Hormonally Active Agents in the Environment

Committee on Hormonally Active Agents in the Environment
Board on Environmental Studies and Toxicology
Commission on Life Sciences
National Research Council

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Hormonally Active Agents in the Environment Committee on Hormonally Active Agents in the Environment Board on Environmental Studies and Toxicology Commission on Life Sciences National Research Council

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Page ii NATIONAL ACADEMY PRESS • 2101 Constitution Avenue, 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 project was supported by Contract No. CX 824040-01-0 between the National Academy of Sciences and the U.S. Environmental Protection Agency and the U.S. Centers for Disease Control and Prevention, and Cooperative Agreement No. 1445-CA09-96-0027 between the National Academy of Sciences and the National Biological Service of the U.S. Department of the Interior. 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. Library of Congress Cataloging-in-Publication Data Hormonally active agents in the environment / Committee on Hormonally Active Agents in the Environment. Board on Environmental Studies and Toxicology, Commission on Life Sciences, National Research Council. p. cm.  Includes bibliographical references (p. ) and index.  ISBN 0-309-06419-8 (case binding)  1. Reproductive toxicology. 2. Endocrine toxicology. 3. Environmental toxicology. I.  National Research Council (U.S.). Committee on Hormonally Active Agents in the  Environment.  RA1224.2.H67    1999  616.4'07 1—dc21                                                                          99-50523  Additional copies of this report are available from: Hormonally Active Agents in the Environment is available from the National Academy Press. 2101 Constitution Ave., NW, Box 285, Washington, DC 20418 (1-800-624-6242 or 202-334-3313 in the Washington metropoliton area: http://www.nap.edu). Copyright 1999 by the National Academy of Sciences. All rights reserved. Printed in the United States of Americabreak

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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.break

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iv BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY GORDON ORIANS (Chair,, University Of Washington, Seattle, Washington DONALD MA=SON (Vice Chair,, March of Dimes, White Plains, New York DAVID ALLEN, University of Texas, Austin, Texas MAY R. BERENBAUM, University of Illinois, Urbana, Illinois EULA BINGHAM, University of Cincinnati, Cincinnati, Ohio PAUL BUSCH, Malcolm Pirnie, Inc., White Plains, New York PETER L. DEFUR, Virginia Commonwealth University, Richmond, Virginia DAVID L. EATON, University of Washington, SeahIe, Washington ROBERTA. FROSCH, Harvard University, Cambridge, Massachusetts JOHN GERHART, University of California, Berkeley, California MARK HARWELL, University of Miami, Miami, Florida ROGENE HENDERSON, Lovelace Respiratory Research Institute, Albuquerque, New Mexico CAROL HENRY, Chemical Manufacturers Association, Arlington, Virginia BARBARA HULKA, University of North Carolina, Chapel Hill, North Carolina DANIEL KREWSKI, Health Canada and University of Ottawa, Ottawa, Ontario JAMES A. MACMAHON, Utah State University, Logan, Utah MARIO J. Mo' INA, Massachusetts Institute of Technology, Cambridge, Massachusetts CHARLES O'MEUA, Johns Hopkins University, Baltimore, Maryland KIRK SMITH, University of California, Berkeley, California MARGARET STRAND, Oppenheimer Wolff Donnelly & Bayh, LLP, Washington, D.C. TERRY F. YOSIE, Chemical Manufacturers Association, Arlington, Virginia Senior Staff JAMES Hi. REISA, Director DAVID Hi. POLICANSKY, Associate Director and Senior Program Director for Applied Ecology CAROL A. MACZKA, Senior Program Director for Toxicology and Risk Assessment RAYMOND A. WASSEL, Senior Program Director for Environmental Sciences and _ . . -nglneerlng KULBIR BAKSHI, Program Director for the Committee on Toxicology LEE R. PAULSON, Program Director for Resource Management

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Page v COMMITTEE ON HORMONALLY ACTIVE AGENTS IN THE ENVIRONMENT ERNST KNOBIL (Chair), The University of Texas-Houston Medical School, Houston, Texas HOWARD A. BERN, University of California, Berkeley, California JOANNA BURGER, Rutgers University, Piscataway, New Jersey D. MICHAEL FRY, University of California, Davis, California JOHN P. GIESY, Michigan State University, East Lansing, Michigan JACK GORSKI, University of Wisconsin, Madison, Wisconsin CHARLES J. GROSSMAN, Department of Veterans Affairs Medical Center, Cincinnati, Ohio, and Xavier University, Cincinnati, Ohio LOUIS J. GUILLETTE, JR., University of Florida, Gainesville, Florida BARBARA S. HULKA, University of North Carolina, Chapel Hill, North Carolina JAMES C. LAMB, IV, Jellinek, Schwartz, & Connolly, Inc., Arlington, Virginia LESLIE A. REAL, Emory University, Atlanta, Georgia STEPHEN H. SAFE, Texas A&M University, College Station, Texas ANA M. SOTO, Tufts University, Boston, Massachusetts JOHN J. STEGEMAN, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts SHANNA H. SWAN, University of Missouri, Columbia, Missouri FREDERICK S. VOM SAAL, University of Missouri, Columbia, Missouri Staff CAROL A. MACZKA, Project Director DAVID J. POLICANSKY, Project Director SUSAN N.J. PANG, Program Officer ABIGAIL E. STACK, Program Officer ROBERTA M. WEDGE, Program Officer KATE KELLY, Technical Editor RUTH E. CROSSGROVE, Technical Editor CATHERINE M. KUBIK, Senior Project Assistant LA VONE WELLMAN, Senior Project Assistant STEPHANIE L. VANN, Senior Project Assistant (through 12/98) ADRIÉNNE S. DAVIS, Senior Project Assistant (through 3/97) KATHRINE J. IVERSON, Technical Information Center Manager Sponsors U.S. Environmental Protection Agency U.S. Department of the Interior U.S. Centers for Disease Control and Preventionbreak

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Page vi BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY GORDON ORIANS (Chair), University of Washington, Seattle, Washington DONALD R. MATTISON (Vice Chair), March of Dimes, White Plains, New York DAVID ALLEN, University of Texas, Austin, Texas INGRID C. BURKE, Colorado State University, Fort Collins, Colorado WILLIAM L. CHAMEIDES, Georgia Institute of Technology, Atlanta, Georgia JOHN DOULL, The University of Kansas Medical Center, Kansas City, Kansas CHRISTOPHER B. FIELD, Carnegie Institute of Washington, Stanford, California JOHN GERHART, University of California, Berkeley, California J. PAUL GILMAN, Celera Genomics, Rockville, Maryland BRUCE D. HAMMOCK, University of California, Davis, California MARK HARWELL, University of Miami, Miami, Florida ROGENE HENDERSON, Lovelace Respiratory Research Institute, Albuquerque, New Mexico CAROL HENRY, Chemical Manufacturers Association, Arlington, Virginia BARBARA S. HULKA, University of North Carolina, Chapel Hill, North Carolina JAMES F. KITCHELL, University of Wisconsin, Madison, Wisconsin DANIEL KREWSKI, University of Ottawa, Ottawa, Ontario JAMES A. MACMAHON, Utah State University, Logan, Utah MARIO J. MOLINA, Massachusetts Institute of Technology, Cambridge, Massachusetts CHARLES O'MELIA, Johns Hopkins University, Baltimore, Maryland WILLEM F. PASSCHIER, Health Council of the Netherlands KIRK SMITH, University of California, Berkeley, California MARGARET STRAND, Oppenheimer Wolff Donnelly & Bayh, LLP, Washington, D.C. TERRY F. YOSIE, Chemical Manufacturers Association, Arlington, Virginia Senior Staff JAMES J. REISA, Director DAVID J. POLICANSKY, Associate Director and Senior Program Director for Applied Ecology CAROL A. MACZKA, Senior Program Director for Toxicology and Risk Assessment RAYMOND A. WASSEL, Senior Program Director for Environmental Sciences and Engineering KULBIR BAKSHI, Program Director for the Committee on Toxicology LEE R. PAULSON, Program Director for Resource Managementbreak

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Page vii COMMISSION ON LIFE SCIENCES MICHAEL T. CLEGG (Chair), University of California, Riverside, California PAUL BERG (Vice Chair), Stanford University, Stanford, California FREDERICK R. ANDERSON, Cadwalader, Wickersham & Taft, Washington, D.C. JOHN C. BAILAR III, University of Chicago, Chicago, Illinois JOANNA BURGER, Rutgers University, Piscataway, New Jersey SHARON L. DUNWOODY, University of Wisconsin, Madison, Wisconsin DAVID EISENBERG, University of California, Los Angeles, California JOHN EMMERSON, Portland, Oregon NEAL FIRST, University of Wisconsin, Madison, Wisconsin DAVID J. GALAS, Keck Graduate Institute of Applied Science, Claremont, California DAVID V. GOEDDEL, Tularik, Inc., South San Francisco, California ARTURO GOMEZ-POMPA, University of California, Riverside, California COREY S. GOODMAN, University of California, Berkeley, California HENRY HEIKKINEN, University of Northern Colorado, Greeley, Colorado BARBARA S. HULKA, University of North Carolina, Chapel Hill, North Carolina HANS J. KENDE, Michigan State University, East Lansing, Michigan CYNTHIA KENYON, University of California, San Francisco, California MARGARET G. KIDWELL, University of Arizona, Tucson, Arizona BRUCE R. LEVIN, Emory University, Atlanta, Georgia OLGA F. LINARES, Smithsonian Tropical Research Institute, Miami, Florida DAVID LIVINGSTON, Dana-Farber Cancer Institute, Boston, Massachusetts DONALD R. MATTISON, March of Dimes, White Plains, New York ELLIOT M. MEYEROWITZ, California Institute of Technology, Pasadena, California ROBERT T. PAINE, University of Washington, Seattle, Washington RONALD R. SEDEROFF, North Carolina State University, Raleigh, North Carolina ROBERT R. SOKAL, State University of New York, Stony Brook, New York CHARLES F. STEVENS, The Salk Institute, La Jolla, California SHIRLEY M. TILGHMAN, Princeton University, Princeton, New Jersey JOHN L. VANDEBERG, Southwest Foundation for Biomedical Research, San Antonio, Texas RAYMOND L. WHITE, University of Utah, Salt Lake City, Utah Staff WARREN R. MUIR, Executive Director JACQUELINE K. PRINCE, Financial Officer BARBARA B. SMITH, Administrative Associate KIT W. LEE, Administrative Assistantbreak

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Page viii OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Waste Incineration and Public Health (1999) Research Priorities for Airborne Particulate Matter: 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) Research Priorities for Airborne Particulate Matter: I. Immediate Priorities and a Long-Range Research Portfolio (1998) 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 (3 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) Hazardous Materials on the Public Lands (1992) Science and the National Parks (1992) Animals as Sentinels of Environmental Health Hazards (1991) Assessment of the U.S. Outer Continental Shelf Environmental Studies Program, Volumes I-IV (1991-1993) Human Exposure Assessment for Airborne Pollutants (1991) Monitoring Human Tissues for Toxic Substances (1991) Rethinking the Ozone Problem in Urban and Regional Air Pollution (1991) Decline of the Sea Turtles (1990) Copies of these reports may be ordered from the National Academy Press (800) 624-6242 (202) 334-3313 www.nap.edubreak

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Page ix Preface There has been increasing public concern about potential adverse effects on human health of various environmental contaminants designated by some as "endocrine disruptors." In response, the National Research Council was asked by the Environmental Protection Agency, the Department of the Interior, the Centers for Disease Control and Prevention, and the United States Congress to help policy makers by independently evaluating the scientific evidence that bears on the issue. This report is the culmination of a long and difficult process that began with the appointment of the Committee on Hormonally Active Agents in the Environment by the National Research Council more than 4 years ago on July 27, 1995. The formal charge to the committee was as follows: review critically the literature on hormone-related toxicants in the environment; identify the known and suspected toxicologic mechanisms and impacts on fish, wildlife, and humans; identify significant uncertainties, limitations of knowledge, and weaknesses in the available evidence; develop a science-based conceptual framework for assessing observed phenomena; and recommend research, monitoring, and testing priorities. To the extent practicable with available information and study resources, the committee [also was asked to] identify particular chemical substances, geographic areas, contaminant sources, human subpopulations, and fish and wildlife populations of special concern with respect to hormone-related toxicants. The membership of the committee represents an attempt to obtain a balance of views regarding the subject as well as scientific expertise in the principal domains that comprise the study of hormonally active agents (HAAs) in the envi-soft

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Page x ronment. The efforts to unambiguously define "endocrine disruptors," by whatever name, and the reasons for renaming them "hormonally active agents" (HAAs), are detailed in the introduction of the report. The committee met on five occasions and received briefings from Dr. Margaret Stasikowski (U.S. EPA), The Honorable Robert Perciasepe (U.S. EPA), Dr. Robert Kavlock (U.S. EPA), and Dr. Robert Hoover (National Cancer Institute). The committee proceeded with its study and deliberations, focusing on our charge, which was first and foremost the critical review of the literature on the subject. The work of the committee was organized to reflect the major biological systems affected by HAAs. These became the chapters of the report. Drafts of these chapters were extensively discussed and critiqued by the committee. The chair and the project directors, acting as editors, modified the original texts accordingly. This process went through dozens of iterations in attempts to achieve a consensus document. This was readily achieved in some chapters but became extraordinarily difficult in others, most notably in the area of reproduction and development, including the issue of declining sperm production in human populations. 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 for reviewing NRC and Institute of Medicine reports. The purpose of this independent review is to provide candid and critical comments that will assist the NRC in making the 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, who are neither officials nor employees of the NRC, for their participation in the review of this report: Donald Brown, Carnegie Institution of Washington; Theo Colborn, World Wildlife Fund; Peter de Fur, Richmond, VA; Ronald Estabrook, University of Texas; Neal First, University of Wisconsin; Ronald Kendall, Texas Tech University; Ellen Ketterson, Indiana University; Dolores Lamb, Baylor College of Medicine; Paul Licht, University of California, Berkeley; Emil Pfitzer, Ramsey, NJ; Lorenz Rhomberg, Harvard School of Public Health; Herbert Rosenkranz, University of Pittsburgh; Antonio Sastre, Midwest Research Institute; George Seidel, Colorado State University; Ellen Silbergeld, University of Maryland; Paul Stolley, Columbia MD; Paolo Toniolo, IARC; and John Wingfield, University of Washington. The individuals above provided many constructive comments and suggestions. It must be emphasized, however, that responsibility for the final content of this report rests entirely with the authorizing subcommittee and the NRC. The work leading to this report, which has taken 4 years to complete, was a challenging and arduous exercise. It is hoped that the long delay in its publication will not unduly impair its utility for those who have the important responsi-soft

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Page xi bility of making policy decisions regarding relevant research and public health agendas. The chair is particularly grateful to Drs. Carol Maczka and David Policansky, the project co-directors, and their staffs for their truly Herculean labors.break ERNST KNOBIL, PH.D. CHAIR, COMMITTEE ON HORMONALLY ACTIVE AGENTS IN THE ENVIRONMENT

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Page xiii Contents Glossary xvii Executive Summary 1 1 Introduction 10 This Study, 12 Issues That Divided the Committee, 15 2 Hormonally Active Agents 27 Hormone-Receptor-Mediated Actions, 28 Hormonally Active Agents, 38 Mechanism of Estrogen Action, 47 Modulation of Estrogen-Induced Responses, 51 Summary and Conclusions, 52 3 Exposures: Sources And Dynamics Of Hormonally Active Agents In The Environment 54 Sources and Releases, 55 Persistence, 58 Monitoring, 59 Exposure, 67 Summary and Conclusions, 80 Recommendations, 81

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Page xiv 4 Dosimetry 82 Uptake, Elimination, and Accumulation, 83 Routes of Exposure, 84 Food-Chain Transfer and Bioaccumulation, 91 Distribution, 92 Metabolism, 100 Species Differences in Metabolism, 108 Factors Influencing Dose-Response Assessment, 109 Summary and Conclusions, 115 Recommendations, 117 5 Effects on Reproduction and Development 119 Laboratory Animal Studies of Selected HAAs, 121 Human Studies, 131 Wildlife Studies, 146 Summary and Conclusions, 167 Recommendations, 170 6 Neurologic Effects 171 Animal Studies, 171 Human Studies, 172 Summary and Conclusions, 184 Recommendations, 185 7 Immunologic Effects 186 HAAs and Steroid Hormones, 187 Halogenated Aromatic Hydrocarbon Compounds, 188 Dichlorodiphenyltrichloroethane, 196 Chlordecone, 198 Endrin, Aldrin, and Dieldrin, 198 Lindane, 198 Chlordane, 202 Toxaphene, 202 Endosulfan, 203 Hexachlorobenzene, 203 Summary and Conclusions, 203 Recommendations, 208 8 HAAs and Carcinogenesis in Animals 210 Bioassays, 211 Summary and Conclusions, 241 Recommendations, 242

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Page xv 9 HAAs and Carcinogenesis in Humans 243 Breast Cancer 244 Endometrial Cancer 263 Endogenous and Exogenous Hormones and Their Effects in Women 264 Testicular Cancer, 266 Prostate Cancer, 269 Summary and Conclusions, 272 Recommendations, 273 10 Ecological Effects 274 Nature of Ecologic Effects, 275 Effects on Populations and Communities, 281 Summary and Conclusions, 295 Recommendations, 295 11 Screening and Monitoring 296 Screening Tools, 297 Biologic Markers of Exposure and Effect, 306 Instrumental Chemical Techniques, 308 Summary and Conclusions, 309 Recommendations, 310 References 311 Appendix A: Reproductive Effects Caused by Diethylstilbesterol 399 Appendix B: Biographical Information on the Committee on Hormonally Active Agents in the Environment 407 Addendum: Endocrine Disruptor Screening and Testing Advisory Committee 410 Index 415

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Page xvii Glossary 16a-OH-E2 estriol ADI acceptable daily intake AF-2 activation function-2 AFP a-fetoprotein Ah aryl hydrocarbon AMS USDA Agricultural Market Survey APE alkylphenol ethoxylate ATSDR Agency for Toxic Substances and Disease Registry b-HCH b-hexachlorocyclohexane B[a]P benzo[a]pyrene BBP butyl benzyl phthalate BKD bacterial kidney disease BKME bleached kraft mill effluent BNBAS Brazelton Neonatal Behavioral Assessment Scales BPA bisphenol A BW body weight CB chlorobiphenyl CF ''E" Carworth Farm "E" strain CI confidence interval CMI cell-mediated immune ConA concanavalin A CYP cytochrome P450 CYP11 side-chain-cleavage enzyme CYP 17 17-hydroxylase CYP 19 aromatase

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Page xviii DBP dibutyl phthalate DDD 1, 1 -dichloro-2,2-bis(p-chlorophenyl )ethane DDE 1, 1 -dichloro-2,2-bis(p-chlorophenyl)ethylene DDT dichlorodiphenyltrichloroethane DEHP iethylhexyl phthalate DES diethylstilbestrol DMBA 7, 12-dimethylbenzathracene DOI Department of the Interior DTH delayed-type hypersensitivity E1 estrone E2 estradiol EDSTAC Endocrine Disruptor Screening and Testing Advisory Committee (U.S. Environmental Protection Agency) EGF epidermal growth factor EPA Environmental Protection Agency ER estrogen receptor ER- estrogen receptor negative ER+ estrogen receptor positive ERE estrogen responsive element FDA Food and Drug Administration FSH follicle-stimulating hormone GLEMEDS Great Lakes embryo mortality, edema, and deformity syndrome GM-CFU granulocyte-macrophage colony-forming unit GnRH gonadotropin-releasing hormone GtH-II gonadotropin hormone-II HAA hormonally active agent HAH halogenated aromatic hydrocarbon HCB hexachlorobenzene hCG human chorionic gonadotropin HCH hexachlorohexane HpCDF hepatochlorodibenzofuran HQ hazard quotient HRT hormone replacement therapy IARC International Agency for Research on Cancer IOM Institute of Medicine IUGR intrauterine growth retardation IVF/ET in vitro fertilization and embryo transfer Kow octanol/water partition coefficient LH luteinizing hormone LPS lipopolysaccharide MAFF Ministry of Agriculture, Fisheries, and Food MDI [Bayley] Mental Development Index MeSO2 methylsulfonyl

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Page xix MTD maximum tolerated dose NAE National Academy of Engineering NAS National Academy of Sciences NCI National Cancer Institute ND none detected NIEHS National Institute of Environmental Health Sciences NOAEL no observed adverse effect level NP nonylphenol NPE nonylphenol ethoxylate NRC National Research Council NTP National Toxicology Program NTR no tumors reported OR odds ratio PAH polycyclic aromatic hydrocarbon PBB polybrominated biphenyl PB-PK physiologically based pharmacokinetic model PCB polychlorinated biphenyl PCDD polychlorinated dibenzo-p-dioxin PCDF polychlorinated dibenzofuran PCDH polychlorinated diaromatic hydrocarbon PCR polymerase chain reaction PDI [Bayley] Psychomotor Development Index PeCB 3,3',4,4',5-pentachlorobiphenyl PeCDF 1,2,3,7,9-pentachlorodibenzofuran PFC plaque-forming cell PHA phytohemagglutinin PHED Pesticide Handlers Exposure Database PSA prostate specific antigen PWA pokeweed mitogen RfD reference dose RPF relative potency factor SAP Scientific Advisory Panel SBP steroid-binding plasma protein SHBG steroid-hormone-binding globulin SIR standardized incidence ratio SMR standardized mortality ratio sGnRH-A synthetic gonadotropin-releasing hormone SPI Society for the Plastics Industry SRBC sheep red blood cell STPE sewage treatment plant effluent T4 3,3',5,5'-tetraiodo-L-thyronine (thyroxin) TBG thyroxine-binding globulin TCB tetrachlorobiphenyl

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Page xx TCDD 2,3,7,8-tetrachlorodibenzo-p-dioxin TCDD-EQ dioxin-like chemical TCDF 2,3,7,8- or 1,3,6,8-tetrachlorodibenzofuran TDS FDA Total Diet Study TEQ toxic equivalent TGF transforming-growth factor TIE toxic identification and evaluation TMRC theoretical maximum residue concentration tT4 total T4 TTP time to pregnancy USDA U.S. Department of Agriculture VLDL very-low-density lipoprotein WHO World Health Organization ZRP zona radiata protein

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HORMONAIIY ACTIVE AGENTS by THE ENVIRONMENT

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