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OCR for page R1
Pharmacokinetics
In
Risk
Assessment
Drinking Water
anc/ Health
Volume ~
Workshop Proceedings
Subcommittee on Pharmacokinetics
in Risk Assessment
Safe Drinking Water Committee
Board on Environmental Studies
and Toxicology
Commission on Life Sciences
National Research Council
NATIONAL ACADEMY PRESS
Washington, D.C. 1987
OCR for page R2
NATIONAL ACADEMY PRESS, 2101 Constitution Ave., NW, Washington, DC 20418
NOTICE: The project that is the subject of this report was approved by the Governing Board of
the National Research Council, whose members are drawn from the councils of the National
Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The
members of the committee responsible for the report were chosen for their special competences
and with regard for appropriate balance.
This report has been reviewed by a group other than the authors according to procedures
approved by a Report Review Committee consisting of members of the National Academy of
Sciences, the National Academy of Engineering, and the Institute of Medicine.
The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distin-
guished scholars engaged in scientific and engineering research, dedicated to the furtherance of
science and technology and to their use for the general welfare. Upon the authority of the charter
granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the
federal government on scientific and technical matters. Dr. Frank Press is president of the National
Academy of Sciences.
The National Academy of Engineering was established in 1964, under the charter of the
National Academy of Sciences, as a parallel organization of outstanding engineers. It is auton-
omous in its administration and in the selection of its members, sharing with the National Academy
of Sciences the responsibility for advising the federal government. The National Academy of
Engineering also sponsors engineering programs aimed at meeting national needs, encourages
education and research, and recognizes the superior achievements of engineers. Dr. Robert M.
White is president of the National Academy of Engineering.
The Institute of Medicine was established in 1970 by the National Academy of Sciences to
secure the services of eminent members of appropriate professions in the examination of policy
matters pertaining to the health of the public. The Institute acts under the responsibility given
to the National Academy of Sciences by its congressional charter to be an adviser to the federal
government and, upon its own initiative, to identify issues of medical care, research, and
education. Dr. Samuel O. Thier is president of the Institute of Medicine.
The National Research Council was organized by the National Academy of Sciences in 1916
to associate the broad community of science and technology with the Academy's purposes of
furthering knowledge and advising the federal government. Functioning in accordance with
general policies determined by the Academy, the Council has become the principal operating
agency of both the National Academy of Sciences and the National Academy of Engineering in
providing services to the government, the public, and the scientific and engineering communities.
The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Frank
Press and Dr. Robert M. White are chairman and vice chairman, respectively, of the National
Research Council.
This project has been funded by the U.S. Environmental Protection Agency under Contract
No. 68-01-3169 with the National Academy of Sciences. The contents of this document do not
necessarily reflect the views and policies of the Environmental Protection Agency, and an official
endorsement should not be inferred.
Library of Congress Catalog Card Number 77-89284
International Standard Book Number 0-309-03775-1
Printed in the United States of America
OCR for page R3
List of Participants
SU BCOMM ITTEE ON PHARMACOKINETICS
JAMES R. GlEEETTE (Co-Chairman), Laboratory of Chemical
Pharmacology, National Heart, Lung, and Blood Institute, National
Institutes of Health, Bethesda, Maryland
DAVID J. JOLLOW (Co-Chairman), Medical University of South
Carolina, Charleston, South Carolina
MEEVIN E. ANDERSEN, Biochemical Toxicology Branch, Harry G.
Armstrong Aerospace Medical Research Laboratory, Wright-
Patterson Air Force Base, Dayton, Ohio
KENNETH B. BISCHOFF, Department of Chemical Engineering, University
of Delaware, Newark, Delaware
MARY E. DAVIS, West Virginia University Medical Center,
Morgantown, West Virginia
ROBERT L. DEDRICK, Biomedical Engineering and Instrumentation
Branch, DRS, National Institutes of Health, Bethesda, Maryland
SEYMOUR E. FRIESS, Drill, Friess, Hays, Loomis & Shaffer, Inc.,
Arlington, Virginia
DANIEL KREWSKI, Environmental Health Directorate, Health Protection
Branch, Health and Welfare Canada, Ottawa, Ontario, Canada
DANIEL B. MENZEL, Departments of Pharmacology and Medicine, Duke
University Medical Center, Durham, North Carolina
RUSSEEE A. PROUGH, University of Louisville, Louisville, Kentucky
RICHARD H. REITZ, Mammalian and Environmental Toxicology, Dow
Chemical USA, Midland, Michigan
. . .
OCR for page R4
iv List of Participants
CURTIS C. TRAVIS, Health and Safety Research Division, Oak Ridge
National Laboratory, Oak Ridge, Tennessee
GRANT R. WILKINSON, Department of Pharmacology, Vanderbilt
University School of Medicine, Nashville, Tennessee
Advisers, Consultants, and Contributors
MARSHAEE W. ANDERSON, Laboratory of Biochemical Risk Analysis,
National Institute of Environmental Health Sciences, Research
Triangle Park, North Carolina
MICHAEL I. ANGELO, Central Research Department, General Foods
Technical Center, Tarrytown, New York
LESLIE BENET, University of California, San Francisco, California
JERRY N. BLANCATO, U.S. Environmental Protection Agency,
Washington, D.C.
GARY E. BLAU, Dow Chemical USA, Midland, Michigan
J. R. BOGER Ill, Departments of Pharmacology and Medicine, Duke
University Medical Center, Durham, North Carolina
ROBERT D. BRUCE, Miami Valley Laboratories, The Procter & Gamble
Co., Cincinnati, Ohio
CHAO W. CHEN, U.S. Environmental Protection Agency, Research
Triangle Park, North Carolina
HARVEY I. CLEWELL Ill, Environmental Toxicology Branch, Harry G.
Armstrong Aerospace Medical Research Laboratory, Wright-
Patterson Air Force Base, Dayton, Ohio
MURRAY S. COHN, U.S. Consumer Product Safety Commission,
Washington, D.C.
JERRY M. COLLINS, Pharmacokinetics Section, Division of Cancer
Treatment, National Cancer Institute, Bethesda, Maryland
RORY B. CONOLLY, Environmental Sciences, Northrop Services, Inc.,
Dayton, Ohio
-
KENNY CRUMP, K. S. Crump and Co., Ruston, Louisiana
RICHARD W. D'SOUZA, Miami Valley Laboratories, The Procter &
Gamble Co., Cincinnati, Ohio
WILLIAM R. FRANCIS, Miami Valley Laboratories, The Procter &
Gamble Co., Cincinnati, Ohio
MICHAEE E. GARGAS, Biochemiocal Toxicology Branch, Harry G.
Armstrong Aerospace Medical Research Laboratory, Wright-
Patterson Air Force Base, Dayton, Ohio
JAMES GIBSON, Chemical Industry Institute of Toxicology, Research
Triangle Park, North Carolina
RICHARD C. GRAHAM, Environmental Sciences, Northrup Services, Inc.,
Research Triangle Park, North Carolina
DAVID HOEL, National Institute of Environmental Health Sciences,
Research Triangle Park, North Carolina
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List of Participants v
FRED F. KADEUBAR, Division of Biochemical Toxicology, National
Center for Toxicological Research, U.S. Food and Drug
Administration, Jefferson, Arkansas
J. M. KOOTSEY, Department of Physiology, Duke University Medical
Center, Durham, North Carolina
STAN E. EINDSTEDT, Department of Zoology and Physiology, University
of Wyoming, Laramie, Wyoming
ROBERT J. LUTZ, Biomedical Engineering and Instrumentation Branch,
National Institutes of Health, Bethesda, Maryland
FREDERICK I. MIELER, Health Effects Research Laboratory, U.S.
Environmental Protection Agency, Research Triangle Park, North
Carolina
PAUL F. MORRISON, Biomedical Engineering and Instrumentation
Branch, National Institutes of Health, Bethesda, Maryland
DUNCAN J. MURDOCH, Environmental Health Directorate j Health
Protection Branch, Health and Welfare Canada, Ottawa, Ontario
Canada
W. BROCK NEELY, EnviroSoft, Inc.
RICHARD J. NOLAN, Mammalian and Environmental Toxicology, Dow
Chemical USA, Midland, Michigan
ELLEN J. O'FLAHERTY, Department of Environmental Health, Kettering
Laboratory, University of Cincinnati College of Medicine,
Cincinnati, Ohio
JOHN H. OVERTON, JR., Environmental Sciences, Northrup Services,
Inc., Research Triangle Park, North Carolina
SANDY PANG, University of Toronto, Toronto, Ontario, Canada
DENNIS I. PAUSTENBACH, Environmental and Occupational Toxicology
Environmental Health and Safety, Syntex, U.S.A., Palo Alto,
California
CARL PECK, Uniformed Services College of Medicine, Bethesda,
Maryland
ALAN B. PRITCHARD, Central Research Department, General Foods
Technical Center, Tarrytown, New York
JOHN RAMSEY, Dow Chemical USA, Midland, Michigan
ALAN M. SCHUMANN, Mammalian and Environmental Toxicology, Dow
Chemical USA, Midland, Michigan
ELAINE D. SMOLKO, Departments of Pharmacology and Medicine, Duke
University Medical Center, Durham, North Carolina
HUGH SPITZER, Office of Research and Development, U.S.
Environmental Protection Agency, Washington, D.C.
THOMAS B. STARR, Chemical Industry Institute of Toxicology, Research
Triangle Park, North Carolina
JIM R. WITHEY, Environmental Health Directorate, Health Protection
Branch, Health and Welfare Canada, Ottawa, Ontario, Canada
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vi List of Participants
R. L. WOLPERT, Departments of Pharmacology and Medicine, Duke
University Medical Center, Durham, North Carolina
JOHN F. YOUNG, Division of Reproductive and Developmental
Toxicology, National Center for Toxicological Research, U.S. Food
and Drug Administration, Jefferson, Arkansas
SAFE DRINKING WATER COMMITTEE
DAVID J. JOLLOW (Chairman), Medical University of South Carolina
Charleston, South Carolina
1,
DAVID E. BICE, Lovelace Inhalation Toxicology Research Institute,
Albuquerque, New Mexico
JOSEPH F. BORZELLECA, Virginia Commonwealth University, Richmond,
Virginia
DAVID J. BRUSICK, Hazleton Laboratories America, Inc., Kensington,
Maryland
EDWARD J. CALABRESE, North East Regional Environmental Public
Health Center, University of Massachusetts, Amherst, Massachusetts
I. DONALD JOHNSON, School of Public Health, University of North
Carolina, Chapel Hill, North Carolina
RONALD E. WYZGA, Electric Power Research Institute, Palo Alto,
California
National Research Council Staff
RICHARD D. THOMAS, Project Director
BRUCE K. BERNARD, Sta~O~icer
EVELYN E. SIMEON, Project Secretary
Sponsoring Agency
JOSEPH COTRUVO and KRISHAN KHANNA, Office of Drinking Water, U.S.
Environmental Protection Agency, Washington, D.C.
PETER PREUSS, Office of Research and Development, U.S.
Environmental Protection Agency, Washington, D.C.
DONALD H. HUGHES, Scientific Committee, American Industrial Health
Council, Washington, D.C.
H. B. MATTHEWS, Systemic Toxicology Branch, National Institute of
Environmental Health Sciences, Research Triangle Park, North
Carolina
E. SOMERS, Health Protection Branch, Health and Welfare Canada,
Ottawa, Ontario, Canada
BARRY JOHNSON, Agency for Toxic Substances and Disease Registry,
Centers for Disease Control, Atlanta, Georgia
OCR for page R7
List of Participants vii
BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY
DONALD F. HORNING (Chairman), School of Public Health, Heard
University, Boston, Massachusetts
ALVIN L. ALM, Thermal Analytical, Inc., Waltham, Massachusetts
RICHARD N. L. ANDREWS, Institute for Environmental Studies,
University of North Carolina, Chapel Hill, North Carolina
RICHARD A. CONWAY, Union Carbide Coloration, South Charleston,
West Virginia
WILLIAM E. COOPER, Michigan State University, East Lansing, Michigan
JOHN DOULL, University of Kansas Medical Center, Kansas City,
Kansas
BENJAMIN G. FERRIS, School of Public Health, H award University,
Boston, Massachusetts
SHELDON K. FRIEDLANDER, National Center Inte~edia Transport
Research, University of California, Los Angeles, California
BERNARD D. GOLDSTEIN, University of Medicine and Dentistry of
New Jersey Robert Wood Johnson Medical School, Piscataway,
New Jersey
PHILIP J. LANDRIGAN, Mount Sinai Medical Center, New York,
New York
PHILIP A. PALMER, E. I. Du Pont de Nemours & Co., Wilmington,
Delaware
EMIL A. PFITZER, Hoffmann-La Roche, Inc., Nutley, New Jersey
PAUL PORTNEY, Resources for the Future, Washington, D.C.
PAUL RISSER, University of New Mexico, Albuquerque, New Mexico
WILLIAM H. RODGERS, School of Law, University of Washington,
Seattle, Washington
F. SHERWOOD ROWLAND, University of California, Irvine, California
LIANE B. RUSSELL, Oak Ridge National Laboratory, Oak Ridge,
r ~
ennessee
ELLEN K. SlEBERGELD, Environmental Defense Fund, Washington, D.C.
PETER S. SPENCER, Institute of Neurotoxicology, Albert Einstein College
of Medicine, Bronx, New York
National Research Council Staff
DEVRA EKE DAVIS, Executive Director
JACQUELINE PRINCE, Stay Assistant
OCR for page R8
OCR for page R9
Preface
Human beings are exposed to many chemicals, natural and synthetic.
To assess whether those chemicals are likely to produce adverse effects
in human populations, toxicity tests are conducted in laboratory animals.
In performing such tests, toxicologists assume that laboratory animals are
reasonable surrogates for humans, that is, that most materials that have
been found safe in laboratory animals will be safe in humans. Nevertheless
the possibility that reliance on data obtained solely with laboratory animals
might lead to mistaken estimates of risk to humans has been of continuing
concern, because interspecies and intraspecies differences in response
clearly exist. Since some of these differences lie in how different species
or individuals within a species handle xenobiotic chemicals, the new
applications of pharmacokinetics discussed in these proceedings are ex-
citing, because they give promise of major improvement in the prediction
of human responses from animal data.
A wide variety of toxicity tests are performed routinely, but risk as-
sessors usually focus attention on chronic tests, i.e., those in which a test
material is administered to animals for most of their natural lifetimes.
Such tests consume a large portion of the resources available for assessing
risk, but are justified by the belief that they provide data that will be
useful in predicting whether long-term exposure of humans to tested ma-
terials will increase the incidence of severely adverse conditions in hu-
mans, especially neoplastic diseases, pulmonary injuries, fetal abnormalities,
and neurotoxicities.
IX
OCR for page R10
x Preface
Tests for carcinogenesis and other chronic conditions are typically started
with homogeneous populations of young healthy animals. For practical
reasons, only small numbers of doses in small numbers of animals can
be evaluated. Consequently, doses are usually set as high as possible
(e.g., the maximum tolerated dose), in the hope of providing maximal
sensitivity, and the test agent is often administered by a route that is
experimentally most convenient. The results of the completed tests are
extrapolated to estimate the likelihood that similar responses will be pro-
duced in human populations exposed to lower concentrations of the same
agent.
According to an NRC report prepared for the National Toxicology
Program, adequate toxicologic data do not exist for most chemicals in
commerce, and the available data seldom include noncancer effects, such
as neurotoxicity or reproductive toxicity. Even when data are available,
quantitative risk estimates still rely on assumptions concerning the mech-
anism of disease, dose-response relationships, effective dose in relation
to exposure, etc., and therefore cannot be wholly accurate. Regulatory
agencies are obliged to make assumptions that they believe to be conser-
vative, so as to avoid underestimation of the risk to the human population.
Unfortunately, overestimating a risk might unnecessarily eliminate jobs
or commercially important materials, thereby decreasing our general stan-
dard of living. Hence, the more that we can replace empirical assumptions
with experimentally validated procedures, the better off we will be in
terms of both human health and economic well-being.
In developing the program of the workshop on pharmacokinetics in risk
assessment, the Safe Drinking Water Subcommittee on Pharmacokinetics
recognized that substances in the environment can lead to the expression
of many kinds of toxicity through many mechanisms. It also recognized
that humans can be exposed to substances at high concentrations for short
periods (e.g., in industrial accidents, during transportation of chemicals,
or in fires) or at low concentrations for long periods in various environ-
mental settings. It acknowledged that risk assessors are required to make
assessments on the basis of incomplete knowledge, particularly when the
duration, route, and intensity of exposure differ from those tested in
laboratory animals. In basing a risk assessment solely on long-term high-
dose toxicity studies, the risk assessor is obliged to accept as working
hypotheses that the incidence of response obtained in test animals receiving
high doses can be used to provide valid estimates of the incidence of
response in test animals exposed to much lower doses, that the response
will also occur in humans, and that the consequences of exposure are
independent of the route of exposure.
In light of these considerations, the subcommittee decided to start the
workshop with a description of the background of quantitative risk as-
OCR for page R11
Preface xi
sessment, the assumptions that must be made when knowledge is sparse,
and the feasible contribution of pharmacokinetics. To put the role of
pharmacokinetics into perspective, it was pointed out that biologic re-
sponses are governed by two general categories of factors: pha~acokinetic
factors, which govern the concentration in target organs and the interaction
of a biologically active substance with putative sites of action; and phar-
macodynamic factors, which govern the sequence of events that result
from the interaction and lead to the manifestation of the toxic response.
The pharmacokinetic factors, in turn, may be subdivided into three groups:
factors that determine the rate and extent of absorption of a substance
from the site of administration; factors that govern the distribution and
elimination of the substance and the formation, distribution, and elimi-
nation of biologically active metabolites, if any; and factors that affect
the rate or extent of reaction of the substance with putative target sub-
stances, such as DNA, enzymes, and receptor sites.
The working hypotheses thus consist of many subhypotheses, each of
which requires several assumptions. Pharmacodynamically, it is assumed
that the toxicity seen in the test species will be seen in all species, that
the mechanism of the toxicity will be the same in all species, and that
other major kinds of toxicity will not occur. Pharmacokinetically, it is
assumed that the bioavailability and time course of absorption, distribu-
tion, and elimination are generally the same in all species and hence that
the exposure of the target to the ultimate toxicant will be similar. It is
also inherently assumed that the concentration (or, when relevant, the area
under the curve) of the toxicant in the target tissue is directly proportional
to the applied dose.
During the last several decades, pharmacokineticists have developed
several mathematical tools to evaluate factors that govern the time course
of substances at putative sites of action. Each of the tools has its uses,
but each has its limitations; both uses and limitations must be taken into
account in selecting the tools that will be appropriate for specific risk
assessments. The tools derive from two general approaches: compart-
mental analysis and physiologically based models. In practice, the phar-
macokinetic models useful for risk assessment incorporate features from
both general approaches, and the features that distinguish the two ap-
proaches have become blurred. The subcommittee therefore decided to
include a session that traces the development of pharmacokinetic models
and their application to risk assessment. Further, to illustrate the inter-
relationships between the two basic approaches to pharmacokinetics and
the possibility that allometric methods of extrapolation are more valid with
some mechanisms of elimination than with others, the subcommittee in-
cluded sessions on the approaches used to generalize and extrapolate
pharmacokinetic data.
OCR for page R12
xli Preface
Clearly, such extrapolations entail uncertainty not only in theory, but
also in the collection of data and in the sources of interspecies and in-
traspecies variation. Indeed, there are even uncertainties in what is as-
sumed to be known of many of these uncertainties. Sessions were therefore
designed to elucidate many of the sources of uncertainty and to illustrate
the experimental use of physiologically based pharmacokinetics in ex-
ploring them.
The subcommittee recognized that scientists differ in their opinions of
the validity of quantitative risk assessments and of the use of pharma-
cokinetic data in making them. To elicit those opinions and the concerns
of scientists, the subcommittee included a poster session to broaden cov-
erage of the subject; and the major issues raised by the posters were
discussed in a plenary session.
Confidence in the validity of quantitative risk assessments will probably
vary with the quantity and quality of toxicity data available and the nature
of the toxicant under examination. Future development of the field of
quantitative risk assessment depends on the growth of the capacity to
decide which toxicants (and kinds of toxicity) yield reasonably accurate
quantitative risk assessments and which do not. The final sessions of the
workshop were designed to illustrate some of these problems and oppor-
tunities.
JAMES R. GIEEE=E, Co-chairman
DAVID JoLLow, Co-chairman
Subcommittee on Pharmacokinetics in Risk Assessment
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Contents
I. INTRODUCTION: THE PROBLEM AND AN APPROACH
Risk Assessment: Historical Perspectives
Seymour L. Friess
Tissue Dosimetry in Risk Assessment, or What's the
Problem Here Anyway? .....................................
Melvin E. Andersen
II. MATHEMATICAL MODELING
Modeling: An Introduction
Ellen J. O'Flaherty
Physiologically Based Pharmacokinetic Modeling
Kenneth B. Bischoff
III. GENERALIZATIONS AND EXTRAPOLATIONS
Allometry: Body Size Constraints in Animal Design
Stan L. Lindstedt
Q
................. 27
.......... 36
....... 65
Prediction of In Vivo Parameters of Drug Metabolism and
Distribution from In Vitro Studies 80
Grant R. Wilkinson
x'''
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XiV Contents
Dose, Species, and Route Extrapolation: General Aspects 96
James R. Gillette
Dose, Species, and Route Extrapolation Using
Physiologically Based Pharmacokinetic Models
Harvey J. Clewell III and Melvin E. Andersen
IV. UNCERTAINTIES: INTEGRATION WITH RISK
ASSESSMENT AND RESOURCES
.. 159
Dealing with Uncertainty in Pharmacokinetic Models Using
SIMUSOLV 185
Gary E. Blau and W. Brock Neely
Interspecies and Dose-Route Extrapolations
Curtis C. Travis
................ 208
Carcinogen DNA-Adducts as a Measure of Biological Dose
for Risk Analysis of Carcinogenic Data .....................
Marshall W. Anderson
Resources Available for Simulation in Toxicology:
Specialized Computers, Generalized Software, and
Communication Networks ...................
Daniel B. Menzel, R. L. Wolpert, J. R. Boger III,
and J. M. Kootsey
V. POSTER SESSION
Introduction ..........
Robert L. Dedrick
..........................
Route-to-Route Extrapolation of Dichloromethane Exposure
Using a Physiological Pharmacokinetic Model ..............
Michael J. Angelo and Alan B. Pritchard
Sensitivity Analysis in Pharmacokinetic Modeling
Murray S. Cohn
Mutation Accumulation: A Biologically Based
Mathematical Model of Chronic Cytotoxicant Exposure ..
Rory B. Conolly, Richard H. Reitz, and Melvin E.
Andersen
221
... 229
......... 253
.......... 265
.. 273
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Contents XV
Physiologically Based Pharmacokinetic Model for Ethylene
Chloride and Its Application in Risk Assessment 286
Richard W. D'Souza, William R. Francis, Robert D.
Bruce, and Melvin E. Andersen
Mathematical Modeling of Ozone Absorption in the Lower
Respiratory Tract 302
John H. Overton, Jr., Richard C. Graham, and
Frederick J. Miller
Development of a Physiologically Based Pharmacokinetic
Model for Multiday Inhalation of Carbon Tetrachlonde
Dennis J. Paustenbach, Harvey J. Clewell III,
Michael L. Gargas, and Melvin E. Andersen
The Delivered/Administered Dose Relationship and Its
Impact on Formaldehyde Risk Estimates
Thomas B. Starr
Pharmacokinetic Simulation as an Adjunct to Experimental
Data in Risk Assessment: Predicting Exposure of the
Bladder Epithelium in Dogs to Urinary N-Hydroxy
Metabolites of Carcinogenic Arylamines
John F. Young and Fred F. Kadlubar
VI. APPLICATIONS OF MATHEMATICAL MODELING
.... 312
.......... 327
............... 334
Hazard Assessment Using an Integrated Physiologically
Based Dosimetry Modeling Approach: Ozone 353
Frederick J. Miller, John H. Overton, Jr., Elaine D.
Smolko, Richard C. Graham, and Daniel B. Menzel
Role of Pharmacokinetic Modeling in Risk Assessment:
Perchloroethylene as an Example
Chao W. Chen and Jerry N. Blancato
.... 369
Development of Multispecies, Multiroute Pharmacokinetic
Models for Methylene Chloride and 1, 1,1-Trichloroethane
(Methyl Chloroform) 391
Richard H. Reitz, Richard J. Nolan, and Alan M.
Schumann
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XVi Contents
Methotrexate: Pharmacokinetics and Assessment of
Toxicity ..................................................
Paul F. Morrison, Robert L. Dedrick, and Robert J.
Lutz
VII. SUMMARY: PROSPECTIVES AND FUTURE
DIRECTIONS
Prospective Predictions and Validations in Anticancer
Therapy ...................................................
Jerry M. Collins
The Application of Pharmacokinetic Data in Carcinogenic
Risk Assessment ..........................................
Daniel Krewski, Duncan J. Murdoch, and Jim R.
Withey
PERSPECTIVES
INDEX ............
.... 410
.... 431
.... 441
........ 471
........ 475
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Pharmacokinetics
In
Risk
Assessment
Drinking Water
and Health
OCR for page R18
