SCIENTIFIC FRONTIERS IN DEVELOPMENTAL TOXICOLOGY AND RISK ASSESSMENT

Committee on Developmental Toxicology

Board on Environmental Studies and Toxicology

Commission on Life Sciences

National Research Council

NATIONAL ACADEMY PRESS
Washington, DC



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Scientific Frontiers in Developmental Toxicology and Risk Assessment SCIENTIFIC FRONTIERS IN DEVELOPMENTAL TOXICOLOGY AND RISK ASSESSMENT Committee on Developmental Toxicology Board on Environmental Studies and Toxicology Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington, DC

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Scientific Frontiers in Developmental Toxicology and Risk Assessment NATIONAL ACADEMY PRESS 2101 Constitution Ave., N.W. 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 the U.S. Department of Defense; (DAMD 17-89-C9086 and DAMD 17-99-C9049), the U.S. Department of Health and Human Services; (PR-470644, PR-470645, 273-MH-901198, 273-MH-913119, P-0158-00-6-00, 0009554547, and 263-MD-635973), the U.S. Environmental Protection Agency; (CR-823615, R-827241-01), the U.S. Department of Veterans Affairs; (V101 P-1578), and the American Industrial Health Council. All contracts and awards were between the sponsoring agency or organization and the National Academy of Sciences. 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 0-309-07086-4 Library of Congress Catalog Card Number 00-106422 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 2000 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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Scientific Frontiers in Developmental Toxicology and Risk Assessment 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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Scientific Frontiers in Developmental Toxicology and Risk Assessment Committee on Developmental Toxicology Elaine M. Faustman (Chair), University of Washington, Seattle, Washington John C. Gerhart (Vice Chair), University of California, Berkeley, California Nigel A. Brown, St. George’s Hospital Medical School, London, United Kingdom George P. Daston, The Procter & Gamble Company, Cincinnati, Ohio Mark C. Fishman, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts Joseph F. Holson, WIL Research Laboratories, Inc., Ashland, Ohio Herman B.W.M. Koëter, Organisation for Economic Cooperation and Development, Paris, France Anthony P. Mahowald, University of Chicago, Chicago, Illinois Jeanne M. Manson, University of Pennsylvania, Phildelphia, Pennsylvania Richard K. Miller, University of Rochester, Rochester, New York Philip E. Mirkes, University of Washington, Seattle, Washington Daniel W. Nebert, University of Cincinnati Medical Center, Cincinnati, Ohio Drew M. Noden, Cornell University, Ithaca, New York Virginia E. Papaioannou, Columbia University College of Physicians and Surgeons, New York, New York Gary C. Schoenwolf, University of Utah, Salt Lake City, Utah Frank Welsch, Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina William B. Wood, University of Colorado, Boulder, Colorado Consultant Paul W.J. Peters, University of Utrecht, The Netherlands Staff Abigail E. Stack, Project Director Ruth E. Crossgrove, Editor Mirsada Karalic-Loncarevic, Information Specialist Leah L. Probst, Senior Project Assistant Emily L. Smail, Project Assistant Sponsors AMERICAN INDUSTRIAL HEALTH COUNCIL CENTERS FOR DISEASE CONTROL AND PREVENTION U.S. DEPARTMENT OF DEFENSE U.S. ENVIRONMENTAL PROTECTION AGENCY U.S. DEPARTMENT OF VETERANS AFFAIRS NATIONAL CENTER FOR TOXICOLOGICAL RESEARCH NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH

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Scientific Frontiers in Developmental Toxicology and Risk Assessment Board on Environmental Studies and Toxicology Gordon Orians (Chair), University of Washington, Seattle, Washington Donald 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, American Chemical Council, Arlington, Virginia Barbara 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, The Hague Kirk Smith, University of California, Berkeley, California Margaret Strand, Oppenheimer Wolff Donnelly & Bayh, LLP, Washington, D.C. Terry F. Yosie, American Chemical Council, 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 S. Bakshi, Program Director for Toxicology Lee R. Paulson, Program Director for Resource Management Roberta Wedge, Program Director for Risk Analysis

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Scientific Frontiers in Developmental Toxicology and Risk Assessment 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. Joanna Burger, Rutgers University, Piscataway, New Jersey James E. Cleaver, University of California, San Francisco, California David Eisenberg, University of California, Los Angeles, California John Emmerson, Fishers, Indiana Neal First, University of Wisconsin, Madison, Wisconsin David J. Galas, Keck Graduate Institute of Applied Life 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 Jon W. Gordon, Mount Sinai School of Medicine, New York, New York David G. Hoel, Medical University of South Carolina, Charleston, South Carolina Barbara S. Hulka, University of North Carolina, Chapel Hill, North Carolina Cynthia Kenyon, University of California, San Francisco, California Bruce R. Levin, Emory University, Atlanta, Georgia 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 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 Laura Holliday, Senior Project Assistant

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Scientific Frontiers in Developmental Toxicology and Risk Assessment Other Reports of the Board on Environmental Studies and Toxicology 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 (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.edu

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Scientific Frontiers in Developmental Toxicology and Risk Assessment Preface Developmental defects are a significant human-health problem. Approximately 3% of human developmental defects are attributed to exposure to toxic chemicals (e.g., lead and mercury) and physical agents (e.g., radiation), including agents found in the environment. Twenty-five percent of developmental defects might be due to a combination of genetic and environmental factors, where those factors are defined broadly to include physical, chemical, and biological agents and conditions, such as infections, nutritional deficiencies and excesses, life-style factors (e.g., alcohol), hyperthermia, ultraviolet radiation, X-rays, and the myriad of manufactured chemicals (e.g., pharmaceuticals, synthetic chemicals, solvents, pesticides, fungicides, herbicides, cosmetics, and food additives) and natural materials (e.g., plant and animal toxins and products). Because of human-health concerns about the developmental toxicity of environmental agents, scientists and regulators have focused efforts on understanding and protecting against the potential hazards of these agents to developing embryos, fetuses, and children. Recent advances in the fields of developmental biology and genomics provide opportunities to further understand the role of environmental agents in human developmental defects and, therefore, the National Research Council (NRC) undertook a project to explore the opportunities in this area. The first phase of the project consisted of a symposium entitled “New Approaches for Assessing the Etiology and Risks of Developmental Abnormalities from Chemical Exposure.” The symposium was held December 11-12, 1995, in Washington, D.C. In the second phase, a multidisciplinary committee with expertise in developmental biology and developmental toxicology was convened by the NRC to prepare this consensus report. In this report, the Committee on Developmental Toxicology evaluates current approaches used to assess risk for developmental defects and identifies key

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Scientific Frontiers in Developmental Toxicology and Risk Assessment areas of uncertainty in those approaches. It also evaluates current understanding of the mechanisms of action of chemicals that result in developmental defects. The committee examines recent advances in developmental biology and genomics to highlight how new scientific information can be used to improve risk assessment for developmental toxicants and to elucidate the mechanisms by which toxicants induce developmental defects. Finally, the committee evaluates how the new information and technologies can be integrated into an overall risk-assessment framework. The number of new discoveries made between late 1995, when the NRC symposium was held, and the beginning of 2000, when this report was completed, is staggering—especially in genomics, human genetics, transgenic mouse studies, and elucidation of signal transduction pathways of central importance to developmental biology and, by extrapolation, to developmental toxicology. The amount of additional information expected in the next 4 years likely will be even more explosive. Hence, it should be emphasized that this report represents a “snapshot in time” during a time of monumental advances in molecular biology and genetic research. We would like to express our thanks and appreciation to Carole Kimmel, U.S. Environmental Protection Agency, who was instrumental in helping the NRC to initiate this project. The committee was generously assisted by the following people who presented valuable background information during the committee’s public sessions: Carole Kimmel; Lewis Holmes, Harvard Medical School; Daniel Krewski, University of Ottawa; Andrew Olshan, University of North Carolina, Chapel Hill; James Ostell, National Center for Biotechnology Information; Allan Spradling, Carnegie Institute of Washington; and Robert Strausberg, National Cancer Institute. We gratefully acknowledge Barbara Abbott, U.S. Environmental Protection Agency, and Patricia Rodier, University of Rochester, who, at the committee’s request, contributed information on the mechanism of action of 2,3,7,8-tetrachlorodibenzo-p-dioxin and on chemicals that may induce autism, respectively. We also gratefully acknowledge Paul Peters from the University of Utrecht. Dr. Peters served as a consultant to the committee and provided valuable information on research being done in European countries to improve risk assessment for developmental defects. The committee wishes to thank the American Industrial Health Council, the Centers for Disease Control and Prevention, the U.S. Department of Defense, the U.S. Environmental Protection Agency, the U.S. Department of Veterans Affairs, the National Center for Toxicological Research, the National Institute of Environmental Health Sciences, the National Institute of Child Health and Human Development, and the National Institute for Occupational Safety and Health for their interest and support of this project. This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise in accordance with procedures ap-

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Scientific Frontiers in Developmental Toxicology and Risk Assessment proved 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 manuscripts 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: John DeSesso, Mitretek Systems; Barbara Hales, McGill University; Lewis Holmes, Harvard Medical School; John Moore, National Toxicology Program Center for the Evaluation of Risks to Human Reproduction; Gary Shaw, California Birth Defects Monitoring Program; Allan Spradling, Carnegie Institution of Washington; and Patrick Wier, Smithkline Beecham Pharmaceuticals. Donald Mattison, March of Dimes Birth Defects Foundation, served as review coordinator. The individuals listed above have provided many constructive comments and suggestions. It must be emphasized, however, that responsibility for the final content of this report rests entirely with the authoring committee and the NRC. We are grateful for the assistance of the NRC staff in the preparation of the report. Staff members who contributed to this effort are Warren Muir, executive director of the Commission on Life Sciences; James Reisa, director of the Board on Environmental Studies and Toxicology; Carol Maczka, director of BEST’s Toxicology and Risk Assessment Program; Ruth Crossgrove, editor; Mirsada Karalic-Loncarevic, information specialist; Leah Probst, senior project assistant; and Emily Smail, project assistant. We are especially indebted to Abigail Stack, who served as project director. In this role, Dr. Stack served tirelessly, both with scientific and administrative support, maintaining the integrity of the report yet gently insisting on timely responses. We thank her for her excellent service in this challenging role. Finally, we would like to thank all the members of the committee for their dedicated efforts throughout the development of this report. We hope this report reflects the exciting deliberations of the committee that led to its genesis. Elaine Faustman, Ph.D. Chair, Committee on Developmental Toxicology John Gerhart, Ph.D. Vice Chair, Committee on Developmental Toxicology

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Scientific Frontiers in Developmental Toxicology and Risk Assessment Contents     LIST OF ABBREVIATIONS   xv     EXECUTIVE SUMMARY   1 1   INTRODUCTION   10      Background,   11      Recent Advances in Developmental Biology and the Promise of Genomics,   13      Committee’s Approach to Its Charge,   15      Organization of the Report,   15 2   DEVELOPMENTAL DEFECTS AND THEIR CAUSES   17      Toxicant Exposure and Developmental Defects,   20      The Chemical Universe,   22      Summary,   25 3   CURRENT PRACTICES FOR ASSESSING RISK FOR DEVELOPMENTAL DEFECTS AND THEIR LIMITATIONS   26      The Developmental Toxicity Risk Assessment Process,   26      Biomarkers,   49      Limitations in Developmental Toxicity Risk Assessments,   54      Summary,   57 4   MECHANISMS OF DEVELOPMENTAL TOXICITY   58      History of Developmental Toxicology: Growth of a New Field,   58      Principles of Teratology,   60

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Scientific Frontiers in Developmental Toxicology and Risk Assessment      Mechanisms of Toxicity,   63      Summary,   86 5   HUMAN GENETICS AND THE HUMAN GENOME PROJECT   88      Genotype, Phenotype, and Multifactorial Inheritance,   89      Polymorphisms,   90      The Human Genome Project,   92      Recent Developments in Molecular Epidemiology,   100      Summary,   107 6   RECENT ADVANCES IN DEVELOPMENTAL BIOLOGY   108      A Brief History of Developmental Biology,   108      Advances in Developmental Biology,   111      Summary,   149 7   USING MODEL ANIMALS TO ASSESS AND UNDERSTAND DEVELOPMENTAL TOXICITY   151      Model Organisms and the Genetic Approach,   151      The Major Model Animals for Genetic Analysis,   158      Possible Applications of Model Animal Research to Developmental Toxicology,   176      Gene Expression as Determined by In Vitro and Engineered Cell Technologies,   191      Summary,   195 8   A MULTILEVEL APPROACH TO IMPROVING RISK ASSESSMENT FOR DEVELOPMENTAL TOXICITY   196      The Multidisciplinary, Multilevel, Interactive Approach,   197      Summary,   219 9   CONCLUSIONS AND RECOMMENDATIONS   220      Conclusions in Relation to the Charge,   220      Recommendations,   226     REFERENCES   245 Appendix A:   GLOSSARY   281 Appendix B:   DATABASE DESCRIPTIONS   290 Appendix C:   SIGNALING PATHWAYS   296 Appendix D:   BIOGRAPHICAL INFORMATION ON THE COMMITTEE ON DEVELOPMENTAL TOXICOLOGY   309     INDEX   313

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Scientific Frontiers in Developmental Toxicology and Risk Assessment List of Abbreviations ACE angiotensin-converting enzyme ADH alcohol dehydrogenase ADI acceptable daily intake ADME absorption, distribution, metabolism, and excretion AER apical ectodermal ridge AHH aryl hydrocarbon hydroxylase AHR aryl hydrocarbon receptor ALDH acetylaldehyde dehydrogenase ARNT aryl hydrocarbon receptor nuclear translocator ASD autism spectrum disorders ATP adenosine triphosphate AUC area under the curve BLAST Basic Local Alignment Search Tool BMD benchmark dose CDC Centers for Disease Control and Prevention cDNA complementary deoxyribonucleic acid CGAP Cancer Genome Anatomy Project CHEST chick embryotoxicity test Cmax peak threshold concentration CNS central nervous system DBCP 1,2-dibromo-3-chloropropane DDBJ DNA Data Bank of Japan DDT dichlorodiphenyltrichloroethane DES diethylstilbesterol Δ7-DHC Δ7-dehydrocholesterol

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Scientific Frontiers in Developmental Toxicology and Risk Assessment DME drug-metabolizing enzyme DNA deoxyribonucleic acid DOE U.S. Department of Energy DPH diphenylhydantoin EBI European Bioinformatics Institute EBV Epstein-Barr virus ED05 best estimate of a dose at a 5% level of response EDSP Endocrine Disruptor Screening Program EGEE ethylene glycol monoethylether EGF epidermal growth factor EGME ethylene glycol monomethyl ether EGP Environmental Genome Project ELSI ethical, legal, and social implications EM extensive metabolizers EMBL European Molecular Biology Library EPA U.S. Environmental Protection Agency ER endoplasmic reticulum ES cell embryonic stem cell EST expressed sequence tag EtO ethylene oxide F1 first filial generation FAE fetal alcohol effects FAK focal adhesion kinases FAS fetal alcohol syndrome FDA U.S. Food and Drug Administration FETAX frog embryo teratogenesis assay-Xenopus FGF fibroblast growth factor FOB functional observational battery FQPA Food Quality Protection Act GFP green fluorescent protein GMS genomic mismatch scanning GR glucocorticoid receptor GRE glucocorticoid response element GSDB Genome Sequence Database hCMV human cytomegalovirus HEPM human embryonic palatal mesenchymal HGP Human Genome Project HOX homeobox Hsp heat-shock promoter HSV-1 herpes simplex virus type 1 ICBD International Clearinghouse for Birth Defects IPCS International Programme on Chemical Safety IRIS Integrated Risk Information System

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Scientific Frontiers in Developmental Toxicology and Risk Assessment JNK c-Jun terminal kinase LANL Los Alamos National Laboratory LCR-MT locus control regions of the metallothionein gene LOAEL lowest-observed-adverse-effect level Mb megabases MeHg methylmercury mm millimeter MMTV LTR mouse mammary tumor virus long-terminal repeat MOE margin of exposure MOT mouse ovarian tumor MRI magnetic resonance imaging mRNA messenger RNA MTD maximum tolerated dose NAREP North American Registry for Epilepsy and Pregnancy NCBI National Center for Biotechnology Information NCGR National Center for Genome Resources NCI National Cancer Institute NCTR National Center for Toxicological Research NHGRI National Human Genome Research Institute NIEHS National Institute of Environmental Health Sciences NIGMS National Institute of General Medical Sciences NIH National Institutes of Health NMDA n-methyl-D-aspartate NOAEL no-observed-adverse-effect level NRC National Research Council OECD Organization for Economic Cooperation and Development ORF open reading frame PAH polycyclic aromatic hydrocarbon PARP poly(ADP-ribose)polymerase PCR polymerase chain reaction PUBS percutaneous umbilical blood sampling PZ progress zone RA retinoic acid Raldh2 retinaldehyde dehydrogenase-2 RAR retinoic acid receptor RAREs retinoic acid response elements RfC reference concentration RfD reference dose RNA ribonucleic acid RNAi RNA-mediated gene interference RT reverse transcription RT-PCR reverse transcription polymerase chain reaction RTECS Registry of Toxic Effects of Chemical Substances

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Scientific Frontiers in Developmental Toxicology and Risk Assessment RTK receptor tyrosine kinase SAR structure-activity relationship SHH Sonic Hedgehog SNP single-nucleotide polymorphism SOT Society of Toxicology SV40 simian virus 40 2,4,5-T 2,4,5-trichlorophenoxyacetic acid TCDD 2,3,7,8-tetrachlorodibenzo-p-dioxin TEF toxicity equivalency factor TGF transforming growth factor Tk thymidine kinase TSCA Toxic Substances Control Act UM ultra-metabolizers VPA valproic acid Wnt Wingless-Int YPLL years of potential life lost ZPA zone of polarizing activity

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