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Lu’s Basic Toxicology
Fundamentals, Target Organs,
and Risk Assessment
Seventh Edition
http://taylorandfrancis.com
Lu’s Basic Toxicology
Fundamentals, Target Organs,
and Risk Assessment
Seventh Edition

Edited by
Byung-Mu Lee
Sam Kacew
Hyung Sik Kim
CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742

© 2018 by Taylor & Francis Group, LLC

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Library of Congress Cataloging‑in‑Publication Data

Names: Byung-Mu Lee, author. | Kacew, Sam, author. | Kim, Hyung Sik, 1966-
author. | Lu, Frank C. Basic toxicology.
Title: Lu’s basic toxicology : fundamentals, target organs, and risk assessment /
Byung-Mu Lee, Sam Kacew, Hyung Sik Kim.
Other titles: Basic toxicology
Description: Seventh edition. | Boca Raton : CRC Press, [2018] | Includes
bibliographical references and index.
Identifiers: LCCN 2017010684| ISBN 9781138089273 (hardback : alk. paper) |
ISBN 9781138032354 (paperback) | ISBN 9781315391700 (ebook) |
ISBN 9781315391694 (ebook) | ISBN 9781315391687 (ebook) |
ISBN 9781315391670 (ebook)
Subjects: LCSH: Toxicology.
Classification: LCC RA1211 .L8 2017 | DDC 615.9--dc23
LC record available at https://lccn.loc.gov/2017010684

Visit the Taylor & Francis Web site at

http://www.taylorandfrancis.com
and the CRC Press Web site at
http://www.crcpress.com
Contents
Preface..................................................................................................................ix
Editors..................................................................................................................xi
Contributors.......................................................................................................xv

Section I: General principles of toxicology

Chapter 1 History of toxicology................................................................... 3

Byung-Mu Lee

Chapter 2 Toxicokinetics of xenobiotics................................................... 23

Kyu-Bong Kim

Chapter 3 Biotransformation of toxicants................................................ 45

Tae Cheon Jeong

Chapter 4 Mechanisms of toxic effects..................................................... 65

Hyung Sik Kim and Pinpin Lin

Chapter 5 Modifying factors of toxic effects........................................... 91

Hyung Sik Kim

Chapter 6 Conventional toxicity studies................................................ 111

Hyung Sik Kim

Chapter 7 Systems toxicology................................................................... 131

Kyu-Bong Kim, Semin Lee, and Jung-Hwa Oh

v
vi Contents

Section II: Testing procedures for nontarget organ toxicities

Chapter 8 Carcinogenesis.......................................................................... 161

Kyung-Soo Chun, Hyung Sik Kim, and Byung-Mu Lee

Chapter 9 Mutagenesis............................................................................... 193

Kyung-Soo Chun and Hyung Sik Kim

Chapter 10 Developmental toxicology...................................................... 215

Helen E. Ritchie and William S. Webster

Chapter 11 Toxicology of lactation............................................................ 233

Ok-Nam Bae

Section III: Target organs and systems

Chapter 12 Toxicology of the liver............................................................. 253

Young-Suk Jung and Byung-Mu Lee

Chapter 13 Toxicology of the kidney........................................................ 271

Young-Suk Jung and Hyung Sik Kim

Chapter 14 Toxicology of the immune system........................................ 295

Tae Cheon Jeong

Chapter 15 Respiratory system toxicology............................................... 309

Kyuhong Lee

Chapter 16 Toxicology of the skin............................................................. 325

Ok-Nam Bae

Chapter 17 Toxicology of the eye............................................................... 339

Sam Kacew

Chapter 18 Toxicology of the nervous system......................................... 353

Ok-Nam Bae

Chapter 19 Toxicology of the cardiovascular systems........................... 373

Ok-Nam Bae

Chapter 20 Toxicology of the reproductive systems.............................. 387

Hyung Sik Kim
Contents vii

Chapter 21 Toxicology of endocrine-disrupting chemicals................. 405

Hyung Sik Kim

Section IV: Toxic substances and risk assessment

Chapter 22 Food additives, contaminants, and safety........................... 435

Sam Kacew and Byung-Mu Lee

Chapter 23 Toxicity of pesticides............................................................... 453

Ramesh C. Gupta

Chapter 24 Nanotoxicology......................................................................... 487

Sang-Hyun Kim and Byung-Mu Lee

Chapter 25 Toxicity of metals..................................................................... 503

Gi-Wook Hwang

Chapter 26 Environmental pollutants...................................................... 529

Sam Kacew and Byung-Mu Lee

Chapter 27 Occupational toxicology.........................................................543

Sam Kacew and Byung-Mu Lee

Chapter 28 Exogenous agents and childhood exposure........................ 559

Sam Kacew

Chapter 29 Clinical toxicology................................................................... 579

Byung-Mu Lee

Chapter 30 Risk assessment and regulatory toxicology........................ 597

Seok Kwon and Byung-Mu Lee

Chemical index................................................................................................ 623

Subject index.................................................................................................... 635

http://taylorandfrancis.com
Preface
Toxicology is an important life science. It is valuable in the protection of
public health hazards associated with toxic substances in food, air, and
water. It also provides a sound basis for formulating measures to protect
the health of workers against toxicants in factories, farms, mines, and other
occupational environments. Toxicology has played and will continue to
play a significant role in the health and welfare of the world. Cognizant of
the importance of toxicology, the World Health Organization (WHO) orga-
nized a toxicology training course in China in 1982, as part of the ongoing
China–WHO collaborative program on medical sciences. The founding
author (FCL) was invited to lectures on basic toxicology. The first edition
of this book originated from those lecture notes.
Over the years, a number of important developments have occurred
in toxicology. Furthermore, some readers of the book have suggested that
discussions on a few groups of important chemicals and toxicants would
not only provide some general knowledge of these substances, but also
facilitate a deeper appreciation of the various aspects of toxicology. The
book has received worldwide acceptance, as evidenced by its repeated edi-
tions and reprintings, and by the appearance of six foreign language ver-
sions (Chinese, French, Indonesian, Italian, Spanish, and Taiwan Chinese).
This new edition, prepared by invited scientists, has been further
updated and expanded to include new chapters on clinical toxicology,
chemicals and children, reproductive toxicology, and systems toxicology.
There are chapters on lactation and occupational toxicology, as well as a
chapter section describing the symptomatology of Gulf War syndrome
and the probable toxicants implicated. The other chapters have been
updated and expanded, notably those on the history of toxicology, car-
cinogenesis, mutagenesis, toxicology of organ systems—skin, liver,
kidney, immune, and nanoparticle, endocrine, and safety/risk assess-
ment. However, details of some toxicity tests have been abbreviated to
keep the size of the book within bounds; the retained material is intended
to portray more clearly the effects of toxicants.

ix
x Preface

It is hoped that these additions and updates will enhance the use-
fulness of the book. In making these changes, the authors have kept in
mind the broad aim of the first edition, namely, a relatively comprehen-
sive coverage of the subjects and brevity, thereby continuing to serve as an
updated introductory text for toxicology students and for those involved in
allied sciences who require a background in toxicology. Further, since toxi-
cology is a vast and rapidly expanding subject, the book is likely to be useful
to those who have become specialized in one or a few areas in toxicology,
but wish to become more familiar in other areas. The extensive chemical
index and subject index will facilitate the retrieval of specific topics.

Byung-Mu Lee
Sam Kacew
Hyung Sik Kim
Editors
Byung-Mu Lee, BS, MS, MSPH, Dr PH, Division of Toxicology, College
of Pharmacy, Sungkyunkwan University, South Korea, is associate edi-
tor of the Journal of Toxicology and Environmental Health, Part A; associ-
ate editor of Food and Chemical Toxicology; editorial board member of
Environmental Health Perspectives; and advisory editor of Archives of
Toxicology. He is currently the vice president of the International Association
of Environmental Mutagenesis and Genomics Society (IAEMGS). He
is the author of 230 papers and reviews, the Encyclopedia of Environmental
Health, and 11 book chapters, as well as the coauthor of Lu’s Basic Toxicology,
Sixth Edition (Informa, 2013).
Prof. Lee has also been a research advisor of the Ministry of Food
and Drug Safety, a committee advisor for the Ministry of Science, ICT,
and Future Planning, the Ministry of Environment, and the Ministry of
Human Health and Welfare in South Korea. He has been the president of
the 13th International Congress of Toxicology (ICT XIII), the Korea Society
of Toxicology (KSOT), and the Korea Environmental Mutagen Society
(KEMS). He has been the vice president of the Asia Society of Toxicology
(ASIATOX). He has organized eight workshops and three international
symposia about toxicology, carcinogenesis, chemoprevention, endocrine
disruption, and risk assessment. He has been a nominating committee
member of the International Union of Toxicology (IUTOX) and deputy
member of the Korean Pharmaceutical Society.
Prof. Lee has received numerous awards, including the Young Scientist
Award, Brookhaven Symposium (U.S.); the Yun Ho Lee Award of Scientific
Merit (International Aloe Science Council (U.S.); and the Merit Award from
the Minister, Ministry of Food Drug Safety (Republic of Korea).
Prof. Lee’s research areas include: carcinogenesis, chemoprevention,
endocrine disruption, molecular epidemiology, biomarkers, systems toxi-
cology, and risk assessment/management.

xi
xii Editors

Sam Kacew, PhD, ATS, is an associate director of Toxicology, McLaughlin

Centre for Population Health Risk Assessment at the University of Ottawa;
professor of pharmacology, University of Ottawa; and scientist, Institute
for Population Health, University of Ottawa.
Prof. Kacew is a visiting professor at the following institutions: the
University of Guildford in Surrey, England; a Colgate-Palmolive visiting
professor at the University of New Mexico; the Institute of Toxicology at
National Taiwan University in Taipei, Taiwan; the Joszef Fodor National
Center of Public Health in Budapest, Hungary; the Department of
Occupational Health, Shanghai Medical University in Shanghai, China;
the Zhehjiang University in Hangzhou, China; Nanjing Medical University,
Nanjing, China; and the Division of Toxicology at Sungkyunkwan
University in Suwon City, Korea.
Prof. Kacew is currently the editor-in-chief of the Journal of Toxicology and
Environmental Health, Part A, Current Issue; editor-in-chief, Journal of Toxicology
and Environmental Health, Part B, Critical Reviews; North American editor,
Toxicological and Environmental Chemistry; associate editor of Toxicology and
Applied Pharmacology; editor, Encyclopedia of Environmental Health; editor, Lu’s
Basic Toxicology (Fourth and Fifth editions); and guest editor of a special issue
of Toxicology and Applied Pharmacology entitled “Toxicological Reviews in Fetal
Childhood Development.” He has edited several texts on pediatric toxicology
and serves on several editorial boards. He has been a peer reviewer for the
Environmental Protection Agency (EPA) on the Integrated Risk Information
System (IRIS) documents, on the U.S. EPA Health Effects Assessment
Summary Table (HEAST) chemicals, on the chemical-specific issue papers
for the Superfund Technical Support Center (STSC) for the U.S. EPA, and has
served on National Institutes of Health (NIH) grant study sections.
Prof. Kacew is a member of the Board on Environmental Studies and
Toxicology (BEST) of the National Academy of Sciences (U.S.) and is a
member of the Science Advisory Council (SAC) of the National American
Flame Retardant Association (NAFRA).
Prof. Kacew has been a member of the board of trustees of Toxicology
Excellence for Risk Assessment (TERA) and a member of the board of
Review for Siloxane D5 appointed by the Minister of Environment of
Canada. He has also been a member of the Committee on Toxicology of
the National Academy of Sciences (NAS) of the United States and served
as a chairman on the NAS Subcommittee on Iodotrifluoromethane; chair-
man on the NAS Subcommittee on Tetrachloroethylene; and a member of
the NAS Subcommittees including Flame Retardants, Jet Propulsion
Fuel-8, and Toxicologic and Radiologic Effects from Exposure to Depleted
Uranium during and after Combat; and a member of the Advisory Expert
Committee of the Canadian Network of Toxicology Centers. He served
as a chairman of a U.S. EPA Panel on Peer Review Assessment of Toxicity
Editors xiii

Values for Total Petroleum Hydrocarbons, member of the Panel on the

Beryllium Lymphocyte Proliferation Screening Test, an expert panel
member on the Breast Milk Monitoring for Environmental Chemicals
in the United States, a core panel member of the Voluntary Children’s
Chemical Evaluation Program (VCCEP), part of a U.S. EPA initiative,
expert panel member on the Pest Management Regulatory Agency of
Health Canada on Citronella Science Review, expert panel member
on drug-induced phospholipidosis to several pharmaceutical com-
panies, expert panel member of the Council of Canadian Academies
on Integrated Testing of Pesticides, and member of the Institute of
Medicine (IOM) Committee on Blue Water Navy Vietnam Veterans and
Agent Orange Exposure.
Prof. Kacew has received the Achievement Award of the Society of
Toxicology of Canada in 1983, the Achievement Award of the Society of
Toxicology in 1986, the ICI (Zeneca) Traveling Lectureship Award in 1991,
the U.S.–China Foundation Award in 1995, the Colgate-Palmolive Visiting
Professorship Award in 1997, and the Public Communications Award.

Hyung Sik Kim, MS, PhD, is a professor of the Division of Toxicology,

College of Pharmacy, Sungkyunkwan University, South Korea.
Prof. Kim earned a PhD performing research on chemical carcino-
genesis and chemoprevention at the College of Pharmacy, after which
he joined the Korea Food and Drug Administration, serving as a senior
researcher, where he was involved in reproductive and developmental
toxicology and endocrine toxicology. He spent 2 years at the National
Institutes of Health (NIH) in Bethesda, Maryland carrying out cancer and
radiopharmaceutical research. Since 2003, he has been an assistant profes-
sor in the Division of Toxicology, College of Pharmacy at Pusan National
University in South Korea.
He is a member of the American Association for Cancer Research
(AACR), the Society of Toxicology (SOT), the International Congress of
Toxicology (ICT), and the Korean Society of Toxicology (KSOT). He has
published more than 210 papers and is the author of several book chap-
ters included in the Encyclopedia of Environmental Health, Reproductive and
Developmental Toxicology, and Endocrine Disruptors, among others. He is
an editorial board member of the Journal of Toxicology and Environmental
Health, Part A, an associate editor of the Journal of Toxicological Sciences, and
an editorial board member of Toxicological Research.
Prof. Kim has served as an advisory committee member of govern-
ment (National Food and Drug Safety, Ministry of Environment, Ministry
of Health and Welfare) and has served as the vice chairman of the National
Scientific Committee for the 13th International Congress of Toxicology
(ICT) held in Seoul, Korea. He has also served as the vice chairman of
xiv Editors

the National Scientific Committee of the 8th International Congress of the

Asian Society of Toxicology, held in Jeju, South Korea in 2015.
His primary research areas of interest are the identification of new
cancer biomarkers, mechanisms of new anticancer agents, and cancer
chemoprevention.
Contributors
Ok-Nam Bae, PhD
(Chapters 11, 16, 18, 19)
College of Pharmacy
Hanyang University
Republic of Korea
Kyung-Soo Chun, PhD
(Chapters 8, 9)
College of Pharmacy
Keimyung University
Republic of Korea
Ramesh C. Gupta, PhD
(Chapter 23)
Murray State University
BVC Toxicology Department
Hopkinsville, Kentucky
Gi-Wook Hwang, PhD
(Chapter 25)
Graduate School of Pharmaceutical
Sciences
Tohoku University
Sendai, Japan
Tae Cheon Jeong, PhD
(Chapters 3, 14)
College of Pharmacy
Yeungnam University
Gyeongsan, Republic of Korea
Young-Suk Jung, PhD
(Chapters 12, 13)
College of Pharmacy
Pusan National University
Busan, Republic of Korea
Sam Kacew, PhD
(Chapters 17, 22, 26, 27, 28)
McLaughlin Centre for Population
Health Risk Assessment
University of Ottawa
Ontario, Canada
Hyung Sik Kim, PhD
(Chapters 4, 5, 6, 8, 9, 13, 20, 21)
Sunkyunkwan University
College of Pharmacy
Gyeonggi-do, Republic of Korea
Kyu-Bong Kim, PhD
(Chapters 2, 7)
College of Pharmacy
Dankook University
Chungnam, Republic of Korea
Sang-Hyun Kim, PhD
(Chapter 24)
Kyungpook National University
School of Medicine
Daegu, Republic of Korea
xv
xvi Contributors

Seok Kwon, PhD Pinpin Lin, PhD

(Chapter 30)
Central Product Safety
Global Product Stewardship
Singapore Innovation Center
Procter & Gamble International
Operations
Singapore
Byung-Mu Lee, Dr PH
(Chapters 1, 8, 12, 22, 24, 26, 27,
29, 30)
Sunkyunkwan University
College of Pharmacy
Gyeonggi-do, Republic of Korea
Kyuhong Lee, PhD
(Chapter 15)
Korea Institute of Toxicology
University of Science and
Technology
Jeollabuk-do, Republic of Korea
Semin Lee, PhD
(Chapter 7)
School of Life Sciences
Ulsan National Institute of Science
and Technology
Ulsan, Republic of Korea
(Chapter 4)
National Health Research Institute
Taiwan
Jung-Hwa Oh, PhD
(Chapter 7)
Department of Predictive
Toxicology
Korea Institute of Toxicology
Daejeon, Republic of Korea
Helen E. Ritchie, PhD
(Chapter 10)
Sydney Medical School
University of Sydney
Lidcombe, Australia
William S. Webster, PhD
(Chapter 10)
Department of Anatomy
and Histology
University of Sydney
Sydney, Australia
section one

General principles of toxicology

http://taylorandfrancis.com
chapter one

History of toxicology
Byung-Mu Lee

Contents
What is toxicology?............................................................................................. 3
Mutiple fields of toxicology and applications................................................ 4
History of toxicology in early stage.................................................................. 6
History of toxicology in modern stage............................................................ 9
Human poisonings and progress in toxicology............................................ 11
Toxicity versus other considerations.............................................................. 12
Toxicology in the future................................................................................... 13
Development and validation of a toxicity test system................................ 14
Adverse outcome pathways....................................................................... 15
About the book.................................................................................................. 16
Appendix 1.1 U.S. laws that have a basis in toxicology.............................. 17
Appendix 1.2 Examples of outbreaks of mass poisoning in humans........ 18
References.......................................................................................................... 19

What is toxicology?
Toxicology (toxicos; poisonous + logy; science) also called toxicological sci-
ence is the fusion of sciences based on biology, chemistry, physics, anat-
omy, physiology, pathology, psychology, zoology, pharmacology, genetics,
biochemistry, statistics, and mathematics. Toxicology is traditionally defined
as the science of poisons which are also termed as toxicants, toxic sub-
stances, toxins, xenobiotics, or stressors. A more descriptive definition of
toxicology is the study of the nature and mechanisms underlying toxic
effects exerted directly or indirectly by substances such as biological,
chemical, physical, genetic, or psychological agents on living organisms
and other biological systems. Toxicology also deals with quantitative or
qualitative assessment of the adverse effects in relation to the concentra-
tion or dosage, duration, and frequency of exposure of the organisms.
The assessment of health hazards of industrial chemicals, environ-
mental pollutants, and other substances represents an important element
in the protection of the health of workers and members of communities.

3
4 Lu’s Basic Toxicology

In-depth studies of the nature and mechanism of the effects of toxicants

are invaluable in the development of specific antidotes and other amelio-
rative measures. Along with other sciences, toxicology contributes to the
development of safer chemicals used as drugs, food additives, and pesti-
cides, as well as many useful industrial chemicals used for the fabrication
of computers, cellular phones, televisions, and electronic equipment. Even
the adverse effects per se are exploited in the pursuit of more effective
insecticides, anthelmintics, antimicrobials, antivirals, and warfare agents.
The purpose of toxicology is to protect humans or ecosystems from expo-
sure to hazardous substances. Therefore, to ensure human safety, risk
assessment which evaluates human safety based upon toxicological data
and human exposure levels, in order to set human safe limits, may be con-
sidered one of the most important goals of toxicology (Song et al., 2013).

Mutiple fields of toxicology and applications

Toxicology is a fusion science composed of multiple fields and has a broad
scope. It deals with toxicity studies of substances used

1. In medicine for diagnostic, preventive, and therapeutic purposes.

2. In the food industry as direct and indirect additives.
3. In agriculture as pesticides, growth regulators, artificial pollinators,
and animal feed additives.
4. In the chemical industry as solvents, components, and intermediates
of plastics, components of electronic devices and many other types
of chemicals. It is also concerned with the health effects of metals
(as in mines and smelters), radiation, petroleum products, paper and
pulp, flame retardants, toxic plants, and animal toxins. Overall, toxi-
cology covers general safety issues in our lives and ecosystem.

Depending on the specific areas of toxicological application, toxi-

cology can be subdivided into analytical toxicology, clinical toxicology,
forensic toxicology, occupational toxicology, environmental toxicology,
regulatory toxicology, and so forth. For example, a person may be
exposed, accidentally or otherwise, to excessively large amounts of a
toxicant and become severely intoxicated. If the identity of the toxicant
is not known, analytical toxicology will be called upon to identify the
toxicant through analysis of body fluids, stomach contents, suspected
containers, and so forth. Those engaged in clinical toxicology administer
antidotes, if available, to counter some specific toxicity, and take other
measures to ameliorate the symptoms and signs and hasten the elimina-
tion of the toxicant from the body. There may also be legal implications,
which is the task of forensic toxicology.
Chapter one: History of toxicology 5

Intoxication may occur as a result of occupational exposure to toxi-

cants. This may result in acute or chronic adverse effects. In either case,
the problem is in the domain of occupational toxicology. The general public
is exposed to a variety of toxicants, via air, water, and soil, or contact with
skin as well as from food containing additives, pesticides, and contami-
nants, often at low levels that may be harmless acutely but may have long-
term adverse effects. In pregnancy, the fetus is exposed via the maternal
circulation while a lactating infant is exposed via breast milk. The sources
of these substances, their transport, degradation, and bioconcentration in
the environment, and their effects on humans are dealt with in environ-
mental toxicology. Regulatory toxicology attempts to protect the public by
setting laws, regulations, and standards to limit or suspend the use of
toxic chemicals as well as defines use conditions for others. Some of the
relevant laws in the United States are listed in Appendix 1.1.
To set meaningful regulations and standards, extensive profiles of
the toxic effects are essential. Such profiles can only be established with
a great variety of relevant and comprehensive toxicological data derived
from in vitro, in vivo, and human studies, which form the foundation of
regulatory toxicology.
The basic part of such studies is referred to as conventional toxicology.
In addition, knowledge of the mechanism of action, provided by mechanis-
tic toxicology, enhances the toxicological evaluation and provides a basis
for other branches of toxicology. The knowledge gained is then utilized to
assess the risk of adverse effects to the environment and humans and is
termed a risk assessment. A health risk assessment constitutes a written
document based upon all pertinent scientific information regarding toxi-
cology, human experiences, environmental fate, and exposure scenario.
These data are subject to critique and interpretation. The aim of a risk
assessment is to estimate the potential of an adverse effect in humans and
wildlife ecological systems caused by exposure to a specific amount of
toxic substances. Risk assessments include several elements such as

1. Description of the potential adverse health effects based on an eval-

uation of results of epidemiological, clinical, preclinical, and envi-
ronmental research.
2. Extrapolation from these results to predict the type and estimate the
extent of adverse health effects in humans under given conditions of
exposure.
3. Assessments as to the number and characteristics of individuals
exposed at various intensities and durations.
4. Summary judgments on the existence and overall magnitude of
the public health problem given the information of (1), (2), and (3)
(Paustenbach, 2002). Risk characterization represents the final and
6 Lu’s Basic Toxicology

the most critical step in the risk assessment process whereby data
on the dose–response relationship of a chemical are integrated with
estimates of the degree of exposure in a population to estimate
the likelihood and severity of human health risk (Williams and
Paustenbach, 2002; Song et al., 2013).

History of toxicology in early stage

In ancient times, human poisonings occurred after exposure to a numer-
ous unknown or known poisons from different sources such as animals,
plants, soil, air, and water. Some plants and heavy metals used for poisons
in the world are listed in Table 1.1.
Ebers Papyrus is probably the oldest document that provides human
toxicological information on poisons in bc 1500. It attests to awareness of
the toxic effects of a number of substances—such as snake venom, poi-
sonous plants like hemlock and aconite, and the toxic heavy metals arse-
nic, lead, and antimony. Some of these were actually used (intentionally
for their adverse effects) for hunting, warfare, suicide, or homicide. For
centuries, homicides with toxic substances were common in Europe, thus
stimulating continual efforts toward the discovery and development of
preventive and antidotal measures. The following are some famous exam-
ples of ancient poisonings in humans.
Socrates (bc 470–399), a Greek philosopher, died of hemlock poisoning
(according to Plato). Hemlock (Conium maculatum) contains coniine, one
of the active toxic ingredients and other toxic alkaloids (cicutoxin, oenan-
thotoxin, virol A, virol C, C17–polyacetylenes) that cause nausea, vomit-
ing, diarrhea, tachycardia, cardiac dysrhythmias, mydriasis, renal failure,
coma, respiratory impairment, and death (Schep et al., 2009). Cleopatra
(bc 69–30), was made Cleopatra VII and became Queen of Egypt when her
father Ptolemy XII died. Although her death is still a mystery, three pos-
sible scenarios for her death were suggested (Wexler, 2014): (a) committed
suicide on August 12, bc 30, by means of an Egyptian serpent, referred to
as her asp (Espinoza, 2001); (b) committed suicide by poison (possibly hid-
den somewhere in her mausoleum); (c) poisoned by Octavian and/or his men
(Orland et al., 1990). Nero (ad 37–68) became Roman Emperor after the death
of his adopted father, the Emperor Claudius in ad 54 (possibly by being poi-
soned with a mushroom). Nero was known as one of the most infamous men
who used poisons to murder his rivals as well as his brother-in-law.
Mithridates VI (131–63 bc), the King Mithridates VI of Pontus, was
known to expose himself and his prisoners to test poisons and antidotes.
He would take small amounts of poison, not exceeding the toxic dosage,
and gradually increase the doses until successfully acquiring immunity
or tolerance. For this reason, the term “mithridatic” was coined meaning
 Table 1.1 List of poisonous plants in the world
Chapter one:

Plants Ingredients Toxic effect Country Year Ref.

Aconite (Aconitum Aconitine, yunaconitin, Cardiotoxicity, Europe, – Chan, 2009
napellus) mesaconitine, neurotoxicity North
hypaconitine America
Chinese tallowtree Toxalbumin, saponin Diarrhea, listlessness, China 1700s Everest et al.,
(Sapium sebiferum) weakness, dehydration 2005; NCSU,
2011
Colchicum Alkaloid colchicine Arrhythmias, liver failure, Europe – Jaeger and
History of toxicology

(Colchicum pancreatitis, alopecia Flesch, 1990;

autumnale) Brvar et al., 2004
Deadly nightshade Atropine, hyoscyamine, Dryness of mouth, ileus, Europe, Roman Rajput, 2013
(Atropa belladonna) scopolamine tachycardia Asia times
Hellebore Cardiac glycosides, Dermatitis, convulsions, Europe 1400 bc Schep et al.,
(Helleborus niger) helleborin, hellebrin, respiratory failure 2009; Cornell
University, 2015
Hemlock (Conium Cicutoxin, virol A, virol C, Tachycardia, mydriasis, North –
maculatum) oenanthotoxin, renal failure, coma America,
C17-polyacetylenes UK
Henbane Atropine, hyoscyamine, Dry mouth, delirium, Europe, 681 ad Alizadeh et al.,
(Hyoscyamus nigar) scopolamine hallucinations, blurred Africa 2014
vision, tachycardia
(Continued)
7
 8

Table 1.1 (Continued) List of poisonous plants in the world

Plants Ingredients Toxic effect Country Year Ref.
Mandrake (Atropa Solanum alkaloids, Mydriasis, blurred vision, Europe – Tsiligianni et al.,
mandragora) tropane alkaloids headache, vomiting 2009
Mushrooms Ibotenic acid, muscinol Confusion, mydriasis, Italy – Michelot &
(Amonita muscaria) drowsiness Melendez-
Howell, 2003
Opium (Papaver Codeine, heroin, Stupor, coma, death, liver Eurasia, 1500 bc Park et al., 2000;
somniferum) morphine, urushiol and kidney toxicity Korea NSM, 2016
Thorn apple (Datura Atropine, scopolamine, Mydriasis, tachycardia, U.S., Asia – Thabet et al.,
stramonium) hyosciamine hallucinations 1999
Yew (Taxus accato) Taxine, paclitaxel, Cardiac arrest, respiratory Canada – Cope, 2005;
cephalomannine paralysis, ataxia, death Perju-Dumbrava
et al., 2013
Lu’s Basic Toxicology
Chapter one: History of toxicology 9

“immunized or tolerable to a poison.” Mithridate (originating from mithri-

datium), a combination of small doses of poisons invented by Mithridates
VI, refers to an antidote or detoxifying agent against poison.
Hippocrates (bc 460–370) was a Greek physician—usually called the
father of medicine—he is considered one of the important contributors for
the development of clinical toxicology. Maimonides (1135–1204) published
his famous medical work Poisons and Their Antidotes in 1198. Paracelsus
(1493–1541) stated: “No substance is a poison by itself. It is the dose (the
amount of the exposure) that makes a substance a poison” and “the right
dose differentiates a poison from a remedy.” These statements laid the
foundation for the concept of the “dose–response relation” and the “ther-
apeutic index” (TI) developed later. In addition, Paracelsus described
in his book Bergsucht (1533–1534) the clinical manifestations of chronic
arsenic and mercury poisoning as well as miner’s disease. He might be
considered the forefather of occupational toxicology. Orfila (1787–1853), a
Spain-born French toxicologist and chemist, wrote an important treatise
(1814–1815) describing a systematic correlation between the chemical and
biological information on certain poisons. He also devised methods for
detecting poisons and pointed to the necessity of chemical analysis for
legal proof of lethal intoxication. The introduction of this approach ush-
ered in a specialty area of modern toxicology: forensic toxicology. Ralph
Waldo Emerson (1803–1882), American poet, essayist, philosopher, and
journalist, had this ironic comment about poison: “Tobacco, coffee, alco-
hol, hashish, prussic acid, strychnine, are weak dilutions: the surest poi-
son is time.” —Old Age

History of toxicology in modern stage

Due to the growing concern of human safety in modern society, people
tend to demand improvements in health and living conditions, including
nutrition, clothing, dwelling, and transportation. To meet this goal, a great
variety of chemicals need to be manufactured and used in a way not to
exceed human safety limits. It has been estimated that tens of thousands
of different chemicals are used in commercial production in industrial-
ized countries. In one way or another, these chemicals come in contact
with various segments of the population, that is, individuals engaged
in manufacturing, handling, usage (e.g., painters, applicators of pesti-
cides), consumption (e.g., drugs, food additives, natural food products,
or nutraceuticals), or misusage (e.g., suicide, accidental poisoning, and
environmental disasters). Further, individuals may be exposed to more
persistent chemicals via various environmental media and be affected
more insidiously. To illustrate the devastating effects of toxicants, some
examples of massive acute and long-term human poisonings are listed in
10 Lu’s Basic Toxicology

Appendix 1.2. In some of these episodes, a considerable amount of sophis-

ticated toxicological investigation was conducted before the etiology was
ascertained. These and other tragic outbreaks of massive chemical poi-
sonings resulted in intensified testing programs, which revealed the great
diversity of the nature and site of toxic effects. This revelation, in turn,
has called for more studies using a greater number of animals, a greater
number of indicators of toxicity, biomonitoring of chemicals, and so forth.
There is, therefore, a need to render the task of toxicologically assessing
the vast number of chemicals (by using increasingly more complex testing
procedures) more manageable. To pursue this goal, criteria have been pro-
posed and adopted for the selection of chemicals to be tested according to
their priority. In addition, the “tier systems” allow decisions to be made
at different stages of toxicological testing, thus avoiding unnecessary
studies. If a chemical is found to be exceedingly toxic using a simplified
“tier 1” screen such as loss of renal creatinine excretion and histopathol-
ogy damage, then the compound is removed from the market does not
require more sophisticated “tier 2” or “tier 3” testing. This procedure is
particularly remarkable because the current testing system for carcinoge-
nicity, mutagenicity, immunotoxicity, and reproductive capacity is quite
expensive and involves a multitude of tests.
Because the number of individuals exposed to these chemicals is
large, society cannot defer appropriate control until serious injuries have
appeared. The modern toxicologist, therefore, needs to attempt to iden-
tify, where possible, indicators of exposure, and early reversible signs
of adverse health effects. These will permit the formulation of decisions
at the appropriate step to safeguard the health of individuals, either as
occupational workers or in exposed communities. Achievements in these
areas have assisted responsible personnel in instituting appropriate medi-
cal surveillance of occupational workers and other exposed populations.
Notable examples are the use of cholinesterase inhibition as an indicator
of exposure to organophosphorus pesticides as well as various biochemi-
cal parameters to monitor exposure to lead. Such “biological markers”
or “biomarkers” are intended to measure exposure to toxicants or their
effects as well as to detect susceptible population groups (NRC, 1987);
they are used for clinical diagnosis, monitoring of occupational workers,
and facilitating safety/risk assessment (WHO, 1993).
An important function of toxicology is to determine safe levels of expo-
sure to natural and synthetic chemicals, thereby preventing the adverse
effects of exposures to toxicants. The U.S. Food and Drug Administration
(FDA) took one of the earliest official actions in this field. It stipulated that
a 100-fold margin was required for the permission to use a food addi-
tive. In other words, a chemical additive should not occur in the total
human diet in a quantity greater than one-hundredth of the amount that
Chapter one: History of toxicology 11

is the maximum safe dosage in long-term animal experiments (Lehman

and Fitzhugh, 1954). While evaluating a number of food additives in 1961,
the World Health Organization (WHO) coined the term “acceptable daily
intake (ADI)” (WHO, 1962). Using the ADI procedure, WHO has since
convened annual meetings of experts in the field of food additives, con-
taminants, residues of veterinary drugs, and pesticides. Assessment of
these chemicals resulted, where appropriate, in the assignment of ADIs.
Since then, the term “ADI” and the WHO evaluations have been adopted
by regulatory agencies in many nations. The inception, evolution, and
application of ADI have been outlined by Lu (1988). For toxicants in the
occupational settings, quantitative assessments are provided in terms of
“threshold limit values” (TLVs) (Federal Register, 1971).
These determinations involve comprehensive studies of the toxic
properties, demonstration of dosages that produce no observable adverse
effects, establishment of dose–effect and dose–response relationships,
and toxicokinetic and biotransformation studies. The greatly increased
scope and the multiplicity of subdisciplines as outlined above provide a
vivid view of recent progress in toxicology.

Human poisonings and progress in toxicology

Rehn (1895), a German surgeon, reported tumors in the urinary bladders
of three men who had worked in an aniline factory. The role of aniline and
aniline dyes as etiological agents was confirmed only some 40 years later
after carrying out much experimental investigations in animals (Hueper
et al., 1938), and extensive epidemiological studies (Case et al., 1954). This
discovery led to improved occupational standards and more stringent
controls of food colors derived from coal tar.
In the late 1950s, thalidomide was widely used as a sedative. It has a
very low acute toxicity and readily met the toxicity-testing protocol pre-
vailing at that time. However, a rare form of congenital malformation,
phocomelia (the virtual absence of extremities), was observed among
some offspring of mothers who had taken this drug during the first tri-
mester (Lenz and Knapp, 1962). This tragedy led to the explosive devel-
opment of teratology (developmental toxicology), an important specialty
area of toxicology. The importance of modifying factors has been drama-
tized by the tragic effect of cobalt among heavy beer drinkers.
The once prevalent lead poisoning in certain areas of industrialized
countries has now largely disappeared. This great accomplishment in the
field of public health has resulted from the implementation of control mea-
sures devised on the basis of the knowledge gained from the numerous
toxicological studies of lead. However, this has now raised new concerns.
Lead has been replaced by the gasoline additive methylcyclopentadienyl
12 Lu’s Basic Toxicology

manganese tricarbonyl (MMT). Combustion of MMT-containing gaso-

line generates tailpipe emissions of manganese (Mn) and studies demon-
strated that Mn produces central nervous system disturbances (Gwiadza
et al., 2007). Thus, it should be kept in mind that the removal and replace-
ment of one chemical with another does not necessarily reduce the risk for
the development of adverse effects.
Many cases of serious illness (that culminated in permanent paraly-
sis and death) were reported in Minamata and Niigata in Japan in the
1950s and 1960s, respectively (Study Group of Minamata Disease, 1968;
Tsubaki and Irukayama, 1977). The cause of the illness was eventually
traced to methylmercury found in fish caught locally. The fish were con-
taminated with this chemical, either discharged untreated into the water
by a factory, or from elemental mercury discharged by the factory and
methylated through microorganisms in the mud. As a result, measures to
rehabilitate the surviving patients and to establish legal controls over the
factories were instituted.
On the other hand, the cause of another mysterious illness in Japan,
known as “itai-itai” disease, remains unsolved, although cadmium appar-
ently played a role. The patients had resided for many years in the vicinity
of mines and where the cadmium levels in rice and water were excessive.
A more solid foundation in the assessment of risks of chemical carcin-
ogens resulted from recent advances in epidemiology, long-term animal
studies, short-term mutagenesis/carcinogenesis tests, and mechanistic
investigations; as well as the realization that carcinogens differ in their
potency, latency, and mode of action depending on species, strains, and
gender.

Toxicity versus other considerations

Human exposure to toxic substances should be avoided, but the human
exposure level needs to be determined considering cost (the severity of
the effects, reduction cost) and benefit (health protection, benefit from
life convenience). Some substances produce mild, transient, or reversible
effects, whereas those of others may be irreversible, serious, and even
fatal. Exposure to the former type of substances might thus be accept-
able, but, as a rule, not the latter. There are exceptions, such as meth-
ylmercury which is extremely toxic and is present in many species of
fish. Because of the nutritional value of fish, permissible levels of meth-
ylmercury are established to minimize the risk, and yet not deny this
valuable source of nutrients. Another is aflatoxin B1, which is one of the
most potent carcinogens present in a variety of foods. However, food in
which it appears is not banned as long as the toxin does not exceed the
permissible levels.
Another random document with
no related content on Scribd:
 [As Baldwine indeede being a minister, had bene most fit to set
forth the life of a cardinall and byshop (for causes belonging to his
knowledge and ministery) so to encourage a writer now aliue to play
the part of a Pasquill, and rather make his pen his plough, then in a
hard season, liue like a labourer that doth seruice to many and litle
good to himselfe, I thought it necessary in a kinde of beneuolence
and curtesy of minde, to bestow some credit on that person that not
only hath preferred my tragedy to the printer, (being of his owne
deuice and penning) but also hath enlarged, by playne and familier
verse, the matter the world desires to heare or read, and makinge
common among a multitude that were secret and priuat among a
fewe. Which study and paynes of his owne purpose procures mee
(as one whom fortune hath flattered and afflicted) to appeare vnto
him, for the hearing of my calamity, and for the setting out both of my
rising vp and falling downe. So, to the whole worlde, by his helpe
and mine owne desire, I step out from the graue, where long I lay in
forgetfulnes, and declare in the voyce of a cardinall, a curious
discourse; yet sadly and sorrowfully tolde, as well vnto Churchyard
(the noter thereof) as to the rest that pleaseth to heare any peece of
my misfortune.]
 How Thomas Wolsey did arise vnto
great authority and gouernment, his
maner of life, pompe, and dignity, and
how hee fell downe into great
disgrace, and was arested of high
treason.
1.

Shall I looke on, when states step on the stage,

And play theyr parts, before the people’s face:
Some men liue now, scarce four score yeares of age,
Who in time past, did know the cardnall’s grace:
A gamesom worlde, when byshops run at bace:
Yea, get a fall, in striuing for the gole,
And body loase, and hazarde seely sole.

2.

Ambitious minde, a world of wealth would haue,

So scrats and scrapes, for scorfe, and scoruy drosse:
And till the flesh, and bones, be layde[2001] in graue,
Wit neuer rests, to grope for mucke and mosse:
Fye on prowde pompe, and gilted bridels’ bosse:
O glorious golde, the gaping after thee,
So blindes men’s eyes, they can no daunger see.

3.

Now note my byrth, and marke how I began,

Beholde from whence rose all this pryde of mine:
My father but, a plaine poore honest man,
And I his son, of wit and iudgement fine,
Brought vp at schoole and prou’d a good diuine,
For which great gifts, degree of schoole I had,
And batchler was, and I a litle lad.

4.

So, tasting some of fortune’s sweete consayts,

I clapt the hoode, on shoulder, braue as son,
And hopt at length to bite at better bayts,
And fill my mouth, ere banket halfe were don:
Thus holding on, the course I thought to ron:
By many a feast my belly grue so big,
That Wolsey streight became a wanton twig.

5.

Lo, what it is to feede on daynty meate,

And pamper vp the gorge with suger plate:
Nay, see how lads, in hope of higher seate,
Rise early vp and study learning late:
But hee thriues best that hath a blessed fate:
And hee speeds worst that worlde will nere aduaunce,
Nor neuer knowes what meanes good lucke nor
chaunce.

6.

My chaunce was great, for from a poore man’s son,

I rose aloft, and chopt and chaungde degree:
In Oxford first my famous name begon,
Where many a day the sholers honourd mee:
Then thought I how I might a courtier bee:
So came to court, and fethred there my wing,
With Henry th’eight, who was a worthy king.
 7.

Hee did with words assay mee once or twice,

To see what wit and ready sprite I had:
And when hee saw I was both graue and wice,
For some good cause, the king was wondrous glad:
Than downe I lookt, with sober countnaunce sad,
But heart was vp, as high as hope could go,
That suttell fox might him some fauour so.

8.

Wee worke with wiles, the mindes of men like wax,

The fauning whelp gets many a peece of bred:
Wee follow kings, with many coning knacks,
By searching out how are their humoures fed:
Hee haunts no court, that hath a doltish hed:
For as in golde, the pretious stone is set,
So finest wits, in court the credit get.

9.

I quickely learnde to kneele and kysse the hand,

To waite at heele, and turne like top about,
To stretch out necke and lyke an image stand,
To taunt, to skoffe, and face the matter out,
To preace in place, among the greatest rout:
Yet like a priest, my selfe did well behaue,
In fayre long gowne, and goodly garments graue.

10.

Where Wolsey went, the world like bees would swarme,

To heare my speach, and note my nature well:
I coulde with tongue vse such a kinde of charme,
That voyce, full cleare, should sounde like siluer bell:
When head deuisde a long discours to tell,
With stories straunge, my speach should spised bee,
 To make the worlde to muse the more on mee.

11.

Each tayle was sweete, each worde a sentence wayde,

Each ear I pleasde, each eye gaue mee the vewe,
Each judgment markt, and paysed what I sayde,
Each minde I fed, with matter rare and newe,
Each day and howre my grace and credit grewe:
So that the king, in hearing of this newes,
Deuysed howe hee might my seruice vse.

12.

Hee made mee then his chaplayne, to say masse

Before his grace, yea, twise or thrise a weeke:
Now had I time, to trym my selfe by glasse,
Now founde I meane, some liuing for to seeke,
Now I became both humble, mylde, and meeke:
Now I applyde my wyts and sences throwe,
To reape some corne, if God would speede the plowe.

13.

Whom most I sawe in fauour with the king,

I followde fast, to get some hap thereby:
But I obserude another finer thing,
That was, to keepe me still in prince’s eye:
As vnder wyng the hawke in winde doth lye,
So for a pray, I prowled heere and there,
And tryed frendes and fortune euery where.

14.

The king at length sent mee beyonde the seas,

Embastour then, with message good and greate:
And in that time, I did the king so pleas,
By short dispatch, and wrought so fine a feate,
That did aduaunce my selfe to higher seate,
The deanrie then of Lincolne hee mee gaue:
And bownty shewde before I gan to craue.

15.

His amner to, hee made mee all in haste,

And threefolde gyftes hee threwe vpon mee still:
His counslour straight listewise was Wolsey plaste,
Thus in shorte time I had the world at will:
Which passed far man’s reason, wit, and skill:
O hap, thou haste great secrets in thy might,
Which long lye hyd from wily worldlyngs sight.

16.

As shures of raine fall quickly on the grasse,

That fading flowres are soone refresht thereby:
Or as with sun the morning dewe doth passe,
And quiet calme makes cleare a troubled skye:
So prince’s powre, at twinkling of an eye,
Sets vp a lofte a favret on the wheele,
When giddy braynes about the streetes doe reele.

17.

They are but blinde that wake where fortune sleepes,

They worke in vayne that striue with streame and tyde:
In double garde, they dwell that destnye keepes,
In simple sorte they liue that lacke a gyde:
They misse the marke that shoote theyr arrowes wide,
They hit the pricke that make theyr flight to glaunce
So nere the white, that shafte may light on chaunce.

18.

Such was my lucke I shot no shafte in vayne,

My bow stoode bent and brased all the yeere:
I wayted harde but neuer lost my payne:
Such wealth came in to beare the charges cleere:
And in the end, I was the greatest peere
Among them all, for I so rulde the land,
By king’s consent, that all was in my hand.

19.

Within on yeare three bishoprickes I had,

And in small space a cardnall I was made:
With long red robes rich Wolsey then was clad,
I walkte in sun when others sate in shade:
I went abroade with such a trayne and trade,
With crosses borne before mee where I past,
That man was thought to bee some god at last.

20.

With sonnes of earles and lordes I serued was,

An hundreth chaynes at leaste were in my trayne:
I dayly dranke in gold, but not in glas,
My bread was made of fynest flowre and grayne:
My daynty mouth did common meates disdayne,
I fed like prince on fowles most deare and straunge,
And bankets made of fine conceites for chaunge.

21.

My hall was full of knightes, and squires of name,

And gentlemen, two hundreth tolde by powle:
Tall[2002] yeomen to did howrely serue the same,
Whose names each weeke I saw within checke rowle:
All went to church, when seruis bell did knowle,
All dinde and supte and slepte at cardinall’s charge,
And all would wayte, when Wolsey tooke his barge.

22.
My householde stuffe, my wealth and siluer plate,
Mighte well suffice a monarke at this day:
I neuer fed but vnder cloth of state,
Nor walkt abroade till ushars clearde the way:
In house I had musitions for to play,
In open streete my trompets lowde did sownde,
Which pearst the skies and seemde to shake the
grownde.

23.

My men most braue, martcht two and two in ranke,

Who helde in length, much more then halfe a mile:
Not one of these, but gaue his maister thanke,
For some good turne, or pleasure got some while:
I did not feede my seruantes with a smile,
Or glosing wordes, that neuer bring forth frute,
But gaue them golde, or els preferde theyr sute.

24.

In surety so, whiles God was pleasde, I stoode,

I knewe I must leaue all my wealth behinde:
I sawe they lou’d mee not for byrth or bloode,
But serude a space to try my noble minde:
The more men gieue the more in deede they finde
Of loue, and troth, and seruice, euery way:
The more they spare, the more doth loue decay.

25.

I ioyde to see my seruantes thriue so well,

And go so gay with little that they gote:
For as I did in honour still excell,
So would I oft the wante of seruantes note:
Which made my men on maister so to dote,
That when I sayde let such a thing bee donne,
They woulde in deede through fyre and water ronne.
 26.

I had in house so many of’sars[2003] still,

Which were obayde and honourde for their place,
That carelesse I might sleepe or walke at will,
Saue that sometyme I wayde a poore man’s case,
And salude such sores whose griefe might breede
disgrace:
Thus men did wayte and wicked world did gaze
On mee and them, that brought vs all in maze.

27.

For worlde was whist, and durst not speake a woorde,

Of that they sawe, my credite curbde them so:
I waded far, and passed ore the foorde,
And mynded not, for to returne I troe:
The worlde was wise, yet scarce it selfe did knoe,
When wonder made, of men that rose by hap:
For fortune rare, falls not in each man’s lap.

28.

I climde the clouds, by knowledge and good wit,

My men sought chaunce by seruice or good lucke:
The worlde walkte lowe when I aboue did sit,
Or downe did come to trample on this mucke:
And I did swim as dainty as a ducke,
When water serues to keepe the body braue,
And to enioy the gyftes that fortune gaue.

29.

And though my pompe surpast all prelates nowe,

And like a prince I liu’d and pleasure tooke:
That was not sure so great a blur in browe,
If on my workes indiffrent eyes doe looke:
I thought great scorne such liuings heare to brooke,
 Except I built some howses for the poore,
And order tooke to gieue great almes at doore.

30.

A colledge fayre in Oxford I did make,

A sumptuous house a stately worke in deede:
I gaue great lands to that, for learning sake,
To bring vp youth and succour scholer’s neede:
That charge of myne full many a mouth did feede,
When I in courte was seeking some good turne,
To mend my torch, or make my candell burne.

31.

More houses gay I builte, then thowsands do

That haue enough, yet will no goodnes shoe:
And where I built I did mayntayne it to,
With such great cost as few bestowes I troe:
Of buildings large I could reherse a roe,
That by mischaunce this day haue lost my name,
Whereof I do deserue the only fame.

32.

And as for sutes, about the king was none

So apte as I, to speake and purchase grace:
Though long before, some say, Shore’s wife was one
That oft kneelde downe before the prince’s face
For poore men’s sutes, and holpe theire woefull case,
Yet shee had not such credite as I gate,
Although a king would beare the parret prate.

33.

My wordes were graue and bore an equall poyes,

In ballaunce iust for many a weighty cause:
Shee pleasde a prince with pretty merry toyes,
And had no sight in state, nor course of lawes:
I coulde perswade and make a prince to pawes,
And take a breath before hee drew the sworde,
And spy the time to rule him with a worde.

34.

I will not say but fancy may do much,

Yet worlde will graunt that wisdom may do more:
To wanton gyrl’s affection is not such,
That prince’s wise will bee abusde therefore:
One sute of mine was surely worth a score
Of her’s indeede, for shee her time must watch,
And at all howres I durst go draw the latch.

35.

My voyce but heard, the dore was open streyght,

Shee might not come, till shee were calde or brought:
I rulde the king by custom, arte, and sleight,
And knew full well the secrets of his thought:
Without my minde all that was done was nought,
In wars, or peace, my counsayle swayed all,
For still the king would for the cardnall call.

36.

I kept a court my selfe, as great as his,

(I not compare vnto my maister heere)
But looke my lords what liuely worlde was this,
That one poore man became so great a peere?
Yet though this tale be very straunge to heere,
Wit wins a worlde; and who hath hap and wit,
With triumph long in princely throne may sit.

37.

What man like mee bare rule in any age,

I shone like sun more cleare then morning star:
Was neuer parte so playde, in open stage,
As mine, nor fame of man flewe halfe so far:
I sate on bench, when thowsands at the bar
Did pleade for right: for I in publique weale
Lorde chaunclour was and had the great broad seale.

38.

Now haue I tolde how I did rise aloft,

And sate with pride and pomp, in golden hall,
And set my feete on costly carpets soft,
And playde at goale with goodly golden ball:
But after, Lord, I must rehearse my fall:
O trembling heart, thou canst not now for teares
Present that tale vnto the hearer’s cares.

39.

Best weepe it out and sodayne silence keepe,

Till priuy pangs make pinched heart complayne:
Or cast thy selfe into some slumbring sleepe,
Till wakened wits remembraunce bring agayne:
When heauy teares, do hollow cheekes distayne,
The world will thinke thy sprits are growne so weake,
The feeble tongue hath sure no powre to speake.

40.

A tale by signes with sighes and sobs set out,

Moues people’s mindes to pity plaged men,
With howling voyce do rather cry and showt,
And so by arte shew forth thy sorrow then:
For if thou speake some man will note with pen
What Wolsey sayde, and what thrue Wolsey downe,
And vnder foote flings Wolsey’s great renowne.

41.
What force of that my fall must needs be herd,
Before I fell I had a time to rise:
As fatall chaunce and fortune mee preferd,
So mischiefe came and did my state despise:
Yf I might pleade my case among the wise,
I could excuse right much of mine offence:
But leaue a while such matter in suspence.

42.

The pope, or pride, or peeuish parts of mine,

Made king to frowne and take the seale from mee:
Now seru’d no words, nor plesaunt speeches fine,
Now Wolsey, lo, must needs disgraced bee:
Yet had I leaue (as dolefull prisner free)
To keepe a house (God wot) with heauy cheere,
Where that I founde no wine, ne bread, nor beere.

43.

My time was come, I coulde no longer liue,

What should I make my sorrow further knowne?
Upon some cause that king, that all did giue,
Tooke all agayne and so possest his owne:
My goods, my plate, and all was ouerthrowne,
And looke what I had gathred many a day,
Within one howre was cleanly swept away.

44.

But harken now how that my fortune fell,

To Yorke I must, where I the bishop was:
Where I by right in grace a while did dwell,
And was in stawle with honour great to pas:
The priors then and abbots gan to smell,
Howe cardinall must bee honourd as hee ought,
And for that day was great prouision brought.
 45.

At Cawood then, where I great buildings made,

And did through cause exspect my stawling day,
The king deuisde a secrete vnder shade,
Howe cardnall shoulde bee reste and brought away:
One Wealsh a knight, came downe in good aray,
And seasned sure, because from courte hee cam,
On Wolsey wolfe that spoyled many a lam.

46.

Then was I led toward courte, like dog in string,

And brought as biefe that Butcherrowe must see:
But still I hoapt to come before the king,
And that repayre was not denyde to mee:
But hee that kept the towre, my guide must bee:
Ah, there I sawe what king thereby did meane,
And so I searcht yf conscience now were cleane.

47.

Some spots I founde, of pryde and popishe partes,

That might accuse a better man then I:
Now Oxford came to minde, with all theire artes,
And Cambridge to, but all not worth a flye:
For schoolemen can no fowle defects supplye:
My sauce was sowre, though meate before was
sweete,
Nowe Wolsey lackte both conning, wit, and spreete.

48.

A deepe conceyte of that, possest my heade,

So fell I sicke, consumde as some did thinke:
So tooke in haste my chamber, and my bed,
On which deuise, perhaps, the worlde might winke:
But in the heart sharpe sorrow so did sinke,
 That gladnes sweete, (forsooke my senses all)
In those extreemes did yeelde vnto my fall.

49.

O let mee curse the popish cardnall hat,

Whose myters big, beset with pearle and stones,
And all the rest of trash, I know not what,
The saints in shrine, theyr flesh and rotten bones,
The maske of monkes, deuised for the nones,
And all the flocke of freers, what ere they are,
That brought mee vp and left mee there so bare.

50.

O cursed priestes, that prate for profit’s sake,

And follow floud and tyde where ere it floes:
O marchaunts fine that no aduauntage take
Of euery grayne, how euer market goes:
O fie on wolues that march in masking cloes,
For to deuoure the lambs when shepperd sleepes,
And woe to you that promise neuer keepes.

51.

You sayd I should be reskude if I neede,

And you would curse, with candell, booke, and bell:
But when yee should now serue my turne indeede,
Yee haue no house I know not where yee dwell:
O freers and monkes your harbour is in hell,
For in this world yee haue no rightfull place,
Nor dare not once in heauen shew your face.

52.

Your fault not halfe so great as was my pryde,

For which offence fell Lucifer from skyes:
Although I would that wilfull folly hyde,
The thing lyes playne before the people’s eyes,
On which hye heart a hatefull name doth ryes:
It hath beene sayde of olde, and dayly will,
Pryde goes before, and shame coms after still.

53.

Pryde is a thing that God and man abores,

A swelling tode, that poysons euery place,
A stinking wounde, that breedeth many sores,
A priuy plague, found out in stately face,
A paynted byrd that keepes a pecock’s pace,
A lothsome lowt that lookes like tinker’s dog,
A hellish hownd, a swinish hatefull hog

54.

That grunts and groanes at euery thing it sees,

And holds vp snowt like pig that coms from draffe:
Why should I make of pride all these degrees,
That first tooke roote from filthy drosse and chaffe,
And makes men stay vpon a broken staffe:
No weaknes more than thinke to stand vpright,
When stumbling blocke makes men to fall downright.

55.

Hee needes must fall that looks not where he goes,

And on the starrs walkes staring goezling like:
On sodayne oft a blostring tempest bloes,
Than downe great trees are tumbled in the dike:
Who knowes the time and howre when God will strike:
Then looke about, and marke what steps yee take,
Before you pace, the pilgrimage yee make.

56.

Run not on head as all the worlde were youres,

Nor thrust them backe that cannot bide a shocke:
Who striues for place his owne decay procures:
Who alway brawles is sure to catch a knocke:
Who beardes a king, his head is neere the blocke:
But who doth stand in feare and worldly dreede,
Ere mischiefe coms had neede to take good heede.

57.

I hauing hap, did make account of none,

But such as fed my humour good or bad:
To fawning dogs, sometimes I gaue a bone,
And flong some scrapps to such as nothing had:
But in my hands still kept the golden gad,
That seru’d my turne and laught the rest to skorne,
As for himselfe was cardnall Wolsey borne.

58.

No, no, good men, wee liue not for ourselues,

Though each one catch as mutch as hee may get:
Wee ought to looke to those that diggs and delues,
That alwayes dwell and liue in endles det,
Yf in such sort wee would our compas set,
Wee should haue loue where now but hate wee finde,
And hedstrong will, with cruell hollow minde.

59.

I thought nothing of duty, loue, or feare,

I snatcht vp all and alwayes sought to clime:
I punisht all and would with no man beare:
I sought for all and so could take the time:
I plide the prince, whiles fortune was in prime,
I fild the bags and gold in hoorde I heapt,
Thought not on those that thresht the corne I reapt.

60.
So all I lost and all I gat was nought,
And all by pride and pompe lay in the dust:
I aske you all what man aliue had thought,
That in this world had beene so litle trust:
Why, all thinges heare with time decline they must:
Than all is vaine so all not worth a flye,
Yf all shall thinke that all are borne to dye.

61.

Yf all bee bace, and of so small a count,

Why doe wee all in folly so abound?
Why doe the meane and mighty seeke to mount,
Beyonde all hope where is no surety found,
And where the wheele is alwayes turning round?
The case is plaine if all bee vnderstood,
Wee are so vaine wee knowe not what is good.

62.

Yet some will say, when they haue heapes of golde,

With flocks of friends, and seruaunts at theyr call,
They liue like gods in pleasure treble folde,
And haue no cause to finde no fault at all:
O blinde conceite, these gloryes are but small,
And as for friends, they change their mindes so mych,
They stay not long with neither poore nor rich.

63.

With hope of friends our selues wee do deceaue,

With feare of foes we threatned are with sleepe:
But friends speake fayre yet men alone they leaue
To sinke or swim, to mourne, to laugh, or weepe:
Yet whan for smiles, the snake begins to creepe,
As world falls out these dayes in compasse iust,
Wee knowe not howe the friend or foe to trust.
 64.

Both can betray the truest man aliue,

Both are to doubt in matters of greate weight,
Both will somtime for goodes and honour striue,
Both seemeth playne, yet both can shewe great sleight:
Both stoups full lowe, yet both can looke on height,
And best of both, not worth a cracked crowne:
Yet least of both, may loase a walled towne.

65.

Talke not of friends, the name thereof is nought,

Then trust no foes, if frendes theire credit loes:
If foes and frendes of on bare earth were wrought,
Blame nere of both though both one nature shoes:
Grace passeth kinde where grace and vertue floes,
But where grace wantes make foes and frends alike,
The on drawes sworde the other sure will strike.

66.

I prou’d that true by tryall twenty times,

When Wolsey stoode on top of fortune’s wheele.
But such as to the height of ladder climes,
Knowe not what led lies hanging on theire heele
Tell mee my mates that heauy fortune feele,
Yf rising vp, breede not a gyddy brayne,
And faling downe, bee not a greuous payne.

67.

I tolde you how from Cawood I was led,

And so fell sicke, when I arested was:
What needeth nowe more wordes heere in bee sed?
I knewe full well I must to pryson passe,
And sawe my state as brittell as a glasse:
So gaue vp ghost, and bad the worlde farewell,
 Wherein, God wot, I could no longer dwell.[2004]

68.

Thus vnto dust and ashes I returnde,

When blase of life and vital breath went out,
Like glowing cole that is to sinders burnde:
All fleshe and bloud so ende, you neede not doubt:
But when the bruite of this was blowne about,
The worlde was glad, the cardnall was in graue,
This is of worlde, lo, all the hope we haue.

69.

Full many a yeare the world lookt for my fall,

And whan I fell, I made as great a cracke,
As doth an oake, or mighty tottring wall,
That whirling winde doth bring to ruin and wracke:
Now babling world wil talke behinde my backe:
A thousand things to my reproache and shame,
So will it to of others do the same.

70.

But what of that? the best is wee are gone,

And worst of all when wee our tales haue tolde,
Our open plagues will warning bee to none,
Men are by hap and courage made so bolde:
They thinke all is theyr owne they haue in holde:
Well let them say and think what thing they please,
This weltring world both flowes and ebs like seas.

qd. Tho. Churchyard.[2005]