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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
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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
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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 . . .
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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
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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
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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
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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-
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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.
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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
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