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Toxicity Testing for Assessment of Environmental Agents: Interim Report Toxicity Testing for Assessment of Environmental Agents Interim Report Committee on Toxicity Testing and Assessment of Environmental Agents Board on Environmental Studies and Toxicology Institute for Laboratory Animal Research Division on Earth and Life Studies NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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Toxicity Testing for Assessment of Environmental Agents: Interim Report THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 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. 68-C-03-081 between the National Academy of Sciences and the U.S. Environmental Protection Agency. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of the organizations or agencies that provided support for this project. International Standard Book Number 0-309-10092-5 (Book) International Standard Book Number 0-309-65652-4 (PDF) Library of Congress Control Number 2006923288 Additional copies of this report are available from The National Academies Press 500 Fifth Street, NW Box 285 Washington, DC 20055 800-624-6242 202-334-3313 (in the Washington metropolitan area) http://www.nap.edu Copyright 2006 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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Toxicity Testing for Assessment of Environmental Agents: Interim Report THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine 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. Ralph J. Cicerone 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. Wm. 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. Harvey V. Fineberg 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. Ralph J. Cicerone and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Toxicity Testing for Assessment of Environmental Agents: Interim Report COMMITTEE ON TOXICITY TESTING AND ASSESSMENT OF ENVIRONMENTALAGENTS Members DANIEL KREWSKI (Chair), University of Ottawa, Ottawa, ON DANIEL ACOSTA, JR., University of Cincinnati, Cincinnati, OH MELVIN ANDERSEN, CIIT Centers for Health Research, Research Triangle Park, NC HENRY ANDERSON, Wisconsin Division of Public Health, Madison JOHN BAILAR III, University of Chicago, Chicago, IL KIM BOEKELHEIDE, Brown University, Providence, RI ROBERT BRENT, Thomas Jefferson University, Wilmington, DE GAIL CHARNLEY, HealthRisk Strategies, Washington, DC VIVIAN CHEUNG, University of Pennsylvania, Philadelphia SIDNEY GREEN, Howard University, Washington, DC KARL KELSEY, Harvard University, Boston, MA NANCY KERKVLIET, Oregon State University, Corvallis ABBY LI, Exponent, Inc., San Francisco, CA GEORGE LUCIER, Consultant, Pittsboro, NC LAWRENCE MCCRAY, Massachusetts Institute of Technology, Cambridge OTTO MEYER, Danish Institute for Food and Veterinary Research, Søborg, Denmark D. REID PATTERSON, Reid Patterson Consulting, Inc., Grayslake, IL WILLIAM PENNIE, Pfizer, Inc., Groton, CT ROBERT SCALA, Exxon Biomedical Sciences (Ret.), Tucson, AZ GINA SOLOMON, Natural Resources Defense Council, San Francisco, CA MARTIN STEPHENS, The Humane Society of the United States, Washington, DC JAMES YAGER, JR., Johns Hopkins University, Baltimore, MD LAUREN ZEISE, California Environmental Protection Agency, Oakland Staff ELLEN MANTUS, Study Director ROBERTA WEDGE, Study Director (through January 2005) JOANNE ZURLO, Board Director JENNIFER OBERNIER, Program Officer NORMAN GROSSBLATT, Senior Editor JENNIFER D. ROBERTS, Postdoctoral Research Associate MIRSADA KARALIC-LONCAREVIC, Research Associate JORDAN CRAGO, Senior Project Assistant LUCY FUSCO, Senior Project Assistant ALEXANDRA STUPPLE, Senior Editorial Assistant Sponsor U.S. ENVIRONMENTAL PROTECTION AGENCY

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Toxicity Testing for Assessment of Environmental Agents: Interim Report BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Members JONATHAN M. SAMET (Chair), Johns Hopkins University, Baltimore, MD RAMÓN ALVAREZ, Environmental Defense, Austin, TX JOHN M. BALBUS, Environmental Defense, Washington, DC THOMAS BURKE, Johns Hopkins University, Baltimore, MD DALLAS BURTRAW, Resources for the Future, Washington, DC JAMES S. BUS, Dow Chemical Company, Midland, MI COSTEL D. DENSON, University of Delaware, Newark E. DONALD ELLIOTT, Willkie Farr & Gallagher LLP, Washington, DC J. PAUL GILMAN, Oak Ridge National Laboratory, Oak Ridge, TN SHERRI W. GOODMAN, Center for Naval Analyses, Alexandria, VA JUDITH A. GRAHAM, American Chemistry Council, Arlington, VA DANIEL S. GREENBAUM, Health Effects Institute, Cambridge, MA WILLIAM P. HORN, Birch, Horton, Bittner and Cherot, Washington, DC ROBERT HUGGETT, Michigan State University (emeritus), East Lansing JAMES H. JOHNSON, JR., Howard University, Washington, DC JUDITH L. MEYER, University of Georgia, Athens PATRICK Y. O’BRIEN, ChevronTexaco Energy Technology Company, Richmond, CA DOROTHY E. PATTON, International Life Sciences Institute, Washington, DC STEWARD T.A. PICKETT, Institute of Ecosystem Studies, Millbrook, NY DANNY D. REIBLE, University of Texas, Austin JOSEPH V. RODRICKS, ENVIRON International Corporation, Arlington, VA ARMISTEAD G. RUSSELL, Georgia Institute of Technology, Atlanta LISA SPEER, Natural Resources Defense Council, New York, NY KIMBERLY M. THOMPSON, Massachusetts Institute of Technology, Cambridge MONICA G. TURNER, University of Wisconsin, Madison MARK J. UTELL, University of Rochester Medical Center, Rochester, NY CHRIS G. WHIPPLE, ENVIRON International Corporation, Emeryville, CA LAUREN ZEISE, California Environmental Protection Agency, Oakland Senior Staff JAMES J. REISA, Director DAVID J. POLICANSKY, Scholar RAYMOND A. WASSEL, Senior Program Officer for Environmental Sciences and Engineering KULBIR BAKSHI, Senior Program Officer for Toxicology EILEEN N. ABT, Senior Program Officer for Risk Analysis K. JOHN HOLMES, Senior Program Officer SUSAN N.J. MARTEL, Senior Program Officer SUZANNE VAN DRUNICK, Senior Program Officer ELLEN K. MANTUS, Senior Program Officer RUTH E. CROSSGROVE, Senior Editor

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Toxicity Testing for Assessment of Environmental Agents: Interim Report INSTITUTE FOR LABORATORY ANIMAL RESEARCH COUNCIL Members PETER A. WARD (Chair), University of Michigan, Ann Arbor STEPHEN W. BARTHOLD, University of California, Davis WILLIAM C. CAMPBELL, Drew University, Madison, NJ JEFFREY EVERITT, GlaxoSmithKline Research & Development, Research Triangle Park, NC MICHAEL F. FESTING, Leicestershire, United Kingdom ESTELLE B. GAUDA, Johns Hopkins University, Baltimore, MD JANET C. GONDER, Pinehurst, NC COENRAAD F.M. HENDRIKSEN, National Institute of Public Health and the Environment, Bilthoven, Netherlands JAY R. KAPLAN, Wake Forest University School of Medicine, Winston-Salem, NC HILTON J. KLEIN, Merck Research Laboratories, West Point, PA WILLIAM MORTON, University of Washington, Seattle RANDALL J. NELSON, University of Tennessee, Memphis ABIGAIL SMITH, University of Pennsylvania, Philadelphia MICHAEL K. STOSKOPF, North Carolina State University, Raleigh PETER THERAN, Massachusetts Society for the Prevention of Cruelty to Animals, Boston Staff JOANNE ZURLO, Director KATHLEEN BEIL, Administrative Assistant

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Toxicity Testing for Assessment of Environmental Agents: Interim Report OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Superfund and Mining Megasites—Lessons from the Coeur d’Alene River Basin (2005) Health Implications of Perchlorate Ingestion (2005) Air Quality Management in the United States (2004) Endangered and Threatened Species of the Platte River (2004) Atlantic Salmon in Maine (2004) Endangered and Threatened Fishes in the Klamath River Basin (2004) Cumulative Environmental Effects of Alaska North Slope Oil and Gas Development (2003) Estimating the Public Health Benefits of Proposed Air Pollution Regulations (2002) Biosolids Applied to Land: Advancing Standards and Practices (2002) The Airliner Cabin Environment and Health of Passengers and Crew (2002) Arsenic in Drinking Water: 2001 Update (2001) Evaluating Vehicle Emissions Inspection and Maintenance Programs (2001) Compensating for Wetland Losses Under the Clean Water Act (2001) A Risk-Management Strategy for PCB-Contaminated Sediments (2001) Acute Exposure Guideline Levels for Selected Airborne Chemicals (4 volumes, 2000-2004) Toxicological Effects of Methylmercury (2000) Strengthening Science at the U.S. Environmental Protection Agency (2000) Scientific Frontiers in Developmental Toxicology and Risk Assessment (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 (4 volumes, 1998-2004) The National Research Council’s Committee on Toxicology: The First 50 Years (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 volumes, 1989-1995) Review of EPA’s Environmental Monitoring and Assessment Program (3 volumes, 1994-1995) Science and Judgment in Risk Assessment (1994) Pesticides in the Diets of Infants and Children (1993) Dolphins and the Tuna Industry (1992) Science and the National Parks (1992) Human Exposure Assessment for Airborne Pollutants (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 Academies Press (800) 624-6242 or (202) 334-3313 www.nap.edu

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Toxicity Testing for Assessment of Environmental Agents: Interim Report INSTITUTE FOR LABORATORY ANIMAL RESEARCH PUBLICATIONS Science, Medicine, and Animals: A Circle of Discovery (2004) The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop (2004) National Need and Priorities for Veterinarians in Biomedical Research (2004) Occupational Health and Safety in the Care and Use of Nonhuman Primates (2003) International Perspectives—The Future of Nonhuman Primate Resources: Proceedings of the Workshop Held April 17-19, 2002 (2003) Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research (2003) Principles and Guidelines for the Use of Animals in Precollege Education (2001) Strategies That Influence Cost Containment in Animal Research (2000) Definition of Pain and Distress and Reporting Requirements for Laboratory Animals: Proceedings of the Workshop Held June 22, 2000 (2000) Monoclonal Antibody Production (1999) Microbial and Phenotypic Definition of Rats and Mice: Proceedings of the 1999 US/Japan Conference (1999) The Psychological Well-Being of Nonhuman Primates (1998) Microbial Status and Genetic Evaluation of Mice and Rats: Proceedings of the 1998 US/Japan Conference (1998) Biomedical Models and Resources: Current Needs and Future Opportunities (1998) Approaches to Cost Recovery for Animal Research: Implications for Science, Animals, Research Competitiveness, and Regulatory Compliance (1998) Occupational Health and Safety in the Care and Use of Research Animals (1997) Chimpanzees in Research: Strategies for Their Ethical Care, Management, and Use (1997) Guide for the Care and Use of Laboratory Animals, 7th ed. (1996) Nutrient Requirements of Laboratory Animals, 4th ed. (1995) Laboratory Animal Management: Dogs (1994) Recognition and Alleviation of Pain and Distress in Laboratory Animals (1992) Infectious Diseases of Mice and Rats (1991) Companion Guide to Infectious Diseases of Mice and Rats (1991) Laboratory Animal Management: Rodents (1990) Immunodeficient Rodents: A Guide to Their Immunobiology, Husbandry, and Use (1989) Use of Laboratory Animals in Biomedical and Behavioral Research (1988) Copies of these reports may be ordered from the National Academies Press (800) 624-6242 or (202) 334-3313 www.nap.edu

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Toxicity Testing for Assessment of Environmental Agents: Interim Report This report is dedicated to the memory of our fellow committee member, Dr. Herbert Rosenkranz

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Toxicity Testing for Assessment of Environmental Agents: Interim Report Abbreviations ACD acute contact dermatitis ACS American Cancer Society ADJ adjustment factor ADME absorption, distribution, metabolism, and excretion AEGL acute exposure guideline level AhR aryl hydrocarbon receptor ARNT AhR nuclear translocator BBDR biologically based dose response BMC benchmark concentration BMD benchmark dose BT Buehler test CDC Centers for Disease Control and Prevention CFR Code of Federal Regulations CNS central nervous system CSA chemical safety assessment CYPs cytochrome P450s DAF dosimetric adjustment factor EC European Commission ECVAM European Centre for the Validation of Alternative Methods EDSP Endocrine Disruptor Screening Program EDSTAC Endocrine Disruptor Screening and Testing Advisory Committee EGP Environmental Genome Project ELISA enzyme-linked immunosorbent assay EPA Environmental Protection Agency

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Toxicity Testing for Assessment of Environmental Agents: Interim Report EPHT environmental public-health tracking EU European Union FDA Food and Drug Administration FEV1 forced expiratory volume in 1 second FFDCA Federal Food, Drug, and Cosmetics Act FIFRA Federal Insecticide, Fungicide, and Rodenticide Act FQPA Food Quality Protection Act GD gestational day GFP green fluorescent protein GMPT guinea pig maximization test HESI Health and Environmental Sciences Institute HPV high-production volume HTS high-throughput screening HUPO Human Proteome Organization IARC International Agency for Research on Cancer IC50 inhibition concentrations 50% ICCVAM Interagency Coordinating Committee on the Validation of Alternative Methods ICH International Conference on Harmonization IgM immunoglobulin M ILSI International Life Sciences Institute IOM Institute of Medicine IPCS International Programme on Chemical Safety LC50 lethal concentration 50% LD50 lethal dose 50% LLNA local lymph node assay LOAEL lowest-observed-adverse-effect level MPCA microbial pest-control agent MTS medium-throughput screening NAAQS national ambient air quality standards NICEATM NTP Interagency Center for the Evaluation of Alternative Toxicological Methods NIEHS National Institute of Environmental Health Sciences NOAEL no-observed-adverse-effect level NRC National Research Council NTP National Toxicology Program OECD Organisation for Economic Co-operation and Development OSHA Occupational Safety and Health Administration PAH polycyclic aromatic hydrocarbon

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Toxicity Testing for Assessment of Environmental Agents: Interim Report PBPK physiologically based pharmacokinetic PBT persistence, bioaccumulation, and toxicity PK pharmacokinetic PMN premanufacturing notice PND postnatal day QSAR quantitative structure-activity relationship REACH Registration, Evaluation and Authorisation of Chemicals RfC Reference concentration RfD Reference dose SAR structure-activity relationship SIDS screening information dataset SNP single-nucleotide polymorphism SRBCs sheep red blood cells TCDD 2,3,7,8-tetrachlorodibenzo-p-dioxin TG testing guideline TGD technical guidance document TSC the SNP Consortium TSCA Toxic Substances Control Act UDP up-down procedure UF uncertainty factor UN United Nations vPvB very persistent and very bioaccumulative WHO World Health Organization

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Toxicity Testing for Assessment of Environmental Agents: Interim Report Contents     SUMMARY   1 1   INTRODUCTION   15      Regulatory Requirements,   16      Toxicity Testing,   16      Challenges to Toxicity Testing and Assessment,   20      Committee’s Task and Approach,   21      Organization of the Report,   23      References,   24 2   ANIMAL AND IN VITRO TOXICITY TESTING   26      Toxicity Testing Characterized by Exposure Duration,   29      Toxicity Testing Characterized by Specific End Point,   35      Mechanistic Testing: Metabolism and Pharmacokinetic Studies,   57      References,   59 3   HUMAN DATA   71      Clinical or Controlled-Exposure Studies,   72      Case Reports,   73      Epidemiologic Studies,   74      Use of Human Data for Regulatory Analyses,   76      Challenges to the Advancement of Epidemiology,   79      Contributions of Emerging Fields to Epidemiology,   80      References,   85

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Toxicity Testing for Assessment of Environmental Agents: Interim Report 4   STRATEGIES FOR TOXICITY TESTING   92      Types of Toxicity-Testing Strategies,   93      Toxicity-Testing Strategies for Pesticides and Food Additives,   94      Toxicity-Testing Strategies for Screening of Industrial Chemicals,   99      Strategies for Screening Chemicals for Effects on Specific Systems and End Points,   102      Committee Observations on Toxicity-Testing Strategies,   112      References,   115 5   USE OF DATA IN HUMAN HEALTH RISK ASSESSMENT   118      Noncancer Risk-Assessment Guidance,   120      Cancer Risk-Assessment Guidance,   133      Committee Observations Concerning Toxicity Data Available for Risk Assessment,   140      References,   144 6   NEW APPROACHES   149      Approaches for Improving Existing Toxicity-Testing Strategies,   151      Committee Evaluation of Suggested Improvements in Testing Strategies,   185      References,   191 7   ALTERNATIVE APPROACHES AND EMERGING TECHNOLOGIES   194      Alternatives to Current Animal-Testing Approaches,   195      Emerging Technologies,   202      Validation,   216      References,   220     APPENDIXES     A.   Biographic Information on the Committee on Toxicity Testing and Assessment of Environmental Agents   230 B.   Testing Protocols   240 BOXES 4-1   Human Health Data to Be Obtained with Basic SIDS Testing Battery,   100 6-1   Roadmap Activities: High-Throughput Screening (HTS),   184

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Toxicity Testing for Assessment of Environmental Agents: Interim Report FIGURES 4-1   Endocrine-disruptor screening program overview,   105 4-2   Developmental-toxicity testing approach,   110 5-1   IPCS (1999) subdivision of interspecies and intraspecies uncertainty factors into pharmacokinetic and pharmacodynamic components,   128 6-1   The four objectives of toxicity testing,   150 6-2   Guideline study designs used to derive the oral reference dose,   153 6-3   Expanded chronic-carcinogenicity study,   156 6-4   ILSI-HESI draft proposed tiered approach for systemic-toxicity evaluation,   169 6-5   ILSI-HESI draft proposed tiered life-stages testing scheme for pesticides,   171 TABLES 1-1   Some Major U.S. Regulatory Agency Authority, Public-Health Goals, and Risk-Management Approaches,   17 2-1   EPA Acute-Toxicity Categories,   30 2-2   Representative Genetic Toxicology Tests,   49 2-3   Representative Validated In Vitro Methods for Cellular-Toxicity Testing,   53 3-1   Examples of Epidemiologic Study Designs,   74 3-2   Examples of Risks or Standards Derived from Human Data,   76 4-1   Battery of Tests Required by EPA for New Pesticide Chemicals,   95 4-2   Toxicity Tests for Microbial Pest-Control Agents,   96 4-3   Concern Levels for Direct Food Additives,   97 4-4   Testing Required for Direct and Indirect Food Additives,   98 4-5   European Union Testing Strategy,   103 4-6   Endocrine-Disruptor Screening Tests,   106 4-7   OECD Conceptual Framework for Testing Endocrine Disruptors,   108 5-1   EPA’s Weight-of-Evidence Approach for Evaluating Degree of Concern for Prenatal and Postnatal Toxicity on the Basis of Human and Animal Data,   131 5-2   Level of Evidence in Carcinogen Classification Schemes or Narrative Descriptions,   135 6-1   REACH Testing Strategy,   178

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Toxicity Testing for Assessment of Environmental Agents: Interim Report Toxicity Testing for Assessment of Environmental Agents Interim Report

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