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Biologic Markers in Reproductive Toxicology Subcommittee on Reproductive and Neurodevelopmental Toxicology Committee on Biologic Markers Board on Environmental Studies and Toxicology Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington, D.C. 1989

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NATIONAL ACADEMY PRESS 2101 Constitution Avenue, NW Washington, IX 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 NationalAcademy of Engineering, and the Institute of Medicine. The NationalAcademy of Sciences is a private, nonprofit, self-perpetuating society of distinguished 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 of 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 autonomous 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. The project was supported by the Environmental Protection Agency; the National Institute of Environmental Health Sciences; the Air Force Office of Scientific Research; and the Comprehensive Environmental Response, Common, and LiabilityAct Trust Fund through cooperative agreement with theAgency for Toxic Substances and Disease Registry, U.S. Public Health Service, Department of Health and Human Services. Library of Congress Cataloging-~n-Publication Data Biologic markers in reproductive toxicology / [Board on End Studies and Toxicology]. p. cm. Bibliography: p. Includes index. ISBN 0-309-03930-4 (cloth); ISBN 0-309-03937-7 (paper) 1. Reproductive toxicology. 2. Biochemical markers. I. National Research Council (U.S.~. Board on Environmental Studies and Toxicology. RA1224.2B56 1989 ~ironmental 616.6'507- -dc19 Copyright 1989 by the National Academy of Sciences 89-3071 CIP (Rev.) No part of this book may be reproduced by any mechanical, photographic, or electronic process, or in the form of a phonographic recording, nor may it be stored in a retrieval system, transmitted, or other copied for public or private use, without written permission from the publisher, except for the purposes of official use by the U.S. government. Printed in the United States of America

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Subcommittee on Reproductive and Neurodevelopmental Toxicology Donald R. Mattison, Chairman, University of Arkansas for Medical Sciences, Little Rock, Arkansas, and National Center for Toxicological Research Panel on Male Reproductive Toxicology Larry L. Ewing, Chairman, Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland Walderico M. Generoso, Oak Ridge National Laboratory, Oak Ridge, Tennessee C. Alvin Paulsen, Pacific Medical Center, Seattle, Washington Bernard Robaire, McGill University School of Medicine, Montreal, Quebec Richard Sherins, National Institute for Child Health and Human Development, Bethesda, Maryland Andrew J. Wyrobek, Lawrence Livermore National Laboratory, University of California, Livermore, California Panel on Female Reproductive Toxicology Maureen C. Hatch, Chairman, Columbia University, New York, New York Robert E. Canfield, Columbia University, New York, New York Caleb Finch, University of Southern California, Los Angeles, California Arthur F. Haney, Duke University Medical Center, Durham, North Carolina Neena Schwartz, Northwestern University, Evanston, Illinois Panel on Pregnancy Richard K. Miller, Chairman, University of Rochester, Rochester, New York J. David Erickson, Centers for Disease Control, Atlanta, Georgia W. Page Faulk, Methodist Hospital of Indiana Medical Research, Indianapolis, Indiana Stanley R. Glasser, Baylor College of Medicine, Houston, Texas Lawrence D. Longo, Loma Linda University, Loma Linda, California · · .

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Panel on Neurodevelopmental Toxicology Herbert L. Needleman, Chairman, University of Pittsburgh, Pittsburgh, Pennsylvania Judith L. Buelke-Sam, Lilly Research Laboratories, Greenfield, Indiana Ellen K. Silbergeld, Environmental Defense Fund, Washington, D.C. Richard G. Skalko, East Tennessee State University, Johnson City, Tennessee Stephen P. Spielberg, The Hospital for Sick Children, Toronto, Ontario Advisers and Contributors Edward M. Eddy, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina Norman Hecht, Tufts University, Medford, Massachusetts Sherry Selevan, U.S. Environmental Protection Agency, Washington, D.C. Allen Wilcox, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 1V

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Committee on Biologic Markers Bernard Goldstein, Chairman, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey James Gibson, Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina Rogene F. Henderson, Lovelace Biomedical and Environmental Research Institute, Albuquerque, New Mexico John E. Hobble, Marine Biological Laboratory, Woods Hole, Massachusetts Philip J. Landrigan, Mount Sinai Medical Center, New York, New York Donald R. Mattison, University of Arkansas for Medical Sciences, Little Rock, Arkansas, and National Center for Toxicological Research Frederica Perera, Columbia University, New York, New York Emil A. Pfitzer, Hoffmann-La Roche, Inc., Nutley, New Jersey Ellen K. Silbergeld, Environmental Defense Fund, Washington, D.C. Project Staff Senior Staff: Devra Lee Davis Alvin G. Lazen Lee R. Paulson Andrew M. Pope Richard D.Thomas Diane K. Wagener Research Staff: Robin Bowers Victor Miller Linda Miller Poore Anne M. Sprague Leslye B. Wakefield Bernidean Williams Editors: Norman Grossblatt Lee R. Paulson Support Staff: Beulah S. Bresler Mireille Mesias Erin Schneider Susan Tawfik Julie Walker

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Board on Environmental Studies and Toxicology Gilbert S. Omenn, Chairman, University of Washington, Seattle, Washington Frederick R. Anderson, Washington School of Law, American University, Washington, D.C. John Bailar, McGill University School of Medicine, Montreal, Quebec David Bates, University of British Columbia Health Science Center Hospital, Vancouver, British Columbia Joanna Burger, Nelson Laboratory, Rutgers University, Piscataway, New Jersey Richard A. Conway, Union Carbide Corporation, South Charleston, West Virginia William E. Cooper, Michigan State University, East Lansing, Michigan Sheldon K. Friedlander, University of California, Los Angeles, California Bernard Goldstein, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey Donald Mattison, National Center for Toxicological Research and University of Arkansas for Medical Sciences, Little Rock, Arkansas Duncan T. Patten, Arizona State University, Tempe, Arizona Emil Pfitzer, Hoffmann-La Roche, Inc., Nutley, New Jersey William H. Rodgers, University of Washington, Seattle, Washington F. Sherwood Rowland, University of California, Irvine, California Liane B. Russell, Oak Ridge National Laboratory Milton Russell, Oak Ridge National Laboratory Ellen K. Silbergeld, Environmental Defense Fund, Washington, D.C. I. Glenn Sipes, University of Arizona, Tucson, Arizona Bruce PI. Alberts, Ex Officio, University of California, San Francisco, California Staff Devra L. Davis, Director James J. Reisa, Associate Director Karen L. Hulebak, Exposure Assessment and Risk Reduction Program Director David J. Policansky, Natural Resources and Applied Ecology Program Director Richard D. Thomas, Human Toxicology and Risk Assessment Program Director Lee R. Paulson, Manager, Toxicology Information Center V1

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Commission on Life Sciences Bruce M. Alberts, Chairman, University of California, San Francisco, California Perry L. Adkisson, Texas A&M University, College Station, Texas Francisco J. Ayala, University of California, Irvine, California J. Michael Bishop, University of California Medical Center, San Francisco, California Freeman J. Dyson, Institute for Advanced Study, Princeton, New Jersey Nina V. Fedoroff, Carnegie Institution of Washington, Baltimore, Maryland Ralph W.F. Hardy, Boyce Thompson Institute for Plant Research (Cornell), Ithaca, New York Richard J. Havel, University of California School of Medicine, San Francisco, California Leroy E. Hood, California Institute of Technology, Pasadena, California Donald F. Hornig, Harvard School of Public Health, Boston, Massachusetts Ernest G. Jaworski, Monsanto Company, St. Louis, Missouri Simon A. Levin, Cornell University, Ithaca, New York Harold A. Mooney, Stanford University, Stanford, California Steven P. Pakes, University of Texas, Dallas, Texas Joseph E. Rall, National Institutes of Health, Bethesda, Maryland Richard D. Remington, University of Iowa, Ames, Iowa Paul G. Risser, University of New Mexico, Albuquerque, New Mexico Richard B. Setlow, Brookhaven National Laboratory, Upton, New York Torsten N. Wiesel, Rockefeller University, New York, New York John E. Burris, Executive Director · — V11

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Sponsors National Institute of Environmental Health Sciences U.S. Air Force Office of Scientific Research U.S. Environmental Protection Agency U.S. Public Health Service, Agency for Toxic Substances and Disease Registry Government Liaison Group John R. Fowle III, Chairman, U.S. Environmental Protection Agency, Washington, D.C. Henry Falk, Centers for Disease Control, Atlanta, Georgia W. Harry Hannon, Centers for Disease Control, Atlanta, Georgia Suzanne Hurd, National Heart, Lung and Blood Institute, Bethesda, Maryland Dennis Jones, Agency for Toxic Substances and Disease Registry, Atlanta, Georgia James Lamb, U.S. Environmental Protection Agency, Washington, D.C. George Lucier, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina Carol Mapes, Food and Drug Administration, Washington, D.C. Michael D. Waters, U.S. Environmental Protection Agency, Washington, D.C. · . . vail

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Preface Biologic markers are powerful tools that can be useful in many ways to environmental health scientists. Markers that indicate the occurrence of an internal dose or a biological- ly effective dose or the presence of an incipient disease can be useful in hazard identifica- tion, for example, as the qualitative step that causally associates an environmental agent with an adverse effect. Markers can also be used to determine dose-response relationships and to estimate risk, especially at the low doses relevant to most environmen- tal chemicals. Thus, the development of biologic markers could enable scientists to make better use of laboratory animal data (usually obtained at high-dose exposures) in estimating the effects of low-dose exposures in humans. Another major role of markers is clarification of the extent of exposure in human populations. Methods of direct or indirect measurement of total exposure through analysis of body fluids are far more likely to be of value in epidemiologic studies than are most of the modeling and ambient monitoring approaches now in use. Biologic markers of exposure also hold the promise of demonstrating which individuals in a potentially affected population (e.g., residents in the neighborhood of a hazardous waste dump) have been exposed to a potentially harmful extent. Developments in the field of biologic markers are also likely to lead to a more accurate determination of the proportion of highly susceptible people within the population and of the results of human exposure. In 1986, the National Academy of Sciences/National Research Council (NAS/NRC) was asked by the Environmental Protection Agency (EPA), the National Institute of Environmental Health Sciences, and the Agency for Toxic Substances and Disease Registry to conduct a study of the scientific basis, current state of development, validation, and use of biologic markers in environmental health research. The project was designed to be conducted by four subcommittees within NRC's Board on Environmental Studies and Toxicology. These subcommittees would evaluate the status of biologic markers for specific biologic systems: markers of reproductive and neurodevelopmental effects; pulmonary system markers of exposure, effect, and susceptibility; markers of immunotox- icity; and markers of ecologic toxicity, including markers of ecosystem exposure and altered processes. As part of the project, the first subcommittee, the Subcommittee on Reproductive and Developmental Toxicology, convened a symposium on January 12- 13, 1987, in Washington, DC, as an information-gathering activity. Invited speakers described their research and its possible application to the development and use of biologic 1X

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x BIOLOGIC AL4RKERS markers in reproductive and developmental toxicology. The proceedings of that sym- posium were published in Environmental Health Perspectives in October 1987 and served as a starting point for this, the subcommittee's report. In this report, the oversight committee (the Committee on Biologic Markers) sets forth in general terms the broad concepts and definitions of biologic markers and, in the introduction, discusses the use of markers in environmental health research. Those presentations are followed by the subcommittees report, which applies the concepts and definitions to reproductive and neurodevelopmental toxicology. To say that biologic markers have generated interest and controversy in recent years would be an understatement. Biologic markers represent the newest and most promising substrate for future developments in environmental health research, and we hope that this report helps catalyze those developments. Finally, the committee expresses its appreciation for the vigilant and effective assistance of the NRC staff with whom it worked in producing this report. Bernard Goldstein Chairman, Committee on Biologic Markers Donald Mattison Chairman, Subcommittee on Reproductive and Neurodevelopmental Toxicology

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Dedication Robert L. Dixon was educated at the University of Califor- nia, Davis, Idaho State University, and the University of Iowa, where he received his PhD in pharmacology/ toxicol- ogy in 1963. His postdoctoral training was in the Labora- tory of Chemical Pharmacology of the National Cancer Institute, where he served as a senior investigator. After four years as assistant and then associate professor in the Department of Pharmacology of the University of Wash- ington School of Medicine, Bob returned to the NCI, where he was appointed chief of the Laboratory of Environmental Toxicology in the chemotherapy program. From 1972-1984 he served the National Institute of Environmental Health Sciences, first as chief of the Laboratory of Environmental Toxicology and later as chief of the Laboratory of Reproduc- tive and Developmental Toxicology. Along with his duties as laboratory chief, he was assistant to the director of the Institute's internation- al programs. During this period, Bob also served on detail as a senior policy analyst in the Office of Science and Technology Policy of the Carter administration. Moving to the Environmental Protection Agency in 1984, Bob was named director of the Office of Health Research, in which position he was responsible for research activities at laboratories in Research Triangle Park, North Carolina, and Cincinnati, Ohio. In 1985 he was recruited by Sterling-Winthrop Research Institute to serve as senior director of toxicology; and in 1987, he became vice-president for drug safety in the Sterling Research Group (SRG), the research and development wing of Sterling Drug, Inc., a subsidiary of Eastman Kodak Company. At the time of his death, he had responsibility worldwide for drug safety related to SRG drug discovery and development efforts. Bob received many awards for the excellence and commitment he brought to toxicol- ogy, including the Society of Toxicology Achievement Award (1972), the NIEHS Direc- tor's Award (1977), and the EPA Distinguished Career Award (1987~. He was also president of the Society of Toxicology during 1982-1983. Bob belonged to 18 scientific societies and was a member of many scientific committees and editorial boards. He was an active writer and during his career published 67 journal articles and 49 conference proceedings or chapters. He was also editor-in-chief of the Target Organ Toxici~v M~n~ar~nh scrips of Raven Press. ~ O~ 0~-- ~ ~~_~} ~~^va~vos ~~e van A—O Bob was known for bringing a critical scientific mind to his work and exercising leadership in the discharge of his responsibilities. Perhaps as important, his warmth X1

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XIV CONTENTS 3 CLINICAL EVALUATION OF MALE INFERTILITY Medical History, 43 Physical Examination, 44 Semen Characteristics, 45 4 BIOLOGIC MARKERS OF TESTICULAR FUNCTION Physical and Chemical Markers of Testicular Function, 48 Leydig Cells, 49 Seminiferous Tubules, 52 43 47 5 BIOLOGIC MARKERS OF EPIDIDYMAL STRUCTURE AND FUNCTION 63 Markers of Epididymal Tissue, 64 Changes in Maturing Spermatozoa, 65 Epididymal Luminal Fluid, 69 Epididymal Epithelial Function, 71 Epididymally Mediated Toxic Drug Effects, 76 6 BIOLOGIC MARKERS OF ACCESSORY SEX ORGAN STRUCTURE AND FUNCTION Physical Markers, 78 Structural Markers, 79 Functional Markers, 79 BIOLOGIC MARKERS OF HUMAN MALE REPRODUCTIVE HEALTH AND PHYSIOLOGIC DAMAGE Needs for Biologic Markers of Human Male Reproductive Health, 83 Epidemiologic Studies of Human Sperm Production and Fertility, 84 Human Spermatogenesis and Development of Semen-Based Markers of Male Reproductive Health, 86 Physical Characteristics of the Human Ejaculate, 88 Presence of Nonsperm Cells in Semen, 88 Sperm Number, 89 Sperm Structure, 91 Sperm Motility, 94 Sperm Viability, 96 Sperm Function, 96 Other Sperm Measurements, 97 Chemical Composition of Seminal Fluid, 98 Promising Research Concepts, 98 Semen Markers of Sertoli Cell and Leydig Cell Function, 104 Recombinant-DNA Methods for Study of Human Spermatogenesis end Semen, 104 8 ASSESSING TRANSMITTED MUTATIONS IN MICE Assessing Markers in Laboratory Animals, 108 Markers of Exposure, 109 Tests in Mice To Determine Transmitted Genetic Effects, 1 10 Needed Research on Genetic Damage in Laboratory Animals, 1 15 9 MARKERS FOR MEASURING GERMINAL GENETIC TOXICITY AND HERITABLE MUTATIONS IN PEOPLE Current Methods for Measuring Human Heritable Mutations, 122 Results of Epidemiologic Studies of Human Heritable Mutations in Exposed Populations, 126 77 83 107 119

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CONTENTS Human Somatic Mutation Methods, 127 New Molecular Approaches for Detecting Human Heritable Mutations, 129 Testicular Markers of Human Germinal Cytogenetic Damage, 135 Semen Markers of Human Germinal Mutations and Genetic Toxicity, 136 Summary, 140 10 CONCLUSIONS AND RECOMMENDATIONS Identification of Markers of Abnormal Physiologic Function, 142 Semen Markers of Abnormal Physiologic Function, 143 Need for Improved Measures of Fertility Status and Exposure, 144 Identification of Markers of Germinal Genetic Toxicity and Heritable Mutations, 144 Criteria for Development and Validation of Markers of Male Reproduction, 145 Strategy for Testing Effect of Toxic Chemicals on Markers of Male Reproduction, 145 II. BIOLOGIC MARKERS IN FEMALE REPRODUCTIVE TOXICOLOGY 1 1 INTRODUCTION Oogenesis, 149 Development of the Female Reproductive Tract, 150 Maturation, 151 Cyclic Ovarian Function, 155 Fertilization, 159 Reproductive Senescence, 159 BIOLOGIC MARKERS OF GENETIC DAMAGE IN FEMALES Markers of Exposure, 164 Markers of Oocyte Toxicity, 164 Markers of Genotoxic Damage or Repair, 165 Markers of Mutational Events, 166 xv 141 149 163 13 BIOLOGIC MARKERS OF REPRODUCTIVE DEVELOPMENT AND AGING 169 Markers of Maturation, 170 Menstruation, 171 Loss of Fertility and Fecundity, 171 Precocious Menopause, 172 Ovarian Oocyte Depletion, 172 Hormones, 173 Nervous System, 173 Observations on the Use of These Markers, 176 14 BIOLOGIC MARKERS OF NONCONCEPTIVE MENSTRUAL CYCLES Specific Markers, 182 Biologic Rationale, 185 15 DEVELOPING ASSAYS OF BIOLOGIC MARKERS FOR EPIDEMIOLOGIC STUDIES: EXPERIENCE WITH A MARKER OF PREGNANCY AND EARLY LOSS Assays ofhCG, 187 Field Studies of Early Fetal Loss: Testing the Utility of the hCG Assay, 190 Future Assay Developments, 191 187

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XVI Other Clinical Opportunities, 195 16 CONCLUSIONS AND RECOMMENDATIONS Special Research Opportunities, 198 Specific Research Recommendations, 198 National Data Base, 202 Experimental Studies, 202 III. BIOLOGIC MARKERS OF TOXICITY DURING PREGNANCY 17 INTRODUCTION The Events of Pregnancy, 206 Maternal Physiology, 206 Embryonic/Fetal Changes, 207 Placental Involvement, 209 18 MOLECULAR BIOLOGY: DEVELOPING DNA MARKERS OF GENOTOXIC EFFECTS Detecting Heritable Genetic Damage, 211 Markers of Exposure, 212 19 REPRODUCTIVE IMMUNOLOGY: BIOLOGIC MARKERS OF COMPROMISED PREGNANCIES Maternal Immunologic Recognition and Reaction During Normal Pregnancy, 215 Tests To Determine Markers of Mechanisms of Recurrent Pregnancy Loss,218 Promising Markers of Maternal-Fetal Interactions, 219 Promising Techniques That Might Yield Biologic Markers, 221 20 CELL BIOLOGY: IDENTIFYING BIOLOGIC MARKERS EXPRESSED DURING EARLY PREGNANCY Implantation, 224 Assessing Endometrial Signals, 225 Trophoblast Biologic Markers, 231 Extrapolation to Human Trophoblasts, 237 21 PHYSIOLOGIC ASSESSMENT OF FETAL COMPROMISE Ultrasonography, 243 Amniocentesis, 244 Chorionic Villus Sampling, 244 Fetoscopy, 245 Fetal Blood and Tissue Sampling, 245 Measuring Fetal Body and Breathing Movements, 245 Electronic Fetal Heart-Rate Monitoring, 245 Biophysical Profile, 246 Magnetic Resonance Imaging, 246 22 BIOLOGIC MARKERS OF EXPOSURE DURING PREGNANCY PHARMACOKINETIC ASSESSMENTS Assessments for Pharmacokinetic Analyses, 248 Current and Promising Markers, 250 CONTENTS 197 205 211 215 223 241 . 247

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CONTEN75 23 CONCLUSIONS AND RECOMMENDATIONS Research Strategies, 253 Accomplishing the Research Goal, 254 Bringing the Assay Out of the Laboratory and Into the Public Health Domain, 255 Assessments of the Status of Specific Markers Related to Pregnancy, 255 Markers of Exposure, 262 IV. BIOLOGIC MARKERS IN NEURODEVELOPMENTAL TOXICOLOGY 24 INTRODUCTION Biologic Markers of Exposure: Pharmacokinetic Considerations, 266 Biologic Markers of Effect: Pharmacodynamic Considerations, 267 · ~ XV11 253 265 DEVELOPMENTAL NEUROBIOLOGY OF THE CENTRAL NERVOUS SYSTEM273 Basic Morphogenesis, 273 Basic Cytogenesis, 274 Neurochemistry of Neuronal Communication, 276 26 MORPHOLOGIC, NEUROCHEMICAL, AND BEHAVIORAL RESPONSES TO TOXIC AGENTS Effects of Time of Exposure and Dose: Irradiation as a Paradigm, 281 Microneuronal Radiation, 282 Application to Other Toxic Substances, 283 Relationship Between Minor Physical Anomalies and Behavioral Effects, 284 Neurochemical Effects, 284 Behavioral Effects, 286 27 METHODOLOGIC ISSUES OF EXTRAPOLATION FROM ANIMAL STUDIES TO HUMAN TOXICANT EXPOSURE Investigation of Underlying Mechanisms, 289 Study of Comparable Functional End, 290 Direct Comparisons Between Animals and Humans, 291 Data Interpretation, 295 28 LEAD AS A PARADIGM FOR THE STUDY OF NEURODEVELOPMENTAL TOXICOLOGY Markers of Exposure to Lead, 297 Markers of Effect, 299 Markers of Susceptibility, 300 Methodologic Considerations in the Establishment and Evaluation of Markers of Development, 300 Adverse Health Effects, 301 29 CONCLUSIONS AND RECOMMENDATIONS Models of Neurodevelopment, 303 Neuroendocrine and Neuroimmunologic Markers, 304 Neurochemical Markers, 306 281 289 297 303

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XV111 APPENDIX: A~E~1~O THE VALIDITY OF BIOLOGIC MARKERS: ALPHA- FElOPROlEIN Assessing the Valldlty of Blologlc ~srkers,313 Vslidlty of Sternal Drum ALP Measurement s B10ioglc Marker of NT~,31 REFERENCES BIOGRAPHIES INDEX 311 319 373 ~ ~ 1 ~0 ~

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Tables and Figures TABLES 7-1 8-1 9-1 Examples of Characteristics of Exogenous Agents, Organisms, or Targets That Influence Choice of Biologic Marker, 18 A Classification of Toxicity-Influencing Factors, 19 Species Differences in Spermatogenesis, Daily Sperm Production, and Epididymal Transit Time, 55 Biologic Markers of Physiologic Damage to Human Male Reproduction, 84 Status of Biologic Markers of Physiologic Damage to Human Male Reproduction, 92 Procedures for Detecting Transmitted Mutations in Mice,111 Potential Markers of Genetic Damage and Heritable Mutations in the Male Germline Reviewed in This Chapter, 121 Candidate Sentinel Phenotypes, 123 Prevalence of Chromosomal Abnormalities at Birth, 125 Status of Human Biologic Markers of Genetic Damage to Male Germline, 136 Human Body Fluids Potentially Useful in Measuring Biologic Markers, 180 Human Tissues Available for Use in Measuring Biologic Markers of Reproductive Toxicity, 181 14-3 Potential Biochemical Markers of Reproductive Toxicity for Evaluation In Vivo, 182 14-4 Potential Biologic Markers of Reproductive Toxicity for Evaluation In Vitro, 183 16- l Status of Current and Potential Markers in Female Reproductive Toxicology, 199 17- 1 Comparisons of Fetal and Adult Cardiovascular Functions, 208 18- 1 Disorders Diagnosable by Analysis of Cellular DNA,212 20- 1 Putative Biologic Markers to Assess Status of Uterine Epithelial Cells, 226 20-2 Putative Biologic Markers to Assess Status of Uterine Stromal Cells, 227 20-3 Putative Biologic Markers to Assess Status of Trophoblast, 232 20-4 Categorization of Pregnancy-Associated Factors, 240 21 - 1 Some Drugs with Potential Adverse Effects on the Neonate, 242 21 -2 Diagnostic Ultrasound and Biologic Indicators, 243 22- 1 Tissues and Fluids Available During Pregnancy for Laboratory Assessments, 248 Ax

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xx Biologic Markers Associated with Pregnancy and Possible Reproductive Hazards, 256 23-2 Biologic Markers Associated with Pregnancy and Possible Reproductive Hazards, by Period of Gestation, 260 Biochemical Markers of Development and Cell Injury in the Nervous . 27-1 27-2 27-3 A-2 A-3 A-4 A-5 A-6 TABLES AND FIGURES _ System, 278 Sequelae of Developmental Exposure to Drugs in Humans and Animals, 290 Examples of Motor Dysfunction After Behavioral-Teratogen Exposures, 293 Examples of Cognitive Dysfunction After Behavioral-Teratogen Exposures, 294 27-4 Examples of Sensory/Perceptual Processing Dysfunction After Behavioral- Teratogen Exposures, 295 28-1 Responses to Lead, 301 29- l Summary of Some Markers of Central Nervous System Development, 304 29-2 Status of Some Markers of Exposure, 305 A- 1 Probabilities of Marker Presence and Absence, Conditional on Disease Presence and Absence, 313 Cross-Classification of Marker and Disease: Hypothetical Data from a Case- Control Study, 314 Probabilities of Disease Presence and Absence, Conditional on Marker Presence and Absence, 314 Cross-Classification of Marker and Disease: Hypothetical Data from a Population Study, 314 AFP by Presence or Absence of Neural Tube Defect, 316 AFP by Presence or Absence of Neural Tube Defect, 316 FIGURES 1 -4 1 -5 4-1 4-2 9-1 9-2 9-3 9-4 9 5 Simplified flow chart of classes of biological markers, 17 Hypothetical male reproductive toxicant used in an industrial process and emitted into air, 31 1-3 Hypothetical female reproductive toxicant with exposure through ingestion, skin, and inhalation, 32 Hypothetical pregnancy toxicant found in air, water, and some foods, 33 Hypothetical developmental toxicant found as a contaminant in food, 34 Spermatogenesis in man, showing life span of each cell and time necessary to reach ejaculate, 48 Sperm concentration and motility during chemotherapy with AMSA [~4'9- acridinylamino) methanesulfon-m-anisidide], 49 Periods of active synthesis of DNA, RNA, and proteins diagrammed for various cell types, 58 Diagrammatic representation of testis, showing duct system and relation of ducts to accessory sex glands and penis, 78 Schematic representation of human germline, including some ot tne ceil types in which genetic damage can be measured, 122 Production of restriction-length polymorphisms using restriction enzymes and separation of different DNA fragment sizes by Agarose gel electrophoresis, 130 Restriction-length polymorphism, 131 One-dimensional denaturing gradient gel electrophoresis, 134 Decondensing human sperm and human sperm chromosomes revealed in the cytoplasm of hamster eggs, 138 ~ ~ _ ~ .r _ _ _ 1 1

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TABLES AND FIGURES 1 l-1 Changes in total population of germ cells in human ovary with increasing age, 150 Life cycle of a female germ cell, 151 Schematic illustration of hypothalamic-pituitary-gonadotropin-gonadal interrelationship in relation to onset of puberty, 152 11-4 Daily plasma LH patterns in a representative prepubertal girl, early pubertal, late pubertal, and young adult males, 153 11-5 Comparisons of age-related changes in ovulatory cycle length distribution from longitudinal studies of C57BL/6J mice and humans, 154 11-6 Selected events occurring during development of an ovulatory follicle, 156 11-7 Age-specific fecundity in selected populations that do not practice contraception: rates per l,OOO married women, 160 1 1 -8 13-1 13-2 13-3 15-1 15-2 15-3 15-4 19-1 20-1 20-2 20-3 20-4 25-1 26-1 28-1 28-2 A-1 Loss of ovarian oocytes during aging in the mouse and human, 161 Frequency profiles of estrous-cycle length transitions in three cohorts of aging virgin mice, 172 Late-midlife onset of some types of parkinsonism might result from early viral lesion that causes loss of substantial nigral dopaminergic neurons or from genetic deficiency, 174 Age-related phenomena might be represented on a 3-dimensional experience surface whose axes are time, dose, and change, 175 Antibodies with specificity to ~ and,8 subunits of hCG, 188 High-affinity circular complex that is formed in a "sandwich" assay, 189 Schematic diagram of procedure for immunoradiometric assay of hCG in urine; sensitivity of hCG detection by immunoradiometric assay, 190 hCG in urine during three consecutive menstrual cycles in human female unaware of pregnancy or early fetal loss, 191 Proposed model of immunologic response, 217 Relative contribution of different states of very early gestation to outcome of early IVF/ET, 224 Schematic diagram of rat conception during midterm pregnancy, 231 Step old production by rat blastocyst outgrowths, 234 Some major events occurring in utero that define pert-implantation period in human, 238 Four biochemical steps in synaptic transmission: synthesis of neurotransmitter, release of transmitter synaptic cleft, binding of transmitter to postsynaptic receptor, and removal or destruction of transmitter substance, 277 Correlation between blood lead and 24-hour urinary excretion in children, 285 Distribution of frequencies of four putative responses to internal lead dose, 299 Intensity of given effect as function of dose, 300 Distribution of concentration of maternal serum alpha-fetoprotein in a population of unaffected pregnancies and in a population of pregnancies in which the fetus has spine bifida cystica, 312 A-2 Multistage prenatal detection of neural tube defects, 313 xx

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Biologic Markers in Reproductive Toxicology

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