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Drinking Water and Health Volume 6 Richard D. Thomas, Study Director and Editor Safe Drinking Water Committee Board on Toxicology and Environmental Health Hazards Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington, D.C. 1986

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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 Research Council was established by the National Academy of Sci- ences in 1916 to associate the broad community of science and technology with the Academy's purposes of furthering knowledge and of advising the federal government. The Council operates in accordance with general policies determined by the Academy under the authority of its congressional charter of 1863, which establishes the Academy as a private, nonprofit, self-governing membership corporation. The Council has become the principal operating agency for both the National Academy of Sciences and the National Academy of Engineering in the conduct of their services to the government, the public, and the scientific and engineering communities. It is admin- istered jointly by both Academies and the Institute of Medicine. The National Academy of Engineering and the Institute of Medicine were established in 1964 and 1970, respectively, under the charter of the National Academy of Sciences. 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 0-309-03687-9 Printed in the United States of America

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List of Participants SAFE DRINKING WATER COMMITTEE DANIEL B. MENZEL (Chairman), Duke University Medical Center, Durham, North Carolina BYRON E. BUrrERWORTH (Vice Chairman), Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina MELVIN E. ANDERSEN, Air Force Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Ohio JAMES V. BRUCKNER, University of Georgia College of Pharmacy, Athens, Georgia SEYMOUR L. MESS, Drill, Friess, Hays, Loomis & Shaffer, Inc., Arlington, Virginia MICHAEL A. GALLO, University of Medicine and Dentistry of New Jersey Rutgers Medical School, Piscataway, New Jersey JOHN N. HATHCOCK, Iowa State University, Ames, Iowa CLARK W. HEATH, JR., Emory University School of Medicine, Atlanta, Georgia MICHAEL E. HOGAN, Princeton University, Princeton, New Jersey DAVID J. JOLLOW, Medical University of South Carolina, Charleston, South Carolina JEANNE M. MANSON, Smith Kline & French Laboratories, Philadelphia, Pennsylvania FREDERICA P. PERERA, Columbia University School of Public Health, New York, New York MARVIN A. SCHNElDERMAN, Uniformed Services University of the Health Sciences, Bethesda, Maryland PETER S. SPENCER, Albert Einstein College of Medicine, Bronx, New York

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iv List of Participants Advisors, Consultants, and Contributors EILEEN HAYES, University of Medicine and Dentistry of New Jersey- Rutgers Medical School, Piscataway, New Jersey DEBRA LASKIN, Rutgers University College of Pharmacy, Piscataway, New Jersey MATTHEW MILLER, Sterling-Winthrop Research Institute, Rensselaer, New York BRADLEY SCHWAB, University of Michigan School of Public Health, Ann Arbor, Michigan GISELA WITZ, University of Medicine and Dentistry of New Jersey- Rutgers Medical School, Piscataway, New Jersey PETER WORKING, Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina National Research Council Staff RICHARD D. THOMAS, Study Director and Editor EESEYE G. WAKENED, Associate Sta~O~cer EDNA B. SMITH, Study Secretary TRACY E. BRANDT, Study Secretary MIRElLLE I. MESTAS, Administrative Secretary Environmental Protection Agency Project Officer KRISHAN KHANNA, EPA Office of Water Supply, Washington, D. C . BOARD ON TOXICOLOGY AND ENVIRONMENTAL HEALTH HAZARDS GERALD N. WOGAN (Chairman), Department of Applied Biological Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts. DONALD HORNING (Co-Vice-Chairman), School of Public Health, Harvard University, Boston, Massachusetts PHILIP LANDRIGAN (Co-Vice-Chairman), Environmental Sciences Laboratory, Department of Community Medicine, Mount Sinai Medical Center, New York, New York JOHN DOULL, Department of Pharmacology, University of Kansas Medical Center, Kansas City, Kansas HERMAN N. ElSEN, Department of Biology and Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts

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EMMANUEL FARBER, Department of Pathology, Un Toronto, Ontario, Canada RICHARD MERRIEE, School of Law, University of Virginia, Charlottesville, Virginia EMIL P~TZER, Department of Toxicology and Pathology, Hoffmann-La Roche, Inc., Nutley, New Jersey LIANE B. RUSSELL, Biology Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee ELLEN SILBERGELD, Toxics Program, Environmental Defense Fund, Washington, D.C. PETER SPENCER, Institute of Neurotoxicology, Albert Einstein College of Medicine, Bronx, New York List of Participants v iversity of Toronto, Ex Officio Members ROY E. ALBERT, Institute of Environmental Medicine, New York University Medical Center, New York, New York, GARY P. CARLSON, Purdue University, School of Pharmacy and Pharmacal Science, Department of Pharmacology and Toxicology, Lafayette, Indiana THOMAS CHALMERS, Mount Sinai Medical Center, New York, New York ARTHUR B. DUBOlS, John B. Pierce Foundation Laboratory, New Haven, Connecticut ALAN M. GOLDBERG, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland MAUREEN M. HENDERSON, Department of Epidemiology, University of Washington, Seattle, Washington ROGER O. MCCEEELAN, Lovelace Inhalation Toxicology Research Institute, Albuquerque, New Mexico DANIEL B. MENZEL, Department of Pharmacology, Duke University Medical Center, Durham, North Carolina NORTON NELSON, Institute of Environmental Medicine, New York University Medical Center, New York, New York National Research Council Staff DEVRA EKE DAVIS, Executive Director JACQUEEINE PENCE, Sta~Assistant

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Preface The Safe Drinking Water Act of 1974 (PL 93-523) mandated that the U.S. Environmental Protection Agency (EPA) establish federal standards to protect humans from harmful contaminants in drinking water. This law authorized EPA to seek the expertise of a National Research Council committee to identify the health effects associated with specified contam- inants, areas of insufficient knowledge, and recommendations for future research. Since 1977, committees of the Research Council have issued five volumes of Drinking Water and Health, each of which includes a review of toxicological data and estimates of the risks associated with specific contaminants found in drinking water. The most recently constituted Safe Drinking Water Committee con- ducted the study reported in this sixth volume of the series. At the request of EPA, the committee examined current practices in risk assessment and identified likely areas of innovation in the assessment of noncancer toxic responses and in the use of toxicokinetic data to estimate delivered dose and response. To respond to the agency's immediate need for assessments, the study also entailed literature reviews and risk assessments for 14 specific compounds of interest to EPA and the research community. Many of the principles examined by the committee are not limited to the exposure of humans to toxicants in drinking water. In addition, dis- cussions of the basic principles of dose-response relationships can be found throughout the various chapters. Thus, this volume should be useful as a general reference work in many areas of toxicology and public health. Developmental and reproductive effects are reviewed in Chapters 2 and 3. The temporal relationships between exposure and effect are discussed v'' -

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viii Preface in detail to provide a framework for the critical examination of dose- response relationships in laboratory animals. Because of the broad spec- trum of possible developmental effects that can occur, the committee reviewed the pathological response mechanisms found in experimental animal studies. Chapter 2 also provides principles for extrapolating from laboratory data to determine potential developmental risks in humans. General concern has been raised about the effect of chemicals on the reproductive ability of males and nonpregnant females. In Chapter 3, the committee addresses this issue in detail, reviewing three aspects of re- productive toxicity in females: impaired maturation of the female repro- ductive system, toxicity to oocytes, and alteration of the reproductive endocrine system. For males, the committee examines effects on the mat- uration of the male reproductive system, spermatogenesis, and fertility. Although these topics are selective, the text provides a comprehensive description of present test systems and their ability to predict human risk for reproductive toxicity. The appendix to Chapter 3 is a summary of test protocols for reproductive toxicity testing. Many compounds have been identified as neurotoxicants in humans, and there are a number of mechanisms whereby chemicals exert neurotoxic effects. In Chapter 4, the committee examines the data on neurotoxicity in both humans and animals. Chemical carcinogenesis is discussed extensively in Chapter 5, which describes the most useful methods of short-term assessment that can be integrated into the prediction of carcinogenesis in humans. The committee uses the principles described in Chapter 8 for the assessment of risk for chemically induced cancer in humans. Some of the chemicals in drinking water are by-products or accidental contaminants of commercial or industrial applications. Many of the dose- response data on these substances, such as small molecular weight sol- vents, were obtained from inhalation exposures. In Chapter 6, using phys- iologically and anatomically based mathematical modeling, the committee presents a method for using inhalation exposure data in estimating the kinetics of exposure by ingestion. The approach departs from earlier meth- ods by its dependence on anatomically based compartments. The collection of human toxicity data through epidemiological studies is discussed in Chapter 7, which focuses on the reliability of these data in estimating human risks. Methods and limitations of such studies are reported. The overall theme of the volume, relating dose-response relationships to estimates of human health risk, is integrated in Chapter 8, Risk As- sessment. The committee presents quantitative risk assessment in concrete rather than abstract terms and delineates those areas in which uncertainty exists.

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Preface ix Chapter 9 is intended by the committee to serve as an example of how the principles of toxicology can be applied to quantitative analysis of risks to humans. Those principles suggested in the preceding chapters are ap- plied whenever possible in assessing the risk from 14 chemical contam- inants in drinking water. Some of the chemicals were examined in earlier volumes of Drinking Water and Health. Thus, only recent data are pre- sented herein. Chemicals not previously reviewed are discussed in greater detail. This volume could not have been completed without the generous, dedicated service of many colleagues. Richard Thomas served as study director of this volume. Leslye Giese Wakefield was professional staff associate. Marvin Schneiderman provided valuable assistance to the com- mittee in analyzing the data used in risk assessments and providing guid- ance on risk assessment methodology as assessments were developed. Linda Starke provided editorial assistance to the staff and committee as the report was being written. Barbara Ream served as bibliographer. In addition, Gail Charnley, Kulbir Bakshi, Victor Miller, Edna Paulson, Andrew Pope, Mary Ellen Scheckenbach, Diane Wagener, and Chris Wendel, staff of the Board on Toxicology and Environmental Health Hazards, provided able assistance in conducting literature reviews, cal- culating the risks, and verifying the risk assessments. Eugenie Pascual assisted in typing the manuscript. Special thanks are extended to Kenneth Crump and Ralph Kodell of K. S. Crump and Company, Charles Brown of the National Cancer Institute, and Murray Cohn of the Consumer Product Safety Commission, who provided the committee with both carcinogenicity risk estimates and help- ful discussions of problems related to these estimates. Eileen Hayes, Debra Laskin, and Gisela Witz of Rutgers University; Matthew Miller, Sterling- Winthrop Research Institute; Bradley Schwab, University of Michigan; Robert Wolpert and Douglas Keller, Duke University; Peter Working, Paul Miller, and Thomas Starr, Chemical Industry Institute of Toxicology; and Michael Symons, University of North Carolina, served as advisers to the committee. Devra Davis, Executive Director of the Board on Toxi- cology and Environmental Health Hazards, provided valuable assistance in developing the program and in final completion of the study. We are grateful for the helpful advice and guidance of Frederick Robbins and Alvin ~ azen, Chairman and Executive Director, respectively, of the Com- mission on Life Sciences. We also acknowledge the generous assistance of members of the EPA's Office of Drinking Water staff, especially Krishan Khanna, Technical Officer, Penelope Fenner-Crisp, Toxicologist, and Joseph Cotruvo, Director. Volume 6 represents many hours of effort by my dedicated colleagues on the Safe Drinking Water Committee. Their hard work and learned

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x Preface discussions are only partly recorded herein. The committee particularly wishes to recognize the contribution of Jeanne Manson to Chapters 2 and 3, Peter Spencer to Chapter 4, and Melvin Andersen to Chapter 6. My thanks to all members of the committee, consultants, collaborators, and especially to the staff and officers of the National Research Council cannot be adequately expressed. The committee notes with regret the death of Sergio Fabro, who pro- vided expert advice on risk assessment in the areas of reproductive and developmental toxicology for this volume. Others who assisted in this field through a workshop were Carole Kimmel, Gary Kimmel, Ellen Silbergeld, and Peter Voytek. Participating in a neurotoxicology risk as- sessment workshop to advise the committee were Mohamed Abou-Donia, Elizabeth Anderson, Kent Anger, Barbara Bass, Richard Butcher, Roger Cortesi, Donald Fox, John O'Donoghue, Charles Rebert, Patricia Rodier, Joseph Rodricks, and William Sette. DANIEE B. MENZEE, Chairman Safe Drinking Water Committee

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Contents l EXECUTIVE SUMMARY DEVELOPMENTAL EFFECTS OF CHEMICAL CONTAMINANTS ....................................... Influence of Time of Exposure ......................... Patterns of Dose Response in Laboratory Animal Studies Extrapolation of Animal Data to Humans .................... Spectrum of End Points, 18 Concordance of Results from Animal and Human Studies, 21 Interpretation of Animal Data .......................... Quality and Quantity of Data, 22 Relationship between Maternal and Developmental Toxicity, 25 Selection of the NOEL/LOEL, 27 . . . 11 12 15 18 ...... 22 Risk Assessment 28 Quantitative Assessment of Developmental Toxicity, 28 Selection of the Safety Factor, 30 3 REPRODUCTIVE TOXICOLOGY 35 Susceptibility of the Nonpregnant Female to Reproductive . Impairment Xl ............. 37

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xli Contents Maturation of the Female Reproductive System, 37 Oocyte Toxicity, 41 Effects of Radiation on Oogenesis, 42 Effects of Xenobiotic Compounds on Oogenesis, 43 Alterations in Reproductive Endocrinology, 45 Test Systems for Detecting Female Infertility, 50 Susceptibility of the Male to Reproductive Impairment Maturation of the Male Reproductive System, 53 Sperm Toxicity, 55 Effects of Radiation on Spermatogenesis, 56 Test Systems for Evaluating Male Reproductive Toxicity in Laboratory Animals, 57 Human Test Systems, 59 Germ Cell Mutagenesis in Males and Females .............. Test Systems for Germ Cell Mutations, 69 Risk Assessment in Reproductive Toxicology ............... Appendix: Details of Test Protocols for Reproductive Toxicology Testing ..................................... Multigeneration Test .......................................... Fertility Assessment by Continuous Breeding ............ Segment I Studies: General Fertility and Reproductive Performance ................................................ Time of Vaginal Opening in the Rat Pup .................... Uterine Epithelial Hypertrophy ............................... Primordial Oocyte Destruction in Juvenile Mice ............. Sperm Production Rates in Rats .............. Assessment of Epididymal Spew Numbers and Transit Times ................................................. Assessment of Sperm Motility ..... Histological Evaluation of the Testis ......... 4 NEUROTOXIC EFFECTS ................................... The Human Nervous System in Health and Disease ....... Gross Structure and Function, 107 Cellular Structure and Function, 110 Normal. Developmental Structure and Function, 113 Neuroteratology and Psychoteratology, 115 Neurotoxic Responses after Birth and at Maturity, 118 Susceptibilities of Special Populations, 124 Studies in Humans Occurrence of Neurological Disease, 127 Epidemiological Studies, 130 Studies in Animals .............................. ..... 53 69 82 .... 83 83 85 87 88 89 89 89 90 90 91 ... 105 107 .................................. 127 ......... 131

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Contents xlli Interspecies Extrapolation ... Risk Assessment ............ 5 MECHANISMS OF CARCINOGENESIS ~ The Multistage Theory of Carcinogenesis Initiation, 140 Promotion, 140 Progression, 141 Cocarcinogenesis, 141 Oncogene Activity Model Systems ....................... Mouse Skin, 143 Rat and Mouse Liver, 145 Other Animal Systems, 147 Studies in Humans, 148 133 133 ...................... 139 .................... 139 ............................................ 142 ......................... 143 Genetic Toxicity 148 The Role of the Immune System in Carcinogenesis 149 Carcinogen Evaluation 151 Animal Bioassays, 151 Short-Term Tests, 152 Structure-Activity Relationships Risk Assessment 6 DOSE-ROUTE EXTRAPOLATIONS: USING INHALATION TOXICITY DATA TO SET DRINKING WATER LIMITS ... Background ..................... Routes of Exposure, 171 Dose-Response Curves, 172 Measurement of Tissue Dose, 173 Pharmacokinetic Models Data-Based Inhalation Models, 178 Physiologically Based Models, 180 Two Examples of Dose-Route Extrapolations Trichloroethylene, 187 Benzene, 188 Interspecies Extrapolation ................ Allometric Relationships, 193 ............. Tissue Dose Scale-Up, 194 Short-Lived Reactive Metabolites, 196 Interspecies PB-PK Model Simulations, 197 Incorporating Time-Dependent Physiological and Metabolic Changes, 200 PB-PK Models in Risk Assessment 156 156 168 ............. 170 .............. 176 ................ 186 ........ 193 ................... 201

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xiv Contents Extending Basic Models to Accommodate Reality, 202 Appendix A: Metabolic Processes in the Respiratory Tract, the Gastrointestinal Tract, and the Liver 205 The Respiratory Tract: Absorption, Metabolism, and Presystemic Elimination 205 Pulmonary Structure and Cell Types, 205 Metabolic Properties of Lung Cells, 206 Other Pulmonary Cells, 207 Elimination of Compounds by the Lung, 208 The Gastrointestinal Tract: Absorption, Metabolism, and Presystemic Elimination The Absorption Process 210 Anatomical Regions of the Gastrointestinal Tract, 211 Presystemic Elimination, 212 Metabolism in the Liver 215 Appendix B: Definitions of Symbols and Abbreviations . . . 218 .......................... 210 7 DATA ON HUMANS: CLINICAL AND EPIDEMIOLOGICAL STUDIES 226 226 228 Clinical Observations: Case Reports Epidemiological Observations Early Studies, 229 Descriptive Epidemiology, 229 Analytical Epidemiology, 230 Case-Comparison and Cohort Studies, 232 Experimental or Intervention Studies, 233 Principles, Problems, and Limitations of Epidemiology 234 Statistical Significance and Power, 235 Study-Related Limitations, 237 Inference and Quantification, 239 Nature of Populations Studied, 240 Mechanisms of Biological Action, 240 Risk Assessment Relative Risk, 241 Attributable Risk, 241 Additivity, 242 Application to Drinking Water Studies, 242 8 RISK ASSESSMENT 250 Previous Safe Drinking Water Committees' Views on Risk Assessment ................... .. 252

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Contents xv Issues Concerning Threshold, 252 Carcinogenic and Mutagenic Effects, 253 Noncarcinogenic Effects, 253 Safety, or Uncertainty, Factors, 253 The Use of Animal Data to Predict Human Risk, 254 Combined Exposures 255 Reliability of Risk Estimation, 256 Noncarcinogens, 256 Estimates of Exposure from Different Sources and Various Routes, 257 Pharmacokinetics ....... Inter- and Intraspecies Extrapolation Carcinogenesis ....................................... 260 ......................... 264 ................................................ 266 The NOEL, 266 Quantitative Assessment, 267 The Multistage Dose-Response Model, 268 Threshold Models, 269 Developmental and Reproductive Effects The NOEL, 272 Quantitative Assessment, 273 Neurotoxicity .............................. The NOEL and LOEL, 277 Quantitative Assessment, 279 Conclusions and Recommendations ..... Carcinogenicity, 282 Developmental and Reproductive Toxicity, 284 Neurotoxicity, 286 271 276 282 294 297 303 303 309 312 314 9 TOXICITY OF SELECTED CONTAMINANTS .............. Acrylamide ............................................. Carbamate Pesticides ......... Aldicarb ................ Diallate ................. Sulfallate ............... Dibromochloropropane ..................... Chloropropanes and Chloropropenes , ....... (1,2-Dichloropropane, 1,2,3-Trichloropropane, and 1,3-Dichloropropene) ...................... Di(2-Ethylhexyl) Phthalate and Mono(2-Ethylhexyl) Phthalate ..................................... EthYlene Dibromide ............................ 326 338 359

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xvi Contents Nitrofen 368 Pentachlorophenol 382 Trichlorfon 394 Conclusions and Reconnnnendations 409 COMMITTEE BIOGRAPHIES ..................................... INDEX 439 443

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DRINKING WATER AND HEALTH

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