile carbonyl compounds in tobacco
headspace and tobacco smoke; 40th Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 40, Paper No. 47, 1986, p. 25.
501. Brunnemann, K.D., B. Prokopczyk, M.V. Djordjevic,
J.E. Cox, and D. Hoffmann: The use of supercriti-
cal fluid extraction for the analysis of tobacco-specific
N-nitrosamines in tobacco and in tobacco smoke;
CORESTA 1992 Symp., Jerez de la Frontera, Spain,
CORESTA Inf. Bull., 1992 Spec. Edition: Paper ST10,
84.
502. Brunnemann, K.D., B. Prokopczyk, M.V. Djordjevic,
and D. Hoffmann: Formation and analysis of tobacco-
specific N-nitrosamines; Crit. Rev. Toxicol. 26 (1996)
121–137.
503. Brunnemann, K.D., B. Prokopczyk, D. Hoffmann, J.H.
Nair, H. Ohshima, and J. Bartsch: Laboratory studies on
oral cancer and smokeless tobacco; Banbury Report No.
23, Cold Spring Harbor Laboratory, Cold Spring Harbor,
NY (1986) 197–213.
504. Brunnemann, K.D., J. Qi, L.P. Bush, and D. Hoffmann:
Alkaloid profile in oral moist snuff tobacco; 55th Tobacco
Science Research Conference, Program Booklet and
Abstracts, Vol. 55, Paper No. 41, 2001, p. 44.
505. Brunnemann, K.D., J. Qi, G.N. Connolly, and D.
Hoffmann: Effects of storage on the levels of tobacco-
specific nitrosamines in oral moist snuff tobacco; 55th
Tobacco Science Research Conference, Program Booklet
and Abstracts, Vol. 55, Paper No. 40, 2001, pp. 43–44.
506. Brunnemann, K.D., J. Qi, and D. Hoffmann: Analytical
comparisons of two types of oral snuff; 54th Tobacco
Science Research Conference, Program Booklet and
Abstracts, Vol. 54, Paper No. 40, 2000, pp. 41–42.
507. Brunnemann, K.D., J. Qi, D. Hoffmann, and G.N.
Connolly: Levels of TSNA in oral moist snuff in the
past 30 years and today; 58th Tobacco Science Research
Conference, Program Booklet and Abstracts, Vol. 58,
Paper No. 38, 2004, pp. 43–44.
507a. Brunnemann, K.D., A. Rivenson, J.D. Adams, S.S. Hecht,
and D. Hoffmann: A study of snuff carcinogenesis; IARC
Sci. Publ. 84 (1987) 457–459.
508. Brunnemann, K.D., A. Rivenson, A. Czech, E.J. LaVoie,
and D. Hoffmann: Isolation, identification, and bioassay
of the tobacco-specific N-nitrosamine 4-methylnitrosami-
no-4-(3-pyridyl)-1-butanol; Proc. Am. Assoc. Cancer
Res. 29 (1988) 84.
509. Brunnemann, K.D., J.C. Scott, N.J. Haley, and D.
Hoffmann: Endogenous formation of N-nitrosoproline
upon cigarette smoke inhalation; in: N-Nitroso com-
pounds: Occurrence, biological effects and relationship to
human cancer, edited by I.K. O’Neill, R.C. von Borstel,
C.T. Miller, J. Long, and H. Bartsch, IARC, Lyon, France,
IARC Sci. Publ. No. 57 (1984) 819–828.
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542. Burton, H.R. and L.P. Bush: Accumulation of tobacco-
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544. Burton, H.R. and G.H. Childs Jr: Influence of atmosphere
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545. Burton, H.R. and G.H. Childs Jr: The thermal decom-
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548. Burton, H.R., N.K. Dye, and L.P. Bush: Distribution of
nitrogen constituents within air-cured tobacco leaf; 45th
Tobacco Chemists’ Research Conference, Program Booklet
and Abstracts, Vol. 45, Paper No. 13, 1991, p. 19.
549. Burton, H.R., N.K. Dye, and L.P. Bush: Distribution of
tobacco constituents in tobacco leaf tissue. 1. Tobacco-
specific nitrosamines, nitrate, nitrite, and alkaloids; J. Agr.
Food Chem. 40 (1992) 1050–1055.
550. Burton, H.R., N.K. Dye, and L. Walton: Differences in
composition of air-cured burley tobacco using modified
field curing structures. 1. Changes in nitrogenous con-
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551. Burton, H.R. and M.J. Kasperbauer: Changes in chemi-
cal composition of tobacco lamina during senescence
and curing. 1. Plastid pigments; J. Agr. Food Chem. 33
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552. Burton, H.R., E. Leggett, and R.E. Phillips: Factors influ-
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553. Burton, H.R. and X. Wei: Distribution of tobacco constit-
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Program Booklet and Abstracts, Vol. 48, Paper No. 31,
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554. Burton, H.R., X. Wei, and W.S. Caldwell: Identification
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555. Burton, H.R. and H.E. Wright Jr: Burley tobacco: The
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567. Byrd, G.D., K.W. Fowler, R.D. Hicks, M.E. Lovette, and
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600. Carmella, S.G., S.S. Hecht, D. Hoffmann, and T.C.
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Tobacco Chemists’ Research Conference, Program
© 2009 by Taylor & Francis Group, LLC
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The Chemical Components of Tobacco and Tobacco Smoke
Booklet and Abstracts, Vol. 23, Paper No. 23, 1969, p.
14.
606a. Carpenter, R.D.: Benzo[a]pyrene content of cigarette
smoke – Comparison of PM Commander, Marlboro, and
Winston; Memorandum to A. Bavley, May 30, 1964, see
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606b. Carpenter. R.D., R.W. Jenkins Jr, R.H. Newman, and
T.S. Osdene: Cigarette smoke formation studies. I.
distribution and mainstream products from added 14C-
dotriacontane-16,17; February 1972, Philip Morris doc-
ument, Bates Numbers HK0703073 /3089, see http://
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pdf&ref=results.
607. Carpenter, R.D., W.J. Martin, and R.B. Seligman:
Quantitative determination of glycerine in cigarette
smoke; 12th Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 12, Paper No. 17,
1958, p. 7.
608. Carpenter, R.D. and R.B. Seligman: The determination
of acids and bases in cigarette smoke. III. The determi-
nation of total bases; 9th Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 9, Paper
No. 3, 1955, p. 2.
609. Carpenter, R.D. and B.R. Warner: The determination of
acids and bases in cigarette smoke. II. The determina-
tion of strong acids; 9th Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 9, Paper
No. 2, 1955, p. 2.
610. Carroll, M.F.: Ketene may be present in tobacco smoke
and be at least one of the causative agents of the observed
bronchial symptoms of smokers, and possibly also of lung
cancer; Biochem. J. 92 (1964) Back Cover.
611. Carruthers W.: Chemical investigations of cigarette
smoke; Med. Res. Council, Ann. Rpt., April 1965-March
1966: 172.
612. Carruthers, W. and R.A.W. Johnstone: Phytosterols
in cigarette smoke; Chem. and Ind. (London) (1958)
1663–1664.
613. Carruthers, W. and R.A.W. Johnstone: Composition of
a paraffin wax fraction from tobacco leaf and tobacco
smoke; Nature 184 (1959) 1131–1132.
614. Carruthers, W. and R.A.W. Johnstone: Alcohols of
tobacco: Solanesol and n-docosanol; Chem. and Ind.
(London) (1960) 867–868.
615. Carruthers, W. and R.A.W. Johnstone: Some pheno-
lic constituents of cigarette smoke; Nature 185 (1960)
762–763.
616. Carruthers, W., R.A.W. Johnstone, and J.R. Plimmer:
Gas liquid partition chromatography of mixtures of aryl
methyl ethers; Chem. and Ind. (London) (1958) 331.
617. Carruthers, W., R.A.W. Johnstone, and J.R. Plimmer: Low
boiling components of cigarette smoke; 15th Tobacco
Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 15, Paper No. 12, 1961, p. 6.
618. Cartwright, W., A. Cornell, and V.S. Olender:
Development of methodology for the determination of
bromide residues in tobacco and tobacco smoke. Factors
affecting the residue levels resulting from methyl bro-
mide fumigation; 35th Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 35,
Paper No. 40, 1981, p. 21.
619. Carugno, N.: Determination of paraffin waxes of tobacco
and tobacco smoke by gas-liquid chromatography; in:
Symposium: Analysis of carcinogenic air pollutants,
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edited by E. Sawicki and K. Cassel, Natl. Cancer Inst.
Monograph 9 (1962) 171–181.
620. Carugno, N. and G. Giovannozzi-Sermanni: Analytical
investigations on tobacco by means of vapour phase chro-
matography. 1. Some components of the gas phase of
cigarette smoke; Il Tabacco 62 (1958) 255–264.
621. Carugno, N. and G. Giovannozzi-Sermanni: Recherches
analytiques sur le tabac par chromatographie en phase
gazeuse. Note I. Quelques substances gazeuses qui com-
posent la fumée des cigarettes [Analytical research on
tobacco by gas chromatography. Note I. Several gaseous
compounds in tobacco smoke]; Proc. 2nd Internat. Tob.
Sci. Cong., Brussels, Belgium (1959) 501–506.
622. Carugno, N., M. Neri, and G. Lionetti: Quantitative
determination of free and protein-bound amino acids of
tobacco; Beitr. Tabakforsch. 7 (1974) 222–227.
623. Carugno, N. and M.A. Perinelli: Determination of trace
metals in cigarette smoke by atomic absorption spectrom-
etry; Proc. 6th Internat. Tob. Sci. Cong., Tokyo, Japan
(1976) 176.
624. Carugno, N. and S. Rossi: Evaluation of polynuclear
hydrocarbons in cigarette smoke by glass capillary col-
umns; 19th Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 19, Paper No. 36,
1965, pp. 49–51.
625. Carugno, N. and S. Rossi: Evaluation of normal, branched
paraffin hydrocarbons and some unsaturated aliphatic
hydrocarbons in cigarette smoke by glass capillary col-
umns; Beitr. Tabakforsch. 3 (1966) 555–562; Proc. 4th
Internat. Tob. Sci. Cong., Athens, Greece, 1966 (1967)
972–978.
626. Carugno, N. and S. Rossi: Evaluation of polynuclear
hydrocarbons in cigarette smoke by glass capillary col-
umns. J. Gas Chromatog. 5 (1967) 103–106.
627. Carugno, N., S. Rossi, and G. Lionetti: Gas-
chromatographic determination of the trimethylsilyl
derivatives of polyhydric humectants in tobacco and
tobacco smoke; Beitr. Tabakforsch. 6 (1971) 79–83.
628. Case, P.D.: The build-up and decay of ambient cigarette
smoke components; 39th Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 39,
Paper No. 46, 1985, p. 25.
629. Casey, W.J. and J.V. Fiore: Identification of cellulose fibers
isolated from reconstituted tobacco; Beitr. Tabakforsch. 8
(1976) 302–313.
630. Casey, W.J. and T.A. Perfetti: Chemistry of Turkish
tobacco; R&DM, 1981, No. 4, February 9, see www.rjrt-
docs.com 508856214 -6237.
630a. Casey, W.J. and T.A. Perfetti: Colorimetric determination
of ammonia in tobacco; RDM, 1979, No. 36, September
6, see www.rjrtdocs.com 507990670 -0690.
631. Cashmore, M.: Alternative smoking regimes: Hoffmann
analyte formation and prediction as a consequence of
changing smoking regimes and filter vent blocking; 56th
Tobacco Science Research Conference, Program Booklet
and Abstracts, Vol. 56, Paper No. 29, 2002, pp. 35–36.
632. Castonguay, A. and H. Van Vanukis: Radioimmunoassay
of N’-nitrosonornicotine; Anal. Biochem. 95 (1979)
387–396.
633. Castaño, J.I., L.A. Cabezas, and F.J. Palacio:
Determination of vanillin, ethylvanillin, and coumarin in
cigarette filler: An SPE-HPLC approach; 44th Tobacco
Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 44, Paper No. 54, 1990, p. 39.
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634. Castaño, J.I., L.R. Vargas, and J.W. Flórez: Determination
of nonvolatile and fatty acids in tobacco by micro-
wave accelerated reaction and gas chromatography;
58th Tobacco Science Research Conference, Program
Booklet and Abstracts, Vol. 58, Paper No. 32, 2004, p.
40.
635. Caton, J.E., M.P. Maskarinec, and G.M. Henderson,
Separation and determination of harman and norhar-
man by liquid chromatography; 33rd Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 33, Paper No. 55, 1979, p. 30.
636. Caton, J.E., J.R. Stokely, and M.R. Guerin: Depletion of
constituents in contained smoke aerosols for inhalation
exposure dosimetry; 29th Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 29,
Paper No. 50, 1975, p. 33.
636a. Cautreels, W. and K. van Cauwenberghe: Determination
of organic compounds in airborne particulate matter
by gas chromatography-mass spectrometry; Atmos.
Environ. 10 (1976) 447–457.
637. Cavalli, A.: Über die Verbrennungsprodukte des Tabaks
[On the combustion products of tobacco]; Selmi 8 (1898)
25.
638. Cederlöf, R. and M.L. Edfors: Tjär och nikotinmängden
i cigarrettrök [Tar and nicotine amounts in cigarette
smoke]; Nord. Hyg. Tidskr. 45 (1964) 83–88.
639. Celanese Fibers Marketing Company: Analysis of total
organic volatiles in cigarette smoke; Celanese Fibers
Marketing Company Bulletin No. 57 (July 1965) pp.
1–15.
640. Celanese Fibers Marketing Company: The selectivity
number: An expression of selective filtration of cigarette
smoke; Celanese Fibers Marketing Company Bulletin
No. 56 (March 1966) pp. 1–16.
641. Celanese Fibers Marketing Company: Cytrel® smoking
material; Celanese Fibers Marketing Company Bulletin
No. 57 (March 1969).
642. Celanese Fibers Marketing Company: Chemical and bio-
logical properties of Cytrel® smoking products; Celanese
Fibers Marketing Company, Product Bulletin (April 1974).
642a. Center for Disease Control (CDC): Endosulfan: 4.
Production, import/export, use, and disposal; pp. 181–
185, see www.atsdr.cdc.gov/toxprofiles/tp41-c4.pdf.
643. Ceschini, P. and D. Cham: Effect of sampling conditions
on the composition of the volatile phase of cigarette
smoke; Beitr. Tabakforsch. 7 (1974) 294–301.
644. Ceschini, P. and R. Chauchaix: Comparative study of
organochlorine residues in the smoke with various blend
and filter types; Proc. 6th Internat. Tob. Sci. Cong., Tokyo,
Japan (1976) 187–188; Transfer of organochlorine pesti-
cide residues into cigarette smoke as a function of tobacco
blends and filter types; Beitr. Tabakforsch. Int. 10 (1980)
134–138.
645. Ceschini, P. and A. Lafaye: Evolution of the gas-vapour
phase and the total particulate matter of cigarette smoke
in a single puff; Beitr. Tabakforsch. 8 (1976) 378–381.
646. Chakraborty, B.B., K.D. Kilburn, and R.E. Thornton:
Reduction in the concentration of aromatic polycy-
clic hydrocarbons in cigarette smoke; Chem. and Ind.
(London) (1971) 672.
646a. Chakraborty, B.B. and R.E. Thornton: Aromatic poly-
cyclic hydrocarbons; Report No. RD 609-R, October 9,
1966, see http://legacy.library.ucsf.edu/tid/boo99e00,
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 1286
647. Chakraborty, M.K. and J.A. Webrew: The chemistry of
tobacco trichomes; Tob. Sci. 7 (1963) 122–127.
648. Chamberlain, W.J.: Chromatographic studies on a polar
lipid fraction of cigarette smoke condensate; 29th Tobacco
Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 29, Paper No. 47, 1975, p. 32; Polar lipid
materials in cigarette smoke condensate; Tob. Sci. 20
(1976) 161–163.
649. Chamberlain, W.J. and R.F. Arrendale: Rapid method for
the analysis of volatile N-nitrosamines in cigarette smoke
by glass capillary chromatography; J. Chromatog. 234
(1982) 478–481.
650. Chamberlain, W.J. and R.F. Arrendale: An alternate
method for the analysis of N`-nitrosonornicotine in
tobacco; J. Agr. Food Chem. 31 (1983) 909–911.
651. Chamberlain, W.J., J.L. Baker, and R.F. Arrendale: A rapid
method for the determination of N`-nitrosonornicotine in
cigarette smoke by glass capillary gas chromatography;
35th Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 35, Paper No. 32, 1981, p.
17.
652. Chamberlain, W.J., J.L. Baker, and O.T. Chortyk:
Characterization of an oxygenated neutral fraction of
cigarette smoke condensate; 33rd Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 33, Paper No. 50, 1979, p. 27.
653. Chamberlain, W.J., J.L. Baker, O.T. Chortyk, and M.G.
Stephenson: N-Nitrosamine formation in tobacco; 39th
Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 39, Paper No. 23, 1985, p.
12.
654. Chamberlain, W.J., J.L. Baker, O.T. Chortyk, and M.G.
Stephenson: Studies on the reduction of nitrosamines in
tobacco; Tob. Sci. 30 (1986) 81–82.
655. Chamberlain, W.J. and O.T. Chortyk: Effects of cur-
ing and fertilization on nitrosamine formation in bright
and burley tobacco; Beitr. Tabakforsch. Int. 15 (1992)
87–92.
656. Chamberlain, W.J., O.T. Chortyk, J.L. Baker, and T.G.
Sutton: Curing effects on contents of tobacco specific
nitrosamines in bright and burley tobaccos; 41st Tobacco
Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 41, Paper No. 53, 1987, p. 40
657. Chamberlain, W.J., O.T. Chortyk, J.E. Leggett, and T.G.
Sutton: Effect of air-curing vs. flue-curing on the con-
centration of tobacco specific nitrosamines in tobacco;
40th Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 40, Paper No. 8, 1986, p. 5.
658. Chamberlain, W.J., R.L. Miller, and R.L. Stedman: Pilot
studies on the composition of a polynuclear-enriched
fraction of smoke condensate; 22nd Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 22, Paper No. 18, 1968, p. 11.
659. Chamberlain, W.J., W.S. Schlotzhauer, and O.T. Chortyk:
Chemical composition of nonsmoking tobacco products;
J. Agr. Food Chem. 36 (1988) 48–50.
660. Chamberlain, W.J., R.F. Severson, and M.G. Stephenson:
Levels of N-nitrosonornicotine in tobacco grown under
various agronomic conditions; Tob. Sci. 28 (1984)
156–158.
661. Chamberlain, W.J., M.E. Snook, J.L. Baker, and O.T.
Chortyk: Gel permeation chromatography of oxygenated
components of cigarette smoke condensate; Anal. Chim.
Acta 111 (1979) 235–241.
© 2009 by Taylor & Francis Group, LLC
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The Chemical Components of Tobacco and Tobacco Smoke
662. Chamberlain, W.J., M.E. Snook, O.T. Chortyk, and J.L.
Baker: Characterization of an aryl nitrile fraction of ciga-
rette smoke condensate; Tob. Sci. 25 (1981) 15–17.
663. Chamberlain, W.J., M.E. Snook, and A.F. Haeberer:
Characteristics of a polar neutral fraction of cigarette
smoke condensate by gel filtration chromatography;
31st Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 31, Paper No. 41, 1977, p. 21;
Analysis of a tumor-inhibiting fraction of tobacco smoke
condensate; J. Anal. Toxicol. 2 (1978) 138–140.
664. Chamberlain, W.J., M.E. Snook, D.B. Walters, and R.L.
Stedman: Isolation of phenols and phenolic acids from
cigarette smoke condensate; 30th Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 30, Paper No. 39, 1976 p. 28.
665. Chamberlain, W.J. and R.L. Stedman: Composition stud-
ies on tobacco. XXIV. High molecular weight pigment
in smoke of various tobaccos; 20th Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 20, Paper No. 17, 1966, p. 21; Tob. Sci. 10 (1966)
162–163.
666. Chamberlain, W.J. and R.L. Stedman: Composition stud-
ies on tobacco. XXVIII. 2,3,6-Trimethyl-1,4-naphtho-
quinone in cigarette smoke; Phytochemistry 7 (1968)
1201–1203.
667. Chamberlain, W.J., M.G. Stephenson, and R.F. Severson:
Levels of alkaloids and N’-nitrosonornicotine in tobacco
grown under different agronomic conditions; 37th Tobacco
Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 37, Paper No. 13, 1983, p. 8.
668. Chamberlain, W.J., D.B. Walters, M.E. Snook, O.T.
Chortyk, and F.J. Akin; Fractionation of cigarette smoke
condensate for biological testing: Concentration of poly-
nuclear aromatic hydrocarbon and weak-acid fractions;
Beitr. Tabakforsch. 8 (1975) 133–135.
669. Chamberlain, W.J., R.E. Williamson, R.F. Severson, J.L.
Baker, and O.T. Chortyk: Determination of free and bound
solanesol in tobacco; 42nd Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 42,
Paper No. 42, 1988, p. 38.
669a. Chamot, D. and C. Kuhlemeier: Differential expression
of genes encoding the hypusine-containing translation
initiation factor, eIF-5A, in tobacco; Nucleic Acids Res.
20 (1992) 665–669.
670. Chan, W.G. and W.P Hempfling: Chemiluminescence
detection of nitric oxide for the analysis of total N-nitroso
compounds in tobacco; 53rd Tobacco Science Research
Conference, Program Booklet and Abstracts, Vol. 53,
Paper No. 86, 1999, pp. 67–68.
671. Chang, K.W., W.W. Weeks, and J.A. Weybrew: Changes
in surface chemistry of tobacco leaves during curing with
particular emphasis on trichomes; Tob. Sci. 29 (1985)
122–127.
672. Chang, M.J., R.L. McDaniel, J.D. Naworal, and D.A.
Self: A unique method for the determination of mercury
in mainstream cigarette smoke using two-stage amalga-
mation cold vapor atomic absorption spectrometry; 55th
Tobacco Science Research Conference, Program Booklet
and Abstracts, Vol. 55, Paper No. 38, 2001, p. 42.
673. VOID
674. Chang, N.C. and R.P. Collins: An analysis of the flower
oil of Nicotiana alata; Flavour Ind. 3 (1972) 569–571.
675. Chang, S.Y. and C. Grunwald: Duvatrienediol, alkanes,
and fatty acids in cuticular wax of tobacco leaves of
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961–963.
676. Chang, S.Y. and C. Grunwald: Duvatrienediols in cuticu-
lar wax of burley tobacco leaves; J. Lipid Res. 17 (1976)
7–11.
677. Chang, Y.P., P.X. Chen, F.K. St. Charles, and S.C.
Moldoveanu: Influence of tip ventilation on Hoffmann
analyte deliveries; 57th Tobacco Science Research
Conference, Program Booklet and Abstracts, Vol. 57,
Paper No. 44, 2003, pp. 45–46.
677a. Chaplin, J.F.: Genetic influence on chemical constitu-
ents of tobacco leaf and smoke; Beitr. Tabakforsch. 8
(1975) 233–240.
677b. Chaplin, J.F. and G.S. Miner: Production factors affect-
ing chemical components of the tobacco leaf; Recent Adv.
Tob. Sci. 6 (1980) 3–63.
678. Chaplin, J.G. and H.W. Spurr Jr: Quantification of tar
and nicotine from selected tobacco cultivars (topped and
not topped) when flue-cured; 29th Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 29, Paper No. 13. 1975, p. 15.
679. Chaplin, J.G. and H.W. Spurr Jr: Altering condensate
levels in tobacco smoke by genetic techniques; Beitr.
Tabakforsch. Int. 11 (1982) 151–160.
680. Chapman, J.C., A.J. Dyakonov, and C.A. Little: Effect
of combustion modifiers on phenolics and carbonyl
compounds delivered in mainstream smoke; 58th
Tobacco Science Research Conference, Program
Booklet and Abstracts, Vol. 58, Paper No. 72, 2004, pp.
66–67.
681. Charles, J.L., H.M. Stahr, and R.M. Ikeda: Automated
determination of nicotine in total particulate matter of
cigarette smoke; Tob. Sci. 13 (1969) 54–58.
682. Chatterjee, R.K., P. Banerji, N.N. Ghosh, and S.D.
Chatterjee: Radium content of tobacco ash; Sci. Cult.
(Calcutta) 31 (1965) 188–189.
683. Cheely, C., T. Hefner, C. Smith, and S.C Moldoveanu:
Analysis of nitro-PAHs in mainstream smoke; 58th
Tobacco Science Research Conference, Program
Booklet and Abstracts, Vol. 58, Paper No. 44, 2004. pp.
47–48.
683a. Chemicalland21: GIBBERELLIN A4+A7; see www.
chemicalland21.com/lifescience/agro/GIBBERE-
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683b. Chen, C.B., S.S. Hecht, N. Hirota, D. Hoffmann, R.M.
Ornaf, and T.C. Tso: Tobacco-specific nitrosamines:
Formation from nicotine in vitro and during tobacco cur-
ing and carcinogenicity in Strain A mice; J. Natl. Cancer
Inst. 60 (1978) 819–824.
684. Chen, C.B., S.S. Hecht, and D. Hoffmann: A study of
chemical carcinogenesis. XI. Metabolic A-hydroxylation
of the tobacco-specific carcinogen N’-nitrosonornicotine;
Cancer Res. 38 (1978) 3639–3645.
685. Chen, C.B., S.S. Hecht, E.J. LaVoie, and D. Hoffmann:
Denitrosation of tobacco specific nitrosamines by
A-hydroxylation: an approach to their reduction in
tobacco; 32nd Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 32, Paper No. 48,
1978, p. 26.
685a. Chen, C.-G., E.C. Cornish, and A.E. Clarke: Specific
expression of an extensin-like gene in the style of
Nicotiana alata; The Plant Cell 4 (1992) 1053–1062.
685b. Chen, L., T.P.J. Garrett, G.B. Fincher, and P.B. Høj: A
tetrad of ionizable amino acids is important for catalysis
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in barley B-glucanases; Am. Soc. Biochem. Molec. Bio.
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686. Chen, P.: Chemistry of cigarette burning process; Beitr.
Tabakforsch. Int. 21 (2004) 105–110.
687. Chen, P.X., H. Burton, and S.C. Moldoveanu: A col-
laborative study for the analysis of minor alkaloids in
tobacco; 57th Tobacco Science Research Conference,
Program Booklet and Abstracts, Vol. 57, Paper No. 33,
2003, p. 39.
688. Chen, P.X. and S.C. Moldoveanu: Mainstream smoke
chemical analyses for 2R4F Kentucky reference ciga-
rette; Beitr. Tabakforsch. Int. 20 (2003) 448–458.
689. Chen, P.X., N. Qian, H.R. Burton, and S.C. Moldoveanu:
Analysis of minor alkaloids in tobacco: A collaborative
study; Beitr. Tabakforsch. Int. 21 (2005) 369–379.
689a. Chen, Z., J. Malamy, J. Henning, U. Conrath, P.
Sanchez-Casas, H. Silva, J. Riciglianoi, and D.F.
Klessig: Induction, modification, and transduction of
the salicylic acid signal in plant defense responses; Proc.
Natl. Acad. Sci. U.S.A. 92 (1995) 4134–4137.
690. Cheng, A.L.S., J.F. Chaplin, and T.C. Tso: Sterol varia-
tion in flue-cured tobacco varieties; Tob. Sci. 12 (1968)
33–34.
691. Cheng, A.L.S. and G.L. Steffens: Maleic hydrazide resi-
dues in Maryland tobacco; Tob. Sci. 20 (1976) 75–76.
692. Cheng, T., C.D. Eaton, X. Shi, H.M. Coburn, and R.D.
Bereman: Quantitative determination of nitrated poly-
cyclic aromatic hydrocarbons in cigarette smoke con-
densate; 57th Tobacco Science Research Conference,
Program Booklet and Abstracts, Vol. 57, Paper No. 79,
2003, pp. 68–69.
693. Cheng, T., C.D. Eaton, X. Shi, H.M. Coburn, D.F.
Price, and R.D. Bereman: Quantitative determination of
nitrated polycyclic aromatic hydrocarbons in cigarette
smoke condensate; Manuscript, December (2004).
694. Cheng, T., N. Hawkins , J. Allen, V. Ding, and J.M.
Keefer: Two PAH specific separation schemes for the
determination of numerous PAHs from mainstream ciga-
rette smoke; 55th Tobacco Science Research Conference,
Program Booklet and Abstracts, Vol. 55, Paper No. 26,
2001, p. 35.
695. Chengming, Z.: The determination of B[a]P in the total
particulate matter of cigarette smoke; 54th Tobacco
Science Research Conference, Program Booklet and
Abstracts, Vol. 54, Paper No. 51, 2000, p. 48.
696. Chenikov, V.V. and E.N. Shapovalov: Separation of the
components of the neutral fraction of tobacco tars; Tabak
(USSR) 25(1) (1964) 43–46.
697. Chenikov, V.V. and E.N. Shapovalov: Tar components of
tobacco and the products of its burning. I; Izv. Vyssikh
Uchebn. Zavednii. Pish. Tekhnol. 1965(5) (1966) 65–66.
698. Chenikov, V.V. and E.N. Shapovalov: Tar components of
tobacco and the products of its burning. II; Izv. Vyssikh
Uchebn. Zavednii. Pish. Tekhnol. 1965(5) (1966) 66–69.
699. Chernova, M.: Synthesis of polycyclic compounds.
II. S.N.Reformatsky’s reaction with 9-methyl-1,2-
benzanthrone-10; J. Gen. Chem. (U.S.S.R.) 9 (1939)
2171–2172.
700. Chesterfield, J. and I.D. Entwhistle: Methods for the sep-
aration of cigarette smoke hydrocarbons; 17th Tobacco
Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 17, Paper No. 24, 1963, pp. 17–18.
701. Chibnall, A.C., S.H. Piper, A. Pollard, E.F. Williams, and
P. Sahai: The constitution of the primary alcohols, fatty
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 1288
acids and paraffins present in plant and insect waxes;
Biochem. J. 28 (1934) 2189–2208.
701a. Chida, M., Y. Sone, and H. Tamura: Aroma character-
istics of stored tobacco cut leaves analyzed by a high
vacuum distillation and canister system; J. Agr. Food
Chem. 52 (2004) 7918–7924.
702. Chmura, M.I.: Characteristics of Nicotiana species;
Sborn. Rabot Khim. Tabak Bull. 125 (1935) 151–162.
702a. Choi, D., H.M. Kim, H.K. Yun, J.-A. Park, W.T. Kim,
and S.H. Bok: Molecular cloning of a metallothionein-
like gene from Nicotiana glufinosa l. and its induction
by wounding and tobacco mosaic virus infection; Plant
Physiol. 112 (1996) 353–359.
703. Chopra, N.M.: Breakdown of chlorinated hydrocarbon
pesticides in tobacco smokes: A short review; in: Proc.
2nd Internat. Cong. Fate of pesticides in the environment,
6 (1972) 245–261.
704. Chopra, N.M.: On pyrolysis, and the possible contribution
of maleic hydrazide towards benzo(a)pyrene in tobacco
smoke; Tob. Sci. 23 (1979) 29–30.
705. Chopra, N.M. and A. Al-Kubaisi: A study of the pyrogen-
esis of PAHs in cigarette smoke: Pyrolysis of benzene,
naphthalene, and B-sitosterol; 8th Internat. Tob. Sci.
Cong., Vienna, Austria, 1984, CORESTA Inf. Bull., Spec.
Edition 1984: Paper S14, 54–55.
706. Chopra, N.M., B.S. Campbell, and J.C. Hurley:
Systematic studies on the breakdown of endosulfan in
tobacco smokes. Isolation and identification of the deg-
radation products from the pyrolysis of endosulfan I in
a nitrogen atmosphere; J. Agr. Food Chem. 26 (1978)
255–258.
707. Chopra, N.M. and J.J. Domanski: Degradation of p,p’-
DDT in tobacco smoke; 23rd Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 23,
Paper No. 25, 1969, p. 19; Systematic studies on the
breakdown of p,p’-DDT in tobacco smokes. III. Isolation
and identification of the nonvolatile degradation products
of p,p’-DDT in p,p’-DDT-treated tobacco smokes; Beitr.
Tabakforsch. 6 (1972) 139–143.
708. Chopra, N.M., J.J. Domanski, and N.B. Osborne:
Systematic studies on the breakdown of p,p’-DDT in
tobacco smokes; Beitr. Tabakforsch. 5 (1970) 167–174.
709. Chopra, N.M. and N.B. Osborne: Isolation and identi-
fication of the degradation products from the pyrolysis
of p,p’-DDT in a nitrogen atmosphere; 23rd Tobacco
Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 23, Paper No. 24, 1969, p. 18.
710. Chopra, N.M., A.V. Rao, and M.M. Verma: Study on
the pyrogenesis of PAH’s in cigarette smoke: Pyrolysis
of 1,3-butadiene + ethylene mixture in a nitrogen atmo-
sphere; 8th Internat. Tob. Sci. Cong., Vienna, Austria,
1984, CORESTA Inf. Bull., Spec. Edition 1984: Paper
PP02, 124–125.
711. Chopra, N.M. and L.R. Sherman: Degradation of p,p’-
DDT in tobacco smokes. Part II. The identification and
estimation of volatile degradation products of p,p’-DDT
in p,p’-DDT-treated tobacco smokes; 24th Tobacco
Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 24, Paper No. 43, 1970, p. 24.
712. Chopra, N.M. and L.R. Sherman: Systematic stud-
ies on the breakdown of p,p’-DDT in tobacco smokes.
Investigation into the presence of methyl chloride, dichlo-
romethane, and chloroform in tobacco smoke; Anal.
Chem. 44 (1972) 1036–1038.
© 2009 by Taylor & Francis Group, LLC
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The Chemical Components of Tobacco and Tobacco Smoke
713. Chopra, N.M. and J.T. Thekkekandam: Estimation of non-
volatile degradation products of p,p’-DDT and p,p’-TDE
in the smoke from p,p’-DDT-treated and p,p’-TDE-treated
tobaccos; 26th Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol 26, Paper No. 31,
1972, pp. 47–48.
714. Chopra, N.M. and J.T. Thekkekandam: A mechanistic
study on the formation of the non-volatile degradation
products of p,p’-DDT and p,p’-TDE in p,p’-DDT- and
p,p’-TDE-treated tobacco smoke; Beitr. Tabakforsch. 7
(1973) 88–92.
715. Chopra, N.M. and M.M. Verma: On the transfer of maleic
hydrazide into tobacco smoke; 7th Internat. Tob. Sci.
Cong., Manila, The Philippines, 1980, CORESTA Inf.
Bull., Spec. Edition 1980: Paper S04 120.
716. Chopra, N.M., M.M. Verma, and T.H. Zuniga: On the
fate of maleic hydrazide in tobacco smokes; J. Agr. Food
Chem. 30 (1982) 672–676.
717. Chopra, N.M. and T.H. Zuniga: The fate of Chlorpyrifos
on tobacco during smoking; Beitr. Tabakforsch. Int. 14
(1990) 387–391.
718. Chortyk, O.T.: Comparative studies on the brown pig-
ments of tobacco; Tob. Sci. 11 (1967) 137–139.
719. Chortyk, O.T.: High molecular weight materials of
tobacco; in: The chemistry of tobacco and tobacco
smoke, edited by I. Schmeltz, Plenum Press, New York,
NY (1972), pp. 21–33.
720. Chortyk, O.T. and W.J. Chamberlain: The application of
solid phase extraction in the analysis of tobacco-specific
nitrosamines (TSNA); 44th Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 44,
Paper No. 44, 1990, p. 33.
721. Chortyk, O.T., J.F. Chaplin, and W.S. Schlotzhauer:
Growing selenium-enriched tobacco; J. Agr. Food Chem.
32 (1984) 64–68.
722. Chortyk, O.T. and W.S. Schlotzhauer: Studies on the
pyrogenesis of tobacco smoke constituents (a review);
Beitr. Tabakforsch. 7 (1973) 165–178.
723. Chortyk, O.T. and W.S. Schlotzhauer: Modification of
an automatic cigarette smoking machine for sidestream
smoke collection; Tob. Sci. 30 (1986) 122–126.
724. Chortyk, O.T. and W.S. Schlotzhauer: Increasing sele-
nium in cigarettes and smoke: Transfer to smoke; Arch.
Environ. Hlth. 39 (1984) 419–424.
724a. Chortyk, O.T. and W.S. Schlotzhauer: Yield and chemical
composition of sidestream smoke produced by a low-tar
cigarette; 42nd Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 42, Paper No. 14,
1988, p. 23; The contribution of low-tar cigarettes to envi-
ronmental tobacco smoke; J. Anal. Toxicol. 13 (1989)
129–134.
725. Chortyk, O.T., W.S. Schlotzhauer, and R.L. Stedman:
Lithium chloride as a gas chromatographic substrate for
polynuclear aromatic hydrocarbons; J. Gas Chromat. 3
(1965) 394–395.
725a. Chortyk, O.T., W.S. Schlotzhauer, and R.L. Stedman:
The pyrolysis of polyphenolic pigments of tobacco;
19th Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 19, Paper No. 18, 1965, pp.
27–29.
726. Chortyk, O.T., W.S. Schlotzhauer, and R.L. Stedman:
Composition studies on tobacco. XXIII. Pyrolytic and
structural investigations on the polyphenol-amino acid
pigments of leaf; Beitr. Tabakforsch. 3 (1966) 422–429.
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727. Chortyk, O.T., R.F. Severson, and H.C. Higman,
Chromatographic determination of hydrocarbon waxes
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Vol. 28, Paper No. 34, 1974, p. 24; Beitr. Tabakforsch. 8
(1975) 204–210.
728. Chou, D., K.D. Brunnemann, J.D. Adams, and D.
Hoffmann: On the isolation and identification of new
tobacco-specific N-nitrosamines; 39th Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 39, Paper No. 22, 1985, p. 12.
729. Christakopoulos, A., H. Norin, K. Feldhusen, A.
Palmqvist, and I. Wahlberg: Estimation of natural levels
of coumarin in different types of tobacco using a mass
fragmentographic technique; 45th Tobacco Chemists’
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Vol. 45, Paper No. 45, 1991, p. 37.
730. Christakopoulos, A., A. Palmqvist, and I. Wahlberg: A
new analytical method for the determination of nitrite
in nanogram levels in tobacco; 47th Tobacco Chemists’
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Vol. 47, Paper No. 39, 1993, p. 45.
731. Chuman, T.: Chemical studies on aroma constituents
of Turkish tobacco; Sci. Papers, Cent. Res. Inst., Japan
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732. Chuman, T., H. Kaneko, T. Fukuzumi, and M. Noguchi:
Isolation of two terpenoid acids 4-isopropyl-7-methyl-5-
E,7-octadienoic acid and 3-isopropyl-6-methyl-4E,6-hep-
tadienoic acid from Turkish tobacco; Agr. Biol. Chem. 38
(1974) 2295–2296.
733. Chuman, T., H. Kaneko, T. Fukuzumi, and M. Noguchi:
Acidic aroma constituents of Turkish tobacco: Terpenoid
acids related to tobacco thunberganoids; Agr. Biol. Chem.
40 (1976) 587–581.
734. Chuman, T., H. Kaneko, and M. Noguchi: Structure of
a new terpenoid acid, 1-Xi-methyl-3-Xi-isopropylcyclo-
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735. Chuman, T. and M. Noguchi: Isolation of a new terpenoid
acid 2-methyl-5-isopropyl-1-cyclopentene-1-carboxylic
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567–568.
736. Chuman, T. and M. Noguchi: Isolation of new terpenoid
acids (-)-3-methyl-6-isopropyl-9-oxo-2E,4E-decadienoic
acid and 3-isopropyl-6-oxo-2Z-heptenoic acid from
Turkish tobacco; Agr. Biol. Chem. 39 (1975) 1169–1171.
737. Chuman, T. and M. Noguchi: The structure of a new ter-
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4E-decenoic acid, isolated from Turkish tobacco; Agr.
Biol. Chem. 40 (1976) 1793–1796.
738. Chuman, T. and M. Noguchi: Acidic aroma constituents of
Turkish tobacco. Agr. Biol. Chem. 41 (1977) 1021–1030.
739. Chuman, T., M. Noguchi, A. Ohkubo, and S. Toda: The
structure of a novel terpenoid acid, 3X-hydroxy-4X,9-
dimethyl-6E,9E-dodecadienedioic, isolated from Turkish
tobacco; Tetrahedron Lett. (1978) 3045–3058.
739a. Chung, F.L. and Y. Xu: Inhibition of tobacco-specific nit-
rosamine lung tumorigenesis by green tea and its poly-
phenol as antioxidants; 204th Natl. Mtg., Am. Chem.
Soc., Washington, DC (1992) Paper No. 129.
739b. Chung, H.-J., G.-C. Jang, and Y.-O. Kim: Moisture sorp-
tion and desorption characteristics by tobacco type; 59th
Tobacco Science Research Conference, Program Booklet
and Abstracts, Vol. 59, Paper No. 13, 2005, pp. 25–26.
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740. Chung, H.L.: Pyrolytic study of leaf alcohol glucoside.
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741. Chung, H.L. and J.C. Aldridge: Thermal study of levu-
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742. Chung, H.L. and J.C. Aldridge: Thermal study of sorbic
acid; R&DM, 1991, No. 513, August 19, see www.rjrt-
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743. Chung, H.L. and J.C. Aldridge: Thermal study of lico-
rice; ACD, 1992, No. 259, September 15, see www.rjrt-
docs.com 508392999 -3005; Thermal study of licorice by
online thermogravimetry/gas chromatography/mass spec-
trometry; 53rd Tobacco Science Research Conference,
Program Booklet and Abstracts, Vol. 53, Paper No. 7,
1999, p. 23.
744. Chung H.L., J.C. Aldridge, M.F. Ogden, and C.H. Risner:
Thermal study of solanesol by thermogravimetry/gas
chromatography/mass spectrometry and pyrolysis/gas
chromatography/mass spectrometry; R&DM, 1991, No.
481, May 31, see www.rjrtdocs.com 507984345 -4366.
745. Chung, H.L. and M.F. Borgerding: An online automated
smoking machine/GC/MS system for analysis and puff-
by-puff study of fresh mainstream vapor phase smoke
constituents; 58th Tobacco Science Research Conference,
Program Booklet and Abstracts, Vol. 58, Paper No. 5,
2004, pp. 23–24.
746. Church, D.F. and W.A. Pryor: Free-radical chemistry
of cigarette smoke and its toxicological implications;
Environ. Hlth. Perspect. 64 (1985) 111–126.
746a. Ciaravolo, S., G. Lionetti, M. Gionti, A. Nunziata, and E.
Pierri: Microwave-assisted extraction: An efficient method
for the determination of polycyclic hydrocarbons in particu-
late phase mainstream cigarette smoke; 2004 CORESTA
Congress, Kyoto, Japan, Poster SS10; Microwave-assisted
extraction: An efficient method for the determination of
polycyclic hydrocarbons in particulate phase mainstream
cigarette smoke; Manuscript, May (2005).
746b. Ciaravolo, S., G. Lionetti, F. Modestia, and A. Nunziata:
Speciation of chromium in mainstream and sidestream
tobacco smoke using inductively coupled plasma optical
emission spectroscopy; Manuscript, May (2005).
746c. Ciaravolo, S., F. Modestia, and L. Nappi: Analytical pro-
cedures for the determination of volatile nitrosamines
in cigarette smoke; 59th Tobacco Science Research
Conference, Program Booklet and Abstracts, Vol. 59,
Paper No. 43, 2005, p. 41.
747. Cigarette Components, Ltd.: The determination of hydro-
gen cyanide in cigarette smoke; Cigarette Components,
Ltd. Pamphlet: pp. 1–8 (March, 1964).
748. Cigarette Components, Ltd.: Method for the determina-
tion of formaldehyde and acrolein in the vapour phase of
cigarette smoke; Cigarette Components, Ltd. Pamphlet:
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749. Clapp, W.L.: Protein reduction in tobacco. Part III. Burley
tests; R&DM, 1988, No. 336, December 21, see www.
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750. Clapp, W.L.: Protein determination in tobacco; R&DM,
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751. Clapp, W.L.: The contribution of individual amino acids
to the Ames activity of cigarette smoke condensate;
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752. Clapp, W.L.: A status report on protein reduction studies;
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753. Clapp, W.L. and B.S. Fagg: Protein reduction in tobacco;
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754. Clapp, W.L. and B.S. Fagg: Protein reduction in tobacco.
Part II. Extract evaluation; R&DM, 1988, No. 257,
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755. Clapp, W.L., B.S. Fagg, and C.J. Smith: Reduction in
Ames Salmonella mutagenicity of mainstream cigarette
smoke condensate by tobacco protein removal; Mutation
Res. 446 (1999) 167–174.
756. Clapp, W.L., B.S. Fagg, C.J. Smith, and D. Peele: The
reduction in Ames Salmonella mutagenicity of mainstream
cigarette smoke condensate by tobacco protein removal;
39th Tobacco Workers Conference, Williamsburg, VA
(2000).
757. Clapp, W.L., B.M. Gordon, and F.N. Wendelboe:
Determination of ethyl carbamate in tobacco products;
50th Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 50, Paper No. 77, 1996, p.
67.
758. Clapp, W.L. and G.R. Shelar: Determination of chlori-
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759. Clapp, W.L., F.A. Thome, and C.E. Lewis: Gas-
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760. Clar, E.: Zur Kenntnis mehrkerniger aromatischer
Kohlenwasserstoffe und ihrer Abkömmlinge. I.
Dibenzanthracene und ihrer Chinone [Knowledge of
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761. Clark, M.S.G., M.J. Rand, and S. Vanov: Comparison of
the pharmacological activity of nicotine and related alka-
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(1965) 363–379.
762. Clark, T.J., J.W. Gee, H.L. Chung, and M.F. Borgerding:
Evaluation of artifact formation in mainstream vapor
phase cigarette smoke trapped in solvent; 52nd Tobacco
Science Research Conference, Program Booklet and
Abstracts, Vol. 52, Paper No. 26, 1998, p. 27.
763. Clark, T.J. and J.E. Bunch: Derivatization/headspace
techniques for the analysis of organic acids in tobacco;
50th Tobacco Chemists’ Research Conference, Program
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44.
764. Clarke, B.B. and E. Brennan: Tobacco leaves accumulate
cadmium from root application of the heavy metal; Tob.
Sci. 27 (1983) 28–29.
764a. Clayton, P. and M. Lane: Measurement of carbonyl
compounds in cigarette mainstream smoke by LC-MS/
MS following derivatization; 60th Tobacco Science
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Vol. 60, Paper No. 31, 2006, pp. 33–34.
765. Clemo, G.R.: Some aspects of the chemistry of tobacco
smoke. I; Tetrahedron 3 (1958) 168–174.
766. Clemo, G.R.: Symposium on atmospheric pollution. (a)
Some aspects of the chemistry of cigarette smoke and
its possible implications; Royal Soc. Hlth. J. 79 (1959)
74–80.
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The Chemical Components of Tobacco and Tobacco Smoke
767. Clemo, G.R.: Further aspects of the chemistry of tobacco
smoke. II; Tetrahedron 11 (1960) 11–14.
768. Cochran, E.W., M.J. Joseph, S.S. Stinson, and S.S.
Summers: Application of a diffusion-denuder method for
the investigation of the effects of “smoke pH” on vapor-
phase nicotine yields from different types of cigarettes;
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769. Cogbill, E.C. and M.E. Hobbs: The transfer of metallic
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770. Cogbill, E.C., W.B. Wartman, and E.S. Harlow: Cigarette
smoke. II. Some variables affecting the water content of
the particulate phase; Tob. Sci. 3 (1959) 136–138.
770a. Coggins, C.R.E., R.K. Haroz, R. Lam, and K.T. Morgan:
The tumorigenicity of smoke condensates from cigarettes
containing different amounts of Cytrel®, as assessed by
mouse skin painting; Toxicology 23 (1982) 177–185.
770b. Coggins, C.R.E., R. Lam, and K.T. Morgan: Chronic
inhalation study in rats, using cigarettes containing
different amounts of Cytrel® tobacco supplement;
Toxicology 22 (1981–1982) 287–296.
771. Cohen, B., M. Eisenbud, and W. Harley: Alpha radio-
activity in cigarette smoke; Radiation Res. 14 (1980)
190–196.
772. Colby, D.A.: Application of liquid chromatography to
the quantitative analysis of nonvolatile tobacco-spe-
cific N-nitrosamines in tobacco and tobacco products;
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773. Colby, D.A.: Analysis of sorbitol in chewing tobacco
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774. Colby, D.A. and G.R. Shelar: Analysis of coumarin in
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774a. Cole, D.L. and J.S. Cole: Field control of sore shin
(Rhizoctoniua solani) of tobacco with Benomyl® and
Benodanil®; Ann. Applied Biol. 90 (1978) 187–193.
775. Coleman, W.M. III: Gas chromatographic-selected ion
monitoring-mass spectrometric determination of ciga-
rette mainstream smoke components with sensory attri-
butes; Beitr. Tabakforsch. Int. 21 (2004) 175–183.
776. Coleman, W.M. III and B.M. Gordon: On the develop-
ment of a very rapid gas chromatographic method for
the analysis of high molecular weight hydrocarbons
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348–354.
777. Colledge, A., W.W. Reid, and R. Russell, The diterpenoids
of Nicotiana species and their potential technological sig-
nificance; Chem. and Ind. (London) (1975) 570–571.
778. Collins, P.F., N.M. Sarji, W.W. Lawrence, and J.F.
Williams: An automated method for the determination of
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779. Collins, P.F., N.M. Sarji, and J.F. Williams: An auto-
mated method for determination of hydrogen cyanide
in cigarette smoke; 23rd Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 23,
Paper No. 10, 1969, p. 7; Tob. Sci. 14 (1970) 12–15.
780. Collins, P.F., N.M. Sarji, and J.F. Williams: A trapping
system for the combined determination of total HCN and
total gas phase aldehydes in cigarette smoke; 26th Tobacco
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mated colorimetric system for the analysis of gas phase of
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783. Collins, P.F., J.F. Williams, and B.H. Gerritsen: An auto-
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783a. Colucci, A.V. and N.W. Sizemore: Fate of smoke constit-
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784. Commins, B.T.: Formation of polycyclic aromatic
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786. Commins, B.T. and A.J. Lindsey: The determination of
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787. Commins, B.T. and A.J. Lindsey: The determination of
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788. Commins, B.T. and A.J. Lindsey: The determination of
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790a. Commoner, B., A.J. Vithayathil, P. Dolara, S. Nair, P.
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790b. Conant, J.B. and L.F. Fieser: Reduction potentials of qui-
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893b. Dalhamn, T. and R. Rylander: Ciliastasis and cigarette
smoke: Varying exposure time; Arch. Otolaryngol. 81
(1965) 379–382.
893c. Dalhamn, T. and R. Rylander: Ciliastasis and cigarette
smoke: Effect of varying composition of smoke; Arch.
Environ. Hlth. 13 (1966) 47–50.
894. Dalhamn, T. and R. Rylander: Ciliotoxicity of cigarette
smoke and its components; Am. Rev. Resp. Dis. 98 (1968)
509–511.
894a. Dalhamn, T. and R. Rylander: Recommendations by indi-
viduals; in: Toward a less harmful cigarette, edited by E.L.
Wynder and D. Hoffmann, Natl. Cancer Inst. Monograph
28 (1968) 273–279, see p. 277.
894b. Dalhamn, T. and J. Sjoholm: Studies on SO2, NO2, and
NH3: Effect on ciliary activity in rabbit trachea of single in
vitro exposure and resorption in rabbit nasal cavity; Acta
Physiol. Scand. 58 (1963) 287–291.
895. d’Andres, S., R. Boudoux, J.-M. Renaud, and J. Zuber:
TSNA levels in the mainstream smoke of simplified blend
prototypes; Beitr. Tabakforsch. Int. 20 (2003) 331–340.
896. Danehower, D.A.: A rapid method for the isolation and
quantitation of the sucrose esters of tobacco; Tob. Sci. 31
(1987) 32–35.
897. Danehower, D.A., R.R. Izac, H.J. Grubbs, M.T. Core, and
S.B. Hassam: A rapid method for the analysis of z-abienol;
Tob. Sci. 31 (1987) 48–51.
898. Danehower, D.A., R.C. Long, M.T. Core, R.R. Izac, and
H.J. Grubbs: Changes in z-abienol levels during growth
and curing of an Oriental and South American flue-cured
tobacco; Tob. Sci. 32 (1988) 49–52.
898a. Daniel, O., M.S. Meier, J. Schlatter, and P. Frischknecht:
Selected phenolic compounds in cultivated plants: Ecologic
functions, health implications, and modulation by pesticides;
Environmental Hlth. Perspectives 107 (1999) 109–114.
899. Dannenburg, W.: Indole compounds and their effect on
the quality of tobacco; RDM, 1958, No. 28, April 3.
900. Dare, D.L., I.D. Entwistle, and R.A.W. Johnstone:
Polyolefins in cigarette smoke; Chem. and Ind. (London)
(1966) 629–630.
901. Dare, D.L., I.D. Entwistle, and R.A.W. Johnstone:
Synthesis of 3-substituted furans and the formation of
3-(4,8,12-trimethyl-tridecyl)furan; J. Chem. Soc., Perkin
Transact. (1973) 1130–1134.
902. Darrall, K.G., J.A. Figgins, R.D. Brown, and G.F.
Phillips: Determination of benzene and associated vola-
tile compounds in mainstream cigarette smoke; Analyst
123 (1998) 1095–1101.
903. D’Arrigo, V. and L. Laghi: Presence of polycyclic aro-
matic hydrocarbons in green and industrially handled
tobacco leaves; Quad. Merceol. 11 (1972) 27–32.
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903a. Da Silva, P., C. Landon, B. Industri, A. Marais, D.
Marion, M. Ponchet, and F. Vovelle: Solution struc-
ture of a tobacco lipid transfer protein exhibiting new
biophysical and biological features; Proteins 59 (2005)
356–367.
904. Dattilo, B.S., S. Gallo, and G. Lionetti: Determination
of residues of eight synthetic pyrethroids in tobacco by
capillary gas chromatography; Beitr. Tabakforsch. Int. 16
(1994) 65–75.
905. Dattilo, B.S., S. Gallo, G. Lionetti, and S.G. Ross:
Determination of free and bound maleic hydrazide resi-
dues in tobacco by high performance liquid chromatogra-
phy; Beitr. Tabakforsch. Int. 16 (1994) 57–64.
905a. Dauben, W.G., W.E. Thiessen, and P.R. Resnick:
Cembrene, a 14-membered ring diterpene hydrocarbon;
J. Am. Chem. Soc. 84 (1962) 2015–2016.
906. Daudel, P. and R. Daudel: Application of wave-motion
mechanics to the study of the mechanism of action of
cancerogenic substances on tissues; Biol. Med. 39 (1950,
No.4) 201–236.
906a. Daudel, P. and R. Daudel: Chemical carcinogenesis and
molecular biology; Interscience Publishers: London,
1966.
907. Davis, B.R., T.H. Houseman, and H.R. Roderick: Studies
of cigarette smoke transfer using radioisotopically labelled
tobacco constituents. Part III. The use of dotriacontane-
16,17–14C as a marker for the deposition of cigarette
smoke in the respiratory system of experimental animals;
Beitr. Tabakforsch. 7 (1973) 148–153.
907a. Davis, D.L.: Sterol distribution within green and air cured
tobacco; Phytochemistry 11 (1972) 489–494.
908. Davis, D.L.: Waxes and lipids and their relationship
to smoking quality and aroma; Recent Adv. Tob. Sci. 2
(1976) 80–111.
909. Davis, D.L.: Tobacco terpenoids and the influence of cur-
ing regimes; in: Recent advances in the chemical com-
position of tobacco and tobacco smoke, edited by J.L.
McKenzie, R.M. Ikeda, T.R. Terrill, D.G. Vickroy, and
D.B. Walters, Proc. Am. Chem. Soc. Symp., New Orleans,
LA (1977) 233–254.
910. Davis, D.L and R.B. Griffith: The distribution of smoke
components in a mainstream-sidestream exposure system;
37th Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 37, Paper No. 42, 1983, p. 23.
910a. Davis, D.L. and M.T. Nielsen (Editors): Tobacco: Prod-
uction, chemistry and technology, Blackwell Science,
Oxford, UK (1999).
911. Davis, D.L, K.L. Stevens, and L. Jurd: Volatile constitu-
ents of air-cured, flue-cured, freeze-dried, and homoge-
nized leaf cured (HLC) tobaccos; 29th Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 29, Paper No. 30, 1975, p. 23.
911a. Davis, H.J. and T.W. George: On the potential for the
selective filtration of cigarette smoke by cellulose acetate
fiber; 16th Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 16, Paper No. 18,
1962, p. 12.
912. Davis, H.J. and T.W. George: A dimensionless measure of
filter selectivity: Geometric factors in cigarette construc-
tion which influence this measure; CORESTA Inf. Bull.
1965(1) 7–21; Beitr. Tabakforsch. 3 (1965) 203–214.
913. Davis, H.J., L.A. Lee, and T.R. Davidson: The fluorimet-
ric determination of benzo[a]pyrene in cigarette smoke
condensate; Anal. Chem. 38 (1966) 1752–1755.
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 1296
914. Davis, R.E.: A combined automated procedure for the
determination of reducing sugars and nicotine alkaloids
in tobacco product using a new reducing sugar method;
Tob. Sci. 20 (1976) 139–144.
915. Davis, R.W. and B.H. Sneade: Determination of total alde-
hydes and acrolein in mainstream vapor phase cigarette
smoke; 24th Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 24, Paper No. 12,
1970, p. 8.
915a. Dawson, R.F.: Tobacco alkaloids; 1st Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 1, Paper No. 6, 1947.
915b. Dawson, R.F.: Method for the quantitative determina-
tion of nicotine and nornicotine. A progress report; 2nd
Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 2, Paper No. 1, 1948.
916. Dawson, R.F.: The cigarette and its smoke; Columbia
Eng. Quart. 8(2) (1955) 10–13, 30, 32.
916a. Dawson, R.F., R.D. Carpenter, F.L. Gager Jr, R. W.
Jenkins Jr, and R.H. Newman: The utility of carbon-14
for ascertaining precursor-product relationships in
cigarette smoke; Proc. World Tob. Sci. Conf. 5 (1970)
105–110.
917. Dawson, R.F. and E. Wada: Flavonoids and depsides of
the green tobacco leaf: I. Rutin and chlorogenic acid; Tob.
Sci. 1 (1957) 47–50.
918. Day, J.M., R.D. Bateman, and E.C. Cogbill: Deter-
mination of trace amounts of nickel in tobacco by neutron
activation analysis; 145th Ann. Mtg., Am. Chem. Soc.,
New York, NY (1963) p. 23A.
918a. DeBardeleben, M.Z., W.E. Claflin, and W.F. Gannon:
Role of cigarette physical characteristics on smoke com-
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919. DeBardeleben, M.Z., J.E. Wickham, and W.F. Kuhn: The
determination of tar and nicotine in cigarette smoke from
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115–148.
920. de Campos, M.D.: Tobacco and cigar smoke; Anais
Faculdade Farm. Odontol. Unic. (Sao Paulo) 1 (1939/1940)
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920a. Decarboxylase: By a search (Google) on the Internet,
inserting the term decarboxylase glycine tobacco pro-
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Peterson, R.B. Regulation of glycine decarboxylase and
L-serine hydroxymethyltransferase activities by glyoxy-
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Physiol. 70 (1982) 61–66. Search for other decarboxy-
lases provides similar references.
921. Decker, C., A. Girardet, P. Golaz, and R. Regamey: A
multiple automatic apparatus for the estimation of nico-
tine and tar in cigarette smoke; Mitt. Gebiete Lebensm.
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922. de Clercque, M. and R. Truhaut: Nicotyrine and its deter-
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(1957) 529–533.
922a. Dehydrogenase: By a search (Google) on the Internet,
inserting the term dehydrogenase proline tobacco provides
numerous references to it, e.g., Kochetov, A.V., S.E. Titov,
et al.: Increase in the level of proline and osmotic pressure
of cytoplasm in transformed tobacco bearing an antisense
suppressor of the proline dehydrogenaase gene; Genetika
40 (2004) 282–285. A similar search for dehydrogenase
xanthine tobacco provides many references, including the
following: Nguyen, J. and A. Nato: In vitro study of the
© 2009 by Taylor & Francis Group, LLC
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The Chemical Components of Tobacco and Tobacco Smoke
xanthene dehydrogenase from illuminated or darken leaves;
Physiol. Plantarum 59 (1983) 73. A similar search for other
dehydrogenases provides numerous references.
922b. de Heil, J.T., J.M. Van Dort, and M. Renes: The (bio-)syn-
thesis of megastigmatrienone; 43rd Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 43, Paper No. 55, 1989, p. 28.
922c. Deichmann, W.D., M.D. Kitzmiller, and S. Witherup: The
effects upon experimental animals of the inhalation of
phenol; Am. J. Clin. Path. 14 (1944) 273.
922d. DeJong, D.W. and J.J. Lam Jr: Protein content of tobacco;
in: Recent advances in the chemical composition of
tobacco and tobacco smoke, edited by J.L. McKenzie,
R.M. Ikeda, T.R. Terrill, D.G. Vickroy, and D.B. Walters,
Proc. Am. Chem. Soc. Symp., New Orleans, LA (1977)
584–592; J. Anal. Toxicol. 1 (1977) 78–103.
923. DeJong, D.W. and W.G. Woodlief: Some factors influenc-
ing tobacco leaf senescence; Beitr. Tabakforsch. Int. 10
(1979) 48–56.
924. de la Burde, R., R.F. Crayton, and A. Bavley: The fate of
carbohydrates during the thermal degradation of tobacco;
16th Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 16, Paper No. 13, 1962, pp.
9–10.
925. de la Burde, R. and S.F. Norman: The isolation and char-
acterization of the pectic substances from tobacco; Tob.
Sci. 12 (1968) 236–240.
926. de la Burde, R. and E.H. Poindexter Jr: Oxidative prod-
ucts of hexoses in thermally treated tobacco; Nature 198
(1963) 1089–1090.
927. de la Burde, R., E.H. Poindexter Jr, and J.H. Bell: The
distribution of amino acids in tobaccos from different
stalk regions; Tob. Sci. 9 (1965) 26–32.
928. Della Porta, G., L. Kolb, and P. Shubik: Induction of tra-
cheobronchial carcinomas in the Syrian golden hamster;
Cancer Res. 18 (1958) 592–597.
928a. Delon, R. and M.-N. Pululu: The chemical control of
tobacco black root rot; Beitr. Tabakforsch. Int. 14 (1989)
189–195.
928b. Deluc, L., F. Barrieu, C. Marchive, V. Lauvergeat, A.
Decendit, T. Richard, J.-P. Carde, J.-M. Mérillon, and
S. Hamdi: Characterization of a grapevine R2R3-MYB
transcription factor that regulates the phenylpropanoid
pathway; Plant Physiol. 140 (2006) 499–511.
929. DeLuca, T.C.: Collection of carbonyl compounds in envi-
ronmental tobacco smoke using 2,4-dinitrophenylhydra-
zine coated silica SEP-PAK cartridges; R&DM, 1987, No.
215, December 21, see www.rjrtdocs.com 512096470
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Program Booklet and Abstracts, Vol. 42, Paper No. 46,
1988, p. 40, for presentation text, see www.rjrtdocs.com
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929a. DeLucia, M.L., C.F. Mattina, and W.A. Selke: Physical
parameters that affect composition of smoke; Recent Adv.
Tob. Sci. 6 (1980) 225–238.
930. DeMarini, D.M.: Mutagenicity of cigarette smoke con-
densate in Saccharomyces cerevisiae; Mutation Res. 53
(1978) 84.
931. DeMarini, D.M.: Mutagenicity of fractions of cigarette
smoke condensate in Neurospora crassa and Salmonella
typhimurium; Mutation Res. 88 (1981) 363–374.
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934. Demetriou, D. and G. Schepers: Determination of
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high-performance liquid chromatography; 53rd Tobacco
Science Research Conference, Program Booklet and
Abstracts, Vol. 53, Paper No. 10, 1999, p. 24.
935. Demian, B.A.: Trace analysis of vanillin in tobacco;
46th Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 46, Paper No. 45, 1992, p.
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936. Demole, E. and D. Berthet: Identification de la dama-
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[Identification of damascenone and B-damascone in bur-
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937. Demole, E. and D. Berthet: A chemical study of burley
tobacco flavour (Nicotiana tabacum L.). I. Volatile to
medium-volatile constituents (b.p. a 84–114°C/0.001
Torr); Helv. Chim. Acta 55 (1972) 1866–1882.
938. Demole, E. and D. Berthet: A chemical study of burley
tobacco flavour (Nicotiana tabacum L.). II. Medium-
volatile, free acidic constituents (~b.p. 84–114°C/0.001
Torr); Helv. Chim. Acta 55 (1972) 1898–1901.
939. Demole, E. and C. Demole: A chemical study of burley
tobacco flavour (Nicotiana tabacum L.). V. Identification
and synthesis of the novel terpenoid alkaloids 1,3,6,6-
tetramethyl-5,6,7,8-tetrahydroisoquinolin-8-one and 3,6,
6-trimethyl-5,6-dihydropyridin-2-one; Helv. Chim. Acta
58 (1975) 523–531.
940. Demole, E. and C. Demole: A chemical study of burley
tobacco flavour (Nicotiana tabacum L.). VII. Identification
and synthesis of twelve irregular terpenoid alkaloids
related to solanone including 7,8-oxabicyclo[3,2,1]octane
and 4,5-dioxabicyclo[3,3,1]nonane; Helv. Chim. Acta 58
(1975) 1867–1880.
941. Demole, E., C. Demole, and D. Berthet: A chemical
study of burley tobacco flavour (Nicotiana tabacum L.).
III. Structure determination and synthesis of 5-(4-meth-
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of 3.4.7-trimethyl-1,6-dioxaspiro[4,5]dec-3-en-2-one
(“spiroxabovolide”). Two new flavor components of bur-
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942. Demole, E., C. Demole, and D. Berthet: A chemical
study of burley tobacco flavour (Nicotiana tabacum
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dioxabicyclo[3,3,1]nonane derivatives; Helv. Chim. Acta
57 (1964) 192–194.
943. Demole, E. and P. Dietrich: A chemical study of bur-
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advances in the chemical composition of tobacco and
tobacco smoke, edited by J.L. McKenzie, R.M. Ikeda,
T.R. Terrill, D.G. Vickroy, and D.B. Walters, Proc. Am.
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943a. Demole, E. and P. Enggist: Novel synthesis of 3,5,5-trim-
ethyl-4-(2-butenylidene)-cyclohex-2-en-1-one, a major
constituent of burley tobacco flavor; Helv. Chim. Acta 57
(1974) 2087–2091.
944. Demole, E. and P. Enggist: A chemical study of burley
tobacco flavour (Nicotiana tabacum L.). VI. Identification
and synthesis of four irregular terpenoids related to
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58 (1975) 1602–1607.
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945. Demole, E. and P. Enggist: A chemical study of Virginia
tobacco flavour (Nicotiana tabacum L.). I. Identification
and synthesis of two bicyclodamascenones; Helv. Chem.
Acta 59 (1976) 1938–1943.
946. Demole, E. and P. Enggist: A chemical study of Virginia
tobacco flavour (Nicotiana tabacum L.). II. Isolation
and synthesis of cis-2-isopropenyl-8-methyl-1,2,3,4-
tetrahydro-1-naphthalenol and 3-isopropenyl-5-methyl-
1,2-dihydronaphthalene; Helv. Chim. Acta 61 (1978)
1335–1341.
947. Demole, E. and P. Enggist: Identification of twenty-one
novel constituents of Oriental tobacco flavor (Nicotiana
tabacum L.), including (E)-3-methylnon-2-en-4-one, penta-
decan-15-olide, 8A,13`,9A,13-diepoxy-15,16-dinorlabdane,
(Z)-octadec-9-en-18-olide and (E)-2-ethylidene-6,10,14-
trimethylpentadecanal; Helv. Chim. Acta 61 (1978)
2318–2327.
948. Demole, E., P. Enggist, M. Winter, A. Furrer, K.H.
Schulte-Elte, B. Egger, and G. Ohloff: Megastigma-5,8-
dien-4-on, ein Aromastoff der gelben Passionsfrucht und
des Virginia Tabaks [Megastigma-5,8-dien-4-one, an
aroma substance of the yellow passion fruit and Virginia
tobacco]; Helv. Chim. Acta 62 (1979) 67.
949. Denissenko, M.F., A. Pao, M. Tang, and G.P. Pfeifer:
Preferential formation of benzo[a]pyrene adducts at lung
cancer mutational hotspots in P53; Science 274 (1996)
430–432.
950. Denissenko, M.F., J.X. Chen, M. Tang, and G.P. Pfeifer:
Cytosine methylation determines hot spots of DNA dam-
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950a. Denslow, S.A., A.A. Walls, and M.E. Daub: Regulation
of biosynthetic genes and antioxidant properties of
vitamin B6 vitamers during plant defense responses;
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950b. Deoxyrinonucleic acid (DNA): By a search (Google) on
the Internet, inserting the term deoxyrinonucleic acid
tobacco clone and the specific clone number provides
numerous references to it, e.g., Ohtani, T., H. Uchimiya,
A. Kato, H. Harada, M. Sugita, and M. Sugiura:
Localization and nucleotide sequence of a tobacco
chloroplast DNA segment capable of replication in the
yeast; Mol. Gen. Genet 195 (1984) 1–4. The search pro-
vides similar references to other deoxyrinonucleic acid
tobacco studies.
950c. DePuy, C.H. and R.W. King: Pyrolytic cis eliminations;
Chem. Rev. 60 (1960) 431–457.
951. de Roton, C., B. Vial, I. Wahlberg, A. Wiernik, H. San, and
J.L. Verrier: Study of factors influencing the concentra-
tion of tobacco-specific nitrosamines (TSNA) in air-cured
tobaccos; 55th Tobacco Science Research Conference,
Program Booklet and Abstracts, Vol. 55, Paper No. 98,
2001, p. 77.
952. Derreux, M., P. Viart, and D. Esnault: The essential oil
of tobacco. Study of the phenol fraction; Ann. Tabac 11
(1973) 121–129.
953. de Souza, T.L. and M. Scherback: The effect of glycerol
added to tobacco on the constituents of cigarette smoke;
Analyst 89 (1964) 735–739.
954. Deutsch, L.J. and A.L. Jeffords: Simultaneous gas
chromatographic nicotine/water analysis in smoke via
split injection on dual capillary columns; 48th Tobacco
Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 48, Paper No. 35, 1994, p. 45.
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955. Deutsch, L.J. and R.M. Robertson: Variability in the
determination of water in tobacco smoke; 45th Tobacco
Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 45, Paper No. 21, 1991, p. 24.
956. Deutsch, L.J. and J. Suthar: Contributions to variability
in the analysis of water in cigarette smoke and cigarette
filters; 56th Tobacco Science Research Conference,
Program Booklet and Abstracts, Vol. 56, Paper No. 45,
2002, p. 47.
956a. Deutsch-Wenzel, R., H. Brune, G. Grimmer, and J.
Misfeld: Local application to mouse skin as a carcinogen
specific test system for nonvolatile N-nitroso compounds;
Cancer Lett. 29 (1985) 85–92.
957. De Voogd, J.G. and A. Van der Linden: Carbon monoxide
in tobacco smoke; Het. Gas 59 (1939) 165–166.
958. Devreux, M., D. Esnault, and F. Gastal: Essential tobacco
oil. Study of the fatty acid fraction; Ann. Tabac, SEITA,
Series 1 1976(14) 111–117.
959. DeVries, A., M. DeBoer, and D. Schürer: A fully auto-
mated ultraviolet method for the determination of nicotine
alkaloids in tobacco and tobacco smoke condensate; Tob.
Sci. 20 (1976) 64–66.
960. de Wet, W.J.: Method for the quantitative determination of
the volatile organic acids in the range C1 to C6 in tobacco
smoke; South African J. Agr. Sci. 6 (1963) 535–540.
960a. Dewitte, W., A. Chiappetta, A. Azmi, E. Witters, M.
Strnad, J. Rembur, M. Noin, D. Chriqui, and H. Van
Onckelen: Dynamics of cytokinins in apical shoot
meristems of a day-neutral tobacco during floral tran-
sition and flower formation; Plant Physiol. 119 (1999)
111–122.
960b. Diamond, L.: Pulmonary toxicity of nitrogen oxides; in: A
safe cigarette? Banbury Report 3, edited by G.B. Gori and
F.G. Bock, Cold Spring Harbor Laboratory, Cold Spring
Harbor, NY (1980) 67–74.
960c. Diana, J.N. and W.A. Pryor (Editors): Tobacco smoking
and nutrition: Influence of nutrition on tobacco-associated
health risks; N. Y. Acad. Sci., New York, Ann. N.Y. Acad.
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961. Dickens, F. and D.K. Black: Chemical and biological
studies on some components of tobacco smoke; Tob.
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962. Dickerson, J.P. and H.E. Moser: Factors affecting nicotine
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963. Dickerson, J.P., I. Neas, G.W. Brown, R.M. Henderson,
W.B. James, W.B. Line, and H.C. Threatt Jr: Evaluation
of once-over low-profile tobacco. Part I. Processing and
leaf analysis; Tob. Sci. 22 (1978) 59–63.
964. Dickerson, J.P., I. Neas, G.W. Brown, R.M. Henderson,
W.B. James, W.B. Line, and H.C. Threatt Jr: Evaluation
of once-over low-profile tobacco. Part II. Smoke chem-
istry and smoking panel evaluation; Tob. Sci. 22 (1978)
67–70.
965. Dickerson, J.P., D.L. Roberts, C.W. Miller, R.A. Lloyd Jr,
and C.E. Rix: Flue-cured tobacco flavor. II. Constituents
arising from amino acid-sugar reactions; Tob. Sci. 20
(1976) 59–63.
966. Dickey, J.B. and G.P. Touey: Tobacco research:
Hydrocarbon components of the gaseous phase of ciga-
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967. Diekmann, J., C. Biefel, R. Stabbert, and K. Rustemeier:
Analysis of unsymdimethylhydrazine in cigarette smoke;
55th Tobacco Science Research Conference, Program
Booklet and Abstracts, Vol. 55, Paper No. 12, 2001, p. 27.
968. Diekmann, J. and K. Rustemeier: A new method for the
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971. Diffee, J.T.: The spectrophotometric determination of
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972. Diffee, J.T.: Spectrophotometric determination of total
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974. Diffee, J.T.: Determination of triethylene glycol, glycerol,
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975. Diffee, J.T. and M. E. Sheppard: An automated method
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994. Djordjevic, M.V., L.P. Bush, S.L. Gay, and H.R. Burton:
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995. Djordjevic, M.V., D. Desai, C. Sigountos, K.D.
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998. Djordjevic, M.V., J.F. Fan, K.D. Brunnemann, and D.
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Self-regulation of smoking intensity: Smoke yields of
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1000. Djordjevic, M.V., J.F. Fan, and D. Hoffmann: Assessment
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Analysis based on supercritical fluid extraction; 48th
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55; Assessment of chlorinated pesticide residues in ciga-
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1001. Djordjevic, M.V., J.F. Fan, and D. Hoffmann: Tobacco-
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1002. Djordjevic, M.V., S.L. Gay, L.P. Bush, and J.F. Chaplin:
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1003. Djordjevic, M.V., S.L. Gay, L.P. Bush, and C.T.
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1004. Djordjevic, M.V. and D. Hoffmann: Nicotine, pH, and
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49th Tobacco Chemists’ Research Conference, Program
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1005. Djordjevic, M.V., D. Hoffmann, K.D. Brunnemann, and
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 1300
tobacco-specific nitrosamines, alkaloids and nitrite in
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1006. Djordjevic, M.V., D. Hoffmann, J.F. Fan, B. Prokopczyk,
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nated pesticides and polychlorinated biphenyls in adi-
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1007. Djordjevic, M.V., D. Hoffmann, S. Thompson, and S.D.
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Science Research Conference, Program Booklet and
Abstracts, Vol. 52, Paper No. 59, 1998, p. 42.
1008. Djordjevic, M.V., J. Krzeminski, K.D. Brunnemann, and
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1009. Djordjevic, M.V., J. Krzeminski, K.D. Brunnemann, and
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1010. Djordjevic, M.V., C.T. MacKown, and L.P. Bush:
Alkaloids, nitrates and nitrosamines in lamina and stem
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39th Tobacco Chemists’ Research Conference, Program
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1011. Djordjevic, M.V., B. Prokopczyk, and W. Zatonski:
Tobacco-specific N-nitrosamines (TSNA) in tobacco
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A comparison with the U.S. and Japanese brands; 2000
CORESTA Congress, Lisbon, Portugal, CORESTA Inf.
Bull., 2000 Spec. Edition: Paper ST1, p. 145.
1012. Djordjevic, M.V., C. Sigountos, K.D. Brunnemann, and D.
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43rd Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 43, Paper No. 27, 1989, p.
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1013. Djordjevic, M.V., C. Sigountos, K.D. Brunnemann, and
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1014. Djordjevic, M.V., C. Sigountos, K.D. Brunnemann, and
D. Hoffmann: Tobacco-specific nitrosamine delivery in
the mainstream smoke of high- and low-yield cigarettes
smoked with varying puff volumes; CORESTA 1990
Symp., Kallithea, Greece, CORESTA Inf. Bull., Spec.
Edition 1990: Paper S04, 209.
1015. Djordjevic, M.V., C. Sigountos, K.D. Brunnemann, M.R.
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tobacco-specific N-nitrosamines and benzo[a]pyrene
delivered to smokers of low- and medium-nicotine cig-
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The Chemical Components of Tobacco and Tobacco Smoke
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1999, pp. 39–40.
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1046. Dontenwill, W., H. Elmenhorst, H.-P. Harke, G. Reckzeh,
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1047. Dontenwill, W., H. Elmenhorst, H.-P. Harke, G.
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Program Booklet and Abstracts, Vol. 36, Paper No. 21,
1982, p. 11; Tob. Sci. 27 (1983) 142–145.
1127a. Ellington, J.J., P.F. Schlotzhauer, and A.I. Schepartz:
Quantitation of tobacco lipids: Analysis of serial samples
of flue-cured tobacco; in: Recent advances in the chemi-
cal composition of tobacco and tobacco smoke, edited by
J.L. McKenzie, R.M. Ikeda, T.R. Terrill, D.G. Vickroy,
and D.B. Walters, Proc. Am. Chem. Soc. Symp., New
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1127b. Elliott, J.M.: Nutrition; Recent Adv. Tob. Res. Inaugural
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1128. Elliott, B.B.: The determination of organic and inor-
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1128a. Elliott, B.B., M.E. Long, and J.D. Shiffert: A method for
the extraction and quantitative determination of glucose,
fructose and sucrose in tobacco; 8th Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 8, Paper 19, 1954, p. 6.
1128b. Ellis, C.L., R.H. Cox, C.H. Callicutt, S.W. Laffoon, K.F.
Podraza, and J.I. Seeman: The effect of ingredients added
to tobacco in a commercial Marlboro Lights cigarette on
FTC nicotine yield, “smoke pH”, and Cambridge filter
trapping efficiency; CORESTA 1999 Conf., Innsbruck,
Austria, CORESTA Inf. Bull., Spec. Edition 1978: Paper
ST2, p. 11; The effect of ingredients, including ammonia
compounds, on the FTC nicotine yield and “smoke pH”
of a commercial Marlboro Lights cigarette; 53rd Tobacco
Science Research Conference, Program Booklet and
Abstracts, Vol. 53, Paper 45, 1999, p. 44.
1129. Elmenhorst, H.: Phenol content in successive puffs smoke
condensate; CORESTA Sci. Comm. Mtg., Vienna, Austria
(1964).
1130. Elmenhorst, H.: Vorversuche zur Bestimmung des Gehalts
von Polonium-210 in Rauchkondensat und Cigaretten
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1131. Elmenhorst, H.: Nachweis von Maltol in Cigarettenrauch
[Detection of maltol in cigarette smoke]; Beitr.
Tabakforsch. 6 (1971) 70–73.
1132. Elmenhorst, H.: Sauren und Phenolen in der “Semivolatile”
Fraktion des Rauches von Blend, Virginia-, Burley-, und
Orient-Cigarettes [Acids and phenols in the “semivola-
tile” fraction of the smokes from blended-, Virginia-, bur-
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6 (1972) 182–188.
1133. Elmenhorst, H.: Nachweis von Methylcyclopentenolon
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Latakiatabak [Detection of methylcyclopentenolone and
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tobacco]; Beitr. Tabakforsch. 6 (1972) 205–209.
1134. Elmenhorst, H.: Dihydro-G-pyrones in tobacco smoke.
Identification of 2,3-dihydro-5-hydroxy-6-methyl-4H-
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Sofia, Bulgaria, CORESTA Inf. Bull., Spec. Edition 1978:
Paper S05, 114–115.
1135. Elmenhorst, H.: Determination of naphthalenes in Latakia
tobacco; 7th Internat. Tob. Sci. Cong., Manila, The
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1136. Elmenhorst, H. and G. Grimmer: Polycyclische
Kohlenwasserstoffe aus Zigarettenrauchkondensat.
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1137. Elmenhorst, H. and H.-P. Harke: Ŭber die Bilanz des
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1138. Elmenhorst, H. and G. Nicolaus: Dihydro-G-pyrone im
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1139. Elmenhorst, H. and G. Reckzeh: Aromatische
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1140. Elmenhorst, H. and G. Schultz: Flüchtige Inhaltsstoffe
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1141. Elson, L.A. and T.E. Betts: Sugar content of the tobacco
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1142. Elson, L.A., T.E. Betts, and R.D. Passey: The sugar con-
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1143. Emami, I., K. Alexandrov, H. Vezinc, and C. Rolando:
New filters based on natural polyphenols scavenge effi-
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Congress, Lisbon, Portugal, CORESTA Inf. Bull., 2000
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1144. Entwhistle, I.D. and R.A.W. Johnstone: Alkenes in ciga-
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1145a. Environmental Health Center: IAQ Fact Sheet:
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1146. Environmental Protection Agency: Second annual report
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1147. Environmental Protection Agency: Maleic hydrazide:
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1148. Environmental Protection Agency: Environmental
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1149a. Enzell, C.R.: Recent progress in the chemistry of sun cured
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of tobacco and tobacco smoke, edited by J.L. McKenzie,
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1151. Enzell, C.R., S.O. Almqvist, and A.J. Aasen: CORESTA
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1152. Enzell, C.R., J. Arnarp, J. Bielawski, B.M. Dahlin, O.
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Vol. 44, Paper No. 66, 1990, p. 45.
1153. Enzell, C.R., D. Bergstedt, T. Dalhamn, and W.H. Johnson:
Tobacco chemistry. 4. Chemical and ciliotoxic studies of
smoke from freeze-dried tobacco; Beitr. Tabakforsch. 6
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1154. Enzell, C.R., D. Bergstedt, T. Dalhamn, and W.H. Johnson:
Tobacco chemistry. 8. Chemical and ciliotoxic studies of
smoke from heat-treated tobacco; Beitr. Tabakforsch. 6
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1155. Enzell, C.R., B. Kimland, and L.E. Gunnarsson: Tobacco
chemistry. 5. Norsolanesene, a C44-isoprenoid hydro-
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1156. Enzell, C.R. and I. Wahlberg: Leaf composition in rela-
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1157. Enzell, C.R., I. Wahlberg, and A.J. Aasen: Isoprenoids and
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1157a. Enzell, C.R., I. Wahlberg, and R. Ryhage: Mass spec-
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1157b. Epstein, S.S., J.J. Andrea, J. Forsyth, and N. Mantel:
The null effect of antioxidants on the carcinogenic-
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1158. Ergle, J.D.: A method for screening the profile of pheno-
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Tobacco Science Research Conference, Program Booklet
and Abstracts, Vol. 56, Paper No. 72, 2002, p. 64.
1159. Erickson, M., D. Lakings, A. Drinkwine, and J. Spigarelli:
Quantitative analysis of N-nitrosodiethanolamine by high
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1160. Ermaloeva-Makovskaya, A.P., L.A. Pertsov, and D.K.
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1161. Essenberg, J. M.: Cigarette smoke and the incidence of
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1162. Essenberg, J.M., M. Horowitz, and E. Gaffney: The inci-
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1163. Essenberg, J. M., A.M. Leavitt, and E. Gaffney: The effect
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1164. Esterle, J.G. and A.R. Campbell: The effect of moisture
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18th Tobacco Chemists’ Research Conference, Program
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1294. Giles, J.A. III: Collaborative study on the determina-
tion of propylene glycol, glycerine, and ethylene gly-
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1295. Giles J.A. III and R.H. Cundiff: Collaborative study of
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1296. Giles, J.A. III and H.L. Gilleland: Determination of
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1297. Giles, J.A. III and J.N. Schumacher: Turkish tobacco.
Isolation and characterization of dehydrosclareolide;
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1298. Giles, J.A. III and J.N. Schumacher: Turkish tobacco.
Isolation and characterization of 12A-hydroxy-13-
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J.N. Schumacher, S.S. Mims, and E. Bernasek: Turkish
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1299. Giles, J.A. III and J.N. Schumacher: Turkish tobacco. I. The
isolation and characterization of A- and B-levantenolide;
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1300. Giles, J.A. III, J.N. Schumacher, and G.W. Young:
Turkish tobacco. II. The isolation and characterization of
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1301. Giles, J.A. III and B.N. Sullivan: Modified determina-
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1302. Gilleland, H.L. and L.A. Lyerly: Triacetin content of
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1303. Gilleland, H.L. and L.A. Lyerly: Gas chromato-
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1304. Gillman, I.G. Jr, J.E. Fossett, N. Finkel, and R.D.
Bereman: Investigations into a rapid method for deter-
mining tobacco-specific N-nitrosamines and volatile
nitrosamines in sidestream tobacco smoke using LC/
MS/MS with positive ion electrospray; 56th Tobacco
Science Research Conference, Program Booklet and
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1305. Gillman, I.G. Jr, and K.A. Wagner: The rapid and quan-
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mainstream tobacco smoke using LC/MS/MS with posi-
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1305a. Giovannozzi-Sermanni, G.: Analytical research on
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acids in three varieties of subtropical tobacco during cur-
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IV. Amino acids in three varieties of subtropical tobacco
during curing and fermentation; Il Tabacco 59 (1955)
335–343; V. Variation of some chemical components of
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1305b. Giovannozzi-Sermanni, G.: Analytical research on
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61 (1957) 349–357.
1306. Giovannozzi-Sermanni, G. and N. Carugno: Analytical
investigations on tobacco by means of vapour phase
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fermentation on the gas substances in smoke. Studies on
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1307. Gladding, R.N., W.B. Wartman, and H.E. Wright: The
isolation of a phytadiene from aged burley tobacco;
11th Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 11, Paper No. 12, 1957;
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1311. Glock, E.: Rapid color test for estimating nornicotine
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1313 Glock, E., R.K. Odland, N.L. Bodenhamer, and R.W.
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1314. Glock, E. and T.H. Vaughan: Quantitative chromato-
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1315. Glock, E. and M.P. Wright: Colorimetric determina-
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1316. Glock, E. and M.P. Wright: The relation of nornicotine
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1317. Glock, E. and M.P. Wright: Determination of nornicotine
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1317a. Glucanase: By a search (Google) on the Internet, insert-
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1324. Gordon, B.M., M.F. Borgerding, and R.S. Dunn:
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1325. Gordon, B.M. and W.M. Coleman III: Determination
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1326. Gordon, B.M., W.M. Coleman III, J.F. Elder Jr, J.A.
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1328. Gordon, B.M., M.S. Uhrig, M.F. Borgerding, W.M.
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1329. Gori, G.B. (Editor): Report No. 1. Toward less hazardous
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1333. Gori, G.B. (Editor): Report No. 4. Toward less hazard-
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1334. Gori, G.B., S.P. Battista, P.S. Thayer, M.R. Guerin, and
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1334a. Gori, G. B., N. L. Benowitz, and C. J. Lynch: Mouth
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1336. Graham, J.F.: Calculation of retention values and selec-
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1343. Grant, S.J.: Catalytic and non-catalytic additives for
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1346. Graves, H.: Determination of water in Cambridge-filtered
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1347. Graves, H.: Rapid analysis of individual component(s) of
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1348. Green, C.R.: Smoke composition: MTP dyed and MTP
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1349. Green, C.R.: Smoke composition: MTP cigarettes
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1350. Green, C.R.: Smoke composition: L7081A and L7081B
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1351. Green, C.R.: Some relationships between tobacco leaf and
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1352. Green, C.R.: Neutral oxygenated compounds in cigarette
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1352a. Green, C.R.: Personal communication (1980).
1353. Green, C.R.: A discussion of smoke generation and ana-
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1354. Green, C.R. and F.W. Best: Smoke composition:
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1355. Green, C.R. and F.W. Best: Smoke composition:
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1356. Green, C.R. and F.W. Best: Pyrolysis products of licorice;
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1357. Green, C.R. and F.W. Best: Pyrolysis products of various
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1358. Green, C.R., F.W. Best, C.C. Morrison, and F.W. Conrad
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An analytical study of vanillin as a cigarette flavor;
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1359. Green, C.R., F.W. Best, C.C. Morrison, and L.W. Eudy:
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1360. Green, C.R., F.W. Best, M.P. Newell, R.A. Lloyd Jr, and
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1366. Green, C.R., M.F. Dube, C.W. Miller, F.W. Best, and T.M.
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1369. Green, C.R., J.M. Martin, and A. Rodgman: Effect of
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1375. Green, C.R. and J.N. Schumacher: Smoke composition:
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1376. Green, C.R. and D.E. Townsend: The effect of casing on
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1377. Green, C.R., L. Vestal, and J.N. Schumacher: The Sutton
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1386. Gregg, E., C. Hill, M. Hollywood, M. Kearney, K.
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1394. Griffiths, W.T., D.R. Trelfall, and T.W. Goodwin:
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1396. Grimmer, G.: Eine Methode zur Bestimmung von 3,4-
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1397. Grimmer, G.: Polycyclische aromatische Kohlenwass-
erstoffe - ihre Vorkommen und ihre Bestimmung [Polycyclic
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1399. Grimmer, G.: Bilanzierung der Krebserzeugenden
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Kohleöfen mit carcinogen-spezifischen Testen [Balancing
the cancer-producing action of the emissions from motor
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1400. Grimmer, G.: Environmental carcinogens: Polycyclic aro-
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1401. Grimmer, G.: Eintrag, Monitoring und Bewertung der
kanzerogenen Umweltbelastung durch polycyclische aro-
matische Kohlkenwasserstoffe [Collection, monitoring,
and estimation of the carcinogenic environmental burden
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from polycyclic aromatic hydrocarbons]; GIT Fachz. Lab.
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1402. Grimmer, G. and H. Böhnke: Bestimmung des
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Kohlenwasserstoffe in Luftstaub und Kraftfahrzeugabgas
mit der Capillar-Gas-Chromatographie [Estimation of the
total content of all polycyclic aromatic hydrocarbons in
air particles and motor vehicles exhaust gas with capil-
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1403. Grimmer, G., H. Böhnke, and H.P. Harke: Passive smok-
ing: Measurement of concentration of polycyclic aromatic
hydrocarbons in rooms after machine smoking of ciga-
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1404. Grimmer, G., H. Böhnke, and H.P. Harke: Passive smok-
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breathing of cigarette smoke-containing air; Internat.
Arch. Occup. Environ. Hlth. 40 (1977) 93–99.
1405. Grimmer, G., H. Brune, G. Dettbarn, J. Jacob, J. Misfeld,
U. Mohr, K.W. Naujack, J. Timm and R. Wenzel-Hartung:
Contribution of polycyclic aromatic hydrocarbons and
other polycyclic aromatic compounds to the carcinoge-
nicity of combustion source and air pollution; Environ.
Sci. Res. 39 (1990) 127–140; Relevance of polycyclic
aromatic hydrocarbons as environmental carcinogens;
Fresenius J. Anal. Chem. 339 (1991) 792–795.
1406. Grimmer, G., H. Brune, G. Dettbarn, K.W. Naujack, U.
Mohr, and R. Wenzel-Hartung: Contribution of polycy-
clic aromatic hydrocarbons to the carcinogenicity of side-
stream smoke of cigarettes evaluated by implantation into
the lung of rats; Cancer Lett. 43 (1988) 173–177.
1406a. Grimmer, G., H. Brune, R. Deutsch-Wenzel, G. Dettbarn,
and J. Misfeld: Contribution of polycyclic aromatic
hydrocarbons to the carcinogenic impact of gasoline
engine exhaust condensate evaluated by implantation
into the lungs of rats; J. Natl. Cancer Inst. 72 (1984)
733–739; Grimmer, G., H. Brune, R. Deutsch-Wenzel,
G. Dettbarn, J. Jacob, K.W. Naujack, U. Mohr, and H.
Ernst: Contribution of polycyclic aromatic hydrocar-
bons and nitro-derivatives to the carcinogenic impact
of diesel exhaust condensate evaluated by implantation
into the lungs of rats; Cancer Lett. 37 (1987) 173–180.
1406b. Grimmer, G., H. Brune, R. Deutsch-Wenzel, K.W.
Naujack, J. Misfeld, and J. Timm: On the contribution
of polycyclic aromatic hydrocarbons to the carcinogenic
impact of automobile exhaust condensate evaluated by
local application onto mouse; Cancer Lett. 21 (1983)
105–113.
1407. Grimmer, G., A. Glaser, and G. Wilhelm: Die Bildung
von Benzo(a)pyren und Benzo(e)pyrene beim
Erhitzen von Tabak in Abhängigkeit von Temperatur
und Strömungsgeschwindigkeit in Luft- und
Stickstoffatmosphäre [The formation of benzo[a]pyrene
and benzo[e]pyrene during the heating of tobacco in cor-
relation to temperature and flow rate in air and nitrogen
atmospheres]; Beitr. Tabakforsch. 3 (1966) 415–421.
1407a. Grimmer, G., J. Jacob, and K.W. Naujack: Characterization
of methylene azaarenes in petroleum by capillary gas
chromatography and mass spectrometry; Anal. Chem. 55
(1983) 2398–2404.
1407b. Grimmer, G., J. Jacob, K.W. Naujack, G. Dettbarn, H.
Brune, R. Deutsch-Wenzel, J. Misfeld, and J. Timm:
Contribution of polycyclic aromatic compounds to the
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1471. Haeberer, A.F. and O.T. Chortyk: High pressure liquid
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1474. VOID
1475. Haeberer, A.F., M.E. Snook, and O.T. Chortyk: Reverse-
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1488. Hale, R.W., R.M. Ikeda, and F.L. Daylor Jr: Transfer of
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1491. Halter, H.H., T. Fazio, and S. Rosenberg: The presence
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1492. Halter, H.M. and T.I. Ito: Effect of tobacco reconstitution
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1495. Hanmer, H.R.: Filter “balances” smoke. New filter has
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1499. Harbin, B.A. and T.W. Stamey: Automated data acqui-
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1500. Hardy, D.R. and M.E. Hobbs: The use of N15 and of N15
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1501. Hardy, D.R. and M.E. Hobbs: Isotope dilution study
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1502. Harke, H.P.: Beitrag zur Analytik von Rauchkondensat
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1503. Harke, H.P.: Zum Problem des Passivrauchens. I. Über
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1504. Harke, H.P. and C.J. Drews: Eine einfache Methode zur
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1505. Harke, H. P., C.J. Drews, and D. Schüller: Über das
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1506. Harke, H. P. and H. Peters: Zum Problem des
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53 (1974) 1121–1133.
1561. Hecht, S.S., S. Carmella, and D. Hoffmann:
Hydroxyphenyl alcohols in tobacco and tobacco
smoke; 31st Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 31, Paper No. 51,
1977, p. 26; Chemical studies on tobacco smoke. LIV.
Determination of hydroxybenzyl alcohols and hydroxy-
phenylethanols in tobacco and tobacco smoke; J. Anal.
Toxicol. 2 (1978) 56–59.
1562. Hecht, S.S., S. Carmella, H. Mori, and D. Hoffmann: A
study of tobacco carcinogenesis. XX. Role of catechol as a
major cocarcinogen in the weakly acidic fraction of smoke
condensate; J. Natl. Cancer Inst. 66 (1981) 163–169.
1562a. Hecht, S.S., S.G. Carmella, S.E. Murphy, S. Akerkar,
K.D. Brunnemann, and D. Hoffmann: A tobacco-specific
lung carcinogen in the urine of men exposed to cigarette
smoke; New Eng. J. Med. 329 (1993) 1543–1546.
1563. Hecht, S.S., C.B. Chen, M. Dong, R.M. Ornaf, D.
Hoffmann, and T.C. Tso: Studies on non-volatile nit-
rosamines in tobacco; Beitr. Tabakforsch. Int. 9 (1977)
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1564. Hecht, S.S., C.B. Chen, N. Hirota, R.M. Ornaf, T.C.
Tso, and D. Hoffmann: A study of tobacco carcinogen-
esis. XVI. Tobacco-specific nitrosamines: Formation
from nicotine in vitro and during curing of tobacco and
carcinogenicity in Strain-A mice; J. Natl. Cancer Inst.
60 (1978) 819–824.
1565. Hecht, S.S., C.B. Chen, and D. Hoffmann: Synthesis of
N-nitrosamine aldehydes; Tetrahedron Lett. 8 (1976)
593–596.
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1567. Hecht, S.S., C.B. Chen, J. LaVoie, and D. Hoffmann:
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1569. Hecht, S.S., C.B. Chen, R. Young, and D. Hoffmann:
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1570. Hecht, S.S., P. Foiles, S. Carmella, N. Trushin, A.
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1571. Hecht, S.S. and D. Hoffmann: Tobacco-specific nitro-
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1571a. Hecht, S.S. and D. Hoffmann: 4-(Methylnitrosamino)-1-
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1572. Hecht, S.S., P.M. Kenney, M. Wang, N. Trushin, S.
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butylated hydroxyanisole, meso-inositol, cucumin, escu-
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1573. Hecht, S.S., M. Loy, R. Maronpot, and D. Hoffmann:
A study of chemical carcinogenesis: Comparative car-
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1573a. Hecht, S.S., S.E. Murphy, and D. Hoffmann: Tobacco-
specific lung carcinogen and exposure to passive smok-
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1574. Hecht, S.S., R.M. Ornaf, C.B. Chen, D. Hoffmann,
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tobacco; 29th Tobacco Chemists’ Research Conference,
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1575. Hecht, S.S., R.M. Ornaf, M. Dong, and D. Hoffmann:
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N-Nitrosoalkaloids in tobacco; 28th Tobacco Chemists’
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1577. Hecht, S.S., R.M. Ornaf, and D. Hoffmann: Determination
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1578. Hecht, S.S., R.M. Ornaf, and D. Hoffmann: Chemical
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1579. Hecht, S.S., R. Raineri, R. Maronpot, D. Hoffmann:
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1580. Hecht, S.S., I. Schmeltz, and D. Hoffmann: Chemical
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1582. Hecht, S.S., R.L. Thorne, and D. Hoffmann: Studies
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1594. Hege, R.B. Jr: Modification of routine thin-layer
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1595. Hege, R.B. Jr: Gas chromatographic determination of
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1598. Hege, R.B. Jr: Determination of neophytadiene in
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1685. Hoffmann, D., J.D. Adams, J.J. Piade, and S.S. Hecht:
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1686. Hoffmann, D., J.D. Adams, N. Vinchkoski, and T.C.
Tso: On the fate of nicotine-C14 during leaf curing and
smoking; CORESTA 1982 Symp., Winston-Salem, NC,
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1687. Hoffmann, D., S. Amin, K.D. Brunnemann, D. Desai,
and A.C. Collins: On the modulation of nicotine: Studies
on 2-methylnicotine; 53rd Tobacco Science Research
Conference, Program Booklet and Abstracts, Vol. 53,
Paper No. 29, 1999, p. 35.
1688. Hoffmann, D., S. Amin, K.D. Brunnemann, B.
Prokopczyk, A. Rivenson, and S.S. Hecht Tobacco-
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biochemical studies; in: S.V. Bhide and K.V.K. Rao:
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1689. Hoffmann, D., N.L. Benowitz, A.K. Armitage, and A.
Leone: Letter to the Editor in response to Editorial by
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1691. Hoffmann, D. and K.D. Brunnemann: On the endog-
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1693. Hoffmann, D., K.D. Brunnemann, and J.D. Adams:
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119–120.
1694. Hoffmann, D., K.D. Brunnemann, and J.D. Adams:
Tobacco-specific N-nitrosamine (TSNA): Recent prog-
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Tob. Sci. Cong., Vienna, Austria, 1984, CORESTA Inf.
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1695. Hoffmann, D., K.D. Brunnemann, J.D. Adams, and N.J.
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1696. Hoffmann, D., K.D. Brunnemann, J.D. Adams, and
S.S. Hecht: Formation and analysis of N-nitrosamines
in tobacco products and their endogenous formation in
consumers; in: N-Nitroso compounds: Occurrence, bio-
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and H. Bartsch, IARC, Lyon, France, IARC Sci. Publ.
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1697. Hoffmann, D., K.D. Brunnemann, J.D. Adams, and S.S.
Hecht: Laboratory studies on snuff-dipping and oral
cancer; Cancer J. 1 (1986) 10–13.
1698. Hoffmann, D., K.D. Brunnemann, J.D. Adams, A.
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Report 12, edited by P.N. Magee, Cold Spring Harbor
Laboratory, Cold Spring Harbor, NY (1982) 211–225.
1699. Hoffmann, D., K.D. Brunnemann, G.B. Gori, and E.L.
Wynder: On the chemistry and carcinogenicity of mari-
juana smoke compared with tobacco cigarette smoke;
Rec. Adv. Phytochem. 9 (1975) 63–81.
1700. Hoffmann, D., K.D. Brunnemann, N.J. Haley, D.W.
Sepkovic, and J.D. Adams: Nicotine uptake by non-
smokers exposed to passive smoking under controlled
conditions and the elimination of cotinine; in: Indoor air,
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1701. Hoffmann, D., K.D. Brunnemann, and I. Hoffmann:
Significance of benzene in tobacco carcinogenesis; Adv.
Mod. Environ. Toxicol. 16 (1989) 99–112.
1702. Hoffmann, D., K.D. Brunnemann, B. Prokopczyk, and
M.V. Djordjevic: Tobacco-specific N-nitrosamines and
Areca-derived N-nitrosamines: Chemistry, biochemis-
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Environ. Hlth. 41 (1994) 1–52.
1703. Hoffmann, D., K.D. Brunnemann, and G. Rathkamp:
Unpublished data noted in D. Hoffmann and E.L.
Wynder: [Chemical studies on tobacco smoke. XVIII]
Smoke of cigarettes and little cigars: An analytical com-
parison; Science; 178 (1972) 1197–1199.
1704. Hoffmann, D., K.D. Brunnemann, A. Rivenson, and S.S.
Hecht: N-Nitrosodiethanolamine: Analysis, formation in
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tobacco products and carcinogenicity in Syrian golden
hamsters; Proc. 7th Internat. Mtg on N-Nitroso
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1705. Hoffmann, D., K.D. Brunnemann, A. Rivenson, and S.S.
Hecht: N-Nitrosodiethanolamine: Analysis, formation in
tobacco products and carcinogenicity in Syrian golden
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(1982) 299–308.
1706. Hoffmann, D., K.D. Brunnemann, I. Schmeltz, and E.L.
Wynder: Trace analysis in respiratory carcinogenesis;
9th Mat. Res. Symp., Natl. Bureau Std., Gaithersburg,
MD. in: Trace organic analysis: A new frontier in ana-
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1707. Hoffmann, D., K.D. Brunnemann, and S. Venitt:
Carcinogenic nitrosamines in oral snuff; Lancet (1988)
1232.
1708. Hoffmann, D., K.D. Brunnemann, and K.S. Webb:
Volatile nitrosamines in tobacco and mainstream
smoke and sidestream smoke and indoor environments;
in: Environmental carcinogens: Selected methods of
analysis, Vol. 6: N-Nitroso compounds, edited by H.
Egan, R. Preussmann, I.K. O’Neill, O. Eisenbrand, B.
Spiegelhalder, and H. Bartsch, IARC, Lyon, France,
IARC Sci. Publ. No.45 (1983) 69–83.
1709. Hoffmann, D., K.D. Brunnemann, and E.L. Wynder:
Chemical studies on tobacco smoke. A comparison of
selected constituents in the smoke of some commercial
cigarettes; Manuscript (1974) see www.rjrtdocs.com
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1710. Hoffmann, D., A. Castonguay, A. Rivenson, and S.S.
Hecht: Comparative carcinogenicity and metabolism
of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and
N’-nitrosonornicotine in Syrian golden hamsters; Cancer
Res. 41 (1981) 2386–2393.
1711. Hoffmann, D., C.H.B. Chen, and S.S. Hecht:
Toxicological dimensions: The role of volatile and non-
volatile N-nitrosamines in tobacco carcinogenesis; in: A
safe cigarette? Banbury Report 3, edited by G.B. Gori
and F.G. Bock, Cold Spring Harbor Laboratory, Cold
Spring Harbor, NY (1980) 113–127.
1712. Hoffmann, D. and M.V. Djordjevic: Chemical compo-
sition and carcinogenicity of smokeless tobacco; Adv.
Dental Res. 11 (1997) 322–329.
1713. Hoffmann, D., M.V. Djordjevic, and K.D. Brunnemann:
New brands of oral snuff; Food Chem. Toxicol. 29
(1991) 65–68.
1714. Hoffmann, D., M.V. Djordjevic, and K.D. Brunnemann:
Changes in cigarette design and composition over time
and how they influence the yields of smoke constituents.
J. Smoking-Related Dis. 6 (1995) 9–23.
1715. Hoffmann, D., M.V. Djordjevic, J. Fan, E. Zang, T.
Glynn, and G.N. Connolly: Five leading U.S. commer-
cial brands of moist snuff in 1994: Assessment of carci-
nogenic N-nitrosamines; J. Natl. Cancer Inst. 87 (1995)
1862–1869.
1716. Hoffmann, D., M.V. Djordjevic, and I. Hoffmann: The
changing cigarette; Prev. Med. 26 (1997) 427–434.
1717. Hoffmann, D., M. Dong, and S.S. Hecht: Origin in
tobacco smoke of N’-nitrosonornicotine, a tobacco-spe-
cific carcinogen. A brief communication; J. Natl. Cancer
Inst. 58 (1977) 1841–1844.
1718. Hoffmann, D., G.B. Gori, and T.C. Tso: The less harm-
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1725. Hoffmann, D. and S.S. Hecht: Nicotine-derived
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1726. Hoffmann, D. and S.S. Hecht: Smokeless tobacco and
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1728. Hoffmann, D., S.S. Hecht, K.D. Brunnemann, and E.L.
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1729. Hoffmann, D., S.S. Hecht, N.J. Haley, K.D. Brunnemann,
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1730. Hoffmann, D., S.S. Hecht, N.J. Haley, K.D. Brunnemann,
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1731. Hoffmann, D., S.S. Hecht, A.A. Melikian, N.J. Haley,
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by chewers, smokers, and non-smokers; Biochem. Mol.
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1732. Hoffmann, D., S.S. Hecht, and R.M. Ornaf: Nonvolatile
N-nitrosamines in tobacco and tobacco smoke; CORESTA
Inf. Bull., 1974 Spec. Edition: Paper No. 36.
1733. Hoffmann, D., S.S. Hecht, R.M. Ornaf, and E.L. Wynder:
N’-Nitrosonornicotine in tobacco; Science 186 (1974)
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1735. Hoffmann, D., S.S. Hecht, I. Schmeltz, K.D.
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1736. Hoffmann, D., S.S. Hecht, and E.L. Wynder: Tumor
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1737. Hoffmann, D. and I. Hoffmann: Significance of expo-
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carcinogens. Method of analysis and exposure measure-
ment. Vol. 9. Passive smoking, edited by I.K. O’Neill,
K.D. Brunnemann, B. Dodet, and D. Hoffmann, IARC,
Lyon, France, IARC Sci. Publ. No. 81 (1987) 8–10.
1738. Hoffmann, D. and I. Hoffmann: On the reduction of
nicotine in cigarette smoke; in: Nicotine, smoking,
and the low-tar programme, edited by N. Wald and
P. Froggatt, Oxford University Press, New York, NY
(1988) 200–211.
1739. Hoffmann, D. and I. Hoffmann: Tobacco consumption
and lung cancer; Cancer Treat. Res. 72 (1995) 1–42.
1740. Hoffmann, D. and I. Hoffmann: [Chemical studies on
tobacco smoke. C.] The changing cigarette: 1950–1995;
J. Toxicol. Environ. Hlth. 50 (1997) 307–364.
1741. Hoffmann, D. and I. Hoffmann: Tobacco smoke com-
ponents. Letter to the Editor; Beitr. Tabakforsch. Int. 18
(1998) 49–52.
1742. Hoffmann, D. and I. Hoffmann: [Cigar smoke:]
Chemistry and toxicology; Smoking and Tobacco
Control Monograph 9 (1998) 55–104.
1743. Hoffmann, D. and I. Hoffmann: The changing ciga-
rette: Chemical studies and bioassays; Chapter 5 in:
Risks associated with smoking cigarettes with low
machine-measured yields of tar and nicotine, NCI
Smoking and tobacco control, Monograph 13, edited
by D.M. Burns and N.L. Benowitz, Bethesda, MD
(2001) 159–191.
1744. Hoffmann, D., I. Hoffmann, and K. El-Bayoumy: The
less harmful cigarette: A controversial issue. A tribute
to Ernst L. Wynder; Chem. Res. Toxicol. 14 (2001)
767–790.
1745. Hoffmann, D., I. Hoffmann, and E.L. Wynder: Lung can-
cer and the changing cigarette; in: Relevance to human
cancer of N-nitroso compounds, tobacco and mycotox-
ins, edited by I.K. O’Neill, J. Chen, and H. Bartsch,
IARC, Lyon, France, IARC Sci. Publ. No. 105 (1991)
449–459.
1746. Hoffmann, D., E.J. LaVoie, and S.S. Hecht: Nicotine:
A precursor for carcinogens; Cancer Lett. 26 (1985)
67–75.
1747. Hoffmann, D., Y. Masuda, and E.L. Wynder:
A-Naphthylamine and B-naphthylamine in cigarette
smoke; Nature 221 (1969) 254–256.
1748. Hoffmann, D. and V. Mazzola: Chemical studies on
tobacco smoke. XI. Dibenzofurans in cigarette smoke;
Beitr. Tabakforsch. 5 (1970) 183–188.
1749. Hoffmann, D., A.A. Melikian, J.D. Adams, K.D.
Brunnemann, and N.J. Haley: New aspects of tobacco
carcinogenesis; in: Carcinogenesis. A comprehensive
11/24/08 2:39:44 PM
 1330
survey, edited by M. Mass et al., Raven Press, New
York, NY (1985) 239–256.
1750. Hoffmann, D., A.A. Melikian, and K.D. Brunnemann:
Studies in tobacco carcinogenesis; in: Relevance to
human cancer of N-nitroso compounds, tobacco and
mycotoxins, edited by I.K. O’Neill, J. Chen, and H.
Bartsch, IARC, Lyon, France, IARC Sci. Publ. No. 105
(1991) 482–484.
1751, Hoffmann, D., A.A. Melikian, and E.L. Wynder:
Scientific challenges in environmental carcinogenesis.
Preventive Med. 25 (1996) 14–22.
1752. Hoffmann, D., C.P. Patrianakos, K.D. Brunnemann, and
G.B. Gori: On the analysis of vinyl chloride in tobacco
smoke; 29th Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 29, Paper No. 17,
1975, p. 17; Hoffmann, D., Patrianakos CP, and K.D.
Brunnemann: Chromatographic determination of vinyl
chloride in tobacco smoke; Anal. Chem. 48 (1976)
47–50.
1753. Hoffmann, D., R. Raineri, S.S. Hecht, R. Maronpot, and
E.L. Wynder: A study of tobacco carcinogenesis. XIV.
Effect of N’-nitrosonornicotine and N’-nitrosoanabasine
in rats; J. Natl. Cancer Inst. 55 (1975) 977–981.
1754. Hoffmann, D. and G. Rathkamp: Unpublished 1966 find-
ings cited in E.L. Wynder and D. Hoffmann: Tobacco
and tobacco smoke: Studies in experimental carcinogen-
esis, Academic Press, New York, NY (1967) 526.
1755. Hoffmann, D. and G. Rathkamp: Chemical studies on
tobacco smoke. III. Primary and secondary nitroal-
kanes in cigarette smoke; Beitr. Tabakforsch. 4 (1968)
124–134.
1756. Hoffmann, D. and G. Rathkamp: Quantitative analy-
sis of chlorinated hydrocarbon insecticides in tobacco
and cigarette smoke; CORESTA Mtg., Stockholm,
Sweden (1968); Chemical studies on tobacco smoke. V.
Quantitative determination of chlorinated hydrocarbon
insecticides in cigarette tobacco and its smoke; Beitr.
Tabakforsch. 4 (1968) 201–214.
1757. Hoffmann, D. and G. Rathkamp: Quantitative determi-
nation of 1-alkylindoles in cigarette smoke; Anal. Chem.
42 (1970) 366–370.
1758. Hoffmann, D. and G. Rathkamp: Quantitative determi-
nation of nitrobenzenes in cigarette smoke; Anal. Chem.
42 (1970) 1643–1647.
1759. Hoffmann, D. and G. Rathkamp [Chemical studies on
tobacco smoke. XIV.] Quantitative determination of
fluorenes in cigarette smoke and their formation by
pyrosynthesis; Anal. Chem. 44 (1972) 899–904.
1760. Hoffmann, D., G. Rathkamp, K.D. Brunnemann and
E.L. Wynder: Chemical studies on tobacco smoke.
XXII. On the profile analysis of tobacco smoke; Sci.
Total Environ. 2 (1973) 157–171.
1761. Hoffmann, D., G. Rathkamp, and Y. Liu: Chemical stud-
ies on tobacco smoke. XXVI. On the isolation of vola-
tile and nonvolatile N-nitrosamines and hydrazines in
cigarette smoke; in: N-Nitrosamines in the environment,
edited by P. Bogovski and E.A. Walker, IARC, Lyon,
France, IARC Sci. Publ. No. 9 (1974) 159–165.
1762. Hoffmann, D., G. Rathkamp, and S. Nesnow: Quantitative
determination of 9-methylcarbazoles in cigarette smoke;
Anal. Chem. 41 (1969) 1256–1259.
1763. Hoffmann, D., G. Rathkamp, S. Nesnow, and E.L.
Wynder: Chemical studies on tobacco smoke. XVI.
Fluoranthenes: Quantitative determination in cigarette
© 2009 by Taylor & Francis Group, LLC
78836_C029.indd 1330
The Chemical Components of Tobacco and Tobacco Smoke
smoke, formation by pyrolysis, and tumor initiation
activity; J. Natl. Cancer Inst. 49 (1972) 1165–1175.
1764. Hoffmann, D., G. Rathkamp, and J. Rubin: Chemical
studies on tobacco smoke. II. Comparison of yields of
several selected components in the smoke from five
major Turkish tobacco varieties; Food Cosmet. Toxicol.
5 (1967) 37–38.
1765. Hoffmann, D., G. Rathkamp, and H. Woziwodzki:
Chemical studies on tobacco smoke. VI. Quantitative
determination of carbazoles in cigarette smoke; Beitr.
Tabakforsch. 4 (1968) 253–263.
1766. Hoffmann, D., G. Rathkamp, and E.L. Wynder:
Comparison of the yields of several selected compo-
nents in the smoke from different tobacco products; J.
Natl. Cancer Inst. 31 (1963) 627–637.
1767. Hoffmann, D., G. Rathkamp, and E.L. Wynder:
Chemical studies on tobacco smoke. IX. Quantitative
analysis of chlorinated hydrocarbon insecticides; Beitr.
Tabakforsch. 5 (1969) 140–148.
1767a. Hoffmann, D., G. Rathkamp, and E.L. Wynder:
Chemical analysis of a PAH concentrate from cigarette
smoke; CORESTA Bull. (1971) 70–71.
1768. Hoffmann, D., A. Rivenson, R. Abbi, and E.L.
Wynder: A study of tobacco carcinogenesis. Effect of
the fat content of the diet on the carcinogenicity of 4-
(methylnitrosamino)-1-(3-pyridyl)-1-butanone in F344
rats; Cancer Res. 53 (1993) 2758–2761.
1768a. Hoffmann, D., A. Rivenson, J.D. Adams A. Juchatz,
N. Vinchkoski, and S.S. Hecht: Effects of route of
administration and dose on the carcinogenicity of
N-nitrosodiethanolamine in the Syrian golden hamster;
Cancer Res. 43 (1983) 2521–2524.
1769. Hoffmann, D., A. Rivenson, S. Amin, and S.S. Hecht:
Dose-response study of the carcinogenicity of tobacco-
specific N-nitrosamines in F344 rats; J. Cancer Res.
Clin. Oncol. 108 (1984) 81–86.
1770. Hoffmann, D., A. Rivenson, K.D. Brunnemann, and S.S.
Hecht, Tobacco-specific N-nitrosamines (TSNA) and
their relevance to human cancer; J. Cancer Res. Clin.
Oncol. 116 (Suppl., Pt. 2) (1990) 1089.
1771. Hoffmann, D., A. Rivenson, F.L. Chung, and S.S. Hecht:
Relevance of nicotine-derived N-nitrosamines in tobacco
carcinogenesis; in: Effects of nicotine on biological
systems, edited by F.X. Adlkofer and K. Thurau, Adv.
Pharmacol. Sci., Biohäuser Verlag, Birkhauser, Basel,
Switzerland (1991) 89–101.
1772. Hoffmann, D., A. Rivenson, F.L. Chung, and S.S. Hecht:
Nicotine-derived N-nitrosamines and their relevance in
tobacco carcinogenesis; Crit. Rev. Toxicol. 21 (1991)
305–311.
1773. Hoffmann, D., A. Rivenson, F.L. Chung, and E.L.
Wynder, Potential inhibitors of tobacco carcinogenesis;
in: Tobacco smoking and nutrition: Influence of nutri-
tion on tobacco-associated health risks, edited by J.N.
Diana and W.A. Pryor, Ann. N.Y. Acad. Sci. 686 (1993)
140–160.
1774. Hoffmann, D., A. Rivenson, and S.S. Hecht: The
role of nicotine in tobacco carcinogenesis. Tribute R.
Truhaut; Fac. Pharm., Univ. Paris, Paris, France (1984)
491–495.
1775. Hoffmann, D., A. Rivenson, and S.S. Hecht: The bio-
logical significance to tobacco-specific N-nitrosamines:
Smoking and adenocarcinoma of the lung; Crit. Rev.
Toxicol. 6 (1996) 199–211.
11/24/08 2:39:44 PM
 Bibliography
1776. Hoffmann, D., A. Rivenson, S.E. Murphy, F.L. Chung,
S. Amin, and S.S. Hecht: Cigarette smoking and adeno-
carcinoma of the lung. The relevance of nicotine derived
N-nitrosamines; J. Smoking Related Dis. 4 (1993)
165–189.
1777. Hoffmann, D., A. Rivenson, E.L. Wynder, and S.S.
Hecht: Formation of tobacco-specific N-nitrosamines,
their carcinogenicity, and the role of dietary fat in their
carcinogenicity; 204th Natl. Mtg., Am. Chem. Soc.,
Washington, DC (1992) Paper No. 119.
1778. Hoffmann, D. and J. Rubin: Chemical studies on tobacco
smoke. I. The quantitative determination of indoles in
cigarette smoke; Beitr. Tabakforsch. 3 (1966) 409–414.
1779. Hoffmann, D., L.D. Sanghvi, and E.L. Wynder:
Comparative chemical analysis of Indian bidi and
American cigarette smoke; Internat. J. Cancer 14 (1974)
49–53.
1780. Hoffmann, D., I. Schmeltz, S.S. Hecht, and E.L.
Wynder: Chemical studies on tobacco smoke. XXIX.
On the identification of carcinogens, tumor promoters
and cocarcinogens in tobacco smoke; in: Modifying the
risk for the smoker. Proc. 3rd World Conf. on Smoking
and Health, 1975, Vol. 1, edited by E.L. Wynder, D.
Hoffmann, and G.B. Gori, DHEW Publ. No. (NIH) 76
1221 (1976) 125–145.
1781. Hoffmann, D., I. Schmeltz, S.S. Hecht, and E.L. Wynder:
Tobacco carcinogenesis; Chapter 4 in: Polycyclic hydro-
carbons and cancer, Vol. 1, Chemistry, molecular biol-
ogy and environment, edited by H.V. Gelboin and P.O.
Ts’o, Academic Press, New York, NY(1978) 85–117.
1782. Hoffmann, D., I. Schmeltz, S.S. Hecht, and E.L. Wynder:
Tobacco carcinogenesis; Chapter 5 in: H.V. Gelboin
and P.O. Ts’o, Polycyclic hydrocarbons and cancer,
Vol. 1, Chemistry, molecular biology and environment,
Academic Press, New York, NY (1978) 119–130.
1783. Hoffmann, D., T.C. Tso, and G.B. Gori: The less harm-
ful cigarette; Prev. Med. 9 (1980) 287–296.
1784. Hoffmann, D. and J. Vais: Analysis of volatile
N-nitrosamines in unaged mainstream smoke of ciga-
rettes; 25th Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 25, Paper No. 23,
1971, p. 14.
1785. Hoffmann, D. and H. Woziwodzki: Chemical studies
on tobacco smoke. IV. The quantitative determination
of free nonvolatile fatty acids in tobacco and tobacco
smoke; Beitr. Tabakforsch. 4 (1968) 167–175.
1786. Hoffmann, D. and E.L. Wynder: Identification of poly-
nuclear aromatic hydrocarbons; 136th Natl. Mtg., Am.
Chem. Soc., Atlantic City, NJ (1959) Paper No. 16U.
1787. Hoffmann, D. and E.L. Wynder: Short-term determi-
nation of carcinogenic aromatic hydrocarbons; Anal.
Chem. 32 (1960) 295–296.
1788. Hoffmann, D. and E.L. Wynder: On the isolation and
identification of polycyclic aromatic hydrocarbons;
Cancer 13 (1960) 1062–1073.
1789. Hoffmann, D. and E.L. Wynder: Die quantitativen
Bestimmung von Phenolen in Tabakrauch [The quan-
titative determination of phenols in tobacco smoke];
Beitr. Tabakforsch. 1 (1961) 101–106.
1790. Hoffmann, D. and E.L. Wynder: Analytical and bio-
logical studies on gasoline engine exhaust; Natl. Cancer
Inst. Monograph 9 (1962) 91–116.
1791. Hoffmann, D. and E.L. Wynder: Die Filtration von
Phenolen aus Cigarettenrauch [The filtration of phenols
© 2009 by Taylor & Francis Group, LLC
78836_C029.indd 1331
1331
from cigarette smoke]; Beitr. Tabakforsch. 2 (1963)
51–66; Filtration of phenols from cigarette smoke; J.
Natl. Cancer Inst. 30 (1963) 67–84.
1792. Hoffmann, D. and E.L. Wynder: Unpublished 1963
results discussed in: Tobacco and tobacco smoke: Studies
in experimental carcinogenesis, by E.L. Wynder and
D. Hoffmann, Academic Press, New York, NY (1967)
246.
1793. Hoffmann, D. and E.L. Wynder: Unpublished 1963
results on different tobacco cut widths described in:
Tobacco and tobacco smoke: Studies in experimen-
tal carcinogenesis, by E.L. Wynder and D. Hoffmann,
Academic Press, New York, NY (1967) 530.
1794. Hoffmann, D. and E.L. Wynder: Proc. Am. Assoc.
Cancer Res. 6 (1965) 29; cited in: Wynder, E.L. and
D. Hoffmann: Tobacco and tobacco smoke: Studies in
experimental carcinogenesis; Academic Press, New
York, NY (1967) 634.
1795. Hoffmann, D. and E.L. Wynder: The tumor initiator in
tobacco smoke; Proc. Am. Assoc. Cancer Res. 7 (1966)
32.
1796. Hoffmann, D. and E.L. Wynder: Beitrag zur carcino-
genen Wirkung von Dibenzopyrenen [On the carcino-
genic activity of dibenzopyrenes]; Z. Krebsforsch. 68
(1966) 137–149.
1797. Hoffmann, D. and E.L. Wynder: The reduction of tum-
origenicity of cigarette smoke condensate by addition
of sodium nitrate to tobacco; Cancer Res. 27 (1967)
172–174.
1798. Hoffmann, D. and E.L. Wynder: Selective reduction
of the tumorigenicity of tobacco smoke. Experimental
approaches; in: Toward a less harmful cigarette, edited
by E.L. Wynder and D. Hoffmann, Natl. Cancer Inst.
Monograph 28 (1968) 151–172.
1799. Hoffmann, D. and E.L. Wynder: Chemical analysis and
carcinogenic bioassays of organic particulate pollutants;
in: Air pollution, Vol. 2, 2nd Edition, edited by A.C.
Stern, Academic Press, New York, NY (1968) 187–247.
1800. Hoffmann, D. and E.L. Wynder: A study of tobacco car-
cinogenesis. XI. Tumor initiators, tumor accelerators,
and tumor promoting activity of condensate fractions;
Cancer 27 (1971) 848–864.
1801. Hoffmann, D. and E.L. Wynder: A study of tobacco car-
cinogenesis. XV. Chemical composition and tumorige-
nicity of tobacco smoke; in: The chemistry of tobacco
and tobacco smoke, edited by I. Schmeltz, Plenum
Publishing Co. (1972) 123–147.
1802. Hoffmann, D. and E.L. Wynder: Selective reduction of
the tumorigenicity of tobacco smoke. II. Experimental
approaches; J. Natl. Cancer Inst. 48 (1972) 1855–1868.
1803. Hoffmann, D. and E.L. Wynder: [Chemical studies on
tobacco smoke. XVIII] Smoke of cigarettes and little
cigars: An analytical comparison; Science 178 (1972)
1197–1199.
1804. Hoffmann, D. and E.L. Wynder: The active fraction
of cigarette smoke in experimental carcinogenesis. A
review; Tob. Res. 1–2 (1975) 89–97.
1805. Hoffmann, D. and E.L. Wynder: Selective reduction
of tumorigenicity of tobacco smoke. III. The reduc-
tion of polynuclear hydrocarbons in cigarette smoke;
in: Modifying the risk for the smoker. Proc. 3rd World
Conf. on Smoking and Health, 1975, Vol. 1, edited by
E.L. Wynder, D. Hoffmann, and G.B. Gori, DHEW
Publ. No. (NIH) 76 1221 (1976) 495–504.
11/24/08 2:39:44 PM
 1332
1806. Hoffmann, D. and E.L. Wynder: Environmental
respiratory carcinogens; in: Chemical carcinogens,
American Chemical Society Monograph 173, 1st
Edition, American Chemical Society, Washington, DC
(1976) 324–365.
1807. Hoffmann, D. and E.L. Wynder: Identifizierung und
Reduktion von Respirationskarzinogenen [Identification
and reduction of respiration carcinogens]; Zent. Bakt.
Parasit., Infekt., Hyg. (Abteil 1, Orig. B) 166 (1978)
113–135.
1807a. Hoffmann, D. and E.L. Wynder: Tobacco and tobacco
smokeóa continuing public health issue; Tabak (Int)
1982 (1) 83–85.
1808. Hoffmann, D. and E.L. Wynder: Chemical constituents
and bioactivity of tobacco smoke; in: Tobacco: A major
health hazard, edited by D.G. Zardidze and R. Peto,
IARC, Lyon, France, IARC Sci. Publ. No. 74 (1986)
145–165.
1809. Hoffmann, D., E.L. Wynder, S.S. Hecht, K.D.
Brunnemann, E.J. LaVoie, and N.J. Haley: Chemical
carcinogens in tobacco; in: Cancer risks. Strategies for
elimination, edited by P. Bannaschor, Springer-Verlag,
New York, NY (1987) 101–113.
1810. Hoffmann, D., E.L. Wynder, A. Rivenson, E.J. LaVoie,
and S.S. Hecht: Skin bioassays in tobacco carcinogen-
esis; Prog. Exp. Tumor. Res. 26 (1983) 43–67.
1811. Hofmann, E.: Semimicro- and microcolorimetric deter-
mination of nicotine in tobacco and tobacco smoke;
Biochem. Z. 260 (1933) 26–33.
1812. Hofmann, E.: Quantitative spektralanalytische
Bestimmung von Nikotin und Pyridin [Quantitative
spectral determination of nicotine and pyridine]; Arch.
Hyg. 128 (1942) 179–186.
1813. Hoffmann, E., H.T. Schreus, and E. Zurhelle:
Beobachtungen zur experimentellen Geschwulste-
rzeugung durch Teer verschiedener Herkunft und
Paraffin [Observations on experimental tumour produc-
tion by tars from different sources and paraffin]; Deut.
Med. Wchnschr. 49 (1923) 633–634.
1814. VOID
1814a. Holden, M.: A study of enzymes that can break down
tobacco-leaf components. 3. Fungal polygalacturonase
on leaf fibre; Biochem J. 47 (1950) 415–420.
1815. Holland, R.H. and A.R. Acevedo: Current status of
arsenic in American cigarettes; Cancer 19 (1966)
1248–1250.
1816. Holland, R.H., R.H. Wilson, A.R. Acevedo, M.S.
McCall, D.A. Clark, and H.C. Lanz: Arsenic in regular-
sized unfiltered and filtered cigarettes; Cancer 11 (1958)
1115–1118.
1817. Holland, R.H., R.H. Wilson, A.R. Acevedo, M.S.
McCall, D.A. Clark, and H.C. Lanz: The cigarette
smoke-arsenic-cancer of the lung problem; 7th Internat.
Cancer Cong., London, England (1958); Acta Unio
Internat. Contra Cancrum 15 (1959) 608–611.
1818. Hollweg, J., H.-J. Schumacher, and F. Seehofer:
Automatisierte gaschromatographische Simultanbestim-
mung von Nicotin und Wasser im Tabakrauchkondensat
[Automatic simultaneous gas chromatographic deter-
mination of nicotine and water in tobacco smoke con-
densate]; Beitr. Tabakforsch. Int. 11 (1981) 39–43.
1819. Holmes, J.C., M.B. Bennett, and E.T. Oakley: A study
of the distribution of the humectant during the smok-
ing process using C14-glycerol as a tracer; 14th Tobacco
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The Chemical Components of Tobacco and Tobacco Smoke
Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 14, Paper No. 6, 1960, p. 6.
1820. Holmes, J.C. and W.B. Cridlin: Moisture in the total
particulate matter and gas phase of cigarette smoke; J.
Assoc. Off. Anal. Chem. 43 (1960) 515–518.
1821. Holmes, J.C. and F.A. Morrell: The mass spectrometer as
a quantitative tool. I. Oscilloscopic presentation of mass
spectra; 9th Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 9, Paper No. 7,
1955, p. 4.
1822. Holzer, G., J. Oró, and W. Bertsch: Gas chromatograph-
ic-mass spectrometric evaluation of exhaled tobacco
smoke; J. Chromatog. 126 (1976) 771–785.
1823. Holtzman, R.B. and F.H. Ilcewicz: Lead-210 and polo-
nium-210 in tissues of cigarette smokers; Science 153
(1966) 1259–1260.
1823a. Homburger, F.: Les rapports entre tabac et cancer:
Pathologie expérimentale [The relationship between
tobacco and cancer: Experimental pathology]; Med.
Hyg. (Switz.) 23 (1965) 179–181.
1823b. Homburger, F. and A. Treger: Effects of intravenous
carcinogen and tobacco condensate injections upon
the incidence of lung tumors in A/He mice; in: Lung
tumors in animals, edited by L. Severi, Division of
Cancer Research, University of Perugia, Italy (1965)
527–536.
1824. Homburger, F., A. Treger, and E. Boger: Experimental
studies on the inhibition of carcinogenesis by cigarette-
smoke condensates and carcinogen-related substances;
in: Toward a less harmful cigarette, edited by E.L.
Wynder and D. Hoffmann, Natl. Cancer Inst. Monograph
28 (1968) 259–270.
1824a. Hong, M., B.A. Zilinskas, D.C. Knipple, and C.K. Chin:
cis-3-Hexanal production in tobacco is stimulated by
16-carbon monounsaturated fatty acids; Phytochemistry
65 (2004) 159–168.
1824b. Hong, T.-Y., C.-W. Cheng, J.-W. Huang, and M. Meng:
Isolation and biochemical characterization of an endo-
1,3-ß-glucanase from Streptomyces sioyaensis contain-
ing a C-terminal family 6 carbohydrate-binding module
that binds to 1,3-ß-glucan; Microbiology 148 (2002)
1151–1159.
1825. Honglin, S., L. Zhong, W. Baoxing, W. Lan, L. Wei, J.
Ciqing, and Y. Guangyu: Determination of volatile phe-
nol in tobacco by solid phase extraction and high per-
formance liquid chromatography; 56th Tobacco Science
Research Conference, Program Booklet and Abstracts,
Vol. 56, Paper No. 26, 2002, pp. 33–34.
1826. Hopkin, J.M. and P.E. Perry: Benzo[a]pyrene does not
contribute to the SCEs induced by cigarette smoke con-
densate; Mutation Res. 77 (1980) 377–381.
1827. Horsewell, H.G. and G.H. Rayner: Improvement relat-
ing to cigarette filters; British Patent No. 999,057 (July
21, 1965).
1828. Horton, A.D. and M.R. Guerin: Quantitative gas chro-
matographic determination of smoke components
using the sulfur-specific photometric detector; 26th
Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 26, Paper No. 17, 1972,
pp. 25–26.
1829. Horton, A.D. and M.R. Guerin: Determination of acetal-
dehyde and acrolein in the gas phase of cigarette smoke
using cryothermal gas chromatography; Tob. Sci. 18
(1974) 19–22.
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1830. Horton, A.D. and M.R. Guerin: Gas-solid chromato-
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smoke; J. Assoc. Off. Anal. Chem. 57 (1974) 1–7.
1831. Horton, A.D. and M.R. Guerin: Quantitative determina-
tion of sulfur compounds in the gas phase of cigarette
smoke; J. Chromatog. 90 (1974) 63–70.
1832. Horton, A.D., M.R. Guerin, and G. Olerich: Sulfur-
containing compounds in the gas phase of cigarette smoke;
25th Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 25, Paper No. 19, 1971, p. 12.
1833. Horton, A.D., M.R. Guerin, J.R. Stokely, and A.S. Meyer:
Determination of nitrogen-containing compounds in the
gas phase of cigarette smoke by use of the Coulson elec-
trolytic conductivity detector; 27th Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 27, Paper No. 25, 1973, p. 20.
1834. Horton, A.D., J.R. Stokely, and M.R. Guerin: Gas chro-
matographic determination of nitric oxide (NO) in ciga-
rette smoke; Anal. Lett. 7 (1974) 177–185.
1835. Horton, A.W., D.T. Denman, and R.P. Trosset:
Carcinogenesis of the skin. II. The accelerating proper-
ties of aliphatic and related hydrocarbons; Cancer Res.
17 (1957) 758–766.
1835a. Hosaka, S., T. Matsushima, I. Hirono, and T. Sugimura:
Carcinogenicity of 3-amino-1-methyl-5H-pyrido[4,3-b]
indole (Trp-P-2), a pyrolysis product of tryptophan;
Cancer Lett. 13 (1981) 23–28.
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1934. Jenkins, R.W. Jr, C. Goldey, and T.G. Williamson:
Neutron activation analysis in tobacco and cigarette
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1946. Jerina, D.M., R. Lehr, M. Schaefer-Ridden, H. Yagi,
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1960. Johnson, R.R., E.D. Alford, and G.W. Kinzer: Formation
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1962. Johnson, R.R., T. Smith, and J.E. Howes: The formation
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2099a. Kisaki, T. and E. Tamaki: Phytochemical studies on the
tobacco alkaloids. III. Observations on the interconver-
sion of DL-nicotine and DL-nornicotine in excised tobacco
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2104. Kissling, R.: Handbuch der Tabakkunds, des Tabakbaues,
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2107. Kissling, R.: Handbuch der Tabakkundse [Handbook of
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2526. McWilliams, D., L.J. Deutsch, and J.D. Gladden:
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2530. Menden, E.E., V.J. Elia, L.W. Michael, and H.G.
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2543. Miller, C.W., M.P. Newell, and R.E. Shackelford:
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2546. Miller, E.G. Jr and J.G. Curran Jr: The selective removal
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2548. Miller, J.E.: Bestimmung von Komponenten im
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2588. Mola, M., G. Lionetti, and A. Nunziata: Determination
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extraction and GC-MS determination of selected organic
compounds in mainstream tobacco smoke; 57th Tobacco
Science Research Conference, Program Booklet and
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2592. Mold, J.D., R.E. Means, and A.G. Kallianos: The isola-
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2593. Mold, J.D., R.E. Means, and J.M. Ruth: The higher fatty
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2595. Mold, J.D., R.K. Stevens, R.E. Means, and J.M. Ruth:
The paraffin hydrocarbons of tobacco: Normal-, iso- and
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2596. Mold, J.D. and T.B. Walker: Isolation of TDE from ciga-
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2596a. Mold, J.D., T.B. Walker, and L.G. Veasey: Selective
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countercurrent distribution with a solvent system con-
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2071–2074.
2597. Mold, J.D., T.B. Walker, and J.B. Williams: Alloöcimene:
Absence in cigarette smoke; Science 144 (1964)
1572–1573.
2597a. Moldoveanu, S.C.: Analysis of protein amino acids in
tobacco using microwave digestion of plant material;
59th Tobacco Science Research Conference, Program
Booklet and Abstracts, Vol. 59, Paper No. 50, 2005, pp.
45–46; Beitr. Tabakforsch. Int. 21 (2005) 451–465.
2598 Moldoveanu, S.C. and M. Kiser: Gas chromatography/
mass spectrometry versus liquid chromatography/fluo-
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90–97.
2599. Moldoveanu, S.C., N.P. Kulshreshtha, and J.M. Wilkins:
Study of the pyrosynthesis of NNN and NNK in main-
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Conference, Program Booklet and Abstracts, Vol. 55,
Paper No. 60, 2001, p. 55.
2600. Moldoveanu, S.C., J.L. Roles, and Q. Zha: Study of the
volatile compounds from tobacco using steam distilla-
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50th Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 50, Paper No. 42, 1996, pp.
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2601. Moldoveanu, S.C., T.A. Sasaki, and J.B. Forehand:
Quantitation of two heterocyclic amines in cigarette
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Science Research Conference, Program Booklet and
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2770. Newell, M.P. and P.H. Latimer: The fate of flavorants of
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2774. Newell, M.P., C.W. Miller, N.C. Sanders, and A.L.
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2776. Newell, M.P. and H.E. Moser: The transfer of menthol
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2777. Newell, M.P., J.N. Schumacher, R.A. Heckman, C.R.
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 1372
Comparison of U.K. More “L9122a” with a white paper
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2780. Newsome, J.R. and C.H. Keith: Variation of the gas
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2781. Newsome, J.R., V. Norman, and C.H. Keith: Smoking
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Program Booklet and Abstracts, Vol. 19, Paper No. 26,
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2782. Newsome, J.R., V. Norman, and C.H. Keith: Vapor phase
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2783. Nicod, J.L.: Toxicité aigue et pouvoir cancérigène de
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2784. Nicolaus, G. and H. Elmenhorst: Nachweis und
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2785. Nie, C., G. Lu, J. Liu, M. Zhao, P. Li, and Y. Hu: Studies
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57th Tobacco Science Research Conference, Program
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2786. Nielsen, M.T.: Altering flavor and aroma constituents in
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2786a. Niki, E., S. Minamisawa, M. Oikawa, and E. Komuro:
Membrane damage from lipid oxidation by free radi-
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2787. Nikolin, B., A. Nikolin, and H. Butmir: Colorimetric
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(1974) 10.
2788. Nisbet M.A. and V.C. Runeckles: Rapid detection and
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2789. Nisbet M.A. and S. Schmeller: Colorimetric deter-
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2789a. Nisbet, M.A. and S. Schmeller: Inhibition of radical
initiated vinyl acetate polymerization by tobacco smoke
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Program Booklet and Abstracts, Vol. 27, Paper No. 11,
1973, p. 16.
2790. Nishi, H., H. Yoshitani, and T. Kamachi: Studies of
tobacco casing. VI. Analytical method of polyols in
cased shredded tobacco by gas chromatography; Sci.
Papers, Cent. Res. Inst., Japan Monopoly Corp. 111
(1970) 85–88.
2791. Nishidawa, A., B. Prokopczyk, A. Rivenson, E. Zang, and
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Carcinogenicity of 3-(methylnitrosamino)propionalde-
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2791a. Nishizawa, O.: Chilling-resistant plants and their pro-
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2792. Nitsch, A., K. Kalcher, H. Greschonig, and R. Pietsch:
Schwermetalle in Tabaken und in Tabakrauch. II:
Spurenelemente Cadmium, Blei, Kupfer, Kobalt
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tobacco and tobacco smoke. II. Trace elements cad-
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Beitr. Tabakforsch. Int. 15 (1991) 19–32.
2793. Noda, S.: Beitrag zur Erklärung der Rauchwirkung
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to the explanation of the action of smoke (strong and mild
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2794. Noguchi, M., H. Sakuma, and E. Tamaki: N-(3-Amino-
3-carboxypropyl)-B-carboxypyridinium betaine: A new
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125 (1968) 1017–1018.
2794a. Noguchi, M., Y. Satoh, K. Nishida, S. Andoh, and E.
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IX. Changes in the content of amino acid-sugar compounds
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2795. Noguchi, M., K. Yamamoto, and E. Tamaki: Studies
on nitrogen metabolism in tobacco plants. A. Part V.
Changes of the free amino acid composition of tobacco
leaves with age; Tob. Sci. 8 (1964) 8–12.
2796. Noma, M., N. Kawashima, and M. Noguchi: Isolation
and characterization of hydroxyvaleric acid derivatives
from tobacco leaves and the hydrolysate of tobacco
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2796a. Noma, N., M. Noguchi, and E. Tamaki: A new amino
acid, nicotianamine, from tobacco leaves; Tetrahedron
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2797. Noma, M., M. Noguchi, and E. Tamaki: Isolation and
characterization of D-alanyl-D-alanine from tobacco
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2798. Norman, A.B., T.A. Perfetti, P.F. Perfetti, and R.G.
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2799. Norman, A.B. and J.H. Reynolds IV: Determination
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2799a. Norman, V.: An overview of the vapor phase, semiv-
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Recent Adv. Tob. Sci. 3 (1977) 28–58.
2800. Norman, V.: Changes in smoke chemistry of modern day
cigarettes; Recent Adv. Tob. Sci. 8 (1982) 141–177.
2801. Norman, V., A.M. Ihrig, T.M. Larson, and B.L. Moss:
The effect of some nitrogenous blend components on
NO/NOx and HCN levels in mainstream and sidestream
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Program Booklet and Abstracts, Vol. 35, Paper No. 48,
1981, p. 25; Beitr. Tabakforsch. Int. 12 (1983) 55–62.
2802. Norman, V. and C.H. Keith: Charged particles in cigarette
smoke; 18th Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 18, Paper No. 21,
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2807. Norpoth, K. and T. Papatheodorou: Thin-layer chromatog-
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2808. Norpoth, K., T. Papatheodorou, and G. Venjakob:
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2808a. Nottbohm, F.E. and F. Mayer: Über das Vorkommen und
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2809. Number of identified tobacco smoke components: A com-
ment: Since the mid-1980s, few newly identified tobacco
and tobacco smoke components have been reported.
Reasonable explanations for why the number of identified
smoke components may exceed 3,900 include: (a) At the
38th TCRC, Arrendale et al. reported the identification
of a series of long-chained aliphatic esters [Arrendale,
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acid and alcohol moieties plus iso and anteiso structures
were found by Arrendale et al. Since each ester reported
by Rodgman et al. was found in tobacco and smoke, logic
dictates that each new tobacco ester found by Arrendale
et al. is also present in smoke. (b) In the PAH studies by
Snook et al. [Snook, M.E., R.F. Severson, H.C. Higman,
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polynuclear aromatic hydrocarbons of tobacco smoke:
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9 (1978) 222–247], numerous peaks are listed as being
mixtures of two or more isomers, a fact ignored by many
© 2009 by Taylor & Francis Group, LLC
78836_C029.indd 1373
1373
cataloguers of smoke components. (c) In tobacco smoke,
several dozen secondary amines exist for which no corre-
sponding NNAs have been reported. Because these NNAs
are known and stable, they probably exist in smoke. (d)
Similarly, the parent amines for several volatile NNAs in
smoke have not been identified in tobacco smoke.
2810. Nystrom, C.W.: The polyphenols of tobacco. I. The
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Chemists’ Research Conference, Program Booklet and
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2813. Nystrom, C.W.: Test of tourmaline filters for removal
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2814. Nystrom, C.W.: Polonium-210: Failure of ion-exchange
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2816. Nystrom, C.W. and N.W. Sizemore: Biosynthesis of fla-
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of five-carbon and six-carbon branched-chain acids in
Turkish tobacco plants grown under different condi-
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2817. Nystrom, C.W. and N.W. Sizemore: Rapid method
for determination of five- and six-carbon acid content
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2817a. Oakley, E.T.: Benzo[a]pyrene delivery of all-burley,
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2822. Obi, Y., M. Mutamatsu, and Y. Shimada: Quality coef-
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Cent. Res. Inst., Japan Monopoly Corp. 107 (1965)
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2825. Occupational Safety and Health Administration
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2826. Ogden, M.W.: High resolution gas chromatography of
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2827. Ogden, M.W.: CORESTA environmental tobacco smoke
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2828. Ogden, M.W.: Quinoline interference in environmental
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2829. Ogden, M.W.: Environmental tobacco smoke (ETS)
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Science Research Conference, Program Booklet and
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2830. Ogden, M.W., R.A. Davis, K.C. Maiolo, M.F. Stiles,
D.L. Heavner, R.B. Hege, and W.T. Morgan: Multiple
measures of personal ETS exposure in a population-
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47th Tobacco Chemists’ Research Conference, Program
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p. 21.
2831. Ogden, M.W., L.W. Eudy, D.L. Heavner, F.W. Conrad
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40th Tobacco Chemists’ Research Conference, Program
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2833. Ogden, M.W. and K.C. Maiolo: Collection and analysis
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42nd Tobacco Chemists’ Research Conference, Program
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2834. Ogden, M.W. and K.C. Maiolo: Comparison of GC and
LC for determining solanesol in environmental tobacco
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Program Booklet and Abstracts, Vol. 44, Paper No. 28,
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2835. Ogden, M.W. and K.C. Maiolo: Comparative evaluation
of diffusive and active sampling systems for determin-
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2836. Ogden, M.W., K.C. Maiolo, P.R. Nelson, D.L. Heavner,
and C.R. Green: Artifacts in determining the vapor-
particulate phase distribution of environmental tobacco
smoke nicotine; 46th Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 46,
Paper No. 5, 1992, p. 22; Artefacts in determining the
vapour-particulate phase distribution of environmental
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779–785.
2837. Ogden, M.W. and P.R. Nelson: Detection of alkaloids
in environmental tobacco smoke; in: Modern methods
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Linskens and J.F. Jackson, Springer-Verlag, Heidelberg,
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2838. Ogden, M.W. and J.D. Richardson: Effect of lighting and
storage conditions on the stability of ultraviolet particu-
late matter, fluorescent particulate matter, and solanesol;
Tob. Sci. 42 (1998) 10–15.
2839. Ogden, M.W. and S.B. Sears: Biases in environmental
tobacco smoke (ETS) risk assessment due to misclassifi-
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2839a. Ogg, C.L.: Effect of ammonia on the determination of
nicotine by the silicotungstic acid method; 2nd Tobacco
Chemists’ Research Conference, Program Booklet and
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2840. Ogg, C.L.: Determination of particulate matter and alka-
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2841. Ogg, C.L.: Report on tobacco, 79th Ann. Mtg. Assoc. Off.
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2842. Ogg, C.L.: Determination of tar and nicotine in cigarette
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2852. Ohshima, H., J. Nair, M.C. Bourgade, M. Friesen, L.
Garren, and H. Bartsch: Identification and occurrence
of two N-nitrosamino acids in tobacco products 3-N-ni-
troso-3-N-methylaminopropionic acid and 4-N-nitroso-
4-N-methylaminobutyric acid; Cancer Lett. 26 (1985)
153–162.
2853. Okada, T., Y. Ishizu, and K. Matsunuma: Determination
of particle-size distribution and concentration of cigarette
smoke by a light-scattering method; Beitr. Tabakforsch.
Int. 9 (1977) 153–160.
2854. Okada, T. and Y. Shibayama: Studies on physical proper-
ties and filtration of cigarette smoke. I. Delivery of water
to particulate and gaseous phases; Sci. Papers, Cent.
Res. Inst., Japan Monopoly Corp. 106 (1964) 151–156.
2855. Okada, T. and Y. Shibayama: Studies on physical proper-
ties and filtration of cigarette smoke. II. Distribution and
amount of water and tar in mainstream smoke and butt;
Sci. Papers, Cent. Res. Inst., Japan Monopoly Corp. 106
(1964) 157–162.
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1375
2855a. Okinaka,Y., Y. Shimada, R. Nakano-Shimada, M.
Ohbayashi, S. Kiyokawa, and Y. Kikuchi: Selective
accumulation of delphinidin derivatives in tobacco
using a putative flavonoid 3`,5`-hydroxylase cDNA from
Campanula medium; Biosci. Biotechnol. Biochem. 67
(2003) 161–165.
2856. Oliver, B.W.: Thin-layer chromatographic separation
of benzo[a]pyrene from cigarette tar; 19th Tobacco
Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 19, Paper No. 35, 1965, pp. 51–53.
2856a. Olson, T.J.: Determination of Nemacur® residues in
tobacco and tobacco smoke; Chemagro Rept. No. 30448
(1971).
2857. Omori, F., N. Higashi, M. Ohida, Y. Sone, and S. Suhara:
Internal standard-based analytical method for tobacco
smoke vapor phase components; Beitr. Tabakforsch. Int.
18 (1999) 131–146.
2858. Onishi, I.: Recent studies on tobacco smoke by the
Japan Monopoly Corporation; Proc. 2nd Internat. Tob.
Sci. Cong., Brussels, Belgium (1959) 553–559.
2859. Onishi, I.: Chemistry of tobacco; Kagaku (Chem.) 14
(1959) 106–110, 308–318.
2860. Onishi, I., T. Fukuzumi, K. Yamamoto, and H. Takahara:
Anthraquinone in tobacco smoke; Sci. Papers, Cent.
Res. Inst., Japan Monopoly Corp. 103 (1961) 25–29.
2860a. Onishi, I. and M. Nagasawa: Studies on the essential
oils of tobacco leaves. Part II. Carbonyl fraction; Bull.
Agr. Chem. Soc. Japan 19 (1955) 143–147; Part VII.
Carbonyl fraction (II); Bull. Agr. Chem. Soc. Japan 21
(1957) 38–42.
2861. Onishi, I., M. Nagasawa, H. Tomita, and T. Fukuzumi:
Studies on the essential oils of tobacco leaves. XVI.
Neutral fraction. (III). Polycyclic aromatic hydrocar-
bons on burley tobacco leaves; Bull. Agr. Chem. Soc. 22
(1958) 17–20.
2861a. Onishi, I., H. Tomita, and T. Fukuzumi: Studies on the
essential oils of tobacco leaves. Part IV. Neutral frac-
tion; Bull. Agr. Chem. Soc. Japan 20 (1956) 61–67; Part
XV. Neutral fraction (II); Bull. Agr. Chem. Soc. Japan
21 (1957) 239–242.
2862. Onishi, I. and K. Yamamoto: Studies on the essential oils
of tobacco leaves. Part III. Phenol fraction; Bull. Agr.
Chem. Soc. Japan 19 (1955) 148–156; Part VI. Phenol
fraction (II); Bull. Agr. Chem. Soc. Japan 20 (1956)
70–73; Part XI. Phenol fraction (III); Bull. Agr. Chem.
Soc. Japan 21 (1957) 90–94; Part XIV Phenol fraction
(IV); Bull. Agr. Chem. Soc. Japan 21 (1957) 181–194.
2862a. Onishi, I. and K. Yamasaki: Studies on the essential oils
of tobacco leaves. Part I. Acid fraction; Bull. Agr. Chem.
Soc. Japan 19 (1955) 137–142; Part IX. Acid fraction of
the American flue-cured tobacco leaf; Bull. Agr. Chem.
Soc. Japan 21 (1957) 82–85; Part X. Acid fraction in the
essential oil of the Japanese flue-cured leaf before redry-
ing and aging; Bull. Agr. Chem. Soc. Japan 21 (1957)
86–89.
2863. Onishi, I. and K. Yamasaki: Studies on the essential oils of
tobacco leaves. Part V. The isolation of B–methylvaleric
acid and 2-furoic acid from tobacco essential oil; Bull.
Agr. Chem. Soc. Japan 20 (1956) 68–69.
2864. Onishi, K.: The essential oils in tobacco leaf; Koryo
(Aromatics) 1960(55) 9–15.
2864a. Oritani, T. and H. Kiyota: Biosynthesis and metabolism
of abscisic acid and related compounds; Nat. Prod. Rept.
20 (2003) 414–425.
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 1376
2864b. Oró, J., J. Han, and A. Vlatkis: Application of high
resolution gas chromatography-mass spectrometry to
the analysis of the pyrolysis of isoprene; Anal. Chem. 3
(1967) 27–32.
2865. Orris, L., B.L. Van Duuren, A.I. Kosak, N. Nelson, and
F.L. Schmitt: The carcinogenicity for mouse skin and
the aromatic hydrocarbon content of cigarette-smoke
condensate; J. Natl. Cancer Inst. 21 (1958) 557–561.
2865a. Osawa, Y., B. Tochigi, M. Tochigi, S. Ohnishi, Y.
Watanabe, K. Bullion, G. Osawa, Y. Nakabayashi, and
C. Yarborough: Aromatase inhibitors in cigarette smoke,
tobacco leaves and other plants; J. Enzyme Inhib. 4
(1990) 187–200.
2866. Osborne, J.S., S. Adamek, and M.E. Hobbs: Some
components of the gas phase of cigarette smoke; Anal.
Chem. 28 (1956) 211–215.
2867. Osborne, J.S. and E.S. Harlow: Gas phase of cigarette
smoke: The effects of changes in smoking techniques on
the CO2:CO concentration ratio; Virginia J. Sci. 7 (1956)
307.
2868. Osborne, J.S. and M.E. Hobbs: Some constituents of
the gas phase of cigarette tobacco smoke; 8th Tobacco
Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 8, Paper No. 25, 1954, p. 8; Osborne,
J.S., S. Adamek, and M.E. Hobbs: Some components of
the gas phase of cigarette smoke; Anal. Chem. 28 (1956)
211–215.
2868a. Oshimura, M. and J.C. Barrett: Chemically induced
aneuploidy in mammalian cells: Mechanisms and bio-
logical significance in cancer; Environ. Mutagenesis 8
(1986) 129–159.
2869. Osman, S. and J. Barson: Volatile bases of cigar smoke;
17th Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 17, Paper No. 15, 1963, pp.
12–13; The volatile bases of cigar smoke; Phytochemistry
3 (1964) 587–590.
2870. Osman, S. and J. Barson: Hydrocarbons of cigar smoke;
Tob. Sci. 8 (1964) 158–160.
2871. Osman, S. and J. Barson: Hydrocinnamyl nitrile in cigar
smoke condensate; Chem. and Ind. (1966) 699.
2872. Osman, S. and J. Barson: The isolation of farnesyl ace-
tone from cigar smoke condensate; Tob. Sci. 10 (1966)
85–87.
2873. Osman, S. and J. Barson: An aromatic acid fraction
of cigar smoke condensate; Phytochemistry 5 (1966)
511–515.
2874 Osman, S. and J. Barson: The chemical comparison of
four cigar filler tobaccos. I. Preliminary investigation of
mainstream and sidestream smoke; Tob. Sci. 12 (1968)
25–27.
2875. Osman, S., J. Barson, and C.J. Dooley: Paraffins of
cigar smoke; J. Assoc. Off. Agr. Chem. 48 (1965)
1059–1062.
2876. Osman, S., I. Schmeltz, H.C. Higman, and R.L.
Stedman: Volatile phenols of cigar smoke; Tob. Sci. 7
(1963) 141–143.
2877. Owen, T.B.: Tar and nicotine from U. S. cigarettes: Trends
over the past twenty years; in: Modifying the risk for the
smoker. Proc. 3rd World Conf. on Smoking and Health,
edited by E.L. Wynder, D. Hoffmann, and G.B. Gori, 1975,
DHEW Publ. No. (NIH) 76–1221 (1976) 1–12.
2878. Owen, W.C. and M.L. Reynolds: The diffusion of gases
through cigarette paper during smoking; Tob. Sci. 11
(1967) 14–20.
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2878a. Owens, W.F. Jr: Effect of cigarette paper on smoke yield
and composition; Recent Adv. Tob. Sci. 4 (1978) 3–24.
2878b. Owttrim, G.W., S. Hofmann, and C. Kuhlemeier:
Divergent genes for translation initiation factor elF-4A
are coordinately expressed in tobacco; Nucleic Acids
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2878c. Owttrim G.W., T. Mandel, H. Trachsel, A.A. Thomas, and
C. Kuhlemeier: Characterization of the tobacco eIF-4A
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2878d. Oxidase: By a search (Google) on the Internet, insert-
ing the term oxidase glycolate tobacco provides numer-
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and posttranscriptional regulation of the glycolate
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45 (2001) 399–407. A search for oxidase diamine
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and J.G. Jelesko: Association of diamine oxidase
and S-adenosylhomocysteine hydrolase in Nicotiana
tabacum extracts; Plant. Mol. Biol. 56 (2004) 299–308.
Search for other oxidases provides similar references.
2878e. Oxygenase: By a search (Google) on the Internet, insert-
ing the term oxygenase benzoate tobacco provides numer-
ous references to it, including the following: Chong, J.,
M.-A. Pierrel, R. Atanassova, D. Werck-Reichhart, B.
Fritig, and P. Saindrenan: Free and conjugated benzoic
acid in tobacco plants and cell cultures. Induced accu-
mulation upon elicitation of defense responses and role
as salicylic acid precursors; Plant Physiol. 125 (2001)
318–328. Search for other oxygenases provides similar
references.
2879. Ozdemir, M. and Y. Yasar: Studies on analytical and
health aspects of cigarette smoke: Nitrogen oxide, nico-
tine, and N-nitrosamine content; Doga Muhendislik
Cevre Bilim. 11 (1987) 273–278.
2880. Paffgen, J.: Verfahren zur Abtrennung von giftigen
Bestandteilen aus dem Tabakrauch [Process for the sep-
aration of the poisonous constituents of tobacco smoke];
German Patent No. 549,413 (1932).
2881 Pailer, M., W. Hübsch, and H. Kuhn: Beitrag zur
Bestimmung des Benzo[a]pyrens in Tabakrauc-
hkondensaten [Contribution to the estimation of
benzo[a]pyrene in tobacco smoke condensate]; Fachl.
Mitt. Österr. Tabakregie, Spec. Issue (1965) i-xi.
2882. Pailer, M., W. Hübsch, and H. Kuhn: Über das
Vorkommen aromatischer Aminen in Zigarettenrauch
[On the occurrence of aromatic amines in cigarette
smoke]; Fachl. Mitt. Österr. Tabakregie 6 (1966)
1448–1451.
2883. Pailer, M., W. Hübsch, and H. Kuhn: Untersuchung der
aliphatischen primären und sekundären Amines des
Zigarettenrauches mit Hilfe der Gaschromatographie
und Massenspektrometrie [Investigation of the primary
and secondary aliphatic amines of cigarette smoke with
the help of gas chromatography and mass spectrometry];
Fachl. Mitt. Österr. Tabakregie 7 (1967) 109–118.
2884. Pailer, M. and H. Klus: Die Bestimmung von
N-Nitrosaminen im Zigarettenrauchkondensat [The
determination of N-nitrosamines in cigarette smoke
condensate]; Fachl. Mitt. Österr. Tabakregie 12 (1971)
203–211.
2885. Pailer, M., H. Klus, Simonitsch E, and H. Kuhn: The
determination of nitrosamines in tobacco smoke con-
densate; CORESTA Bull. (1971) 71.
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cigarettes-connection]; Pharm. Zentralhalle 73 (1932)
257–260.
3011. Pyriki, C.: On the absorption of nicotine in cigarette
smoking; Z. Untersuch. Lebensm. 64 (1932) 163–171.
3012. Pyriki, C.: Über das Auftreten von Nikotin im
Zigarettenrauch. II [On the occurrence of nicotine in
cigarette smoke. II]; Z. Untersuch. Lebensm. 64 (1932)
263–277; III; Z. Untersuch. Lebensm. 65 (1933) 566–
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Z. Untersuch. Lebensm. 70 (1935) 527–535.
3013. Pyriki, C.: Distribution of nicotine in the smoking of
cigarettes; Chem. Ztg. 58 (1934) 543.
© 2009 by Taylor & Francis Group, LLC
78836_C029.indd 1382
The Chemical Components of Tobacco and Tobacco Smoke
3014. Pyriki, C.: Über die Anreicherung des Nikotins in
Zigarettenstummel [On the concentration of nicotine in
cigarette butts]; Pharm. Zentralhalle 76 (1935) 513–517.
3015. Pyriki, C.: Über den Zigarettenrauch und dessen
Nikotin [On cigarette smoke and its nicotine]; Pharm.
Zentralhalle 78 (1937) 313–318.
3016. Pyriki, C.: Beiträge zur Frage des Tabakrauchens
[Contribution to the question of tobacco smoke]; Pharm.
Zentralhalle 78 (1937) 533–534.
3017. Pyriki, C.: Über harzartige Bestandteile des Orient
Tabaks und dessen Rauchs [Resinous constituents of
Oriental tobacco and its smoke]; Z. Untersuch. Lebensm.
80 (1940) 42–61.
3018. Pyriki, C.: Monosacchariden, Saccharose und Maltose
im Tabak [Monosaccharides, saccharose, and maltose in
tobacco]; Z. Untersuch. Lebensm. 82 (1941) 401–416.
3019. Pyriki, C.: Beitrag zur Standardisierung der
Nikotinbestimmung [Contribution to the standardiza-
tion of nicotine determination]; Acta Nicotiana 2 (1943)
116–121.
3020. Pyriki, C.: Information über Tabak und Tabakchemie für
Jedermann [Tobacco information and tobacco chemis-
try for everybody]; Deut. Tabakztg. 12 (1943) 1; Deut.
Tabakztg. 13 (1943) 2.
3021. Pyriki, C.: Über die Nikotinanreicherung in Zigaretten-
stummeln und seine Beziehung zur Reaktion des
Hauptstromrauchs [Nicotine accumulation in cigarette
stubs and its relation to reaction of the main smoke
stream]; Z. Untersuch. Lebensm. 85(1943) 337–346.
3022. Pyriki, C.: Untersuchungen über den Rauch von
Zigaretten [Investigation of the smoke from cigarettes];
Z. Untersuch. Lebensm. 88 (1948) 254–269.
3023. Pyriki, C.: Untersuchungen von neue angebauten
Deutschen Tabaken [Investigation of newly generated
German tobacco]; Z. Untersuch. Lebensm. 90 (1950) 276.
3024. Pyriki, C.: Der Tabakrauch und seine Wirkung [Tobacco
smoke and its action]; Pharm. Zentralhalle 92 (1953)
242–248.
3025. Pyriki, C.: Verhalten des Nikotins und anderer Stoffe
im Rauch von Zigaretten aus einheimischen Tabaken
[The behavior of nicotine and other components in the
smoke from domestic tobacco cigarettes]; Ber. Inst.
Tabakforsch. Dresden 1 (1954) 62–93.
3026. Pyriki, C.: The influence of tobacco composition on the
flavor effect on smoking; Lebensm. Ind. 1 (1954) 264.
3027. Pyriki, C.: The nicotine content of tobacco and its
combustion products as well as its fate on smoking;
Pharmazie 8 (1954) 806–812.
3028. Pyriki, C.: Distribution of nicotine in the smoking of
cigarettes; Chem. Ztg. 58 (1958) 279, 543.
3029. Pyriki, C.: Relations entre la composition chimique du
tabac et les caractères de la fumée [Relationship between
the chemical composition of tobacco and the character-
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Brussels, Belgium, 1958 (1959) 460–488, 489–495.
3030. Pyriki, C.: Polycyclische Kohlenwasserstoffe im
Zigarettenrauch [Polycyclic hydrocarbons in cigarette
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14(2) (1960) 27–29.
3031. Pyriki, C.: Das Verhalten von Oxynikotin beim
Verrauchen [The retention of nicotine N-oxide during
smoking]; Die Nahrung 4 (1960) 310–323.
3032. Pyriki, C.: The appearance of polycyclic hydrocarbons in
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3034. Pyriki, C.: and W. Endemann: The reduction of the
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3035. Pyriki, C. and J. Fritzsche: Zur Frage der Wirkung von
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3036. Pyriki, C. and F. Homann: Die Paraffinkohlenwassertoffe
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3039. Pyriki, C. and W. Moldenauer: Auf Frage des intermit-
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3040. Pyriki, C. and W. Moldenauer: Adsorptionswirkungen
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3041. Pyriki, C. and W. Moldenauer: Contribution to nicotine
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3043. Pyriki, C. and W. Moldenauer: On the efficiency of com-
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3044. Pyriki, C. and W. Moldenauer: On the determination
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3045. Pyriki, C. and W. Moldenauer: Das Verhalten von
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before spectrophotometric determination of alkaloids in
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3046. Pyriki, C., W. Moldenauer, and T.W. Knappe: Zur Frage der
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© 2009 by Taylor & Francis Group, LLC
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in deren Rauch [The question of the treatment of cigarette
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3047. Pyriki, C. and R. Müller: Über das Auftreten von poly-
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3048. Pyriki, C. and R. Müller: Beeinflussung der Qualität
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Inst. Tabakforsch. Dresden 8 (1961) 258–273.
3049. Pyriki, C., R. Müller, and W. Moldenauer: Über das
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im Zigarettenrauch. II. Untersuchung des lipophilen
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81–102.
3050. Qian, N., J. Wilkins, and S.C. Moldoveanu: Formation
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nornicotine present in tobacco; 58th Tobacco Science
Research Conference, Program Booklet and Abstracts,
Vol. 58, Paper No. 60, 2004, pp. 58–59.
3051. Qian, N., Q. Zha, and S.C. Moldoveanu: Analysis of
acrylamide in mainstream cigarette smoke; 58th Tobacco
Science Research Conference, Program Booklet and
Abstracts, Vol. 58, Paper No. 45, 2004, p. 48.
3052. Qiu, J. and X. Jin: Organic acid analysis in tobacco by ion
chromatography with conductivity detection; 55th Tobacco
Science Research Conference, Program Booklet and
Abstracts, Vol. 55, Paper No. 73, 2001, pp. 62–63.
3053. Quin, L.D.: Gas chromatographic identification and
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3054. Quin, L.D.: The separation and partial identification of
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12th Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 12, Paper No. 14, 1958.
3055. Quin, L.D.: Chromatographic identification and deter-
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3056. Quin, L.D.: Alkaloids of tobacco smoke. I. Fractionation
of some tobacco alkaloids and of the alkaloid extract of
burley cigarette smoke by gas chromatography; J. Org.
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3057. Quin, L.D.: Alkaloids of tobacco smoke. II. Identification
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3058. Quin, L.D.: 3-Pyridyl methyl ketone and 3-pyridyl
ethyl ketone as constituents of burley tobacco cigarette
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3059. Quin, L.D.: Chemical studies on tobacco and its smoke;
Selecta Chim. 2 (1962) 37–62.
3060. Quin, L.D., W. George, and B.S. Menefee: Some semi-
quantitative gas chromatographic studies on the organic
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 1384
acids of tobacco and its smoke; J. Assoc. Off. Agr.
Chem. 44 (1961) 367–373.
3061. Quin, L.D. and M.E. Hobbs: Analysis of the nonvolatile
acids in cigarette smoke by gas chromatography of their
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3062. Quin, L.D., B.S. Menefee, and N.A. Pappas: Alkaloids
of tobacco smoke. III. Methyl and ethyl 3-pyridyl ketone
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3063. Quin, L.D. and N.A. Pappas: Quantitative determination
of individual alkaloids in tobacco by gas chromatogra-
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3064. Quin, L.D., P. Wilder, and M.E. Hobbs: Chromatographic
determination of steam-volatile acids in cigarette smoke;
Anal. Chem. 30 (1958) 546–547.
3065. Quincy, R.B., G.W. Wilson, and M.R. Guerin: Series II
experimental cigarettes. Summary of chemical analyti-
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3066. Radford, E.P. Jr: Polonium-210 in tobacco could endan-
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3067. Radford, E.P. Jr: Polonium-210 alpha radiation as a can-
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223.
3068. Radford, E.P. Jr and V.R. Hunt: Polonium-210: A vol-
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247–249.
3069. Radford, E.P. Jr and V.R. Hunt: Cigarettes and poloni-
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3070. Radford, E.P. Jr, V.R. Hunt, and J.B. Little: Polonium-
210 in cigarette smokers; Science 146 (1964) 87.
3071. Radford, E.P. Jr, J.B. Little, V.R. Hunt, and C. Nelson:
Polonium-210 in tobacco smoke as a tracer for particle
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3072. Rainey, P., K. Tincher, G. Gillman, and R. Bereman:
Plant steroids: Their role in the formation of polycyclic
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of tobacco; 56th Tobacco Science Research Conference,
Program Booklet and Abstracts, Vol. 56, Paper No. 16,
2002, p. 28.
3072a. Räisänen, U., I. Pitkänen, H. Halttunen, and M. Hurtta:
Formation of the main degradation compounds from ara-
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J. Thermal Anal. Calorimetry 72 (2003) 481–488.
3072b. Rakieten, N., M.L. Rakieten, D. Feldman, and M.J.
Boykin Jr: Mammalian ciliated respiratory epithelium:
Studies with particular reference to effects of menthol,
nicotine, and smoke of mentholated cigarettes; Arch.
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3073. Ralapati, S.: High performance capillary electropho-
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regulated tobacco products: A regulatory perspective;
50th Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 50, Paper No. 40, 1996, pp.
43–44.
3074. Ralapati, S.: High performance capillary electrophoresis
(HPCE) for the quantitative analysis of nicotine in ATF-
regulated tobacco products: A regulatory proposal; 51st
Tobacco Chemists’ Research Conference, Program Booklet
and Abstracts, Vol. 51, Paper No. 57, 1997, p. 59.
3075. Ramusino, M.C., B.S. Dattilo, A. Lucibello, and S.G.
Rossi: Determination of 25 low molecular weight
© 2009 by Taylor & Francis Group, LLC
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The Chemical Components of Tobacco and Tobacco Smoke
carbohydrates in tobacco by high performance ion chro-
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3076. Rand, H.J., E.T. Alvord, S.Z. Cardon, and A. Burhan:
A study of cigarette smoke and cigarette paper smoke
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3077. Rand, H.J., S.Z. Cardon, E.T. Alvord, and A. Burhan:
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3078. Randolph, H.R.: A gas chromatographic determination
of nicotine from an isopropyl alcohol extract of TPM;
27th Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 27, Paper No. 19, 1973, p.
12; A gas chromatographic determination of nicotine in
an isopropyl alcohol extract of smoke particulate matter;
Tob. Sci. 18 (1974) 133–135.
3079. Ratcliff, M.A., E.E. Medley, and P.G. Simmonds:
Pyrolysis of amino acids. Mechanistic considerations; J
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3080. Rathkamp, G., D.K. Chao, and D. Hoffmann: Analytical
studies on nonvolatile N-nitrosamines in cigarette
smoke; 27th Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 27, Paper No. 26,
1973, p. 20.
3081. Rathkamp, G. and D. Hoffmann: The inhibition of the
pyrosynthesis of several selective smoke components.
Experimental findings and theoretical considerations;
23rd Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 23, Paper No. 29, 1969,
p. 21.
3082. Rathkamp, G. and D. Hoffmann: Chemical studies on
tobacco smoke. XIII. Inhibition of the pyrosynthesis of
several selective smoke constituents; Beitr. Tabakforsch.
5 (1970) 302–306.
3083. Rathkamp, G. and D. Hoffmann: Fluorenes and fluo-
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Research Conference, Program Booklet and Abstracts,
Vol. 24, Paper No. 28, 1970, p. 20.
3084. Rathkamp, G. and D. Hoffmann: Polynuclear aromatic
hydrocarbon profiles of tobacco smoke; 26th Tobacco
Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 26, Paper No. 9, 1972, p. 14.
3085. Rathkamp, G., D. Hoffmann, and E.L. Wynder:
Experiments on the reduction of polynuclear aro-
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Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 20, Paper No. 19, 1966, p. 23.
3086. Rathkamp, G., D. Hoffmann, and E.L. Wynder: Primary
and secondary nitrohydrocarbons in cigarette smoke;
21st Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 21, Paper No. 25, 1967, p.
14; Chemical studies on tobacco smoke. III. Primary
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3087. Rathkamp, G., T.C. Tso, and D. Hoffmann: On the cor-
relation between various leaf constituents and selected
smoke components; 25th Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 25,
Paper No. 6, 1971, p. 5.
3088. Rathkamp, G., T.C. Tso, and D. Hoffmann: Chemical
studies on tobacco smoke. XX. Smoke analyses of ciga-
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stalk position; Beitr. Tabakforsch. 7 (1973) 179–189.
3089. Rayburn, C.H.: Tobacco smoke: Influence of certain
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Booklet and Abstracts, Vol. 4, Paper No. 10, 1950.
3090. Rayburn, C.H.: Chemical analysis of tobacco and
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Conference, Program Booklet and Abstracts, Vol. 6,
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Research Conference, Program Booklet and Abstracts,
Vol. 11, Paper No. 14, 1957, p. 11.
3092. Rayburn, C.H., W.B. Wartman Jr, and P.M. Pedersen:
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3093. Reddick, E.M., G.L. Dooly, and S.C. Moldoveanu:
Analysis of phenols in sidestream cigarette smoke using
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Conference, Program Booklet and Abstracts, Vol. 56,
Paper No. 61, 2002, p. 57.
3093a. Reddy, A.S. and T.L. Thomas: Expression of a cyanobac-
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3093c. Reductase: By a search (Google) on the Internet, insert-
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specified enzyme.
3094. Reece, J.B., C.H. Risner, and W.T. Morgan: A collabora-
tive investigations of two tobacco TSNA methods; 56th
Tobacco Science Research Conference, Program Booklet
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3095. Registry of Toxic Effects of Chemical Substances
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3096. Reid, W.W. Jr: Some aspects of polyphenols of tobacco;
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3097. Reid, W.W. Jr: Biosynthesis of solanesol and sterols in
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3097a. Reid, W.W. Jr: The action of inhibitors on the incorpora-
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3099. Reid, W.W. Jr and D. Hellier: Resins of tobacco and
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3100. Reif, G.: Die Bestimmung von Äthylenglykol im
Tabakrauch mittels 2-Naphthol [Demonstration of
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3101. Reif, H.: The use of the ion-selective electrode for cya-
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3102. Reif, H. and H. Kuhn: Die Bestimmung von
Kohlenmonoxid und Kohlendioxid in Zigarettenrauch
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[The determination of carbon monoxide and carbon
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Tabakregie 14 (1973) 239–251.
3103. Reigh, D.L., S. Wender, and E.C. Smith: Phenolic inhi-
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3104. Remington, R.E.: A hitherto unsuspected source of arse-
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3104a. Resnik, F.E.: Thin layer chromatographic separation
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3105. Resnik, F.E., W.H. Danker, and F.L. Daylor: Flavour
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Internat. Tob. Sci. Cong., Salisbury, Rhodesia, 1963
(1964) 522–533.
3106. Resnik, F.E. and J.C. Holmes: New techniques of smoke
analysis. II. Mass spectrometric identification of smoke
constituents from gas chromatography fractions; 9th
Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 9, Paper No. 5, 1955,
pp. 2–3.
3107. Resnik, F.C., L.A. Lee, and W.A. Powell: Chromato-
graphy of organic acids in cured tobacco; Tob. Sci. 1
(1957) 23–27.
3108. Resnik, F.E. and R.B. Seligman: New techniques of
smoke analysis. III. Mass spectrometric identifica-
tion of compounds separated by paper chromatog-
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Program Booklet and Abstracts, Vol. 9, Paper No. 6,
1955, p. 3
3108a. Reunova, G.D., A.G. Trubitsyn, and V.G. Reifman:
Effect of actinomycin D on tobacco mosaic virus (TMV)
accumulation in isolated tobacco protoplasts under vary-
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3109. Reuveni, M.and Y. Cohen: Growth retardation and
changes in phenolic compounds with special reference
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3110. Reynolds, J.H. IV: A survey of the literature regarding
carbon monoxide, with special reference to its occur-
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3111. Reynolds, J.H. IV: Evaluation of filter additives for
selective removal of phenols from cigarette smoke;
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3112. Reynolds, J.H. IV: Experiments in removal of CO from
cigarette smoke; RDM, 1970, No. 81, August 21, see
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3113. Reynolds, J.H. IV: Evaluation of the Stanford Research
Institute CO filter. I; RDM, 1970, No. 86, September 11,
see www.rjrtdocs.com 500614989 -4992.
3114. Reynolds, J.H. IV: Evaluation of the Stanford Research
Institute CO filter. II; RDM, 1970, No. 87, September
11, see www.rjrtdocs.com 500614993 -4998.
3115. Reynolds, J.H. IV: Evaluation of the Stanford Research
Institute CO filter. III; RDM, 1970, No. 88, September
11, see www.rjrtdocs.com 500614999 -5012.
3116. Reynolds, J.H. IV: Changes in smoke composition in
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 1386
3116a. Reynolds J.H. IV: Basic study of air dilution. I.
Determination of air dilution volumes in cigarettes using
a novel method; RDR, 1972, No. 20, November 2, see
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3117. Reynolds, J.H. IV: Evaluation of the Stanford Research
Institute CO filter. IV; RDM, 1975, No. 40, November
10, see www.rjrtdocs.com 511500239 -0246.
3118. Reynolds, J.H. IV and M.N. Andrews: Removal of car-
bon monoxide from cigarette smoke. II. Development
and application of a rapid method for screening prospec-
tive carbon monoxide removal agents; RDR, 1971, No.
16, July 29, see www.rjrtdocs.com 514902024 -2043.
3119. Reynolds, J.H. IV and B.P. Hege: Experiments in
removal of carbon monoxide from cigarette smoke. III.
Successful catalytic removal of carbon monoxide from
smoke; RDM, 1973, No. 120, March 19, see www.rjrt-
docs.com 508566003 -6012.
3119a. Reynolds, J.H. IV and J.P. Wheeler: Basic study of air
dilution. II. Some experimental air dilution filters; RDR,
1973, No. 5, August 2, see www.rjrtdocs.com 501003079
-3100; III. Air dilution and gas and particulate phase
product formation in a series of experimental air dilu-
tion cigarettes; RDR, 1973, No. 7, August 14, see www.
rjrtdocs.com 501003133 -3166; IV. Study of the puff-
by-puff behavior of air diluted cigarettes; RDR, 1973,
No. 6, September 4, see www.rjrtdocs.com 501003101
-3132; V. Studies of gas flows in air diluted cigarettes.
RDR, 1973, No. 8, October 12, see www.rjrtdocs.com
501003167 -3207; VI. Simulation of air dilution by puff
volume reduction; RDM, 1973, No. 30, October 19, see
www.rjrtdocs.com 500606288 -6300; VII. A more rapid
method for the measurement of air dilution; RDM, 1975,
No. 30, August 8, see www.rjrtdocs.com 500616350
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3120. Reynolds, J.H. IV and J.P. Wheeler: A method for the
study of air diluted cigarettes; 30th Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 30, Paper No. 14, 1976, p. 16; Tob. Sci. 21 (1977)
85–90.
3121. Reynolds, M.L.: Factors affecting the delivery of cig-
arette smoke vapor phase; 19th Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 19, Paper No. 21, 1965, pp. 31–33.
3121a. Reynolds, M.L.: Influence of filter additives on smoke
composition; Recent Adv. Tob. Sci. 4 (1978) 47–67.
3122. Rhee, M.S.: Quantitative analysis of trans-unsaturated
fatty acids in cigarette smoke; 8th Internat. Tob. Sci.
Cong., Vienna, Austria, 1984, CORESTA Inf. Bull.,
Spec. Edition 1984: Paper ST10, 72.
3123. Rhoades, J.W. and D.E. Johnson: Gas chromatography
and selective detection of N-nitrosamines; J. Chromat.
Sci. 8 (1970) 616–617.
3124. Rhoades, J.W. and D.E. Johnson: DMN in cigarette
smoke; Chem. Eng. News (December 6, 1971) 15–16;
N-Dimethylnitrosamine in tobacco smoke condensate;
Nature 236 (1972) 307–308; Method for the determina-
tion of N-dimethylnitrosamine in tobacco smoke con-
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3125. Rhodes, P.R. and J.A. Saunders: Selective adsorption of
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Tabakforsch. Int. 12 (1983) 21–27.
3126. Ribeiro, F.: The irritant action of cigar smoke; Arch.
Hyg. Saude Publ. 2 (1937) 289–290, see Chem. Abstr.
33 (1939) 7959.
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The Chemical Components of Tobacco and Tobacco Smoke
3126a. Ribonucleic acid clone: By a search (Google) on the
Internet, inserting the term ribonucleic acid tobacco
clone provides numerous references to the numerous
variations of it.
3126b. Ricci, P., F. Trentin, P. Bonnet, P. Venard, F. Mouton-
Perronnet, and M. Bruneteau: Differential production
of parasiticein, an elicitor of necrosis and resistance in
tobacco, by isolates of Phytophthora parasitica; Plant
Pathol. 41 (1992) 298–307.
3126c. Ricciuti, C. and C.O. Willits: Determination of nornico-
tine by amperometric titration; 4th Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 4, Paper No. 6, 1950.
3127. Rice, E.W.: Furfural content of cigarette smoke and its
determination; Proc Soc. Exptl. Biol. Med. 87 (1954)
533–535.
3128. Rice, J.E., E.J. LaVoie, and D. Hoffmann: Synthesis of
isomeric phenols and the trans-2,3-diol of fluoranthene;
J. Org. Chem. 48 (1983) 2360–2363.
3129. Rice, W.Y. Jr and J.R. Hayes: Comparison of paramag-
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of cigarettes that burn tobacco and cigarettes that heat
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3130. Rice, W.Y. Jr, A.J. Sensabaugh Jr, M.L. Raker, and A.T.
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of cigarette smoke condensate; R&DM, 1986, No. 7,
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3131. Rice, W.Y. Jr, R.H. Steele, and J.R. Hayes: A compari-
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3132. Rickards, J.C. and W.F. Owens Jr: Effect of porous
cigarette papers on the yield of the major vapor phase
and certain particulate phase components of cigarette
smoke; 20th Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 20, Paper No. 20,
1966, p. 25; August 25, 1972 Revision.
3133. Rickert, W.S., K.S. Brown, R. Walker, and M.J.
Kaiserman: Levels of ETS particulates, nicotine, and
carbonyls in a random selection of homes in a mid-
size Canadian city; 49th Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 49,
Paper No. 24, 1995, pp. 30–31.
3134. Rickert, W.S., P. Joza, and J. Wu: Determination of
the amount of free radicals generated from gas phase
and particulate phase in mainstream tobacco smoke;
58th Tobacco Science Research Conference, Program
Booklet and Abstracts, Vol. 58, Paper No. 14, 2004, pp.
28–29.
3135. Rickert, W.S. and M.J. Kaiserman: Cigarette emissions
of fourteen ETS constituents by five types of cigarettes
estimated from growth curves in a controlled environ-
ment; 47th Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 47, Paper No. 9,
1993, pp. 22–23.
3136. Rickert, W.S. and M.J. Kaiserman: Estimates of removal
rates for fourteen constituents of ETS based on a nonlin-
ear regression of growth curves; 47th Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 47, Paper No. 10, 1993, p. 23.
3137. Rickert, W.S. and M.J. Kaiserman: An assessment of the
relative contributions of burning wood, candles, lamps,
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Research Conference, Program Booklet and Abstracts,
Vol. 49, Paper No. 30, 1995, pp. 34–35.
3138. Rickert, W.S. and M.J. Kaiserman: Chemical character-
ization of cigarette tobacco and mainstream smoke from
Canadian cigarettes: 1968 to 1994, 26 years of change;
50th Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 50, Paper No. 58, 1996, pp.
54–55.
3139. Rickert, W.S. and M.J. Kaiserman: A comparison
of yields of “tar”, nicotine, and CO by 115 brands of
Canadian cigarettes tested under various conditions;
51st Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 51, Paper No. 7, 1997, pp.
26–27.
3140. Rickert, W.S. and M.J. Kaiserman: Development of a
numerical index for expressing the relative toxicity of
mainstream tobacco smoke based on chemical com-
position; 52nd Tobacco Science Research Conference,
Program Booklet and Abstracts, Vol. 52, Paper No. 63,
2003, p. 44.
3141. Rickert, W.S., R. Momin, A. Trivedi, and W. Wright:
A comparative study of the mutagenicity of tar from
cigarettes sold in Canada over the past three decades
(1969/1970–2002); 57th Tobacco Science Research
Conference, Program Booklet and Abstracts, Vol. 57,
Paper No. 42, 2003, pp. 44–45.
3142. Rickert, W.S., J.C. Robinson, D.F. Bray, B. Roberts, and
N. Collishaw: Characterization of tobacco products: A
comparative study of the tar, nicotine and carbon mon-
oxide yield of cigars, manufactured cigarettes and cig-
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3143. Rickert, W.S., J.C. Robinson, and N. Collishaw: Yields
of tar, nicotine and carbon monoxide in the sidestream
smoke from 15 brands of Canadian cigarettes; Am. J.
Publ. Hlth. 74 (1984) 228–231.
3144. Rickert, W.S., J.C. Robinson, and M.J. Kaiserman:
Quantitation of “tar” color with specific reference to
estimating yields, quantifying ETS and the produc-
tion of color scales; 48th Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 48,
Paper No. 36, 1994, pp. 45–46.
3144a. Rickert, W.S., M. Shariel, J. Wu, and P. Joza: TSNAs
in cigarette filler and mainstream smoke from Canadian
cigarettes 2003–2006: A period of major change;
60th Tobacco Science Research Conference, Program
Booklet and Abstracts, Vol. 60, Paper No. 52, 2006,
p. 48.
3145. Rickert, W.S. and P.B. Stockwell: Automated determi-
nation of hydrogen cyanide, acrolein, and total alde-
hydes in the gas phase of cigarette smoke; J. Automation
Chem. 1 (1979) 152–154.
3146. Rickert, W.S., A. Trivedi, and W. Wright: Effect of smok-
ing condition and method of collection on TA 98 and TA
100 response to crude smoke condensate (CSC) from
control cigarettes (Kentucky Reference 1R4F, 1R5F
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Congress, Paper ST 7.
3147. Rickert, W., A. Trivedi, and W. Wright: Specific activ-
ity (mutagenicity) of crude tobacco smoke condensate
(CSC) in relation to method of collection, smoking
© 2009 by Taylor & Francis Group, LLC
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conditions, and cigarette type; 56th Tobacco Science
Research Conference, Program Booklet and Abstracts,
Vol. 56, Paper No. 30, 2002, p. 36.
3148. Rickert, W.S., A. Trivedi, and W. Wright: Relative cyto-
toxicity of tobacco smoke vapour and particulate phases
when cigarettes are smoked under ISO and Canadian
intense conditions; 57th Tobacco Science Research
Conference, Program Booklet and Abstracts, Vol. 57,
Paper No. 15, 2003, p. 27.
3148a. Rickert, W.S. and W. Wright: Yields of selected main-
stream smoke constituents in relation to smoking regime
and smoking machine type; 60th Tobacco Science
Research Conference, Program Booklet and Abstracts,
Vol. 60, Paper No. 55, 2006, pp. 49–50.
3149. Rickert, W.S., W. Wright, M. Bao, P. Joza, and M.
Sharifi: Yield of selected carbonyls, NO, HCN and poly-
nuclear aromatic hydrocarbons from cigarettes sold in
Canada (1969–2002); 57th Tobacco Science Research
Conference, Program Booklet and Abstracts, Vol. 57,
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3151. Richter, M.: Über die gaschromatographische
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3152. Richter, M.: On the gas chromatographic determina-
tion of organochlorine pesticide residues in tobacco:
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(1977/1978) 80–84.
3153. Riehl, T.F.: Effect of plasticizers on menthol transfer to
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3154. Riehl, T.F., L.L. Shockley, and M.L. Reynolds: Menthol
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3155. Riemenschneider, R.W., R.M. Speck, and E.G. Beinhart:
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see Table 4, Compound 253.
3158. Risner, C.H.: The determination of benzo[a]pyrene and
benz[a]anthracene in the total particulate matter of ciga-
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11/24/08 2:39:55 PM
 1388
total particulate matter of cigarette smoke; J. Chromat.
Sci. 26 (1988) 113–120.
3159. Risner, C.H.: Analysis of applied vanillin in tobacco
by high-performance liquid chromatography; R&DM,
1986, No. 114, August 4, see www.rjrtdocs.com
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3160. Risner, C.H.: Quantitation of some tobacco anions by
eluent suppressed anion exchange chromatography
using conventional liquid chromatography equipment;
Tob. Sci. 30 (1986) 85–90.
3161 Risner, C.H.: A high-performance liquid chromatogra-
phy method for the analysis of chlorogenic acid, caffeic
acid, p-coumaric acid, ferulic acid, 7-hydroxycoumarin,
scopoletin, rutin and kaempferol 3-rutinoside, quer-
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3162. Risner, C.H.: The determination of benzo[a]pyrene and
benz[a]anthracene in mainstream and sidestream smoke
of Reference Cigarette 1R4F and a cigarette which heats
but does not burn tobacco: A comparison; R&DM, 1988,
No. 173, June 29, see www.rjrtdocs.com 512059871
-9894; Risner, C.H.: The determination of benzo[a]
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stream smoke of Kentucky Reference Cigarette 1R4F
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comparison; Beitr. Tabakforsch. Int. 15 (1991) 11–17.
3163. Risner, C.H.: A high-performance liquid chromato-
graphic method for the determination of maltitol, glyc-
erin, propylene glycol, and sorbitol in tobacco and
maltol and sorbitol in raw materials; R&DM, 1989, No.
262, September 21, see www.rjrtdocs.com 508295580
-5603.
3164. Risner, C.H. and S. Cash: A high-performance liquid
chromatographic determination of major phenolic com-
pounds in tobacco smoke; J. Chromatog. Sci. 28 (1990)
239–243.
3165. Risner, C.H.: The quantification of hydroquinone, cat-
echol, phenol, 3-methylcatechol, and m- + p- cresol in
indoor air; J. Liq. Chrom. 16 (1991) 4117–4140.
3166. Risner, C.H.: An improved method for the quantifica-
tion of selected phenolic compounds in ambient air;
46th Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 46, Paper No. 8, 1992, p. 24,
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3167. Risner, C.H.: Collection and ion chromatographic
determination of nitrous acid in air; Tob. Sci. 37 (1993)
49–53.
3168. Risner, C.H.: The determination of scopoletin in indoor
air; R&DM, 1993, No. 6, March 26, see www.rjrtdocs.
com 508398264 -8306; The determination of scopoletin
in environmental tobacco smoke by high-performance
liquid chromatography; J. Liq. Chrom. 17 (1994) 2723–
2736; Risner, C.H., S.V. Parsons, and L.S. Winkler:
The determination of scopoletin in mainstream tobacco
smoke; Tob. Sci. 38 (1994) 68–71.
3169. Risner, C.H.: High performance liquid chromatographic
determination of major carbonyl compounds from vari-
ous sources in ambient air; J. Chrom. Sci. 33 (1995)
168–176.
3170. Risner, C.H.: The determination of +A-tocopherol in
tobacco and mainstream tobacco smoke; 50th Tobacco
Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 50, Paper No. 46, 1996, p. 47; Risner, C.H.
© 2009 by Taylor & Francis Group, LLC
78836_C029.indd 1388
The Chemical Components of Tobacco and Tobacco Smoke
and P.R. Nelson: The determination of +A-tocopherol in
environmental tobacco smoke; 51st Tobacco Chemists’
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3171. Risner, C.H. and S.L. Cash: A high performance liquid
chromatographic method for the determination of hyd-
roquinone, resorcinol, catechol, phenol, m- + p-cresol,
and o-cresol in tobacco smoke; R&DM, 1988, No. 233,
September 2, see www.rjrtdocs.com 507039723 -9766.
3172. Risner, C.H. and S.L. Cash: The determination of major
phenolic compounds in tobacco smoke; 42nd Tobacco
Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 42, Paper No. 43, 1988, p. 38, for presen-
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3173. Risner, C.H. and S.L. Cash: A high performance liq-
uid chromatographic method for the determination of
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environmental tobacco smoke; R&DM, 1989, No. 184,
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determination of hydroquinone, catechol, phenol, and
mp-cresols in indoor air samples by high performance
liquid chromatography; Environ. Tech. 11 (1990)
345–352.
3174. Risner, C.H. and S.L. Cash: The quantification of ETS
phenols; 43rd Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 43, Paper No. 52,
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3175. Risner, C.H. and S.L. Cash: A high-performance liquid
chromatographic determination of major phenolic com-
pounds in tobacco smoke; J. Chromat. Sci. 28 (1990)
239–244.
3176. Risner, C.H. and J.M. Conner: Quantification of 4- to
6-ring polynuclear aromatic hydrocarbons in indoor
air; R&DM, 1990, No. 162, August 3, see www.rjrt-
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6-ring polynuclear aromatic hydrocarbons in indoor air
samples; 44th Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 44, Paper No. 31,
1990, p. 26; The quantification of 4- to 6-ring poly-
nuclear aromatic hydrocarbons in indoor air samples
by high-performance liquid chromatography; J. Liq.
Chrom. 14 (1991) 437–464.
3176a. Risner, C.H., J.B. Reece, and W.T. Morgan: The deter-
mination of tobacco-specific nitrosamines in tobacco:
A collaborative investigation of current methodology;
Recent Adv. Tob. Sci. 27 (2001) 47–73.
3177. Risner, C.H. and F.N. Wendelboe: Quantification of
tobacco-specific nitrosamines; Tob. Sci. 38 (1994) 1–5.
3178. Rivenson, A., M.V. Djordjevic, S. Amin, and D.
Hoffmann: A study of tobacco carcinogenesis. XLIV.
Bioassay in A/J mice of some N-nitrosamines; Cancer
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3179. Rivenson, A., K. Furuya, S.S. Hecht, and D. Hoffmann:
Experimental nasal cavity tumors induced by tobacco-
specific nitrosamines; Nasal Tumors Anim. Man 3
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3180. Rivenson, A., S.S. Hecht, and D. Hoffmann:
Observations on lung tumors arising from metaplastic
squamous epithelium in rats treated chronically with the
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3186. Rix, C.E.: Headspace analysis of tobacco using
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3197. Roberts, D.L.: Macrocyclic diterpenes, A- and B-4,8,13-
duvatriene-1,3-diols, from tobacco; RDR, 1962, No. 36,
October 10, see www.rjrtdocs.com 500939614 -9636.
3198. Roberts, D.L.: Burley tobacco components. III. Studies
on condensate from the denicotinization process;
RDR, 1963, No. 23, March 25, see www.rjrtdocs.com
500961418 -1447.
3199. Roberts, D.L.: Burley tobacco components. IV.
Isolation, characterization, and synthesis of compound
BV-20; RDR, 1963, No. 44, June 6, see www.rjrtdocs.
com 500961892 -1897.
3200. Roberts, D.L.: Burley tobacco components. V. Isolation,
characterization, and synthesis of compound BV-21;
RDR, 1963, No. 49, July 18, see www.rjrtdocs.com
500961976 -1983.
3201. Roberts, D.L.: Burley tobacco components. VI. Isolation,
characterization, and synthesis of 2-acetyl-5-methylpyr-
role; RDR, 1963, No. 59, November 20, see www.rjrt-
docs.com 500962164 -2181.
3202. Roberts, D.L.: Burley tobacco components. VII. Isolation,
characterization, and synthesis of 2-acetylpyrazine;
RDR, 1963, No. 60, December 9, see www.rjrtdocs.com
500962182 -2187.
3203. Roberts, D.L.: Burley tobacco components. VIII.
Isolation, characterization and synthesis of two pyr-
rolecarboxaldehydes; RDR, 1964, No. 1, January 6, see
www.rjrtdocs.com 500963219 -3226.
3204. Roberts, D.L.: Burley tobacco components. IX. Further
isolation and synthesis of 2-acetylpyrazine and related
compounds; RDR, 1964, No. 9, February 11, see www.
rjrtdocs.com 500963380 -3391.
3205. Roberts, D.L.: Burley tobacco components. X.
Components of condensate from denicotinization pro-
cess, 1963; RDM, 1964, No. 28, March 5, see www.rjrt-
docs.com 500602185 -2195.
3206. Roberts, D.L.: Burley tobacco components. XI. Isolation
and synthesis of tobacco constituents; RDR, 1964, No.
47, October 2, see www.rjrtdocs.com 500964124 -4139.
3207. Roberts, D.L.: Preparation of the G-lactone and G-lactam
of methyl-4-oxo-2-hexanoic acid; J. Org. Chem. 29
(1964) 2785.
3208. Roberts, D.L.: Burley tobacco components. XII.
Synthesis and characterization related to SM2C;
RDR, 1965, No. 5, January 21, see www.rjrtdocs.com
500965598 -5605.
11/24/08 2:39:56 PM
 1390
3209. Roberts, D.L.: Burley tobacco components. XIII.
Attempted synthesis of SM40C; RDR, 1965, No. 9,
February 9, see www.rjrtdocs.com 500965629 -5638.
3210. Roberts, D.L.: Burley tobacco components. XIV.
Attempted synthesis of isophorone-related compounds;
RDR, 1965, No. 12, February 26, see www.rjrtdocs.com
500965690 -5701.
3211. Roberts, D.L.: The structure of a new sesquiterpene—1-
keto-A-cyperone - isolated from tobacco; 25th Tobacco
Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 25, Paper No. 17, 1971, p. 11.
3212. Roberts, D.L.: The structure of a new sesquiterpene iso-
lated from tobacco; Phytochem, 11 (1972) 2077–2080.
3213. Roberts, D.L.: Chemical and physical modification of
tobacco. Literature survey; RDM, 1972, No. 49, October
31, see www.rjrtdocs.com 500615796 -5833.
3214. Roberts, D.L.: Ammonia and nicotine migration in
tobacco; RDM, 1974, No. 11, April 8, see www.rjrtdocs.
com 514901109 -1114.
3215. Roberts, D.L.: Natural tobacco flavor; Recent Adv. Tob.
Sci. 14 (1988) 49–81.
3216. Roberts, D.L., R.A. Heckman, B.P. Hege, and S.A.
Bellin: Synthesis of (RS)-abscisic acid; J. Org. Chem.
33 (1968) 3566–3569.
3217. Roberts, D.L. and C.E. Lewis: Tobacco and stem essen-
tial oils; RDR, 1974, No. 2, January 8, see www.rjrt-
docs.com 510646975 -6985.
3218. Roberts, D.L., C.W. Miller, and R.A. Lloyd Jr: Tobacco
carotenoids; 27th Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 27,
Paper No. 43, 1973, p. 29.
3219. Roberts, D.L. and W.A. Rohde: Isolation and identifica-
tion of flavor components of burley tobacco; Tob. Sci. 16
(1972) 107–112.
3220. Roberts, D.L. and R.L. Rowland: Characterization of
M-II-f as A-3,8,14-duvatriene-1,5-diol; RDR, 1962, No.
29, August 1, see www.rjrtdocs.com 500939496 -9504.
3221. Roberts, D.L. and R.L. Rowland: Macrocyclic diterpenes.
A- and B-4,8,13-duvatriene-1,3-diols from tobacco;
J. Org. Chem. 27 (1962) 3989–3995.
3222. Roberts, D.L. and J.N. Schumacher: Isolation and char-
acterization of compound XI. A macrocyclic diterpene
isolated from tobacco; RDR, 1963, No. 26, April 4, see
www.rjrtdocs.com 500961494 -1500.
3223. Roberts, D.L. and J.N. Schumacher: Isolation, char-
acterization and synthesis of compound XXVI;
RDR, 1963, No. 36, May 13, see www.rjrtdocs.com
500961631 -1648.
3224. Roberts, D.L., J.N. Schumacher, R.A. Lloyd Jr, R.A.
Heckman, and A. Rodgman: List of tobacco and smoke
constituents; RDM, 1975, No. 15, April 16, see www.
rjrtdocs.com 514901435 -1636.
3225. Roberts, D.L., J.N. Schumacher, R.A. Lloyd Jr, and R.A.
Heckman: Carbohydrate pyrolysis products: A review of
the literature; RDM, 1976, No. 7, February 4, see www.
rjrtdocs.com 500616624 -6642.
3226. Roberts, D.L., J.N. Schumacher, R.A. Lloyd Jr, and R.A.
Heckman: Literature study of pyrolysis of amino acids
and proteins; RDM, 1976, No. 9, February 11, see www.
rjrtdocs.com 500616651 -6671.
3227. Roberts, D.L., J.N. Schumacher, R.A. Lloyd Jr, and R.A.
Heckman: Nicotine pyrolysis products: A review of the
literature; RDM, 1977, No. 5, January 25, see www.rjrt-
docs.com 501009926 -9932, 504019634 -9640.
© 2009 by Taylor & Francis Group, LLC
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The Chemical Components of Tobacco and Tobacco Smoke
3228. Roberts, K.C. and P. Watts: The automatic gas chromato-
graph analysis of water, menthol, phenol, nicotine and
triacetin in the ethanol extract of tobacco smoke con-
densate; 29th Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 29, Paper No. 40,
1975, p. 28.
3229. Robertson, L.S.: Carcinogens in cigarette smoke; South
Afr. Tydsk. Geneeskunde (1964) 617.
3230. Robinson, D.P., M.A.J. Bevan, and C.F. Hewett: An
assessment of solanesol as a marker for environmen-
tal tobacco smoke; 46th Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 46,
Paper No. 7, 1992, p. 23.
3231. Robinson, M.F.: Determination of selected car-
bonyl components in sidestream smoke; R&DM,
1986, No. 83, May 22, see www.rjrtdocs.com
50493 8679–8690.
3232. Rocchietta, S.: Recent research on the identification of
3,4-benzpyrene in the components of tobacco smoke;
Minerva Med. (Torino) 47 (1956) 1831.
3233. Rodgman, A.: Carcinogens and carcinogen precursors
present in tobacco substances: A survey; Memorandum,
15 October 1954, pp. 1–59.
3234. Rodgman, A.: The carcinogenicity of arsenic com-
pounds; Memorandum, 18 October, 1954, pp. 1–16.
3235. Rodgman, A.: The carcinogenicity of 3,4-benzpyrene;
Memorandum, 18 October 1954, pp. 1–13.
3235a. Rodgman, A.: The synthesis of various substituted phe-
nols for use as flavorants in tobacco products; RDM,
1954, No. 31, December 17, see www.rjrtdocs.com
500610091 -0108.
3236. Rodgman, A.: The fractionation of cigarette smoke and
tars; RDM, 1955, No. 13, April 29, see www.rjrtdocs.
com 501009739 -9746.
3237. Rodgman, A.: Chemical and biological investigations
of tobacco tar and smoke; Memorandum, August 1955,
pp. 1–26, see http://tobaccodocuments.org/bliley_rjr/list
500185802 -5849, 502815162 -5189.
3237a. Rodgman, A.: Chemical carcinogenesis; Memorandum,
September 1955, pp. 1–69, see http://tobaccodocuments.
org/bliley_rjr/list 500508429 -8497, 502815208 -5279.
3238. Rodgman, A.: Arsenic or arsenic compounds:
Carcinogenesis studies; Memorandum, October 1955,
pp. 1–10, see http://tobaccodocuments.org/bliley_rjr/list
502815457 -5460, 502815461 -5471.
3239. Rodgman, A.: Data discussed by Dr. Ernst L. Wynder in
speech “Human and experimental relationship of cancer
and tobacco” presented at the symposium on “Tobacco”
before the Metropolitan Long Island Subsection of
the American Chemical Society, February 24, 1956;
RDM, 1956, No. 9, March 16, see www.rjrtdocs.com
501009747 -9754.
3240. Rodgman, A.: The analysis of cigarette smoke conden-
sate. I. The isolation and/or identification of polycyclic
aromatic hydrocarbons in Camel cigarette smoke; RDR,
1956, No. 9, September 28, see www.rjrtdocs.com
501008241 -8293.
3240a. Rodgman, A.: The preparation of some phenolic fla-
vorants; RDR, 1956, No. 10, October 1, see www.rjrt-
docs.com 500930142 -0155.
3241. Rodgman, A.: The analysis of cigarette smoke con-
densate. II. The pretreatment of Camel blend tobacco;
RDR, 1956, No. 12, November 1, see www.rjrtdocs.com
501008294 -8336, 504912107 -2148, 515839741 -9783.
11/24/08 2:39:56 PM
 Bibliography
3242. Rodgman, A.: The analysis of cigarette smoke conden-
sate. III. Flue-cured tobacco; RDR, 1957, No. 4, March
14, see www.rjrtdocs.com 501008337 -8377.
3243 Rodgman, A.: Tobacco tar fractionation and the pre-
treatment of tobacco: A conversation with Dr. George F
Wright of the University of Toronto, Toronto, Ontario,
Canada; RDM, 1957, No. 25, July 22, see www.rjrtdocs.
com 500610651 -0656.
3244. Rodgman, A.: The analysis of cigarette smoke conden-
sate. IV. 3,4,8,9-Dibenzpyrene in Camel cigarette smoke
condensate; RDR, 1957, No. 13, October 7, see www.
rjrtdocs.com 501008378 -8386.
3245. Rodgman, A.: Components reported in tobacco smoke;
RDM, 1958, No. 32, April 17, see www.rjrtdocs.com
500610933 -0997.
3246. Rodgman, A.: The analysis of cigarette smoke conden-
sate. VI. The influence of solvent pretreatment of tobacco
and other factors on the polycyclic hydrocarbon content
of smoke condensate; RDR, 1959, No. 1, January 29,
see www.rjrtdocs.com 501008529 -8591.
3247. Rodgman, A.: The analysis of cigarette smoke conden-
sate. IX. Phytadienes; RDR, 1959, No. 11, May 18, see
www.rjrtdocs.com 500933338 -3372; The composition
of cigarette smoke. III. Phytadienes; J. Org. Chem. 24
(1959) 1916–1924.
3248. Rodgman, A.: The analysis of cigarette smoke con-
densate. X. The effect of porous paper and/or filter tip
materials or aluminized paper and/or alumina additive
(Reynolds Metals Company) on total polycyclic hydro-
carbons; RDM, 1959, No. 80, July 16, see www.rjrtdocs.
com 501009793 -9797.
3249. Rodgman, A.: The analysis of cigarette smoke conden-
sate. XIX. The determination of polycyclic aromatic
hydrocarbons; RDR, 1961, No. 1, January 6, see www.
rjrtdocs.com 500935976 -5996.
3250. Rodgman, A.: The analysis of cigarette smoke conden-
sate. XXXIII. Polycyclic hydrocarbons in Lark cigarette
smoke; RDM, 1963, No. 37, May 13, see www.rjrtdocs.
com 500612598 -2601.
3251. Rodgman, A.: The analysis of cigarette smoke conden-
sate. XXXV. A summary of an eight-year study; RDR,
1964, No. 10, February 12, see www.rjrtdocs.com
501008855 -8928.
3252. Rodgman, A.: Components reported in tobacco smoke:
An addendum; RDM, 1965, No. 59, August 6, see www.
rjrtdocs.com 504381941 -1944.
3253. Rodgman, A.: Components reported in tobacco smoke:
An addendum; RDM, 1967, No. 58, September 26, see
www.rjrtdocs.com 500613525 -3528.
3253a. Rodgman, A.: Chemical composition and biologi-
cal properties of tobacco smoke; Presentation to R. J.
Reynolds Tobacco Company R&D Personnel (April,
1985).
3254. Rodgman, A.: G13-expanded tobacco and Freon 11®;
R&DM, 1984, No. 6, February 13; G13-expanded
tobacco and Freon 11®; December, 1972, pp. 1–66, see
www.rjrtdocs.com 521189661 -9727; G13-expanded
tobacco and Freon 11®, 1st Revision; February, 1974,
pp. 1–77, see www.rjrtdocs.com 521189578 -9660;
G13-Expanded tobacco and Freon 11®, 2nd Revision;
October, 1977, pp. 1–152, see www.rjrtdocs.com
515991960 -2115; G13-expanded tobacco and Freon
11®, 3rd Revision; December, 1979, pp. 1–104, see
www.rjrtdocs.com 515979463 -9566.
© 2009 by Taylor & Francis Group, LLC
78836_C029.indd 1391
1391
3255. Rodgman, A.: A comparison of the chemical, physical,
and biological properties of cigarette mainstream smoke
(MS), cigarette sidestream smoke (SS), and environmen-
tal tobacco smoke (ETS); Report submitted to the U. S.
Environmental Protection Agency (December 1991;
revised July 1992), pp. i-vii + 1–117, see www.rjrtdocs.
com 512527469 -7599, 521184527 -4657, 521187004
-7125.
3255a. Rodgman, A.: Environmental tobacco smoke; Regul.
Toxicol. Pharmacol. 16 (1992) 223–244.
3256. Rodgman, A.: The N-nitrosamines in tobacco and
tobacco smoke; October, 1993: pp. i-xv, 1–259, see
www.rjrtdocs.com 509752851 -3134, 522101837 -2121.
3257. Rodgman, A.: The chemical composition of environmen-
tal tobacco smoke: Some comments on the Occupational
Safety and Health Administration’s notice on “Indoor
Air Quality”; Document submitted to the Occupational
Safety and Health Administration, 5 August, 1994, pp.
i-xiii + 1–172, see www.rjrtdocs.com. 515923456 -3645,
515926646 -6833, 517582702 -2904, 521186677 -6881,
521187802 -7991.
3258. Rodgman, A.: FTC “tar” and nicotine in cigarette main-
stream smoke: A retrospective; Recent Adv. Tob. Sci. 23
(1997) 5–74, see pp. 49–52.
3259. Rodgman, A.: Comments on BPDE experiments of
Denissenko et al.; Memorandum (November 26, 1996),
pp. 1–10.
3260. Rodgman, A.: Tobacco smoke components. Letter to the
Editor; Beitr. Tabakforsch. Int. 18 (1998) 127–129.
3261. Rodgman, A.: “Smoke pH”: A review; Beitr. Tabakfo-
rsch. Int. 19 (2000) 117–139; Erratum notice; Beitr.
Tabakforsch. Int. 19 (2001) 229–235.
3262. Rodgman, A.: Studies of polycyclic aromatic hydro-
carbons in cigarette mainstream smoke: Identification,
tobacco precursors, control of levels: A review; Beitr.
Tabakforsch. Int. 19 (2001) 361–379.
3263. Rodgman, A.: Some studies of the effects of additives
on cigarette mainstream smoke properties. I. Flavorants;
Beitr. Tabakforsch. Int. 20 (2002) 83–103.
3264. Rodgman, A.: Some studies of the effects of additives on
cigarette mainstream smoke properties. II. Casing mate-
rials and humectants; Beitr. Tabakforsch. Int. 20 (2002)
279–299.
3265. Rodgman, A.: The composition of cigarette smoke:
Problems with lists of tumorigens; Beitr. Tabakforsch.
Int. 20 (2003) 402–437.
3266. Rodgman, A.: Some studies of the effects of additives on
cigarette mainstream smoke properties. III. Ingredients
reportedly used in various commercial cigarette prod-
ucts in the USA and elsewhere; Beitr. Tabakforsch. Int.
21 (2004) 47–104.
3267. VOID
3268. Rodgman, A. and C.K. Chappell: Stigmasterol and
B-sitosterol from Camel cigarette smoke; RJRT
Notebook 56151–56156 (April, 1957).
3269. Rodgman, A. and L.C. Cook: The analysis of cigarette
smoke condensate. V. The polycyclic hydrocarbon pre-
cursors in tobacco; RDR, 1958, No. 18, December 1, see
www.rjrtdocs.com 501008387 -8441, 504912197 -2250.
3270. Rodgman, A. and L.C. Cook: The analysis of cigarette
smoke condensate. VII. Solanesol and solanesyl acetate;
RDR, 1958, No. 22, December 31, see www.rjrtdocs.
com 500932470 -2484; The composition of cigarette
smoke. I. Solanesyl acetate; Tob. Sci. 3 (1959) 86–88.
11/24/08 2:39:56 PM
 1392
3271. Rodgman, A. and L.C. Cook: The analysis of cigarette
smoke condensate. XI. A-Tocopherol; RDR, 1959, No.
23, September 29, see www.rjrtdocs.com 500933614
-3620; The composition of cigarette smoke. IV.
A-Tocopherol; Tob. Sci. 4 (1960) 7–8.
3272. Rodgman, A. and L.C. Cook: The analysis of ciga-
rette smoke condensate. XIII. Sclareolide from Turkish
tobacco smoke; RDR, 1960, No. 8, April 1, see www.
rjrtdocs.com 500934533 -4541.
3273. Rodgman, A. and L.C. Cook: The analysis of cigarette
smoke condensate. XIV. Polycyclic aromatic hydrocar-
bons; RDR, 1960, No. 20, May 26, see www.rjrtdocs.
com 501008592 -8660.
3274. Rodgman, A. and L.C. Cook: The analysis of ciga-
rette smoke condensate. XVII. The effect of alumina-
supported catalysts on total polycyclic hydrocarbons;
RDR, 1960, No. 36, December 2, see www.rjrtdocs.com
501008682 -8694.
3275. Rodgman, A. and L.C. Cook: The analysis of cigarette
smoke condensate. XVIII. Chloranil and 2,4,7-trini-
trofluorenone as filter tip additives; RDR, 1960, No.
38, December 7, see www.rjrtdocs.com 501008695
-8704.
3276. Rodgman, A. and L.C. Cook: The analysis of cigarette
smoke condensate. XX. A note on the normal long-
chained primary alcohols: An addendum to RDR, 1960,
No. 22; RDR, 1961, No. 5, January 26, see www.rjrt-
docs.com 500936097 -6106.
3277. Rodgman, A. and L.C. Cook: The analysis of cigarette
smoke condensate. XXI. Phenols; RDR, 1961, No. 10,
February 23, see www.rjrtdocs.com 501008731 -8772.
3278. Rodgman, A. and L.C. Cook: The analysis of ciga-
rette smoke condensate. XXIV. 6-Acetyl-2,3,4-tris-d-
B-methylvaleryl-B-D-glucopyranoside from Turkish
tobacco smoke; RDR, 1961, No. 42, August 18, see
www.rjrtdocs.com 500937292 -7299.
3279. Rodgman, A. and L.C. Cook: The analysis of cigarette
smoke condensate. XXVI. Heterocyclic nitrogen com-
pounds from Turkish tobacco smoke; RDR, 1962, No.
14, June 21, see www.rjrtdocs.com 500938892 -8910;
The composition of cigarette smoke. XI. Heterocyclic
nitrogen compounds from Turkish tobacco smoke; 16th
Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 16, Paper No. 23, 1962,
p. 14, for presentation text, see www.rjrtdocs.com
521189920 -9945; Tob. Sci. 6 (1962) 176–179.
3280. Rodgman, A. and L.C. Cook: The analysis of ciga-
rette smoke condensate. XXVII. Phenols from Turkish
tobacco smoke: Eugenol and isoeugenol; RDR, 1962,
No. 15, June 21, see www.rjrtdocs.com 501008799
-8811; Eugenol and isoeugenol from Turkish tobacco
smoke; 18th Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 18, Paper No. 22,
1964, pp. 33–35, for presentation text, see www.rjrt-
docs.com 521188506 -8516; The composition of ciga-
rette smoke. XIII. Eugenol and isoeugenol from Turkish
tobacco smoke; Tob. Sci. 8 (1964) 161–162.
3281. Rodgman, A. and L.C. Cook: The composition of ciga-
rette smoke. X. 12A-Hydroxy-13-epimanoyl oxide from
Turkish tobacco smoke; Tob. Sci. 6 (1962) 125–126.
3282. Rodgman, A. and L.C. Cook: The analysis of cigarette
smoke condensate. XXIX. Phytol (3,7,11,15-tetrameth-
yl-2-hexadecen-1-ol); RDR, 1963, No. 9, February 6,
see www.rjrtdocs.com 500961174 -1190.
© 2009 by Taylor & Francis Group, LLC
78836_C029.indd 1392
The Chemical Components of Tobacco and Tobacco Smoke
3283. Rodgman, A. and L.C. Cook: The analysis of cigarette
smoke condensate. XXXI. A-1,5-Dimethyl-12-isopropyl-
9-methylene-5,8-oxido-3,13-cyclotetradecadien-1-ol
and A-12-isopropyl-5,9-oxido-1,5,9-trimethyl-3,9,13-
cyclotetradecatrien-1-ol from Turkish tobacco smoke;
RDR, 1963, No. 24, March 25, see www.rjrtdocs.com
500961449 -1470.
3284. Rodgman, A. and L.C. Cook: The analysis of cigarette
smoke condensate. XXXII. Isoprenoid alcohols; RDR,
1963, No. 35, May 8, see www.rjrtdocs.com 500961612
-1629.
3285. Rodgman, A. and L.C. Cook: Unsaturated alcohols
from Turkish tobacco smoke; 17th Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 17, Paper No. 17, 1963, p. 14, see www.rjrtdocs.
com 521340001 -0012; The composition of cigarette
smoke. XII. Unsaturated alcohols from Turkish tobacco
smoke; Tob. Sci. 7 (1963) 151–157.
3286. Rodgman, A. and L.C. Cook: The composition of ciga-
rette smoke; Presented at Sigma Xi Meeting, Wake
Forest University, Winston-Salem, NC, 17 March, 1965,
see www.rjrtdocs.com 501521599 -1606; the American
Chemical Society Section Meeting, Columbus, GA,
2 May 1968, and the Chemistry Club, Chemistry
Department, Columbus College, Columbus, GA, 2 May
1968, see www.rjrtdocs.com 501521608 -1615; and
the Central North Carolina Section Meeting, American
Chemical Society, Greensboro, NC, 14 October 1969,
for presentation text and slides, see www.rjrtdocs.com
501521658 -1700.
3287. Rodgman, A. and L.C. Cook: The analysis of ciga-
rette smoke condensate. XXXVII. A phytyl ester frac-
tion from Turkish tobacco smoke; RDR, 1965, No. 37,
August 18, see www.rjrtdocs.com 521188824 -8843;
Some ketones and phytyl esters from Turkish tobacco
smoke; 19th Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 19, Paper No. 30,
1965, p. 45, for presentation text, see www.rjrtdocs.com
521188860 -8878; The composition of cigarette smoke.
XV. Phytyl esters from Turkish tobacco smoke; Tob. Sci.
9 (1965) 158–165.
3288. Rodgman, A. and L.C. Cook: The analysis of cigarette
smoke condensate. XXXIV. 4-(2-Butenylidene)-iso-
phorones from Turkish tobacco smoke; RDR, 1966, No.
3, February 7, see www.rjrtdocs.com 500966768 -6776.
3289. Rodgman, A. and L.C. Cook: Some factors influenc-
ing the filtration of the vapor phase of cigarette smoke;
RDR, 1966, No. 12, April 13 [Paper XXXVIII in the
series The analysis of cigarette smoke condensate], see
www.rjrtdocs.com 521188922 -8970.
3290. Rodgman, A. and L.C. Cook: Treatment of 44X flue-
cured tobacco with hydrogen cyanide: Its effect on
hydrogen cyanide in cigarette smoke; RDM, 1967, No.
52, September 14 [Paper XLI in the series The analysis
of cigarette smoke condensate], see www.rjrtdocs.com
521188989 -8994.
3291. Rodgman, A. and L.C. Cook: The composition of ciga-
rette smoke. Precursor studies; Unpublished manuscript,
see www.rjrtdocs.com 501525257 -5284, 521184403
-4430.
3292. Rodgman, A. and L.C. Cook: The composition of ciga-
rette smoke. Some minor components of the neutral-
acidic fraction; Unpublished manuscript, see www.
rjrtdocs.com 501525285 -5340, 521184431 -4483.
11/24/08 2:39:56 PM
 Bibliography
3293. Rodgman, A. and L.C. Cook: Branch-chained acids
in Turkish tobacco smoke; 22nd Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 22, Paper No. 19, 1968, p. 11.
3294. Rodgman, A., L.C. Cook, S.A. Bellin, S.S. Mims, and
G.W. Young: The analysis of cigarette smoke conden-
sate. XXII. The composition of an aliphatic ester fraction
from tobacco and tobacco smoke; RDR, 1961, No. 15,
March 27, see www.rjrtdocs.com 521188124 -8152; The
composition of cigarette smoke. IX. The composition
of an aliphatic ester fraction from tobacco and tobacco
smoke; 15th Tobacco Chemists’ Research Conference,
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Sci. 31 (1987) 57–60.
3462. Schlotzhauer, W.S., R.M. Martin, R.F. Severson, O.T.
Chortyk, and R.E. Williamson: Pyrolytic determination
of the effect of leaf composition on levels of catechol and
11/24/08 2:39:58 PM
 1400
other smoke phenols; 34th Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 34,
Paper No. 9, 1980, p. 5; Schlotzhauer, W.S., R.M.
Martin, M.E. Snook, and R.E. Williamson: Pyrolytic
studies on the contribution of tobacco leaf constituents
to the formation of smoke catechols; J. Agr. Food Chem.
30 (1982) 372–374.
3463. Schlotzhauer, W.S. and I. Schmeltz: Non-alkaloidal
bases from pyrolysis of tobacco leaf pigment at the
approximate burn temperature of a cigarette; Tob. Sci.
11 (1967) 89–90.
3464. Schlotzhauer, W.S. and I. Schmeltz: 3,5-Xylenol and
other products from pyrolysis of sodium acetate; 22nd
Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 22, Paper No. 23, 1968,
p. 18.
3465. Schlotzhauer, W.S. and I. Schmeltz: Pyrogenesis of
aromatic hydrocarbons present in cigarette smoke. I.
Role of the hexane soluble fraction of tobacco; Beitr.
Tabakforsch. 4 (1968) 176–181.
3466. Schlotzhauer, W.S. and I. Schmeltz: Pyrogenesis of
aromatic hydrocarbons present in cigarette smoke. II.
Pyrolysis products of some representative constitu-
ents of the hexane soluble fraction of tobacco; Beitr.
Tabakforsch. 5 (1969) 5–8.
3467. Schlotzhauer, W.S. and I. Schmeltz: Role of the hexane
soluble fraction of tobacco in the formation of aromatic
hydrocarbons present in tobacco smoke; 23rd Tobacco
Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 23, Paper No. 28, 1969, p. 20.
3468. Schlotzhauer, W.S., I. Schmeltz, and L.C. Donio: Pyrolytic
formation of phenols from high molecular weight tobacco
leaf constituents; 20th Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 20, Paper
No. 28, 1966, pp. 35–37; Schlotzhauer, W.S., I. Schmeltz,
and L.C. Hickey: Pyrolytic formation of phenols from
some high molecular weight tobacco leaf constituents and
non-tobacco materials; Tob. Sci. 11 (1967) 31–34.
3469. Schlotzhauer, W.S., I. Schmeltz, and S.F. Osman:
Evidence for the origin of monoalkenes in cigarette
smoke; Chem. and Ind. (London) (1970) 1377–1378.
3470. Schlotzhauer, W.S., R.F. Severson, O.T. Chortyk, R.F.
Arrendale, and H.C. Higman: Pyrolytic formation of
polynuclear aromatic hydrocarbons from petroleum
ether extractable constituents of flue-cured tobacco leaf;
J. Agr. Food Chem. 24 (1976) 992–997.
3471. Schlotzhauer, W.S., R.F. Severson, O.T. Chortyk,
P.D. Cole, and H.G. Cutler: Chemical, biological, and
thermal properties of acyl and hydroxy acylnornico-
tines from Nicotiana species; 44th Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 44, Paper No. 37, 1990, p. 30.
3472. Schlotzhauer, W.S., R.F. Severson, O.T. Chortyk, and
M.E. Snook: Pyrolytic precursors of polynuclear aro-
matic hydrocarbons in the petroleum ether extract of
tobacco; 29th Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 29, Paper No. 43,
1975, p. 30.
3473. Schlotzhauer, W.S., R.F. Severson, R.M. Martin, and
K.L. McDuffie: The contribution of sucrose esters to
tobacco smoke composition; 38th Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 38, Paper No. 31, 1984, p. 17; Schlotzhauer, W.S.,
R.F. Severson, and R.M. Martin: The contribution of
© 2009 by Taylor & Francis Group, LLC
78836_C029.indd 1400
The Chemical Components of Tobacco and Tobacco Smoke
sucrose esters to tobacco smoke composition; Beitr.
Tabakforsch. Int. 13 (1986) 229–238.
3474. Schlotzhauer, W.S., D.B. Walters, M.E. Snook, and H.C.
Higman: The separation and identification of the constit-
uents of a catechol-containing subfraction of cigarette
smoke condensate; 31st Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 31,
Paper No. 40, 1977, p. 21; Characterization of catechols,
resorcinols, and hydroquinones in an acid fraction of
cigarette smoke condensate; J. Agr. Food Chem. 26
(1978) 1277–1281.
3475. Schmalfuss, H.: Diacetyl – Ein Aromabestandteil des
Tabakrauches [Diacetyl: A constituent contributing to
the aroma of tobacco smoke]; Tabak (Berlin) 3 (1939)
19-21; Diacetyl: An aroma component of tobacco
smoke; Rev. Internat. Tabaks 25 (1950) 89, see Chem.
Abstr. 45 (1951) 1303e.
3476. Schmeltz, I.: Cigarette smoke: Formation of compo-
nents and modification of composition by use of addi-
tives; Proc. 5th Internat. Tob. Sci. Cong., Hamburg FRG
(1970) 85–94.
3477. Schmeltz, I.: Nicotine and other tobacco alkaloids; in:
Naturally occurring insecticides, edited by M. Jacobson
and D.G. Crosby, Marcel Dekker, New York, NY (1971)
pp. 99–136.
3478. Schmeltz, I. (Editor): The chemistry of tobacco and
tobacco smoke; Plenum Press, New York, NY (1972).
3479. Schmeltz, I.: Chapter in: The chemistry of tobacco and
tobacco smoke, edited by I. Schmeltz, Plenum Press,
New York, NY (1972) pp. 77–97.
3480. Schmeltz, I., S. Abidi, and D. Hoffmann:
Tumorigenic agents in unburned processed tobacco:
N-Nitrosodiethanolamine and 1,1-dimethylhydrazine;
Cancer Lett. 2 (1977) 125–131.
3481. Schmeltz, I., K.D. Brunnemann, and D. Hoffmann: Trace
analysis in agricultural products. Methods for hydra-
zines, carbamates, N-nitrosodiethanolamine and other
compounds; in: Trace organic analysis. A new frontier
in analytical chemistry, edited by H.S. Hertz and S.N.
Chesler, National Bureau of Standards, Gaithersburg,
MD (1979) 297–309.
3482. Schmeltz, I., K.D. Brunnemann, D. Hoffmann, and A.
Cornell: On the chemistry of cigar smoke: Comparisons
between experimental little and large cigars; 29th
Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 29, Paper No. 41, 1975,
p. 29; Beitr. Tabakforsch. 8 (1976) 367–377.
3483. Schmeltz, I., K.G. Ching, and D. Hoffmann: Formation
and determination of ethyl carbamate in tobacco and
tobacco smoke; J. Anal. Toxicol. 2 (1978) 265–268.
3484. Schmeltz, I., A. de Paolis, and D. Hoffmann: Quantitative
analysis of major phytosterols in tobacco and smoke;
28th Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 28, Paper No. 43, 1974, p. 29;
Chemical studies on tobacco smoke. XXXI. Phytosterols
in tobacco: Quantitative analysis and fate in tobacco com-
bustion; Beitr. Tabakforsch. 8 (1975) 211–218.
3485. Schmeltz, I., J. Dooley, R.L. Stedman, and W.J.
Chamberlain: Composition studies on tobacco. XXII.
The nitromethane-soluble neutral fraction of cigaret
smoke; Phytochemistry 6 (1967) 33–38.
3486. Schmeltz, I., L.C. Hickey, and W.S. Schlotzhauer:
Phenols from pyrolysis of leaf acids; Tob. Sci. 11 (1967)
52–53.
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 Bibliography
3487. Schmeltz, I., E.B. Higman, W.S. Schlotzhauer, and A.R.
Bruzel: Characteristic products from pyrolysis of nitro-
gen-containing compounds found in tobacco and else-
where; 24th Tobacco Chemists’ Research Conference,
Program Booklet and Abstracts, Vol. 24, Paper No. 18,
1970, p. 11.
3488. Schmeltz, I., H.C. Higman, and R.L. Stedman: Phenols
of cigar smoke; 16th Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 16,
Paper No. 17, 1962, pp. 11–12.
3489. Schmeltz, I. and D. Hoffmann: Formation of polynuclear
aromatic hydrocarbons from combustion of organic
matter; in: Carcinogenesis. Polynuclear aromatic hydro-
carbons: Chemistry, metabolism, and carcinogenesis,
edited by R.I. Freudenthal and P.I. Jones, Raven Press,
New York, NY (1973) 225–239.
3490. Schmeltz, I. and D. Hoffmann: Chemical studies on
tobacco smoke. XXXVIII. The physicochemical nature
of cigarette smoke; in: Modifying the risk for the smoker.
Proc. 3rd World Conf. on Smoking and Health, 1975,
Vol. 1, edited by E.L. Wynder, D. Hoffmann, and G.B.
Gori, DHEW Publ. No. (NIH) 76 1221 (1976) 13–34.
3491. Schmeltz, I. and D. Hoffmann: Nitrogen-containing
compounds in tobacco and tobacco smoke; Chem. Rev.
77 (1977) 295–311.
3492. Schmeltz, I., J. Tosk, and D. Hoffmann: Naphthalenes in
tobacco smoke: Analysis and formation; 29th Tobacco
Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 29, Paper No. 22, 1975, p. 19; Schmeltz,
I., J. Tosk, and D. Hoffmann: Formation and determina-
tion of naphthalenes in cigarette smoke; Anal. Chem. 48
(1976) 645–650.
3493. Schmeltz, I., D. Hoffmann, and E.L. Wynder: Toxic and
tumorigenic agents in tobacco smoke: Analytical meth-
ods and modes of origin; in: Proc. 8th Ann. Conf. Trace
Substances in Environmental Hlth., edited by D.D.
Hemphill, Columbia, MO (1974) 281–295.
3494. Schmeltz, I., D. Hoffmann, and E.L. Wynder: The influ-
ence of tobacco smoke on indoor atmospheres. I. An
overview; Prev. Med. 4 (1975) 66–82.
3495. Schmeltz, I. and W.S. Schlotzhauer: Volatile acids of
cigar smoke; Tob. Sci. 5 (1961) 92–94.
3496. Schmeltz, I. and W.S. Schlotzhauer: Nonvolatile acids
of cigar smoke; 15th Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 15,
Paper No. 13, 1961, p. 7; Tob. Sci. 6 (1962) 90–91.
3497. Schmeltz, I. and W.S. Schlotzhauer: Benzo[a]pyrene,
phenols, and other products from pyrolysis of the
cigarette additive, (d,l)-menthol; Nature 219 (1968)
370–371.
3498. Schmeltz, I. and W.S. Schlotzhauer: 3,5-Dimethylphe-
nol and other products from pyrolysis of sodium acetate;
Chem. Comm. (1969) 681–682.
3499. Schmeltz, I., W.S. Schlotzhauer, and E.B. Higman:
Characteristic products from pyrolysis of nitroge-
nous organic substances; Beitr. Tabakforsch. 6 (1972)
134–138.
3500. Schmeltz, I., W.S. Schlotzhauer, and T.C. Jones:
Pyrolysis (800°C) of benzene, toluene and phenol in
nitrogen and in air; 21st Tobacco Chemists’ Research
Conference, Program Booklet and Abstracts, Vol. 21,
Paper No. 14, 1967, p. 9.
3501. Schmeltz, I. and R.L. Stedman: Pyridin-3-ol in cigar
smoke; Chem. Ind. (1962) 1244–1245.
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78836_C029.indd 1401
1401
3502. Schmeltz, I., R.L. Stedman, J.S. Ard, and W.J.
Chamberlain: Myristicin in cigarette smoke; Science
151 (1966) 96–97.
3503. Schmeltz, I., R.L. Stedman, and W.J. Chamberlain:
Improved method for the determination of benzo[a]
pyrene in cigarette smoke condensate; Anal. Chem. 36
(1964) 2499–2500.
3504. Schmeltz, I., R.L. Stedman, and W.J. Chamberlain:
Benzyl benzoate in cigarette smoke; 19th Tobacco
Chemists’ Research Conference, Program Booklet and
Abstracts, Vol. 19, Paper No. 29, 1965, pp. 43–45.
3505. Schmeltz, I., R.L. Stedman, W.J. Chamberlain, and D.
Burdick: Composition studies on tobacco. XX. Bases of
cigarette smoke; J. Sci. Food Agr. 15 (1964) 774–781.
3506. Schmeltz, I., R.L. Stedman, W.J. Chamberlain, and C.D.
Stills: Benzyl esters, indoles and carbazoles in cigarette
smoke; Chem. Ind. (1965) 2009–2010.
3507. Schmeltz, I., R.L. Stedman, and R.L. Miller: Steam-
volatile acids from various tobaccos; 17th Tobacco
Chemists’ Research Conference, Program Booklet
and Abstracts, Vol. 17, Paper No. 13, 1963, pp. 11–12;
Composition studies on tobacco. XVI. Steam volatile
acids; J. Assoc. Off. Anal. Chem. 46 (1963) 779–784.
3508. Schmeltz, I., C.D. Stills, W.J. Chamberlain, and R.L.
Stedman: Analysis of cigarette smoke fractions by com-
bined gas chromatography-infrared spectrophotometry;
Anal. Chem. 37 (1965) 1614–1616.
3509. Schmeltz, I., J. Tosk, J. Hilfrich, N. Hirota, and D.
Hoffmann: Bioassays of naphthalene and alkylnaphtha-
lenes for cocarcinogenic activity. Relation to tobacco
carcinogenesis; in: Polynuclear aromatic hydrocarbons.
Vol. 3, edited by P.W. Jones and R.I. Freudenthal, Raven
Press, New York, NY (1978) 47–60.
3509a. Schmeltz, I., J. Tosk, and D. Hoffmann: Chemical stud-
ies on tobacco smoke. XLVI. Formation and determina-
tion of naphthalenes in cigarette smoke; Anal. Chem. 48
(1976) 645–650.
3510. Schmeltz, I., J. Tosk, G. Jacobs and D. Hoffmann: The
redox potential and quinone content of cigarette smoke;
30th Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 30, Paper No. 44, 1976, p.
31; Redox potential and quinone content of cigarette
smoke; Anal. Chem. 49 (1977) 1924–1929.
3511. Schmeltz, I., A. Wenger, D. Hoffmann, and T.C. Tso: Use
of radioactive tobacco isolates for studying the formation
of selected smoke components; 30th Tobacco Chemists’
Research Conference, Program Booklet and Abstracts,
Vol. 30, Paper No. 35, 1976, p. 26; Chemical studies on
tobacco smoke. 53. Use of radioactive tobacco isolates
for studying the formation of smoke components; J. Agr.
Food Chem. 26 (1978) 234–239.
3512. Schmeltz, I., A. Wenger, D. Hoffmann, and T.C. Tso:
Use of radioactive tracers to determine cigarette smoke
components that arise from nicotine during combustion;
31st Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 31, Paper No. 17, 1977, p. 9;
Chemical studies on tobacco smoke. 63. On the fate of
nicotine during pyrolysis and in a burning cigarette; J.
Agr. Food Chem. 27 (1979) 602–608.
3513. Schmid, E.: Versuche zur Verminderung des
Ruckstandsgehaltes von Dithiocarbamates an Tabak
[Study of the lowering of the residual content of dithio-
carbamates in tobacco]; Deut. Tabakrau 50(5) (1970)
45–48.
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 1402
3514. Schmid, E.R., G. Allmaier, G. Bachlechner, K. Varmuza,
and H. Klus: Determination of oxygen and/or sulfur
containing polycyclic aromatic compounds in cigarette
smoke condensate; 8th Internat. Tob. Sci. Cong., Vienna,
Austria, 1984, CORESTA Inf. Bull., Spec. Edition
1984: Paper S16, 56; Schmid, E.R., G. Bachlechner,
K. Varmuza, and H. Klus: Determination of polycyclic
aromatic hydrocarbons, polycyclic aromatic sulfur and
oxygen heterocycles in cigarette smoke condensate;
Fresenius Z. Anal. Chem. 322 (1985) 213–219.
3515. Schmid, K.: Report on the scientific research carried out
at the Tobacco Institute of Forchheim, West Germany.
III. Biochemistry and chemistry; Proc. 1st Internat. Tob.
Sci. Cong., Paris, France, 1954: (1955) 106–111.
3516. Schmid, K.: Chemisch-Physikalische Beschaffenheit des
Tabakrauches [The chemical-physical nature of tobacco
smoke]; Fortschr. Biol. Aerosol-Forsch. 1957/1961
(1963) 160–168.
3517. Schmidt, F.: Der Nikotingehalt von Tabak und Tabakrauch
[The nicotine content of tobacco and tobacco smoke];
Thesis, Würzburg University (1904) pp. 1–46.
3518. Schmidt, J.A.: Improvement of the chemical composi-
tion of tobacco from the viewpoint of agricultural and
chemical analysis of tobacco and smoke; Deut. Tabakrau
58 (1978) 1–3.
3519. Schmidt, J.A., E.D. Fischbach, and F. Burkhart: Cadmium
Untersuchungen im Bereich von Umwelt-, Boden und
Sorteneinflüssen bei Tabak sowie der Cadmium Übergang
in den Zigarettenrauch [Cadmium investigations in the
area of the effect of environment, soil and type on tobacco
as well as cadmium emission in cigarette smoke]; Z.
Lebensm. Untersuch. Forsch. 180 (1985) 306–311.
3519a. Schmidt, O.K. and W.H. Hoge: Tobacco sheet rein-
forced with hardwood pulp; U.S. Patent No. 4,306,578
(December 22, 1981).
3519b. Schmidt, R. and E. Hecker: Biological assays for irri-
tant, tumor-initiating and tumor-promoting activities.
II. Standardized initiation/promotion protocol and
semiquantitative estimation of promoting (or initiating)
potencies in skin of NMRI mice; J. Cancer Res. Clin.
Oncol. 115 (1989) 516–524.
3519c. Schmitter, J.M., H. Colin, J.L. Excoffier, P. Arpino,
and G. Guiochon: Identification of triaromatic nitrogen
bases in crude oils; Anal. Chem. 54 (1982) 769.
3520. Schoental, R.: Carcinogenic activity of 3,4,9,10-dibenz-
pyrene; Acta Unio Internat. Contra Cancrum 15 (1959)
216–219.
3521. Schöller, R.: Nikotingehalt des Rauches feuchter und
trockener Zigarren [Nicotine content of smoke of moist
and dry cigars]; Fachliche Mitt. Österr. Tabakregie
1927/1928(2) 2–4.
3522. Schöller, R.: Der Gehalt des Tabakrauches an Kohlenoxid
[The carbon monoxide content of tobacco smoke];
Fachliche Mitt. Österr. Tabakregie 1929(3) 1–9.
3523. Schöller, R.: 3-Pyridyläthylketon im Tabakrauch
[3-Pyridyl ethyl ketone in tobacco smoke]; Fachliche
Mitt. Österr. Tabakregie 1935(3) 7.
3524. Schöller, R.: Über den Gehalt des gasförmigen
und des fest-flüssigen Anteils des Tabakrauches an
Cyanwasserstoff [On the content of hydrogen cyanide
in the gas and particulate phases of tobacco smoke];
Fachliche Mitt. Österr. Tabakregie 1938(1) 7–10.
3525. Schöller, R.: Schwefelwasserstoff und Rhodanwasserstoff
in den gasförmigen und fest-flüssigen Anteilen des
Tabakrauches [Hydrogen sulfide and thiocyanic acid
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The Chemical Components of Tobacco and Tobacco Smoke
in the gas and particulate phases of tobacco smoke];
Fachliche Mitt. Österr. Tabakregie 1938(2) 1–4.
3526. Schöller, R. and E. Molinari: Beitrag zur Qualität-
sbestimmung von Tabaken durch chemisch-physikalische
Untersuchungen. Teil II [Contribution to the determination
of tobacco quality through physicochemical research. Part
II]; Fachliche Mitt. Österr. Tabakregie 1937(2) 1–5.
3527. Schonherr, H.H., J. Klimisch, and H.P. Harke: Aging of
cigarette smoke condensate. Quantitative investigation
of artifact formation by gas and particulate phase reac-
tion; Beitr. Tabakforsch. 7 (1973) 18–23.
3528. Schonhofer, F. and H.T. Schreus: Unterzuchung
zur Tabakrauch [Investigation of tobacco smoke];
Arzneimittelforschung 4 (1954) 75–79.
3528a. Schreiber, K.: Identification and characterization of an
endogenous cytometallophore of general distribution in
plants; Pure Appl. Chem. 58 (1986) 745–752.
3529. Schrek, R., L.A. Baker, G.P. Ballard, and S. Dolgoff:
Tobacco smoking as an etiologic factor in disease;
Cancer Res. 10 (1950) 49–58.
3530. Schüller, D., C.J. Drews, and H.P. Harke: Analytische
Untersuchungen an Gasphasenkondensat [Analytical
examination of the gas phase of cigarette smoke]; Beitr.
Tabakforsch. 6 (1971) 84–88.
3531. Schultz, F.J. and A.W. Spears: Determination of moisture
in total particulate matter; Tob. Sci. 10 (1966) 75–76.
3532. Schumacher, J.N.: Turkish tobacco. Third Progress
Report on the isolation and identification of some of its
constituents; RDR, 1957, No. 2, January 30, see www.
rjrtdocs.com 500931176 -1200.
3533. Schumacher, J.N.: Turkish tobacco - Fourth Progress Report
- Isolation and identification of sclareolide; RDR, 1957, No.
9, June 13, see www.rjrtdocs.com 500931302 -1322.
3534. Schumacher, J.N.: Turkish tobacco. Isolation and iden-
tification of sclaral; RDR, 1959, No. 10, May 18, see
www.rjrtdocs.com 500933308 -3336.
3535. Schumacher, J.N.: Turkish tobacco. Isolation, characteriza-
tion, and synthesis of 6-acetyl-2,3,4-tris-d-3-methylvaleryl-
B-D-glucopyranoside; RDR, 1960, No. 16, May 12, see www.
rjrtdocs.com 500934742 -4763; The isolation of 6-O-acetyl-
2,3,4-O-tris-[(+)-3-methylvaleryl]-B-D-glucopyranose from
tobacco; Carbohydrate Res. 13 (1970) 1–8.
3536. Schumacher, J.N.: Turkish sand. Progress report on the
isolation of some of its constituents; RDR, 1960, No. 40,
December 16, see www.rjrtdocs.com 500935090 -5118.
3537. Schumacher, J.N.: Flavoring acids in Turkish tobacco;
RDR, 1955, No. 7, April 8, see www.rjrtdocs.com
501663231 -3249.
3538. Schumacher, J.N.: Turkish tobacco. Isolation and char-
acterization of dehydroambreinolide and the isolation of
compounds XVI and XVII; RDR, 1961, No. 12, March
3, see www.rjrtdocs.com 500936127 -6143.
3539. Schumacher, J.N.: Turkish tobacco. The characteriza-
tion of the “coconut oil” fraction. Identification and
synthesis of mariolide (Compound XIII); RDR, 1961,
No. 25, May 16, see www.rjrtdocs.com 500936549
-6572.
3540. Schumacher, J.N.: Turkish tobacco. The molecular dis-
tillation of Turkish tobacco extract. The isolation of
two tobacco flavorant precursors (sclareol oxide and
Compound XXIII); RDR, 1962, No. 3, January 12, see
www.rjrtdocs.com 500938648 -8668.
3541. Schumacher, J.N.: Turkish tobacco. The characteriza-
tion of bovolide (Compound XXXI); RDR, 1962, No.
28, July 31, see www.rjrtdocs.com 500939479 -9495.
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3542. Schumacher, J.N.: Turkish tobacco. The isolation of acid
carriers from Turkish tobaccos; RDR, 1963, No. 48, July
8, see www.rjrtdocs.com 500961963 -1975.
3543. Schumacher, J.N.: Turkish tobacco. The investigation of
the steam condensate; RDR, 1964, No. 42, September 9,
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3544. VOID
3545. Schumacher, J.N.: Turkish tobacco. Investigation of the
steam condensate. Part II; RDR, 1965, No. 31, July 9,
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3546. Schumacher, J.N.: Turkish tobacco: Investigation of
the steam condensate - New and confirmed structures;
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3547. Schumacher, J.N.: Turkish tobacco essential oil; RDM,
1978, No. 27, September 14, see www.rjrtdocs.com
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3548. Schumacher, J.N.: Ecusta TOD 08715 low sidestream
paper (magnesium oxide-filled paper containing 5%
glass fiber); RDM, 1980, No. 17, May 5, see www.rjrt-
docs.com 500617683 -7687.
3549. Schumacher, J.N.: Composition of supercritical
“extracts” of tobacco; R&DM, 1981, No. 34, August 31,
see www.rjrtdocs.com 500609595 -9602.
3550. Schumacher, J.N.: Maryland tobacco; R&DR, 1982,
No. 4, February 12, see www.rjrtdocs.com 501006126
-6151; Flavor composition of Maryland tobacco; 36th
Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 36, Paper No. 25, 1982,
p. 13; CORESTA 1982 Symp., Winston-Salem, NC,
CORESTA Inf. Bull., Spec. Edition 1982: Paper S11,
21–22; Beitr. Tabakforsch. Int. 12 (1982) 271–278.
3551. Schumacher, J.N.: Review on pyrolysis of various
tobacco additives; R&DM, 1983, No. 37, August 15, see
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3552. Schumacher, J.N. and E. Bernasek: Turkish tobacco.
Isolation and characterization of ambreinolide; RDR,
1959, No. 12, May 21, see www.rjrtdocs.com 500933373
-3386.
3553. Schumacher, J.N., F.W. Best, and C.R. Green: Smoke
composition: A detailed investigation of the water-soluble
portion of cigarette smoke; RDR, 1974, No. 7, September
5, see www.rjrtdocs.com 501003488 -3512; Schumacher,
J.N., C.R. Green, and F.W. Best: The composition of the
water-soluble portion of cigarette smoke particulate phase;
29th Tobacco Chemists’ Research Conference, Program
Booklet and Abstracts, Vol. 29, Paper No. 38, 1975, p. 27;
Schumacher, J.N., C.R. Green, F.W. Best, and M.P. Newell:
Smoke composition. An extensive investigation of the water-
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