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CRC REVIVALS CRC REVIVALS
Edited by James S. Robertson

Compartmental Distribution Of Radiotracers
Compartmental Distribution
Of Radiotracers
Edited by
James S. Robertson
ISBN 978-1-138-50575-9
,!7IB1D8-fafhfj!
www.crcpress.com
CRC SERIES IN RADIOTRACERS IN
BIOLOGY AND MEDICINE
Editor-in-Chief
Lelio G. Colombetti, Sc.D.

Loyola University
Stritch School of Medicine
Maywood, Illinois
STUDIES OF CELLULAR FUNCTION BIOLOGIC APPLICATIONS OF

USING RADIOTRACERS RADIOTRACERS
Mervyn W. Billinghurst, Fh.D. Howard J. Glenn, Ph.D.
Radiopharmacy University of Texas System Cancer Center
Health Sciences Center M.D. Anderson Hospital and Tumor
Winnipeg, Manitoba, Canada Institute
Houston, Texas
BIOLOGICAL TRANSPORT OF
GENERAL PROCESSES OF RADIOTRACER
RADIOTRACERS
LOCALIZATION
Leopold J. Anghileri, D.Sc.
Loyola University
Laboratory of Biophysics
University of Nancy
Maywood, Illinois
Nancy, France
BASIC PHYSICS OF RADIOTRACERS
W. Earl Barnes, Ph.D.
RADIATION BIOLOGY Nuclear Medicine Service
Donald Pizzarello, Ph.D. Edward Hines, Jr., Hospital
Department of Radiology Hines, Illinois
New York University Medical Center
New York, New York RADIOBIOASSAYS
Fuad S. Ashkar, M.D.
Radioassay Laboratory
Jackson Memorial Medical Center
RADIOTRACERS FOR MEDICAL
University of Miami School of Medicine
APPLICATIONS
Miami, Florida
Garimella V. S. Rayudu, Ph.D.
Nuclear Medicine Department
COMPARTMENTAL DISTRIBUTION OF
Rush University Medical Center
RADIOTRACERS
Presbyterian-St. Luke’s Hospital
James S. Robertson, M.D., Ph.D.
Chicago, Illinois
Mayo Medical School
Mayo Clinic
Rochester, Minnesota
RECEPTOR-BINDING RADIOTRACERS
William C. Eckelman, Ph.D. RADIONUCLIDES PRODUCTION
Department of Radiology Frank Helus, Sc.D.
George Washington University School of Institute of Nuclear Medicine
Medicine German Cancer Research Center
Washington, D.C. Heidelberg, Germany
Compartmental
Distribution
of
Radiotracers
Editor
James S. Robertson, M.D., Ph.D.

Professor of Laboratory Medicine
Mayo Medical School
Consultant, Diagnostic Nuclear Medicine
Mayo Clinic
Rochester, Minnesota
Editor-in-Chief
CRC Series in Radiotracers in Biology and Medicine

Loyola University
Maywood, Illinois
First published 2000 by CRC Press
Taylor & Francis Group
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Boca Raton, FL 33487-2742
Reissued 2018 by CRC Press
© 1983 by Taylor & Francis

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FOREWORD
This series of books on Radiotracers in Biology and Medicine is on the one hand an
unbelievably expansive enterprise and on the other hand, a most noble one as well. Tools
to probe biology have developed at an accelerating rate. Hevesy pioneered the application
of radioisotopes to the study of chemical processes, and since that time, radioisotopic
methodology has probably contributed as much as any other methodology to the analysis of
the fine structure of biologic systems. Radioisotopic methodologies represent powerful tools
for the determination of virtually any process of biologic interest. It should not be surprising,
therefore, that any effort to encompass all aspects of radiotracer methodology is both desirable
in the extreme and doomed to at least some degree of inherent failure. The current series
is assuredly a success relative to the breath of topics which range from in depth treatises of
fundamental science or abstract concepts to detailed and specific applications, such as those
in medicine or even to the extreme of the methodology for sacrifice of animals as part of a
radiotracer distribution study. The list of contributors is as impressive as is the task, so that
one can be optimistic that the endeavor is likely to be as successful as efforts of this type
can be expected to be. The prospects are further enhanced by the unbounded energy of the
coordinating editor. The profligate expansion of application of radioisotopic methods relate
to their inherent and exquisite sensitivity, ease of quantitation, specificity, and comparative
simplicity, especially with modem instrumentation and reagents, both of which are now
readily and universally available. It is now possible to make biological measurements which
were otherwise difficult or impossible. These measurements allow us to begin to understand
processes in depth in their unaltered state so that radioisotope methodology has proved to
be a powerful probe for insight into the function and perturbations of the fine structure of
biologic systems. Radioisotopic methodology has provided virtually all of the information
now known about the physiology and pathophysiology of several organ systems and has
been used abundantly for the development of information on every organ system and kinetic
pathway in the plant and animal kingdoms. We all instinctively turn to the thyroid gland
and its homeostatic interrelationships as an example, and an early one at that, of the use of
radioactive tracers to elaborate normal and abnormal physiology and biochemistry, but this
is but one of many suitable examples. Nor is the thyroid unique in the appreciation that a
very major and important residua of diagnostic and therapeutic methods of clinical importance
result from an even larger number of procedures used earlier for investigative purposes and,
in some instances, advocated for clinical use. The very ease and power of radioisotopic
methodology tempts one to use these techniques without sufficient knowledge, preparation
or care and with the potential for resulting disastrous misinformation. There are notable
research and clinical illustrations of this problem, which serve to emphasize the importance
of texts such as these to which one can turn for quidance in the proper use of these powerful
methods. Radioisotopic methodology has already demonstrated its potential for opening new
vistas in science and medicine. This series of texts, extensive though they be, yet must be
incomplete in some respects. Multiple authorship always entails danger of nonuniformity of
quality, but the quality of authorship herein assembled makes this likely to be minimal. In
any event, this series undoubtedly will serve an important role in the continued application
of radioisotopic methodology to the exciting and unending, yet answerable, questions in
science and medicine!
Gerald L. DeNardo, M.D.

Professor of Radiology, Medicine,
Pathology and Veterinary Radiology
University of California, Davis-
Sacramento Medical School
Director, Division of Nuclear Medicine
THE EDITOR-IN-CHIEF
Lelio G. Colombetti, Sc.D., is professor of Pharmacology at Loyola University Stritch

School of Medicine in Maywood, 111. and a member of the Nuclear Medicine Division Staff
at Michael Reese Hospital and Medical Center in Chicago, 111.
Dr. Colombetti graduated from the Litoral University in his native Argentina with a Doctor
in Sciences degree (summa cum laude), and obtained two fellowships for postgraduate studies
from Georgetown University in Washington, D.C., and from M.I.T. in Cambridge, Mass.
He has published more than 150 scientific papers and is the author of several book chapters.
He has presented over 300 lectures at meetings held in both the U.S. and abroad. He organized
the First International Symposium on Radiopharmacology, held in Innsbruck, Austria, in
May 1978. He also orgainized the Second International Symposium on Radiopharmacology
which took place in Chicago in September, 1981, with active participation of more than
500 scientists, representing over 30 countries. He is a founding member of the International
Association of Radiopharmacology, a nonprofit organization, which congregates scientists
from many disciplines interested in the biological applications of radiotracers. He was its
first president (1979/1981).
Dr. Colombetti is a member of various scientific societies, including the Society of Nuclear
Medicine (U.S.) and the Gesellschaft fiir Nuklearmedizin (Europe), and is an honorary
member of the Mexican Society of Nuclear Medicine. He is also a member of the Society
of Experimental Medicine and Biology, the Coblenz Society, and Sigma Xi. He is a member
of the editorial boards of the journals Nuklearmedizin and Research in Clinic and Laboratory.
PREFACE
The availability of isotopic varieties of the chemical elements has had a strong impact on
many branches of science. For some procedures isotopic tracers make possible methods that
are simply easier or more accurate or more convenient than other methods. More importantly,
however, there are some processes, particularly those involving steady-state conditions, that
before the advent of isotopic tracers were considered to be not accessible to investigation,
but which can be studied with these tracers. In biological studies the radioactive tracers have
been especially useful because external detection methods can be employed in noninvasive
or minimally invasive studies.
The growth of the uses of radioactive tracers has been closely associated with the devel
opment of various mathematical methods for describing the kinetics, or the time course of
distribution of the tracers in the systems of interest. One group of such mathematical pro
cedures is collectively known as compartmental analysis. As is discussed in the text, the
use of comp.'*Tmental analysis involves making a set of simplifying assumptions, called a
model, for the system. A typical model subdivides the system into regions called compart
ments which communicate with each other and with the outside world through the transfer
of material. Compartmental analysis is used in two ways in application to such systems.
First, if the parameters of the system, that is, the compartment sizes and transfer rates, are
known, the mathematical relationships can be used to predict the kinetics of the distribution
of a tracer introduced into the system. The second, or reverse problem is more difficult and
also more fruitful. This involves deducing numerical values for the system parameters from
measurements of the concentration of the tracer. Applications of this have been particularly
fruitful in studies of steady-state systems.
The systems studied by compartmental analysis have grown from those that can be solved
by desk-top, or pencil-and-paper methods to those that require large computers to handle
the multiple relationships and complicated interactions that are involved. Even so, simple
systems remain important and an understanding of them is essential to an appreciation of
the limitations as well as the value of analyses of the more complex systems.
Several excellent books on compartmental analysis have been published. The justification
for another volume on compartmental analysis perhaps lies in the greater emphasis on the
details of computer methods and on the statistical aspects. For those who are new to the
field an historical account of early developments in compartmental analysis is given, and
the basic principles, with some details of the analysis for one, two and three compartment
systems are presented. These also serve to introduce the reader to the terminology and the
notation used. With more than three compartments the mathematical difficulties rapidly
increase, and the use of computers becomes a necessity. In Chapter 3 the mathematical basis
for the analysis of multicompartment systems is developed in detail with emphasis on the
matrix methods for solving systems of linear differential equations. Chapter 4 gives a survey
of various computer programs that have been applied to compartmental analysis, and Chapter
5 presents the details needed for the use of Mones Berman’s SAAM program. The SAAM
program is currently the most comprehensive computer program that has been developed
for compartmental analysis. It has had a marked influence on the development of the field,
and copies of the program are in use in a number of laboratories.
Chapter 6 addresses the problem of the role of statistical analysis in compartmental
analysis. The general field of compartmental analysis has sometimes been criticized for the
lack of attention to the relationships between the inevitable errors, or uncertainty, in the
input data and the confidence limits that can be assigned to the solution values. Chapter 7
should help meet the requirement for treatment of this aspect of the problem.
Mones Berman assisted as a consultant in the preparation of several chapters of this book
and it is a pleasure to acknowledge his contributions. The editors also wish to thank the
individual authors for taking time to write their chapters and for their patience in the long
process between writing and publication.
James S. Robertson
Lelio G. Colombetti
THE EDITOR
James S. Robertson, M.D., Ph.D., is a consultant in the Diagnostic Nuclear Medicine

Section of the Department of Laboratory Medicine at the Mayo Clinic and Professor of
Laboratory Medicine in the Mayo Medical School, Rochester, Minnesota.
Dr. Robertson received his B.S. in 1943, M.B. in 1944, and M.D. in 1945 each from
the University of Minnesota. In 1949 he received his Ph.D. from the University of California.
For 25 years Dr. Robertson served as Head of the Medical Physics Division in the Medical
Department at the Brookhaven National Laboratory in Upton, New York.
Currently, Dr. Robertson is a member of several professional organizations. These include
the American Association for the Advancement of Science, the American Physiological
Society, the Health Physics Society, the Mathematical Association of America, the Radiation
Research Society, Sigma Xi, and the Society of Nuclear Medicine. In addition, Dr. Robertson
is a member of two national committees, Medical Internal Radiation Dose Committee of
the Society of Nuclear Medicine and Chairman, Scientific Committee SC-55, Experimental
Verification of Internal Radiation Dose Calculations, of the National Council for Radiation
Protection and Measurements.
Dr. Robertson has published over 100 papers on tracer theory, radiation dosimetry and
nuclear medicine topics. Radiation dosimetry is his current research interest.
To the memory of Mones Berman
CONTRIBUTORS
Ray C. Boston, Ph.D. Aldo Rescigno, Ph.D.

School of Agriculture Section of Neurosurgery
La Trobe University Yale University School of Medicine
Bundoora, Australia New Haven, Connecticut
and Department of Chemistry
David M. Foster, Ph.D. Brookhaven National Laboratory
Center for Bioengineering Upton, New York
University of Washington
Seattle, Washington
Richard Moore, Ph.D. Ajit K. Thakur, Ph.D.

Department of Radiology Principal Scientist (Biostatistics)
University of Minnesota Hospitals Hazleton Laboratories America, Inc.
Minneapolis, Minnesota Vienna, Virginia
TABLE OF CONTENTS
Chapter 1
Historical Development......................................................................................................... 1
James S. Robertson
Chapter 2
Basic Principles.................................................................................................................... 11
James S. Robertson
Chapter 3
Mathematical M ethods.........................................................................................................29
Aldo Rescigno
Chapter 4
Application of Computers for Obtaining Numerical Solutions to Compartmental
Models.................................................................................................................................. 67
Richard Moore
Chapter 5
The Use of Computers in Compartmental Analysis: The SAAM and CONSAM
Programs............................................................................................................................... 73
David M. Foster and Ray C. Boston
Chapter 6
Some Statistical Principles in Compartmental Analysis.................................................... 143
Ajit K. Thakur
Chapter 7
Applications.........................................................................................................................177
James S. Robertson
Index 187
1
Chapter 1
HISTORICAL DEVELOPMENT
James S. Robertson
TABLE OF CONTENTS
I. Introduction................................................................................................................. 2
II. Tracers......................................................................................................................... 2
III. Mathematical Developments......................................................................................3
IV. State of the A r t ...........................................................................................................6
References................................................................................................................................7
2 Compartmental Distribution of Radiotracers
I. INTRODUCTION
The history of compartmental analysis is linked to that of tracer theory, the discoveries
of radioactivity and the isotopic composition of the natural elements, mathematical devel
opments, and the development of analog and digital computers. In particular, the availability
of radioactive tracers has made possible the noninvasive study of biological systems, and
has opened for investigation areas that previously had been considered to be inaccessible.
II. TRACERS
The word “ tracer” has many meanings. The post office uses it to designate a method
for determining the fate of lost mail. The military uses it to mean a type of ammunition that
marks the trajectory of projectiles by leaving a trail of smoke or fire. In the present context
the term tracer will be restricted to meaning a marked form of a substance that is used to
determine certain properties of the labeled substance in biological systems. These properties
include the exchangeable mass or volume of the substance, its localization, its pathway
through chemical reactions, and its transfer rates into, out of, and through components of
the system.
In general the principles involved in analyzing the behavior of tracers in biological systems
are applicable through analogy to other systems and vice versa. In particular, the principle
of determining a volume by dilution is valid for many systems. Ocean currents and the flow
of liquids through pipes can be studied by use of tracers. The mathematical relationships
applicable to compartmented systems are often formally identical with those found in other
physical systems, in particular in electrical circuits. Nevertheless, the theoretical development
and the examples presented in this book will usually involve the assumption that a biological
system is the objective of the study. Even with this restriction, the use of tracers has become
so widespread that only the early developments can be reviewed here.
The origins of the tracer concept are lost in antiquity, if this is taken to include such
examples as the use of a cowbell to locate a herd and similar applications. The major impetus
for the development of modem tracer theory, however, began with the discovery of radio
activity by Becquerel in 1896. Previously Hering1 had used potassium ferrocyanide to
measure the velocity of blood flow, and others had improved on this method by using dyes
such as fluorescein. In 1897 Stewart2 first reported on the use of the dye indicator-dilution
method to measure cardiac output. Although dye methods remain useful for circulatory
studies,3 their utility is much more restricted than are isotopic methods.
Among the early radiotracer studies of interest is the pioneering work of Hevesy.4 In
particular, Hevesy’s work is often regarded as the beginning of the concept that a chemical
of interest could have an isotopic variant as its label. In 1911 Rutherford had asked Hevesy
to separate radium D (now known to be lead-210) from lead. After 2 years of unsuccessful
efforts, he thought to avail himself of the fact that radium D is inseparable from lead and
to label small amounts of lead by the addition of radium D of known activity. Hevesy and
Paneth first used this method to determine the solubility in water of sparingly soluble salts
such as lead sulfide and lead chromate. They were also able to show that the electrode
potentials of radium D peroxide and lead peroxide were the same, providing further evidence
of the identity of radium D with lead. Later, with other associates, Hevesy first measured
the rate of self-diffusion in lead. His work with mixtures of labeled and unlabeled electrolytes
provided a direct proof of the correctness of the theory of electrolytic dissociation.
In 1924, Hevesy introduced Schoenheimer to the tracer method and they studied the
distribution of labeled lead compounds between cancerous and normal tissue in rabbits.
(Later, Schoenheimer and Rittenberg made important contributions to biochemistry through
studies of labeled materials, particularly in the determination of the turnover rates of body
3
constituents.5) Perhaps the first biological kinetic study with a radioactive tracer was Hevesy’s
study of the uptake of lead by bean seedlings. These studies were only the beginning of
many experiments conducted by Hevesy and his associates with radiotracers in biological
systems, which included permeability studies, red cell labeling, clinical investigations with
water, phosphorus, potassium, and thorium-B, iron metabolism, and the turnover rates of
nucleic acids. His 1935 paper with Chievitz6 on phosphorus metabolism in rats has been
cited7 as being the first radioindicator study in the life sciences with an artificial radionuclide.
Other aspects of the history of isotopic methodology have been reviewed by Hevesy.8 In
recognition of his basic contributions to basic chemistry and to biochemistry, Hevesy received
the 1943 Nobel prize for chemistry.
Of course other workers also soon found applications of the radiotracer method. Some of
the first clinical studies with this method were conducted by Blumgart et al.9 11 in extensive
investigations of the right arm-to-left arm blood circulation time. They achieved their meas
urements by counting the gamma ray tracks from radium C (214Bi) in a Wilson cloud chamber.
Brucer12 has suggested that the honorary title, “ The father of nuclear medicine,” be shared
by Hevesy and Blumgart, with the emphasis on nuclear for Hevesy and on medicine for
Blumgart.
The use of radiotracers to study the kinetics and the basic processes involved in the
transport of substances across biological membranes has been reviewed by Ussing.13' 14
Among tracer methods, the flux ratio analysis has been used extensively for deciding whether
a certain species penetrates membranes by simple diffusion, exchange diffusion, single file
diffusion, or active transport. Active transport is defined as the transfer of a substance against
a chemical potential gradient, or, in the case of charged ions, from a lower to a higher
electrochemical potential. The combined use of tracers and electrophysiological techniques
proved to be powerful tools in the quantification of basic transport processes as well as in
the elucidation of the nature of these processes. The use of radionuclides such as 24Na and
42K made possible studies of such processes as the coupling of active sodium and potassium
transport across cell membranes. Another contribution made possible by tracers is the de
velopment of a three-compartment model (involving two barriers in series) for transepithelial
transport. Ussing15 16 himself was one of the early and prolific contributors to the field of
membrane transport.
Some aspects of the impact of isotopic tracers on physiological concepts were reviewed
by Robertson.18 In particular, studies of the path of carbon in photosynthesis18 and other
metabolic pathways were made possible by the availability of isotopic tracers.
The development of modem imaging instrumentation has been a major factor in promoting
the growth of the use of radioactive tracers in diagnostic nuclear medicine. Radiopharma
ceuticals which more or less selectively localize in certain organs, or in tumors, or at sites
of infection are commercially available and make the study of many internal processes
possible by noninvasive methods.
III. MATHEMATICAL DEVELOPMENTS
In many applications of tracer methods in biological systems, acquiring knowledge of the

kinetics of the tracer in the system would be a sterile pastime if this information could not
be used to provide information about the kinetics of the tracee (defined20 as the substance
marked by the tracer). However, the relationships between the kinetics of the tracer (which
can be observed) and the kinetics of the tracee (which is the entity of interest) are not as
simple and straightforward as might be imagined. The use of mathematical methods to
analyze these relationships is a relatively recent development.
The full effectiveness of the use of tracer methods in kinetic studies could not be realized
without the use of modem analog and digital computers. These devices make possible the
analysis of complex systems for which the mathematics would be much too unwieldy to
achieve by desk methods. However, the basic principles underlying the analysis of the
kinetics of tracers have their origins in classical mathematical approaches. Some of these
principles were established by Teorell21’22 in studies of the kinetics of drugs. In his first
paper, Teorell formulated a system of linear simultaneous differential equations describing
the absorption, excretion, and intercompartmental transfer rates of drugs administered by
extravascular modes, and solved these using operator notation and determinants to obtain a
second order differential equation, which in turn was solved to yield a multiexponential
expression. These results were used to predict the time course of the concentration of the
drug in blood and tissues of the body. In his second paper, Teorell presented a similar
treatment for drugs administered intravenously as a single injection, this mode being con
sidered as a limiting form of the modes previously considered, and for continuous infusion.
Some experimental data were presented which showed the validity of the equations in
predicting tissue concentrations of the drugs studied.
Solutions of one-compartment and two-compartment models are readily achieved with
elementary mathematical methods.23 These have been, and are, tremendously useful models.
One of the noteworthy early applications was reported by Zilversmit, Entenman, and Fishier24
who in effect used a two-compartment open system to determine the turnover rates of
substances in biochemical reactions. Their analysis of precursor - product relationships is
formally analogous to the parent-daughter relationship found in radioactive decay chains.
The three-compartment and four-compartment systems are the most complex that can be
solved in closed form. In general, solutions for five-compartment systems involve requiring
solutions of at least fourth degree algebraic equations, and higher-order systems require
correspondingly higher-order equations, for which there are no expressions that give exact
solutions. As will be discussed in other chapters, modem digital computer programs char
acteristically use iterative numerical methods to obtain solutions for the complex systems.
The solutions for three-compartment systems are dependent on the initial boundary con
ditions which specify the initial distribution of the label. The solution for the three-com
partment closed system with the label initially in the center compartment was published by
Gellhom, Merrell, and Rankin.25 This is complemented by the solution with the label initially
in an end compartment published by Cohn and Brues.26 A unified presentation of these two
solutions, with explicit formulas for solving for the parameters of the system (compartment
sizes and intercompartment transfer rates) in terms of observations on the tracer, is given
by Robertson, Tosteson, and Gamble,27 and a solution for the complete three-compartment
open system is given by Skinner et al.28
Sheppard and Householder29 recognized a need for a more fundamental treatment of the
mathematical principles involved in compartmental analysis. Their paper begins by showing
the mathematical analogy between interfusion (defined as the mixing of labeled and unlabeled
species of a substance) and the mixing of a solute with a solvent by diffusion. Earlier,
Sheppard30 had introduced the matrix equation method to express the relationships involved
among the constants appearing in differential equations describing transfers between com
partments. This method is again used in the second paper29 to obtain a formula for the
general solution for an n-compartment system, which is then applied to the two- and three-
compartment systems. They discuss the effect of lumping two peripheral compartments in
the three-compartment system and give expressions for handling a system with a continuous
distribution of peripheral compartments.
Berman and Schoenfeld31 recognized the difficulty of obtaining the data necessary to solve
the systems of equations involved in the higher order multicompartment systems, and began
the development of the computer program now called SAAM which is described in another
chapter of this book. This is an iterative program that is capable of producing least-squares
solutions in multicompartmented systems with incomplete data, and to define the boundaries
5
within which the physically possible solutions can lie. Although this program requires a
large computer for execution, its availability has had a major impact on the utilization of
the methods of compartmental analysis.
Hart32'39 considered a number of applications of the compartmental method to noncon
servative steady-state and nonsteady-state systems and to multicompartment systems imbed
ded in nonhomogeneous inaccessible media. This work extends compartmental analysis to
systems in which diffusion gradients are significant in determining transfer rates.
During the 1950s and 1960s, interest in multicompartmental analysis grew rapidly and
there were many contributors to the theoretical developments. Most of the approaches involve
the use of linear differential equations with constant coefficients, in effect treating the
problems of compartmental systems as applications of linear analysis.40 42 There are, how
ever, some systems that can be represented better with integral equations or integro-differ-
ential equations.39’43'46
Along with the purely theoretical developments in compartmental analysis went numerous
practical applications. Matthews47 applied the theory of Rescigno4849 for an open four-
compartment mammillary system to studies of labeled plasma proteins in humans and ani
mals. Other early applications of compartmental analysis in the determination of transfer
rates in, biological systems were reviewed by Robertson.50 A wide-ranging set of theoretical
and applied articles, some of which have already been cited, were presented at a New York
Academy of Sciences conference in 1962.51 Another collection of applications of compart
mental analysis is found among the articles presented at an Oak Ridge symposium.52 More
recently, Spetsieris and Hart53 and Spetsieris54 have analyzed the requirements for the meas
urements necessary in a complex compartmented system to obtain complete solutions. That
is, for a solution to be mathematically feasible, assuming perfect (error-free) data, there is
a certain minimal amount of data that are required. Using an eigenvector approach, they
attempt to define this minimal information requirement. It is recognized that experimental
errors can make a precise solution impossible.
Excellent summaries of the mathematical methods that have been developed in connection
with compartmental analysis appear in several textbooks.55'58 To a large extent, the math
ematical formalism is not uniquely suited to compartmental analysis. The mathematical
analogy to electrical circuits provides a basis for solving compartment problems by analog
computer methods. Other analogies are to be found in the mathematics of heat transfer and
diffusion.
A relatively recent development in the general methods used for solving linear differential
and integro-differential equations is the use of transform methods. These methods convert
differention and integration problems to ones of multiplication and division and therefore
are often simpler to use than the classical methods, but are not applicable to every situation.
In particular, an exposition of the La Place transform method is given in the book by Cheng.59
Another useful transform, particularly when convolution problems are encountered is the
Fourier transform which is treated, for example, in the book by Bracewell.60
Another recent development is the expansion of the compartmental model concept to
include the use of time-varying or stochastic variables as parameters of the system. Matis
and Tolley61 discuss the need for a stochastic approach and give a good introduction to the
mathematics of this approach. They point out that in the real world the simple deterministic
models involve some unlikely restrictions, and the introduction of modifications to allow
for all possibilities creates a system with an intractable number of variables. A relatively
simple stochastic model can often be substituted for a complex deterministic model with
probabilistic variations supplanting the need for detailed causal mechanisms. Interesting
results with this approach have been obtained by Thakur and Rescigno.62 Other recent
references pertinent to this method are Agrafiotis,63 Mehata and Selvam,64 Karmeshu and
Gupta,65 and Parthasarathy and Mayilswani.66 Stochastic models are considered in some
detail in Chapter 3 of this book.
IV. STATE OF THE ART
Although to a large extent our purpose is to present the positive aspects of compartmental
analysis, users of this method should be aware of the numerous shortcomings and pitfalls
inherent in the method. With dependence on computerized analysis for the more complex
systems, an obvious but often overlooked hazard is the unquestioning acceptance of computed
results. With real data there is usually an error range associated with the nominal fit of the
model to the data, so that multiple configurations of the model are statistically compatible
with the data. In any event, goodness of fit is not by itself an adequate test for whether the
model is correct.
Julius67 showed that multiexponential functions are relatively insensitive to variations in
the individual parameters. Three functions having two or three exponential terms each but
with quite different constants produced calculated values of the functions within 5% of each
other for a given time point.
Cocchetto et al.68 discuss the problems arising from the use of pooled data. Using simulated
data they show that averaging the data (concentration in plasma) before subjecting them to
compartmental analysis tends to underestimate the rate constants. Pooling of mono-expo
nential data can result in the introduction of spurious exponential components because of
intersubject variability. They recommend analysis of the individual data sets before averaging
if the experimental situation permits this.
Some authors are skeptical concerning the merits of compartmental analysis in general.
In particular, Zierler69 presents a critique of many aspects of compartmental analysis, in
cluding a discussion of the origins of the method, a definition of compartment, and a
discussion of the question, “ When is compartmental analysis appropriate?” His answer to
this question is, in part, “ In general, however, with the exception of clear-cut physical
phenomenon known on independent grounds to be described by first-order linear equations,
there is usually no a priori case for compartmental analysis. This means that when com
partmental analysis is used, it must be used only as an exercise in curve-fitting, in which
no real-world meaning is attributed to the coefficients and exponents or to the number of
terms; or, if it is the investigator’s aim to associate these with properties of the biological
system, there must be tests of the validity of these assignments.” The critique continues
with discussions of how to carry out the analysis and a review of common errors. The latter
include violation of assumptions (such as using compartmental analysis when there are no
real compartments), inadequate data, and errors in analysis.
Brown70 gives a concise but comprehensive survey of the definitions, methods, and
applications of compartmental analysis. The methods are discussed under several classes of
compartmental structures:
1. Nonlinear compartment models

2. Perturbation and tracer models
3. Time varying linear compartment models
4. Stochastic compartment models
He briefly reviews the current state of application of compartmental analysis in four major
fields: pharmacokinetic modeling, metabolic modeling, ecosystem modeling, and chemical
kinetic modeling. At least for the first category, he expresses an urgent need for more
empirical data as contrasted to “ black-box” modeling.
7
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of administration, Arch. Internal. Pharmacodynamie. 57, 226, 1937.
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dogs, Am. J. Physiol., 142, 407, 1944.
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compartment steady-state closed systems through the use of tracers, J. Lab. Clin. Med., 49, 497, 1957.
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model in steady state after single injection of radioactive trace, Am. J. Physiol., 196, 238, 1959.
29. Sheppard, C. W. and Householder, A. S., The mathematical basis of interpretation of tracer experiments
in closed steady-state systems, J. Applied Phys., 22, 510, 1951.
30. Sheppard, C. W., The theory of the study of transfers within a multi-compartment system using isotopic
tracers, J. Appl. Phys., 19, 70, 1948.
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17, 87, 1955.
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Math. Biophys., 20, 281, 1958.
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Math. Biophys., 27, 417, 1965.
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Math. Biophys., 27, 329, 1965.
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homogeneous inaccessible media, Bull. Math. Biophys .. 28, 261, 1966.
39. Hart, H. E., Analysis of tracer experiments. VIII. Integro-differential equation treatment of partly acces-
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41. Stephenson, J, L. and Jones, A. P., Application of linear analysis to tracer kinetics, Ann. N.Y. Acad.
Sci .. 108, 15, 1963.
42. Hearon, J, Z., Theorems on linear systems, Ann. N.Y. Acad. Sci., 108, 36, 1963.
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44. Bronson, H., The integral equation representation of reactions in compartment systems, Ann. N.Y. Acad.
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15, 269, 1953.
47. Matthews, C. M. E., The theory of tracer experiments with 131 I-Iabelled plasma proteins, Phys. Bioi.
Med .• 2, 36, 1957.
48. Rescigno, A., A contribution to the theory of tracer methods, Biochim. Biophys. Acta, 15, 340, 1954.
49. Rescigno, A., A contribution to the theory of tracer methods. II. Biochim. Biophys. Acta, 21, Ill, 1956.
50. Robertson, J, S., Theory and use of tracers in determining transfer rates in biological systems, Physiol.
Revs., 37, 133, 1957.
51. Hart, H. E. (Conference Chairman), Berger, E. Y., Berkowitz, J, M., Berman, M., Britten, R.,
Bronson, H., Brownell, G. L., Callahan, A. B., Callahan, R., Chance, B., Cohn, S. H., Gardner,
D. G., Garfinkel, D., Gregg, E. C., Hearon, J, Z., Hetenyi, G., Jr., Higgins, J., Higginbotham, W.
A., Jones, A. P., Landahl, H. D., Perl, W., Potter, D. W., Rescigno, A., Robertson, J. S., Schoenfeld,
R. L., Schwartz, L., Sheppard, C. W., Sherman, J, L., Shore, M. L., Sharney, L., Stephenson, J.
L., Sugarman, R. M., Tendler, D., Wasserman, L. R., Wrenshall, G. A., and Zierler, K. L.,
Multicompartment analysis of tracer experiments, Ann. N.Y. Acad. Sci .. 108, I, 1963.
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AEC Symposium Series No. II, U.S. Atomic Energy Commission, 1967 (Available as CONF-661010
from National Technical Information Service, Springfield, VA 22151).
9
53. Spetsieris, P. and Hart, H. E., Complete sets of experimental measurements in multicompartmental tracer
analysis, Phys. Can., 32 (Abstr.), 22.6, 1976.
54. Spetsieris, P., Complete measurement sets in multicompartment systems analysis — a reference com
partment criterion, Diss. Abstr. Int., 41, No. 1214B, 1980.
55. Sheppard, C. W., Basic Principles of the Tracer Method, John Wiley & Sons, New York, 1961.
56. Rescigno, A. and Segre, G., Drug and Tracer Kinetics, Blaisdell, Waltham, Mass., 1966.
57. Jacquez, J. A., Compartmental Analysis in Biology and Medicine, Elsevier, Amsterdam, 1972.
58. Lassen, N. A. and Perl, W Tracer Kinetic Methods in Medical Physiology, Raven Press, New York,
1979.
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60. Bracewell, R., The Fourier Transform and its Applications, McGraw-Hill, New York, 1965.
61. Matis, J. H. and Tolley, H. D., On the stochastic modeling of tracer kinetics, Fed. Proc., Fed. Am. Soc.
Exp. Biol., 39, 104, 1980.
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reversible systems, Bull. Math. Biol., 40, 237, 1978.
63. Agrafiotis, G. K., On the stochastic theory of compartments: the leaving process of the two-compartment
systems, Bull. Math. Biol., 43, 201, 1981.
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Math. Biol., 43, 549, 1981.
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Biol., 43, 503, 1981.
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Bull. Math. Biol., 43, 347, 1981.
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5, 473, 1972.
68. Cocchetto, D. M., Wargin, W. H., and Crow, J. W., Pitfalls and valid approaches to pharmacokinetic
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11
Chapter 2
BASIC PRINCIPLES
James S. Robertson
TABLE OF CONTENTS
I. Introduction............................................................................................................... 12
II. Tracers........................................................................................................................12
III. Compartments............................................................................................................ 12
IV. Volume of Dilution...................................................................................................12
V. Transfer Rates............................................................................................................ 13
VI. One-Compartment Open Steady-StateSystem.......................................................... 14
VII. Two Compartments in Series.................................................................................... 15
VIII. Two-Compartment Steady-State ClosedSystem.......................................................17
IX. Three-Compartment Steady-StateClosed System..................................................... 19

A. Series or Catenary C a se ..............................................................................20
B. Parallel or Mammillary C a se ......................................................................22
X. Complex Systems..................................................................................................... 23
XI. Curve Fitting..............................................................................................................24
XII. Cumulated A ctivity.................................................................................................. 24
References 27
I. INTRODUCTION
In this chapter some very elementary applications of tracers will be discussed, as a way
of introducing the subject of compartmental analysis. More complicated applications will
be discussed at appropriate locations in following chapters.
II. TRACERS
For the moment, a tracer will be considered to be any substance that remains detectable
by the observer when mixed with other substances.
In general, the purpose of a tracer experiment is to deduce certain properties of the system
being studied from observations of the behavior of the tracer when it is introduced into the
system. In particular, the distribution kinetics of tracers provide a basis for determining the
volumes or masses of components of the system and the rates of transfer of substances
among these components.
III. COMPARTMENTS
It is often useful to consider the body as consisting of a finite number of interconnected

subdivisions, within each of which an adequate level of homogeneity with regard to the
substance of interest can be assumed. These subdivisions of the system are called com
partments. Compartmental analysis is one of several possible methods that can be used to
express relationships between the system parameters of interest (volumes, transfer rates) and
the observable behavior of the tracer.
Ideally, a tracer introduced into a compartment is instantaneously uniformly distributed
throughout the compartment, so that the concentration or specific activity in the outflow
from the compartment is equal to that within the compartment at that instant of time. In
practice this ideal can usually only be approximated, and the deviation from the ideal becomes
a limiting factor in the interpretation of the results. If mixing requires an appreciable length
of time, the assumption of perfect mixing is valid only for processes having time constants
that are long relative to the mixing time.
For some purposes it is satisfactory, from the standpoint of analyzing the data, to regard
the body as consisting of only a very few compartments.
IV. VOLUME OF DILUTION
The volume of a single compartment can be determined by an application of the dilution

principle, which is expressed in Equation 1
(1)
where Q is the quantity of the substance used as a tracer, V is the volume within which Q
is distributed, and C is the concentration of Q in V.
Solving Equation 1 for V gives Equation 2
( 2)
Experimentally, V is determined by introducing a known quantity, Q, of some substance

such as a dye into the volume of interest, measuring the concentration, and calculating V
by using Equation 2. For example if 1 g of the tracer is put into a beaker of water, and
after dissolving and mixing the concentration is found to be 1 mg/m€, the volume of the
water is 1 €.
13
It is apparent that if mixing is incomplete the measured concentration in the above example
could be either too high or too low, depending on the sampling point, and the resulting
estimate of the volume would have a corresponding error.
Of course in a beaker it is easy to obtain good mixing, but if the volume of interest is in
the body, for example the blood plasma volume, the application of the dilution principle is
somewhat less straightforward. Mixing in the blood is attained as the blood circulates through
the various organs and returns to the central blood pool. Each round trip of the blood takes
of the order of 10 to 20 sec. In normal subjects, mixing in the blood is essentially complete
in 20 min or less after an intravenous injection of the tracer, but under some pathological
conditions it can take longer.
In the above example, it is assumed that the tracer does not leave the circulation. In
practice this assumption is often not valid. However, if the rate of leakage out of the
circulation is relatively slow, a correction can be introduced by determining the apparent
volume of dilution in several serial samples taken at intervals of time and extrapolating back
to time zero.
The dilution principle is applicable to masses as well as to volumes. In particular, the
concentration of a radioactive isotope relative to the total mass of the labeled element is
called the specific activity. For example, if 100 |xCi of the radioactive species is mixed with
a quantity of that element and the specific activity is found to be 1 |xCi/g, the total mass is
100 g. This principle has been used to determine the exchangeable masses of electrolytes
in the body from measurements of the specific activity in blood samples.
V. TRANSFER RATES
The rates of flow of substances between compartments are called transfer rates. Other
terms are also used in certain situations. In particular, when the transfer rates in opposite
directions between two compartments are equal they are called the exchange rate. When the
rate of flow of a given substance into a compartment equals its rate of flow out of the
compartment, so that the quantity present in the compartment remains constant, the com
partment is said to be in a steady-state and the flow rates in and out are called the turnover
rate. The ratio of the turnover rate to the quantity present in a compartment is defined as
the turnover rate constant.
The steady-state is of special interest. Although the quantity present in a compartment is
constant, the identity of this amount is continuously changing when it is described in terms
of its atomic or molecular content. Before tracers became available it was difficult or
impossible to study turnover rates in steady-state systems.
An ideal tracer would be identical with its unlabeled counterpart, the tracee, except for
being detectable by the observer. This ideal is most closely attained with isotopic tracers
although even with these there is a slight difference in the masses of any two isotopes. For
most physiological processes this slight difference produces a negligible effect in the kinetics,
but in some biochemical reactions what is called the isotope effect can be significant.
For the development of the mathematical theory of compartmental analysis, ideal tracers
are assumed. In symbols, the relationship between an ideal tracer and the tracee is expressed
in Equation 3
( 3)
where k is the transfer rate constant, R is the transfer rate of the tracee, Q is the quantity
of the tracee in the compartment, r is the transfer rate of the tracer, and q is the quantity
of the tracer in the compartment. In words, this states that for an ideal tracer the transfer
rate constant (or turnover rate constant) for the tracer is equal to that of the tracee. This
FIGURE 1. Diagram of one-compart

ment open system. The arrows indicate
inflow and outflow of the compartment.
important relationship makes it possible to deduce the transfer rates for the unlabeled material
in compartmented systems from observations made on the behavior of tracers in these
systems.
VI. ONE-COMPARTMENT OPEN STEADY-STATE SYSTEM
To illustrate the method of calculating transfer rates, we begin with a one-compartment

open system in the steady-state (Figure 1). It is first assumed that the tracer is instantaneously
inserted into the compartment at time zero, and that at all subsequent times the tracer and
tracee are mixed homogeneously. We also tentatively assume that the inflow to the com
partment contains no tracer. Under these conditions, the tracer will be “ washed out” , that
is, will disappear from the compartment, at a rate proportional to the amount present at any
time. The mathematical description of this process is formally analogous to that for radio
active decay.
That is
(4 )
from which:
(5 )
where q(t) is the amount of tracer present at time t, k is the transfer rate constant, dq(t)/dt
is the rate of change of q(t), and e is the base of the natural logarithms (e = 2.71828...).
Equation 5 provides the basis for determining k from experimentally obtained values of
q(t). A semilogarithmic plot of several values of q(t) vs. time can be fitted by a straight
line. The slope of this line is usually most conveniently characterized by its half-time,
Tl/2. The exponential constant, which in this case is also the transfer rate constant, k, is
then obtained by use of the relationship
(6)
where ln2 is the natural logarithm of 2 (ln2 = 0.69315...).

To calculate the flow rate, R, it is also necessary to know the amount of the tracee, Q,
in the compartment. One way to determine Q is from the initial concentration, C, of q(0)
relative to Q, by an application of the dilution principle:
(7 )
Then:
(8)
provides the final result.

15
Alternatively, the one-compartment open steady-state system can be studied by introducing

the tracer via the inflow. In this case it is assumed that at time zero there is no tracer in the
compartment but that starting at time zero the tracer enters the compartment according to
some function of time, f(t). The differential equation describing this is
(9)
The solution of Equation 9 depends on the explicit form of f(t). A particularly simple solution
is obtained if f(t) represents a constant rate of inflow of the tracer:
( 10 )
giving:
(11)
A plot of q(t) has a value of zero at time zero and approaches r/k as a limiting value as time
extends to infinity. It should also be apparent that the final concentration in the compartment
approaches that in the inflow.
Again, k can be determined by use of a semilogarithmic plot. However, instead of q(t),
the value to be plotted is the limiting value r/k minus q(t):
( 12)
This serves to determine k and r. The calculation of the flow rate R requires either that the
concentration of the tracer relative to that of the tracee in the inflow be known or that Q is
determined independently.
Another important form of the input function for an open compartment is
(13)
where C and \ are constants. Since the outflow from an initially labeled compartment has
this form, it is convenient to treat this case by considering two compartments in series.
VII. TWO COMPARTMENTS IN SERIES
It will be assumed that the outflow from compartment 1 is the inflow for compartment 2
(Figure 2). The mathematics describing this case is analogous to that for the production and
decay of radioactive daughter products. The Bateman1 equations are applicable to chains of
such relationships. The parameters of the two compartments will be distinguished by the
subscripts 1 and 2. For k x ^ k2:
(14)
giving:
( 15)
It is also of interest to consider the corresponding equations for specific activity, x, instead
of the quantity of the tracer. These variables are related by the formula:
FIGURE 2. Diagram of two-compartment system in series without feedback, and semil-

ogarithmic plot of theoretical curves for specific activity in the two compartments, assuming
that the activity is initially in compartment 1 and that there is no activity in its inflow. The
straight line represents the specific activity in compartment 1. The other three curves represent
the specific activity in compartment 2, depending upon the indicated ratio of the sizes of the
compartments. The middle curve, with Q2 = Q, is described by Equation 23, the other two
by Equation 19.
(16)
Since when the two flow rates are equal
(17)
The specific activity equations are
(18)
and
(19)
In either Equation 15 or Equation 19 the variable starts at time zero with a value of zero
goes through a maximum at time f , and then approaches zero as time extends to infinity
The time f corresponding to the maximum value is given by the formula:
(20)
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place. I was convinced that the greatest calamity that ever befell the
benighted nations of the ancient world was in their having passed
away without a knowledge of the actual existence of Duluth; that
their fabled Atlantis, never seen save by the hallowed vision of the
inspired poesy, was, in fact, but another name for Duluth; that the
golden orchard of the Hesperides, was but a poetical synonym for the
beer-gardens in the vicinity of Duluth. I was certain that Herodotus
had died a miserable death, because in all his travels and with all his
geographical research he had never heard of Duluth. I knew that if
the immortal spirit of Homer could look down from another heaven
than that created by his own celestial genius upon the long lines of
pilgrims from every nation of the earth to the gushing fountain of
poesy opened by the touch of his magic wand, if he could be
permitted to behold the vast assemblage of grand and glorious
productions of the lyric art called into being by his own inspired
strains, he would weep tears of bitter anguish that, instead of
lavishing all the stores of his mighty genius upon the fall of Illion, it
had not been his more blessed lot to crystalize in deathless song the
rising glories of Duluth. Yes, sir, had it not been for this map, kindly
furnished me by the legislature of Minnesota, I might have gone
down to my obscure and humble grave in an agony of despair,
because I could nowhere find Duluth. Had such been my melancholy
fate, I have no doubt that with the last feeble pulsation of my
breaking heart, with the last faint exhalation of my fleeting breath, I
should have whispered, “Where is Duluth?”
But, thanks to the beneficence of that band of ministering angels
who have their bright abodes in the far-off capital of Minnesota, just
as the agony of my anxiety was about to culminate in the frenzy of
despair, this blessed map was placed in my hands; and as I unfolded
it a resplendent scene of ineffable glory opened before me, such as I
imagined burst upon the enraptured vision of the wandering peri
through the opening gates of Paradise. There, there, for the first
time, my enchanted eye rested upon the ravishing word, “Duluth!”
This map, sir, is intended, as it appears from its title, to illustrate the
position of Duluth in the United States; but if gentlemen will
examine it, I think they will concur with me in the opinion, that it is
far too modest in its pretensions. It not only illustrates the position
of Duluth in the United States, but exhibits its relations with all
created things. It even goes further than this. It hits the shadowy vale
of futurity, and affords us a view of the golden prospects of Duluth
far along the dim vista of ages yet to come.
If gentlemen will examine it, they will find Duluth not only in the
center of the map, but represented in the center of a series of
concentric circles one hundred miles apart, and some of them as
much as four thousand miles in diameter, embracing alike, in their
tremendous sweep the fragrant savannas of the sunlit South and the
eternal solitudes of snow that mantle the ice-bound North. How
these circles were produced is perhaps one of those primordial
mysteries that the most skilled paleologist will never be able to
explain. But the fact is, sir, Duluth is pre-eminently a central point,
for I am told by gentlemen who have been so reckless of their own
personal safety as to venture away into those awful regions where
Duluth is supposed to be, that it is so exactly in the center of the
visible universe that the sky comes down at precisely the same
distance all around it.
I find, by reference to this map, that Duluth is situated somewhere
near the western end of Lake Superior, but as there is no dot or other
mark indicating its exact location, I am unable to say whether it is
actually confined to any particular spot, or whether “it is just lying
around there loose.” I really cannot tell whether it is one of those
ethereal creations of intellectual frostwork, more intangible than the
rose-tinted clouds of a summer sunset; one of those airy exhalations
of the speculator’s brain which, I am told, are very flitting in the form
of towns and cities along those lines of railroad, built with
government subsidies, luring the unwary settler as the mirage of the
desert lures the famishing traveler on, and ever on, until it fades
away in the darkening horizon; or whether it is a real, bona fide,
substantial city, all “staked off,” with the lots marked with their
owners’ names, like that proud commercial metropolis recently
discovered on the desirable shores of San Domingo. But, however
that may be, I am satisfied Duluth is there, or thereabouts, for I see it
stated here on the map that it is exactly thirty-nine hundred and
ninety miles from Liverpool, though I have no doubt, for the sake of
convenience, it will be moved back ten miles, so as to make the
distance an even four thousand.
Then, sir, there is the climate of Duluth, unquestionably the most
salubrious and delightful to be found anywhere on the Lord’s earth.
Now, I have always been under the impression, as I presume other
gentlemen have, that in the region around Lake Superior it was cold
enough for at least nine months in the year to freeze the smoke-stack
off a locomotive. But I see it represented on this map that Duluth is
situated exactly half way between the latitudes of Paris and Venice,
so that gentlemen who have inhaled the exhilarating air of the one,
or basked in the golden sunlight of the other, may see at a glance that
Duluth must be the place of untold delight, a terrestrial paradise,
fanned by the balmy zephyrs of an eternal spring, clothed in the
gorgeous sheen of ever blooming flowers, and vocal with the silvery
melody of nature’s choicest songsters. In fact sir, since I have seen
this map, I have no doubt that Byron was vainly endeavoring to
convey some faint conception of the delicious charms of Duluth
when his poetic soul gushed forth, in the rippling strains of that
beautiful rhapsody—
“Know ye the land of the cedar and the vine,
Whence the flowers ever blossom, the beams ever shine;
Where the light wings of Zephyr, oppressed with perfume,
Wax faint o’er the gardens of Gul in her bloom;
Where the citron and olive are fairest of fruit,
And the voice of the nightingale never is mute;
Where the tints of the earth and the hues of the sky,
In color though varied, in beauty may vie?”
As to the commercial resources of Duluth, sir, they are simply

illimitable and inexhaustible, as is shown by this map. I see it stated
here that there is a vast scope of territory, embracing an area of over
two millions of square miles, rich in every element of material wealth
and commercial prosperity, all tributary to Duluth. Look at it, sir,
(pointing to the map.) Here are inexhaustible mines of gold,
immeasurable veins of silver, impenetrable depths of boundless
forest, vast coal measures, wide extended plains of richest pasturage
—all, all embraced in this vast territory—which must, in the very
nature of things, empty the untold treasures of its commerce into the
lap of Duluth. Look at it, sir, (pointing to the map); do not you see
from these broad, brown lines drawn around this immense territory,
that the enterprising inhabitants of Duluth intend some day to
inclose it all in one vast corral, so that its commerce will be bound to
go there whether it would or not? And here, sir, (still pointing to the
map), I find within a convenient distance the Piegan Indians, which,
of all the many accessories to the glory of Duluth, I consider by far
the most inestimable. For, sir, I have been told that when the small-
pox breaks out among the women and children of the famous tribe,
as it sometimes does, they afford the finest subjects in the world for
the strategical experiments of any enterprising military hero who
desires to improve himself in the noble art of war, especially for any
valiant lieutenant-general whose
“Trenchant blade, Toledo trusty,
For want of fighting has grown rusty,
And eats into itself for lack,
Of somebody to hew and hack.”
Sir, the great conflict now raging in the Old World has presented a
phenomenon in military science unprecedented in the annals of
mankind, a phenomenon that has reversed all the traditions of the
past as it has disappointed all the expectations of the present. A great
and warlike people, renowned alike for their skill and valor, have
been swept away before the triumphant advance of an inferior foe,
like autumn stubble before a hurricane of fire. For aught I know the
next flash of electric fire that simmers along the ocean cable may tell
us that Paris, with every fibre quivering with the agony of impotent
despair, writhes beneath the conquering heel of her loathed invader.
Ere another moon shall wax and wane, the brightest star in the
galaxy of nations may fall from the zenith of her glory never to rise
again. Ere the modest violets of early spring shall ope their
beauteous eyes, the genius of civilization may chant the wailing
requiem of the proudest nationality the world has ever seen, as she
scatters her withered and tear-moistened lilies o’er the bloody tomb
of butchered France. But, sir, I wish to ask if you honestly and
candidly believe that the Dutch would have overrun the French in
that kind of style if General Sheridan had not gone over there, and
told King William and Von Moltke how he had managed to whip the
Piegan Indians.
And here, sir, recurring to this map, I find in the immediate
vicinity of the Piegans “vast herds of buffalo” and “immense fields of
rich wheat lands.” [Here the hammer fell.]
[Many cries: “Go on!” “go on!”]
The Speaker—Is there any objection to the gentleman from
Kentucky continuing his remarks? The chair hears none. The
gentleman will proceed.
Mr. Knott—I was remarking, sir, upon these vast “wheat fields”
represented on this map in the immediate neighborhood of the
buffaloes and Piegans, and was about to say that the idea of there
being these immense wheat fields in the very heart of a wilderness,
hundreds and hundreds of miles beyond the utmost verge of
civilization, may appear to some gentlemen as rather incongruous, as
rather too great a strain on the “blankets” of veracity. But to my mind
there is no difficulty in the matter whatever. The phenomenon is very
easily accounted for. It is evident, sir, that the Piegans sowed that
wheat there and ploughed it in with buffalo bulls. Now, sir, this
fortunate combination of buffaloes and Piegans, considering their
relative positions to each other and to Duluth, as they are arranged
on this map, satisfies me that Duluth is destined to be the best
market of the world. Here, you will observe, (pointing to the map),
are the buffaloes, directly between the Piegans and Duluth; and here,
right on the road to Duluth, are the Creeks. Now, sir, when the
buffaloes are sufficiently fat from grazing on those immense wheat
fields, you see it will be the easiest thing in the world for the Piegans
to drive them on down, stay all night with their friends, the Creeks,
and go into Duluth in the morning. I think I see them, now, sir, a vast
herd of buffaloes, with their heads down, their eyes glaring, their
nostrils dilated, their tongues out, and their tails curled over their
backs, tearing along toward Duluth, with about a thousand Piegans
on their grass-bellied ponies, yelling at their heels! On they come!
And as they sweep past the Creeks, they join in the chase, and away
they all go, yelling, bellowing, ripping and tearing along, amid clouds
of dust, until the last buffalo is safely penned in the stock-yards at
Duluth.
Sir, I might stand here for hours and hours, and expatiate with
rapture upon the gorgeous prospects of Duluth, as depicted upon this
map. But human life is too short, and the time of this house far too
valuable to allow me to linger longer upon this delightful theme. I
think every gentleman upon this floor is as well satisfied as I am that
Duluth is destined to become the commercial metropolis of the
universe and that this road should be built at once. I am fully
persuaded that no patriotic representative of the American people,
who has a proper appreciation of the associated glories of Duluth and
the St. Croix, will hesitate a moment that every able-bodied female in
the land, between the ages of eighteen and forty-five, who is in favor
of “woman’s rights,” should be drafted and set to work upon this
great work without delay. Nevertheless, sir, it grieves my very soul to
be compelled to say that I cannot vote for the grant of lands provided
for in this bill.
Ah, sir, you can have no conception of the poignancy of my
anguish that I am deprived of that blessed privilege! There are two
insuperable obstacles in the way. In the first place my constituents,
for whom I am acting here, have no more interest in this road than
they have in the great question of culinary taste now, perhaps,
agitating the public mind of Dominica, as to whether the illustrious
commissioners, who recently left this capital for that free and
enlightened republic, would be better fricasseed, boiled, or roasted,
and, in the second place, these lands, which I am asked to give away,
alas, are not mine to bestow! My relation to them is simply that of
trustee to an express trust. And shall I ever betray that trust? Never,
sir! Rather perish Duluth! Perish the paragon of cities! Rather let the
freezing cyclones of the bleak northwest bury it forever beneath the
eddying sands of the raging St. Croix.
Henry Carey’s Speech on the Rates of
Interest.
In the Pennsylvania Constitutional Convention, 1873.

In the Constitutional Convention, in Committee of the Whole on
the article reported from the Committee on Agriculture, Mining,
Manufactures, and Commerce, the first section being as follows:—“In
the absence of special contracts the legal rate of interest and discount
shall be seven per centum per annum, but special contracts for
higher or lower rates shall be lawful. All national and other banks of
issue shall be restricted to the rate of seven per centum per annum.”
Mr. H. C. Carey made an address in favor of striking out the section.
The following is an abstract of his remarks:—
Precisely a century and a half since, in 1723, the General Assembly
of Pennsylvania reduced the legal charge for the use of money from
eight to six per cent. per annum. This was a great step in the
direction of civilization, proving, as it did, that the labor of the
present was obtaining increased power over accumulations of the
past, the laborer approaching toward equality with the capitalist. At
that point it has since remained, with, however, some change in the
penalties which had been then prescribed for violations of the law.
Throughout the recent war the financial policy of the National
Government so greatly favored the money-borrower and the laborer
as to have afforded reason for believing that the actual rate of
interest was about to fall permanently below the legal one, with the
effect of speedily causing usury laws to fall into entire disuse. Since
its close, however, under a mistaken idea that such was the real road
to resumption, all the Treasury operation of favoring the money-
lender; the result exhibiting itself in the facts that combinations are
being everywhere formed for raising the price of money; that the
long loans of the past are being daily more and more superseded by
the call loans of the present; that manufacturer and merchant are
more and more fleeced by Shylocks who would gladly take “the
pound of flesh nearest the heart” from all over whom they are
enabled to obtain control.
Anxious for the perpetuation of this unhappy state of things, these
latter now invite their victims to give their aid towards leveling the
barriers by which they themselves are even yet to a considerable
extent protected, assuring them that further grant of power will be
followed by greater moderation in its exercise. Misled thereby,
money borrowers, traders, and manufacturers are seen uniting, year
after year with their common enemy in the effort at obtaining a
repeal of the laws in regard to money, under which the State has so
greatly prospered. Happily our working men, farmers, mechanics,
and laborers fail to see that advantage is likely to accrue to them
from a change whose obvious tendency is that of increasing the
power of the few who have money to lend over the many who need to
borrow; and hence it is that their Representatives at Harrisburg have
so steadily closed their ears against the siren song by which it is
sought to lead their constituents to give their aid to the work of their
own destruction.
Under these circumstances is it that we are now asked to give place
in the organic law to a provision by means of which this deplorable
system is to be made permanent, the Legislature being thereby
prohibited, be the necessity what it may, from placing any restraint
upon the few who now control the supply of the most important of all
the machinery of commerce, as against the many whose existence,
and that of their wives and children, is dependent upon the obtaining
the use thereof on such terms as shall not from year to year cause
them to become more and more mere tools in the hands of the
already rich. This being the first time in the world’s history that any
such idea has been suggested, it may be well, before determining on
its adoption, to study what has been elsewhere done in this direction,
and what has been the result.
Mr. Carey then proceeded to quote at great length from recent and
able writers the results that had followed in England from the
adoption of the proposition now before the convention. These may
be summed up as the charging of enormous rates of interest, the
London joint stock banks making dividends among their
stockholders to the extent of twenty, thirty, and almost forty per
cent., the whole of which has ultimately to be taken from the wages
of labor employed in manufactures, or in agriculture. At no time, said
Mr. Carey, in Britain’s history, have pauperism and usury traveled so
closely hand in hand together; the rich growing rich to an extent that,
till now, would have been regarded as fabulous, and the
wretchedness of the poor having grown in like proportion.
After discussing the effects of the repeal of the usury laws in some
of the American States, Mr. Carey continued:—
“We may be told, however, that at times money is abundant, and
that even so late as last summer it was difficult to obtain legal
interest. Such certainly was the case with those who desired to put it
out on call; but at that very moment those who needed to obtain the
use of money for long periods were being taxed, even on securities of
unexceptionable character, at double, or more than double, the legal
rates. The whole tendency of the existing system is in the direction of
annihilating the disposition for making those permanent loans of
money by means of which the people of other countries are enabled
to carry into effect operations tending to secure to themselves control
of the world’s commerce. Under that system there is, and there can
be, none of that stability in the price of money required for carrying
out such operations.
Leaving out of view the recent great combination for the
maintenance and perpetuation of slavery, there has been none so
powerful, none so dangerous as that which now exists among those
who, having obtained a complete control of the money power, are
laboring to obtain legal recognition of the right of capital to perfect
freedom as regards all the measures to which it may be pleased to
resort for the purpose of obtaining more perfect control over labor.
Already several of the States have to some extent yielded to the
pressure that has been brought to bear upon them. Chief among
these is Massachusetts, the usury laws having there been totally
repealed, and with the effect, says a distinguished citizen of that
State, that “all the savings institutions of the city at once raised the
rate from six to seven per cent.; those out of the city to seven and a
half and eight per cent. and there was no rate too high for the greedy.
The consequence,” as he continues, “has been disastrous to industrial
pursuits. Of farming towns in my county, more than one quarter
have diminished in population.” Rates per day have now to a great
extent, as I am assured, superseded the old rates per month or year;
two cents per day, or $7.30 per annum, having become the charge for
securities of the highest order. What, under such circumstances,
must be the rate for paper of those who, sound and solvent as they
may be, cannot furnish such security, may readily be imagined. Let
the monopoly system be maintained and the rate, even at its
headquarters, New England, will attain a far higher point than any
that has yet been reached; this, too, in despite of the fact that her
people had so promptly secured to themselves a third of the whole
circulation allowed to the 40,000,000 of the population of the Union
scattered throughout almost a continent. How greatly they value the
power that has been thus obtained is proved by the fact that to every
effort at inducing them to surrender, for advantage of the West or
South, any portion thereof, has met with resistance so determined
that nothing has been yet accomplished.
Abandonment of our present policy is strongly urged upon us for
the reason that mortgages bear in New York a higher rate of interest.
A Pennsylvanian in any of the northern counties has, as we are told,
but to cross the line to obtain the best security at seven per cent.
Why, however, is it that his neighbors find themselves compelled to
go abroad when desirous of obtaining money on such security? The
answer to this question is found in the fact that the taxation of
mortgages is there so great as to absorb from half to two-thirds of the
interest promised to be paid.
Again, we are told that Ohio legalizes “special contracts” up to
eight per cent. and, that if we would prevent the efflux of capital we
must follow in the same direction. Is there, however, in the exhibit
now made by that State, anything to warrant us in so doing? Like
Pennsylvania, she has abundant coal and ore. She has two large
cities, the one fronting on the Ohio, and the other on the lakes, giving
her more natural facilities for maintaining commerce than are
possessed by Pennsylvania; and yet, while the addition to her
population in the last decade was but 306,000, that of Pennsylvania
was 615,000. In that time she added 900 to her railroad mileage,
Pennsylvania meantime adding 2,500. While her capital engaged in
manufactures rose from 57 to 141 millions, that of Pennsylvania grew
from 109 to 406, the mere increase of the one being more than fifty
per cent. in excess of the total of the other. May we find in these
figures any evidence that capital has been attracted to Ohio by a
higher rate of interest, or repelled from our State by a lower one?
Assuredly not!
What in this direction is proposed to be done among ourselves is
shown in the section now presented for our consideration. By it the
legal rate in the absence of “special contracts” is to be raised to seven
per cent., such “contracts,” however ruinous in their character, and
whatsoever the nature of the security, are to be legalized; the only
exception to these sweeping changes being that national banks,
issuing circulating notes are to be limited to seven per cent. Shylock
asked only “the due and forfeit of his bond.” Let this section be
adopted, let him then present himself in any of our courts, can its
judge do other than decide that “the law allows it and the court
awards it,” monstrous as may have been the usury, and discreditable
as may have been the arts by means of which the unfortunate debtor
may have been entrapped? Assuredly not. Shylock, happily, was
outwitted, the bond having made no provision for taking even “one
jot of blood.” Here, the unfortunate debtor, forced by his flinty-
hearted creditor into a “special contract” utterly ruinous, may, in
view of the destruction of all hope for the future of his wife and
children, shed almost tears of blood, but they will be of no avail; yet
do we claim to live under a system whose foundation-stone exhibits
itself in the great precept from which we learn that duty requires of
us to do to others as we would that others should do unto ourselves.
By the English law the little landowner, the mechanic who owns
the house in which he lives, is protected against his wealthy
mortgagee. Here, on the contrary, the farmer, suffering under the
effects of blight or drought, and thus deprived of power to meet with
punctuality the demands of his mortgagee, is to have no protection
whatsoever. So, too, with the poor mechanic suffering temporarily by
reason of accidental incapacity for work, and, with the sheriff full in
view before him, compelled to enter into a “special contract”
doubling if not trebling, the previous rate of interest. Infamous as
may be its extortion the court may not deny the aid required for its
enforcement.
The amount now loaned on mortgage security in this State at six
per cent. is certainly not less than $400,000,000, and probably
extends to $500,000,000, a large portion of which is liable to be
called for at any moment. Let this section be adopted and we shall
almost at once witness a combined movement among mortgagees for
raising the rate of interest. Notices demanding payment will fly thick
as hail throughout the State, every holder of such security knowing
well that the greater the alarm that can be produced and the more
utter the impossibility of obtaining other moneys the larger may be
made the future rate of interest. The unfortunate mortgagor must
then accept the terms, hard as they may be, dictated to him, be they
8, 10, 12, or 20 per cent. Such, as I am assured has been the course of
things in Connecticut, where distress the most severe has been
produced by a recent abandonment by the State of the policy under
which it has in the past so greatly prospered. At this moment her
savings’ banks are engaged in compelling mortgagers to accept eight
per cent. as the present rate. How long it will be before they will carry
it up to ten or twelve, or what will be the effect, remains to be seen.
Already among ourselves the effects of the sad blunders of our great
financiers exhibit themselves in the very unpleasant fact that sheriffs’
sales are six times more numerous than they were in the period from
1861 to 1867, when the country was so severely suffering under the
waste of property, labor, and life, which had but then occurred. Let
this section be adopted, giving perfect freedom to the Shylocks of the
day, and the next half dozen years will witness the transfer, under the
sheriff’s hammer, of the larger portion of the real property of both
the city and the State. Of all the devices yet invented for the
subjugation of labor by capital, there is none that can claim to be
entitled to take precedence of that which has been now proposed for
our consideration.
Rightly styled the Keystone of the Union, one duty yet remains to
her to be performed, to wit: that of bringing about equality in the
distribution of power over that machinery for whose use men pay
interest, which is known as money. New England, being rich and
having her people concentrated within very narrow limits, has been
allowed to absorb a portion of that power fully equal to her needs,
while this State, richer still, has been so “cabined, cribbed, confined,”
that her mine and furnace operators find it difficult to obtain that
circulating medium by whose aid alone can they distribute among
their workmen their shares of the things produced.—New York,
already rich, has been allowed to absorb a fourth of the permitted
circulation, to the almost entire exclusion of the States south of
Pennsylvania and west of the Mississippi; and hence it is that her
people are enabled to levy upon those of all these latter such
enormous taxes. To the work of correcting this enormous evil
Pennsylvania should now address herself. Instead of following in the
wake of New Jersey and Connecticut, thereby giving to the monopoly
an increase of strength, let her place herself side by side with the
suffering States of the West, the South, and the Southwest,
demanding that what has been made free to New York and New
England shall be made equally free to her and them. Let her do this,
and the remedy will be secured, with such increase in the general
power for developing the wonderful resources of the Union as will
speedily make of it an iron and cloth exporting State, with such
power for retaining and controlling the precious metals as will place
it on a surer footing in that respect than any of the powers of the
Eastern world. The more rapid the societary circulation, and the
greater the facility of making exchanges from hand to hand, and
from place to place, the greater is the tendency toward reduction in
the rate of interest, toward equality in the condition of laborer and
employer, and toward growth and power to command the services of
all the metals, gold and silver included.
It will be said, however, that adoption of such measures as have
been indicated would tend to produce a general rise of prices; or, in
the words of our self-styled economists, would cause “inflation.” The
vulgar error here involved was examined some thirty years since by
an eminent British economist, and with a thoroughness never before
exhibited in reference to any other economic question whatsoever,
the result exhibiting itself in the following brief words of a highly
distinguished American one, published some twelve or fifteen years
since, to wit:
“Among the innumerable influences which go to determine the general rate of
prices, the quantity of money, or currency, is one of the least effective.”
Since then we have had a great war, in the course of which there
have been numerous and extensive changes in the price of
commodities, every one of which is clearly traceable to causes widely
different from those to which they so generally are attributed. Be
that, however, as it may, the question now before us is one of right
and justice, and not of mere expediency. North and east of
Pennsylvania eight millions of people have been allowed a greater
share of the most important of all powers, the money one, than has
been allotted to the thirty-two millions south and west of New York,
and have thus been granted a power of taxation that should be no
longer tolerated. The basis of our whole system is to be found in
equality before the law, each and every man, each and every State,
being entitled to exercise the same powers that are permitted to our
people, or other States. If the Union is to be maintained, it can be so
on no terms other than those of recognition of the existence of the
equality that has here been indicated. To the work of compelling that
recognition Pennsylvania should give herself, inscribing on her
shield the brief words fiat justitia, ruat cœlum—let justice be done
though the heavens fall!
Speech of Gen. Simon Cameron.
On the benefits derived by Pennsylvania from the Policy of Internal

Improvements.
Any one will see, who will take the trouble to read the debates on
the location of the National Capital, that the decision of that question
seems to have been made solely with reference to a connection of the
East with the then great wilderness of the West. All the sagacious
men then in public life looked to the time when the West, with its
wonderful productive soil brought under subjection by industry,
would exercise a controlling influence on the destiny of the country.
Columbia, in the State of Pennsylvania, was at one time within one
vote of becoming the site of the Capital; and Germantown, near, and
now a part of, Philadelphia, was actually decided on as the proper
location by a majority of one. The first of these was favored because
it was believed to be a favorable point from which to begin a slack
water route to the west. Germantown near the Schuylkill, was chosen
for the same reason. All looked forward to a system of canals which
would accomplish this desirable object, and experience has fully
demonstrated their wisdom in that great design. About 1790, General
Washington and the great financier Robert Morris, traveled on
horseback from Philadelphia to the Susquehanna river, with a view
of deciding whether a canal could be built over that route.
Shortly after this, some gentlemen near Philadelphia actually
began building a canal to the west, did some work on its eastern end,
built one or two locks on the dividing ridge near Lebanon, and for
want of sufficient funds and knowledge of the subject the work was
stopped. The money expended on the enterprise was lost.
But the progressive men of the country, keeping their minds on the
subject, continued to agitate the popular mind on it until 1820, when
the Legislature of Pennsylvania chartered the Union Canal Company,
and appropriated one million dollars to aid its construction. In a few
years the canal was completed between the Schuylkill and
Susquehanna. Although very small, this improvement did a great
deal of good. And the most remarkable thing about it was its
unpopularity with the masses. Not only the members of General
Assembly who passed the bill, but Governor Heister, who signed the
act of incorporation, were driven from office at the first opportunity
legally presented for testing public opinion, and the party to which
they belonged went into a minority. I remember well what a mighty
sum a million dollars seemed to be; and the political revolution
caused by this appropriation showed me that the idea of its vastness
was not confined by any means to myself.
Our system of canals was completed, and the benefits derived from
them were incalculable. When they were commenced our State was
poor. Industry languished. The interchange of her products was
difficult. Population was sparse. Intelligence was not generally
diffused. Manufactures struggled weakly along. Work was not
plentiful. Wages were low. When they were finished the busy hum of
industry was heard on every hand. Our population had grown until
we numbered millions. Our iron ore beds were yielding their
precious hoards for human use. Coal mines, unknown or useless
until means were provided for transporting their wealth to market,
now sent millions of tons in every direction. Progress in every walk of
advanced civilization was realized, and we were on the high road to
permanent prosperity. But in the meantime a new and better means
of communication had been discovered, and the building of railroads
quickly reduced the value of canals, and the works we had completed
at so much cost, and with such infinite labor, were suddenly
superseded. We lost nearly all the money they had cost us, but this
investment was wisely made. The return to our State was many times
greater than the outlay.
Like all great projects intended for the public good, that of Internal
Improvement progressed. In 1823, the New York canal—which had
been pushed through against the prejudiced opposition of the
people, by the genius of De Witt Clinton—was opened. Its success
caused a revolution in the public mind all over the country. The
effect was so marked in the State, that in 1825 a convention was
called to consider the subject. Every county in the State was
represented, I believe. That body pronounced in favor of a grand
system of public works, which should not only connect the East and
West, but also the waters of the Susquehanna with the great lakes,
the West and the Northwest. Appropriations were recommended to
the amount of three millions of dollars, and in 1826, I think the work
began. This sum seemed to be enormous, and the estimates of the
engineers reached a total of six millions of dollars. Meeting an ardent
friend of the system one day, he declared that a sum of that
magnitude could never be expended on these works. I ventured to
reply, with great deference to his age and experience, that I thought
it would be insufficient, and before they were completed I would not
be surprised if ten millions would be found necessary. Looking at me
steadily for a few moments, he closed the conversation by
exclaiming, “Young man, you are a d——d fool!” I was thus left in full
possession of his opinion of me. But after we had spent
$41,698,594.74 in the construction of these works, I found my
estimate of his judgment was singularly in harmony with my opinion
of his politeness. His candor I never doubted.
In the convention of 1825, there were two gentlemen who voted for
railways instead of canals. One was professor Vethake of Dickinson
College, Carlisle; and the other was Jacob Alter, a man of very little
education, but of strong understanding. The professor was looked
upon as a dreamer, and was supposed to have led his colleague
astray in his vagaries. But they both lived to see railroads extended
over the whole world. As a part of our system of public works, we
built a railroad from the Delaware to the Susquehanna, from
Philadelphia to Columbia, and one from the eastern base of the
Allegheny mountains to their western base. They were originally
intended to be used with horse power. In the meantime the railroad
system had been commenced, and the Pennsylvania Railroad, under
the charge of a man of extraordinary ability, John Edgar Thompson,
was rapidly pushed to completion. Another great railway, the
Philadelphia and Reading, was built to carry anthracite coal from the
Schuylkill mines to the market. A railroad was built each side of the
Lehigh river, that another part of our coal territory might find a
market in New York. Another was built from the north branch of the
Susquehanna, connecting with the New York roads, and leading to
the northern coal field. And yet another was built along the
Susquehanna, through the southern coal basin, to the city of
Baltimore. The total cost of these roads, independent of the
Pennsylvania railroad, was $95,250,410.10, as shown by official
reports. Their earnings last year are officially given at
$24,753,065.32. Each of these was forced to contend with difficulty
and prejudice. All were unpopular, and all were looked upon with
suspicion until they actually forced their usefulness on the public
mind. Those who made the fight for canals were forced to go over the
whole ground again for railroads, and their double victory is greater
than the success generally vouchsafed to the pioneers in any cause.
These roads, with the Pennsylvania railroad and the lesser lines of
improvements running through the coal region cost over
$207,000,000.
The Reading Railroad will serve to illustrate the struggle of these
great schemes. Its stock, now worth over par, once sold for twenty
cents on the dollar; and at one time it was forced to sell its bonds at
forty cents on the dollar to pay operating expenses. The vindication
of the sagacity of the pioneers in these great enterprises is complete.
All these lines are now profitable, and it has been demonstrated
everywhere in the United States, that every new railroad creates the
business from which its stockholders receive their dividends. It
seems, therefore, scarcely possible to fix a limit to our profitable
railroad expansion. They open new fields of enterprise, and this
enterprise in turn, makes the traffic which fills the coffers of the
companies.
I cannot now look back to the struggle to impress the people with
the advantages of railways, without a feeling of weariness at the
seeming hopeless struggle, and one of merriment at the general
unbelief in our new-fangled project. Once at Elizabethtown in this
State a public meeting had been called for the purpose of securing
subscriptions to the stock of the Harrisburg and Lancaster Railroad.
This road was intended to complete the railway between
Philadelphia and Harrisburg, one hundred and five miles. A large
concourse had gathered. Ovid F. Johnson, Attorney-General of our
State, and a brilliant orator, made an excellent speech; but the effect
was not in proportion to the effort. I determined to make an appeal,
and I gave such arguments as I could. In closing I predicted that
those now listening to me would see the day when a man could
breakfast in Harrisburg, go to Philadelphia, transact a fair day’s
business there, and returning, eat his supper at home. Great
applause followed this, and some additional subscriptions. Abram
Harnly, a friend of the road, and one of the most intelligent of his
class, worked his way to me, and taking me aside whispered, “That
was a good idea about going to Philadelphia and back to Harrisburg
the same day;” and then, bursting with laughter, he added,—“But you
and I know better than that!” We lived to see the road built; and now
people can come and go over the distance twice a day, which Abram
seemed to consider impossible for a single daily trip.
The peculiar condition of the States then known as “the West” was
the subject of anxiety to many. They had attracted a large population,
but the people were exclusively devoted to agriculture. Lacking
diversified industry, they were without accumulated wealth to enable
them to build railways; nor were the States in condition to undertake
such an onerous duty, although several of them made a feeble
attempt to do so. At one time the bonds of Illinois, issued to build her
canals, sold as low as thirty cents on the dollar. So with Indiana. Both
States were supposed to be bankrupt. It became, therefore, an
important problem as to how means of communication should be
supplied to the people of the West. Congress, in 1846, gave a grant of
land to aid in building a railroad in Illinois. Every alternate section
was given to the Company, and each alternate section was reserved
by the Government. The road was built; and the one-half of the land
retained by the government sold for a great deal more than all was
worth before the road was constructed. This idea was original, I
think, with Mr. Whitney of Mass., who spent two winters in
Washington, about 1845, endeavoring to induce Congress to adopt
that plan for the construction of a Trans-Continental Railway.
He died before seeing his scheme succeed. Others have built a road
across the continent on the Central route. Another on the Northern
route is now progressing, and the wealth and enterprise of those
having it in charge renders its completion certain. And it yet remains
for us to give the people of the Southern route a road to the Pacific
which shall develop the magnificent region through which it will
pass, and give the country one route to the great ocean protected
from the ordinary difficulty of climate with which railroads must
contend over so large a part of our territory. But I am admonished by
the value of your space to confine myself to the limits of my own
State.
I have said that the outlay we have made in building our public
works was of great benefit to us even when the canals had been
rendered almost valueless through the competition of railroads. This
is paradoxical, but it is true nevertheless. That expenditure gave our
people a needed knowledge of our vast resources. It familiarized
them with large expenditures when made for the public good. And it
showed them how a great debt may be beneficially incurred, and yet
not break down the enterprise of the people. We at one time owed
$41,698,595.74. By a steady attention to our finances, it is now
reduced to $31,000,000, with resources,—the proceeds of the sale of
public works—on hand amounting to $10,000,000. And while we
have been steadily reducing our State debt, we have built 5,384 miles
of railway on the surface of the earth, and 500 miles underground in
our mines, at a cost of not less than $350,000,000, for a mile of
railroad in Pennsylvania means something. We sent 368,000 men to
the Federal Army. And our credit stands high on every stock
exchange. Gratifying as this progress is, it is only a fair beginning.
There is a large part of our territory rich in timber and full of iron,
coal, and all kinds of mineral wealth, so entirely undeveloped by
railroads that we call it “the Wilderness.” To open it up is the
business of to-day, and I sincerely hope to see it done soon.
Forty years ago George Shoemaker, a young tavern-keeper of more
vigor and enterprise than his neighbors, came to the conclusion that
anthracite coal could be used as fuel. He went to the expense of
taking a wagon load of it to Philadelphia, a hundred miles away, and,
after peddling it about the streets for some days, was forced to give it
away, and lose his time, his labor and his coal. He afterwards saw a
great railway built to carry the same article to the same point, and
enriching thousands from the profits of the traffic. But his experience
did not end there. He saw a thousand dollars paid eagerly for an acre
of coal land, which at the time of his venture to Philadelphia, no one
would have, and he could not give away.
I have thought that a retrospective survey of our wonderful
development might point plainly to the duty of the future. For if the
experience of what has gone before is not useful to cast light on what
is yet to come, then it will be difficult indeed to discover wherein its
value lies. It teaches me to devote time and labor for the
advancement of all Public Improvements, and I trust it may have a

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Compartmental Distribution Of

Radiotracers 1st Edition James S.

Forensic Examination of Fibres 3 ed. Third Edition

Basic Physics Of Radiotracers: Volume I 1st Edition W.

Robertson on Library Security and Disaster Planning 1st

Fundamentals of Ramsey Theory 1st Edition Aaron

About A Girl Rebekah Robertson

Evolution of Broadcast Content Distribution 1st Edition

The Crossroads of Civilization A History of Vienna

Marcus Aurelius 3rd Edition Donald J. Robertson

Edited by James S. Robertson

Lelio G. Colombetti, Sc.D.

STUDIES OF CELLULAR FUNCTION BIOLOGIC APPLICATIONS OF

James S. Robertson, M.D., Ph.D.

Lelio G. Colombetti, Sc.D.

Reissued 2018 by CRC Press

© 1983 by Taylor & Francis

No claim to original U.S. Government works

A Library of Congress record exists under LC control number: 82017915

ISBN 13:978-1-138-50575-9 (hbk)

Gerald L. DeNardo, M.D.

Lelio G. Colombetti, Sc.D., is professor of Pharmacology at Loyola University Stritch

James S. Robertson, M.D., Ph.D., is a consultant in the Diagnostic Nuclear Medicine

Ray C. Boston, Ph.D. Aldo Rescigno, Ph.D.

Richard Moore, Ph.D. Ajit K. Thakur, Ph.D.

III. Mathematical Developments......................................................................................3

IV. State of the A r t ...........................................................................................................6

III. MATHEMATICAL DEVELOPMENTS

In many applications of tracer methods in biological systems, acquiring knowledge of the

IV. STATE OF THE ART

1. Nonlinear compartment models

IV. Volume of Dilution...................................................................................................12

VI. One-Compartment Open Steady-StateSystem.......................................................... 14

VII. Two Compartments in Series.................................................................................... 15

VIII. Two-Compartment Steady-State ClosedSystem.......................................................17

IX. Three-Compartment Steady-StateClosed System..................................................... 19

XI. Curve Fitting..............................................................................................................24

XII. Cumulated A ctivity.................................................................................................. 24

It is often useful to consider the body as consisting of a finite number of interconnected

IV. VOLUME OF DILUTION

The volume of a single compartment can be determined by an application of the dilution

Experimentally, V is determined by introducing a known quantity, Q, of some substance

FIGURE 1. Diagram of one-compart­

VI. ONE-COMPARTMENT OPEN STEADY-STATE SYSTEM

To illustrate the method of calculating transfer rates, we begin with a one-compartment

where ln2 is the natural logarithm of 2 (ln2 = 0.69315...).

provides the final result.

Alternatively, the one-compartment open steady-state system can be studied by introducing

VII. TWO COMPARTMENTS IN SERIES

FIGURE 2. Diagram of two-compartment system in series without feedback, and semil-

Since when the two flow rates are equal

The specific activity equations are

For q2 the maximum value is

As to the commercial resources of Duluth, sir, they are simply

In the Pennsylvania Constitutional Convention, 1873.

On the benefits derived by Pennsylvania from the Policy of Internal

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FIGURE 1. Diagram of one-compart