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EVALUATING CHEMICAL AND OTHER AGENT EXPOSURES FOR REPRODUCTIVE AND DEVELOPMENTAL TOXICITY

Subcommittee on Reproductive and Developmental Toxicology

Committee on Toxicology

Board on Environmental Studies and Toxicology

Commission on Life Sciences

National Research Council

NATIONAL ACADEMY PRESS
Washington, D.C.



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Page i EVALUATING CHEMICAL AND OTHER AGENT EXPOSURES FOR REPRODUCTIVE AND DEVELOPMENTAL TOXICITY Subcommittee on Reproductive and Developmental Toxicology Committee on Toxicology Board on Environmental Studies and Toxicology Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington, D.C.

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Page ii NATIONAL ACADEMY PRESS 2101 Constitution Ave., N.W. Washington, D.C. 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 project was supported by Contract Nos. DAMD 17-89-C9086 and DAMD 17-99-C9049 between the National Academy of Sciences and the U.S. Department of Defense. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number 0-309-07316-2 Additional copies of this report are available from: National Academy Press 2101 Constitution Ave., NW Box 285 Washington, DC 20055 800-624-6242 202-334-3313 (in the Washington metropolitan area) http://www.nap.edu Copyright 2001 by the National Academy of Sciences . All rights reserved. Printed in the United States of America

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Page iii THE NATIONAL ACADEMIES National Academy of Sciences National Academy of Engineering Institute of Medicine National Research Council The National Academy 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 on scientific and technical matters. Dr. Bruce M. Alberts 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. William A. Wulf 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. Kenneth I. Shine 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. Bruce M. Alberts and Dr. William A. Wulf are chairman and vice chairman, respectively, of the National Research Council.

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Page iv

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Page v SUBCOMMITTEE ON REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY CAROLE A. KIMMEL (Chair), U.S. Environmental Protection Agency, Washington, D.C. GERMAINE M. BUCK, University at Buffalo, State of New York MAUREEN H. FEUSTON, Sanofi Pharmaceuticals, Inc., Malvern, Pa. PAUL M.D. FOSTER, Chemical Industry Institute of Toxicology, Research Triangle Park, N.C. J. M. FRIEDMAN, University of British Columbia, Vancouver JOSEPH F. HOLSON, WIL Research Laboratories, Inc., Ashland, Ohio CLAUDE L. HUGHES, JR., Cedars-Sinai Medical Center, Los Angeles, Calif. JOHN A. MOORE, Institute for Evaluating Health Risks, Washington, D.C., and Sciences International, Alexandria, Va. BERNARD A. SCHWETZ, National Center for Toxicological Research, Rockville, Md. ANTHONY R. SCIALLI, Georgetown University Medical Center, Washington, D.C. WILLIAM J. SCOTT, JR., University of Cincinnati College of Medicine, Cincinnati, Ohio CHARLES V. VORHEES, University of Cincinnati College of Medicine, Cincinnati, Ohio BARRY R. ZIRKIN, The Johns Hopkins University School of Hygiene and Public Health, Baltimore, Md. Staff KULBIR S. BAKSHI, Program Director for the Committee on Toxicology ABIGAIL STACK, Project Director KATE KELLY, Editor MIRSADA KARALIC-LONCAREVIC, Information Specialist LEAH PROBST, Senior Project Assistant EMILY SMAIL, Project Assistant Sponsor U.S. DEPARTMENT OF DEFENSE

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Page vi

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Page vii COMMITTEE ON TOXICOLOGY BAILUS WALKER, JR. (Chair), Howard University Medical Center and American Public Health Association, Washington, D.C. MELVIN E. ANDERSEN, Colorado State University, Denver GERMAINE M. BUCK, National Institutes of Health, Washington, D.C. ROBERT E. FORSTER II, University of Pennsylvania, Philadelphia WILLIAM E. HALPERIN, National Institute for Occupational Safety and Health, Cincinnati, Ohio CHARLES H. HOBBS, Lovelace Respiratory Research Institute and Lovelace Biomedical and Environmental Research Institute, Albuquerque, N.M. SAM KACEW, Department of Pharmacology Faculty of Medicine and University of Ottawa, Ontario NANCY KERKVLIET, Oregon State University, Agricultural and Life Sciences, Corvallis MICHAEL J. KOSNETT, University of Colorado Health Sciences Center, Denver MORTON LIPPMANN, New York University School of Medicine, Tuxedo ERNEST E. MC CONNELL, ToxPath, Inc., Raleigh, N.C. THOMAS E. MCKONE, Lawrence Berkeley National Laboratory and University of California, Berkeley HARIHARA MEHENDALE, The University of Louisiana at Monroe, Monroe DAVID H. MOORE, Battelle Memorial Institute, Bel Air, Md. LAUREN ZEISE, California Environmental Protection Agency, Oakland

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Page viii Staff KULBIR S. BAKSHI, Program Director SUSAN N.J. MARTEL, Program Officer ABIGAIL E. STACK, Program Officer RUTH E. CROSSGROVE, Publications Manager KATHRINE J. IVERSON, Manager, Toxicology Information Center AIDA C. NELL, Senior Project Assistant EMILY L. SMAIL, Project Assistant

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Page ix BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY GORDON ORIANS (Chair), University of Washington, Seattle JOHN DOULL, University of Kansas Medical Center, Kansas City DAVID ALLEN, University of Texas, Austin INGRID C. BURKE, Colorado State University, Fort Collins THOMAS BURKE, The Johns Hopkins University, Baltimore, Md. GLEN R. CASS, Georgia Institute of Technology, Atlanta WILLIAM L. CHAMEIDES, Georgia Institute of Technology, Atlanta CHRISTOPHER B. FIELD, Carnegie Institute of Washington, Stanford, Calif. JOHN GERHART, University of California, Berkeley J. PAUL GILMAN, Celera Genomics, Rockville, Md. DANIEL S. GREENBAUM, Health Effects Institute, Cambridge, Mass. BRUCE D. HAMMOCK, University of California, Davis ROGENE HENDERSON, Lovelace Respiratory Research Institute, Albuquerque, N.M. CAROL HENRY, American Chemistry Council, Arlington, Va. ROBERT HUGGETT, Michigan State University, East Lansing JAMES F. KITCHELL, University of Wisconsin, Madison DANIEL KREWSKI, University of Ottawa, Ottawa, Ontario JAMES A. MACMAHON, Utah State University, Logan CHARLES O'MELIA, The Johns Hopkins University, Baltimore, Md. WILLEM F. PASSCHIER, Health Council of The Netherlands, The Hague ANN POWERS, Pace University School of Law, White Plains, N.Y. KIRK SMITH, University of California, Berkeley TERRY F. YOSIE, American Chemistry Council, Arlington, Va. Senior Staff JAMES J. REISA, Director DAVID J. POLICANSKY, Associate Director and Senior Program Director for Applied Ecology RAYMOND A. WASSEL, Senior Program Director for Environmental Sciences and Engineering KULBIR BAKSHI, Program Director for the Committee on Toxicology ROBERTA M. WEDGE, Program Director for Risk Analysis K. JOHN HOLMES, Senior Staff Officer

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Page x COMMISSION ON LIFE SCIENCES MICHAEL T. CLEGG (Chair), University of California, Riverside PAUL BERG (Vice Chair), Stanford University, Stanford, Calif. FREDERICK R. ANDERSON, Cadwalader, Wickersham & Taft, Washington, D.C. JOANNA BURGER, Rutgers University, Piscataway, N.J. JAMES E. CLEAVER, University of California, San Francisco DAVID S. EISENBERG, University of California, Los Angeles NEAL L. FIRST, University of Wisconsin, Madison DAVID J. GALAS, Keck Graduate Institute of Applied Life Science, Claremont, Calif. DAVID V. GOEDDEL, Tularik, Inc., South San Francisco, Calif. ARTURO GOMEZ -POMPA, University of California, Riverside COREY S. GOODMAN, University of California, Berkeley JON W. GORDON, Mount Sinai School of Medicine, New York, N.Y. DAVID G. HOEL, Medical University of South Carolina, Charleston BARBARA S. HULKA, University of North Carolina, Chapel Hill CYNTHIA J. KENYON, University of California, San Francisco BRUCE R. LEVIN, Emory University, Atlanta, Ga. DAVID M. LIVINGSTON, Dana-Farber Cancer Institute, Boston, Mass. DONALD R. MATTISON, March of Dimes, White Plains, N.Y. ELLIOT M. MEYEROWITZ, California Institute of Technology, Pasadena ROBERT T. PAINE, University of Washington, Seattle RONALD R. SEDEROFF, North Carolina State University, Raleigh ROBERT R. SOKAL, State University of New York, Stony Brook CHARLES F. STEVENS, The Salk Institute for Biological Studies, La Jolla, Calif. SHIRLEY M. TILGHMAN, Princeton University, Princeton, N.J. RAYMOND L. WHITE, DNA Sciences, Inc., Mountain View, Calif. Staff WARREN R. MUIR, Executive Director JACQUELINE K. PRINCE, Financial Officer BARBARA B. SMITH, Administrative Associate LAURA T. HOLLIDAY, Senior Program Assistant

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Page xi OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Toxicological Effects of Methylmercury (2000) Strengthening Science at the U.S. Environmental Protection Agency: Research-Management and Peer-Review Practices (2000) Scientific Frontiers in Developmental Toxicology and Risk Assessment (2000) Modeling Mobile-Source Emissions (2000) Toxicological Risks of Selected Flame-Retardant Chemicals (2000) Copper in Drinking Water (2000) Ecological Indicators for the Nation (2000) Waste Incineration and Public Health (1999) Hormonally Active Agents in the Environment (1999) Research Priorities for Airborne Particulate Matter: I. Immediate Priorities and a Long-Range Research Portfolio (1998); II. Evaluating Research Progress and Updating the Portfolio (1999) Ozone-Forming Potential of Reformulated Gasoline (1999) Risk-Based Waste Classification in California (1999) Arsenic in Drinking Water (1999) Brucellosis in the Greater Yellowstone Area (1998) The National Research Council's Committee on Toxicology: The First 50 Years (1997) Toxicologic Assessment of the Army's Zinc Cadmium Sulfide Dispersion Tests (1997) Carcinogens and Anticarcinogens in the Human Diet (1996) Upstream: Salmon and Society in the Pacific Northwest (1996) Science and the Endangered Species Act (1995) Wetlands: Characteristics and Boundaries (1995) Biologic Markers (5 reports, 1989-1995) Review of EPA's Environmental Monitoring and Assessment Program (three reports, 1994-1995) Science and Judgment in Risk Assessment (1994) Ranking Hazardous Waste Sites for Remedial Action (1994) Pesticides in the Diets of Infants and Children (1993) Issues in Risk Assessment (1993) Setting Priorities for Land Conservation (1993) Protecting Visibility in National Parks and Wilderness Areas (1993) Dolphins and the Tuna Industry (1992)

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Page xvi for their interest and support of this project. We also gratefully acknowledge the following persons who provided valuable background information to the subcommittee: Stacy Arnesen (National Library of Medicine), George Daston (Procter and Gamble Company), James Donald (California Environmental Protection Agency), Elaine Faustman (University of Washington), Michael Shelby (National Institute of Environmental Health Sciences), and John Weiner (University at Buffalo, State of New York). The subcommittee thanks R. Woodrow Setzer, Jr. (U.S. Environmental Protection Agency) for providing guidance on statistical methods discussed in this report. This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the NRC's Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: James Chen (National Center for Toxicological Research), George Daston (Procter and Gamble Company), Jerry Heindel (National Institute of Environmental Health Sciences), Grace Lemasters (University of Cincinnati), and John Young (National Center for Toxicological Research). Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Donald Mattison (March of Dimes Birth Defects Foundation), appointed by the Commission on Life Sciences, who was responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution. We are also grateful for the assistance of NRC staff in the prepara-

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Page xvii tion of this report. The subcommittee acknowledges Kulbir Bakshi, program director of the Committee on Toxicology and, in particular, Abigail Stack, project director for this report, without whose leadership and assistance this project could not have been completed. Other staff members contributing to this report were James Reisa, director of the Board on Environmental Studies and Toxicology (BEST); Carol Maczka, formerly BEST's senior program director for toxicology and risk assessment; Ruth Crossgrove, publications manager; Leah Probst, senior project assistant; and Emily Smail, project assistant. Finally, we thank all the members of the subcommittee for their expertise and dedicated effort throughout the study. Carole A. Kimmel, Ph.D. Chair, Subcommittee on Reproductive and Developmental Toxicology Bailus Walker Jr., Ph.D., M.P.H. Chair, Committee on Toxicology

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Page xix Contents ABBREVIATIONS xxi SSUMMARY 1 1     INTRODUCTION 11     Subcommittee Task, 20     Organization of the Report, 22 2     THE EVALUATIVE PROCESS: PART I. ASSESSING THE AVAILABLE DATA 24     Principles and Objectives, 24     General Description, 30     Details of the Evaluative Process, 31 3     THE EVALUATIVE PROCESS: PART II. INTEGRATION OF TOXICITY AND EXPOSURE INFORMATION 57     Interpretation of Toxicity Data, 57     Quantitative Evaluation, 64     Summary, 79 4     INCOMPLETE OR INSUFFICIENT DATA SETS 81     Principles to Minimize Risk, 81     Practical Application, 83     Reducing Uncertainty, 84

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Page xx 5     RECOMMENDATIONS 86     General Recommendations, 86     Research Recommendations, 89 REFERENCES 92 APPENDIXES     A     APPLICATION OF THE RECOMMENDED EVALUATIVE PROCESS TO SPECIFIC CHEMICALS 117     B     ASCERTAINING INFORMATION ON THE REPRODUCTIVE AND DEVELOPMENTAL TOXICITY OF AGENT EXPOSURES 168     C     HUMAN STUDY DESIGNS 198     D     EXPERIMENTAL ANIMAL AND IN VITRO STUDY DESIGNS 206

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Page xxi Abbreviations ACGIH American Conference of Governmental Industrial Hygienists ADI acceptable daily intake AIHA American Industrial Hygiene Association ATSDR Agency for Toxic Substances and Disease Registry AUC area under the curve BMD benchmark dose CAS Chemical Abstract Service CDC Centers for Disease Control and Prevention CFC chlorofluorocarbon Cmax peak threshold concentration DART developmental and reproductive toxicology EC European Commission ECETOC European Centre for Ecotoxicology and Toxicology of Chemicals EPA U.S. Environmental Protection Agency ETICBACK Environmental Teratology Information Center Backfile F1 first filial generation FDA U.S. Food and Drug Administration HEC human equivalent concentration HFC 134a 1,1,1,2-tetrafluoroethane HFC hydrofluorocarbon

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Page xxii HSDB Hazardous Substance Data Base IARC International Agency for Research on Cancer ILO International Labor Organization IPCS International Programme on Chemical Safety IRIS Integrated Risk Information System (Administered by the U.S. Environmental Protection Agency) JP-8 jet propellant-8 LC50 lethal concentration for 50% of the test animals LD50 lethal dose for 50% of the test animals LHRH luteinizing hormone releasing hormone LOAEL lowest-observed-adverse-effect level MDI metered dose inhaler MeSH medical subject headings MOE margin of exposure MTD maximum tolerated dose NCEA National Center for Environmental Assessment NIEHS National Institute of Environmental Health Sciences NIH National Institutes of Health NIOSH National Institute for Occupational Safety and Health NOAEL No-observed-adverse-effect level NRC National Research Council NTIS National Technical Information Service NTP National Toxicology Program OECD Organization for Economic Cooperation and Development OR odds ratio ORD Office of Research and Development P generation parental animals PEL permissible exposure limit RACB reproductive assessment of continuous breeding RfD reference dose RR relative risk RTECS Registry of Toxic Effects of Chemical Substances SIDS screening information data set SOP standard operating procedure STEL Short-Term Exposure Limit

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Page xxiii TLV Threshold Limit Value TOXNET Toxicology Data Network UEL unlikely effect level UF uncertainty factor UNEP United Nations Environmental Program WHO World Health Organization

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Page xxv EVALUATING CHEMICAL AND OTHER AGENT EXPOSURES FOR REPRODUCTIVE AND DEVELOPMENTAL TOXICITY

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