TOXICITY TESTING IN THE 21ST CENTURY

A VISION AND A STRATEGY

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 in the 21st Century: A Vision and a Strategy TOXICITY TESTING IN THE 21ST CENTURY A VISION AND A STRATEGY 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 in the 21st Century: A Vision and a Strategy 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 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 view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-10992-5 (Book) International Standard Book Number-10: 0-309-10992-2 (Book) International Standard Book Number-13: 978-0-309-10993-2 (PDF) International Standard Book Number-10: 0-309-10993-0 (PDF) Library of Congress Control Number: 2007935052 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 2007 by the National Academy of Sciences. All rights reserved. Printed in the United States of America.

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Toxicity Testing in the 21st Century: A Vision and a Strategy 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. Charles M. Vest 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. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Toxicity Testing in the 21st Century: A Vision and a Strategy COMMITTEE ON TOXICITY TESTING AND ASSESSMENT OF ENVIRONMENTAL AGENTS Members DANIEL KREWSKI (Chair), University of Ottawa, ON, Canada DANIEL ACOSTA, JR., University of Cincinnati, OH MELVIN ANDERSEN, The Hamner Institutes for Health Sciences, Research Triangle Park, NC HENRY ANDERSON, Wisconsin Division of Public Health, Madison JOHN BAILAR III, University of 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 LAWRENCE MCCRAY, Massachusetts Institute of Technology, Cambridge OTTO MEYER, The National Food Institute, Technical University of Denmark, Søborg, Denmark D. REID PATTERSON, Reid Patterson Consulting, Inc., Elkhorn, WI 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, Project Director JENNIFER OBERNIER, Program Officer RUTH CROSSGROVE, Senior Editor NORMAN GROSSBLATT, Senior Editor MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center JORDAN CRAGO, Senior Project Assistant Sponsor U.S. ENVIRONMENTAL PROTECTION AGENCY

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Toxicity Testing in the 21st Century: A Vision and a Strategy 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 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 MARY R. ENGLISH, University of Tennessee, Knoxville RUTH DEFRIES, University of Maryland, College Park J. PAUL GILMAN, Oak Ridge Center for Advanced Studies, Oak Ridge, TN SHERRI W. GOODMAN, Center for Naval Analyses, Alexandria, VA JUDITH A. GRAHAM, American Chemistry Council, Arlington, VA WILLIAM P. HORN, Birch, Horton, Bittner and Cherot, Washington, DC WILLIAM M. LEWIS, JR., University of Colorado, Boulder JUDITH L. MEYER, University of Georgia, Athens DENNIS D. MURPHY, University of Nevada, Reno PATRICK Y. O’BRIEN, ChevronTexaco Energy Technology Company, Richmond, CA DOROTHY E. PATTON (retired), Chicago, IL DANNY D. REIBLE, University of Texas, Austin JOSEPH V. RODRICKS, ENVIRON International Corporation, Arlington, VA ARMISTEAD G. RUSSELL, Georgia Institute of Technology, Atlanta ROBERT F. SAWYER, University of California, Berkeley 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 KARL E. GUSTAVSON, Senior Program Officer K. JOHN HOLMES, Senior Program Officer ELLEN K. MANTUS, Senior Program Officer SUSAN N.J. MARTEL, Senior Program Officer STEVEN K. GIBB, Program Officer for Strategic Communications RUTH E. CROSSGROVE, Senior Editor

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Toxicity Testing in the 21st Century: A Vision and a Strategy INSTITUTE FOR LABORATORY ANIMAL RESEARCH COUNCIL Members STEPHEN W. BARTHOLD (Chair), University of California, Davis KATHRYN A. BAYNE, Association for Assessment and Accreditation of Laboratory Animal Care International, Waikoloa, HI MYRTLE A. DAVIS, Lilly Research Laboratories, Greenfield, IN JEFFREY I. EVERITT, GlaxoSmithKline Research and Development, Research Triangle Park, NC JAMES G. FOX, Massachusetts Institute of Technology, Cambridge NELSON L. GARNETT, (formerly) Johns Hopkins University, Baltimore, MD ESTELLE B. GAUDA, Johns Hopkins University, Baltimore, MD COENRAAD F.M. HENDRIKSEN, Netherlands Vaccine Institute, Bilthoven JON H. KAAS, Vanderbilt University, Nashville, TN JOSEPH W. KEMNITZ, University of Wisconsin, Madison JUDY A. MCARTHUR CLARK, (formerly) Pfizer Global R&D, Groton, CT LETICIA V. MEDINA, Abbott Laboratories, Abbott Park, IL BERNARD E. ROLLIN, Colorado State University, Fort Collins ABIGAIL L. SMITH, University of Pennsylvania, Philadelphia STEPHEN A. SMITH, Virginia Polytechnic Institute and State University, Blacksburg Staff JOANNE ZURLO, Director LIDA ANESTIDOU, Program Officer KATHLEEN BEIL, Administrative Coordinator RHONDA HAYCRAFT, Senior Project Assistant SUSAN VAUPEL, Managing Editor, ILAR Journal

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Toxicity Testing in the 21st Century: A Vision and a Strategy OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Models in Environmental Regulatory Decision Making (2007) Sediment Dredging at Superfund Megasites: Assessing the Effectiveness (2007) Environmental Impacts of Wind-Energy Projects (2007) Scientific Review of the Proposed Risk Assessment Bulletin from the Office of Management and Budget (2007) Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues (2006) New Source Review for Stationary Sources of Air Pollution (2006) Human Biomonitoring for Environmental Chemicals (2006) Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment (2006) Fluoride in Drinking Water: A Scientific Review of EPA’s Standards (2006) State and Federal Standards for Mobile-Source Emissions (2006) 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 (five volumes, 2000-2007) 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 (2000) Hormonally Active Agents in the Environment (1999) Research Priorities for Airborne Particulate Matter (four 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 (five volumes, 1989-1995) Review of EPA's Environmental Monitoring and Assessment Program (three volumes, 1994-1995) Science and Judgment in Risk Assessment (1994)

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Toxicity Testing in the 21st Century: A Vision and a Strategy 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 in the 21st Century: A Vision and a Strategy 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 in the 21st Century: A Vision and a Strategy Preface Over the past few decades, several toxicity-testing strategies have emerged for evaluating the hazards or risks associated with exposure to drugs, food additives, pesticides, and industrial and other chemicals. New testing technologies, methods, and approaches also have emerged in recent years. The U.S. Environmental Protection Agency (EPA) recognized the need to conduct a comprehensive review of toxicity-testing methods and strategies and requested that the National Research Council (NRC) conduct such a review and propose a long-range vision and strategy for toxicity testing. In its 2006 interim report, the NRC Committee on Toxicity Testing and Assessment of Environmental Agents reviewed current toxicity-testing methods and strategies and selected aspects of several reports by EPA and others that described initiatives or proposals to improve current methods or strategies. The committee now presents its long-range vision and strategic plan to advance toxicity testing and considers its vision within the current regulatory framework. Although the committee was not charged to review government programs related to toxicity testing, some federal programs that are relevant to the subject of this report may be of interest to readers. For example, EPA has established a National Center for Computational Toxicology (http://www.epa.gov/comptox/index.html) that is developing new software and methods for predictive toxicology. The National Institute of Environmental Health Sciences, through the National Toxicology Program's Roadmap for the Future (http://ntp.niehs.nih.gov/files/NTPrdmp.pdf), has initiated a partnership with the Chemical Genomics Center of the National Institutes of Health to develop and carry out high- and medium-throughput screening assays to test more chemicals in less time and at less cost.

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Toxicity Testing in the 21st Century: A Vision and a Strategy This report has been reviewed in draft form by persons chosen for their diverse perspectives and technical expertise in accordance with procedures approved by the NRC’s Report Review Committee. The purposes of this independent review are 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 of 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 for their review of this report: Cynthia Afshari (Amgen, Inc.), Frederic Bois (INERIS), James Bus (Dow Chemical), Vincent James Cogliano (International Agency for Research on Cancer), David Dorman (The Hamner Institutes for Health Sciences), Alan Goldberg (Johns Hopkins University), Carole Kimmel (consultant), Gilbert Omenn (University of Michigan), Lorenz Rhomberg (Gradient Corporation), Joseph Rodricks (ENVIRON), Leslie Stayner (University of Illinois), and Helmut Zarbl (Fred Hutchinson Cancer Research Center). 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 the review coordinator, Rogene Henderson (Lovelace Respiratory Research Institute), and the review monitor, Donald Mattison (National Institutes of Health). Appointed by the NRC, they were 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 committee and the institution. The committee gratefully acknowledges the following for making presentations to the committee: Thomas Hartung (ECVAM), William Greenlee (The Hamner Institutes for Health Sciences), Carl Barrett (Novartis Institute for BioMedical Development), Robert Chapin (Pfizer, Inc.), Michael Festing (private consultant), William Stokes (National Institute of Environmental Health Sciences), Edward Calabrese (University of Massachusetts-Amherst), John Doull (University of Kansas Medical Center), Bette Meek (Health Canada), Michael Firestone (EPA), Clifford Gabriel (EPA), Lee Hoffman (EPA), Jim Jones (EPA), Deidre Murphy (EPA), Rita Schoeny (EPA), and Charles Auer (EPA). The committee especially thanks Dorothy Patton (retired from EPA) for her contributions to the report and consultation on toxicity testing in regulatory contexts. The committee is also grateful for the assistance of the NRC staff in preparing this report. Staff members who contributed to the effort are Ellen Mantus, project director; Joanne Zurlo, director of the Institute for Laboratory Animal Research; James Reisa, director of the Board on Environmental Studies and Toxicology; Jennifer Obernier, program officer; Ruth Crossgrove, senior editor; Norman Grossblatt, senior editor; Mirsada Karalic-Loncarevic, manager of the Tech-

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Toxicity Testing in the 21st Century: A Vision and a Strategy nical Information Center; Jordan Crago, senior project assistant; and Radiah Rose, senior editorial assistant. I would especially like to thank all the members of the committee for their efforts throughout the development of this report. Daniel Krewski, Chair Committee on Toxicity Testing and Assessment of Environmental Agents

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Toxicity Testing in the 21st Century: A Vision and a Strategy Contents     SUMMARY   1 1   INTRODUCTION   18      Historical Perspective of Regulatory Toxicology,   19      Risk Assessment,   23      The Committee’s First Task and Key Points from its Interim Report,   25      The Committee’s Second Task and Approach,   29      Organization of the Report,   32      References,   33 2   VISION   35      Limitations of Current Testing Strategies,   38      Design Criteria for a New Toxicity-Testing Paradigm,   42      Options for a New Toxicity-Testing Paradigm,   43      Overview of Committee’s Long-Range Vision for Toxicity Testing,   48      References,   53 3   COMPONENTS OF THE VISION   56      Component A:  Chemical Characterization,   57      Component B:  Toxicity Testing of Compounds and Metabolites,   60      Component C:  Dose-Response and Extrapolation Modeling,   68      Component D:  Population-Based and Human Exposure Data,   75      Component E:  Risk Contexts,   80      Toxicity-Testing Strategies in Practice,   84      Toxicity Testing and Risk Assessment,   90      References,   91 4   TOOLS AND TECHNOLOGIES   98      Tools and Technologies for Chemical Characterization,   98      Mapping Toxicity Pathways,   102      Tools and Technologies for Dose-Response and Extrapolation Modeling,   110      References,   113

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Toxicity Testing in the 21st Century: A Vision and a Strategy 5   DEVELOPING THE SCIENCE BASE AND ASSAYS TO IMPLEMENT THE VISION   120      Scope of Scientific Knowledge, Methods, and Assay Development,   122      Strategy for Knowledge and Assay Development and Validation,   132      Building a Transformative Research Program,   155      Concluding Remarks,   162      References,   163 6   PREREQUISITES FOR IMPLEMENTING THE VISION IN REGULATORY CONTEXTS   166      Institutional Change to Meet the Vision,   167      Regulatory Use of New Methods,   171      References,   181 APPENDIX   BIOGRAPHIC INFORMATION ON THE COMMITTEE ON TOXICITY TESTING AND ASSESSMENT OF ENVIRONMENTAL AGENTS   184 BOXES S-1   Key Questions to Address in Implementation   13 2-1   Key Terms Used in the Report   38 3-1   Example of Components of Signaling Pathway That Could Be Modeled   73 5-1   Key Research Questions in Developing Knowledge to Support Pathway Testing   124 5-2   Main Questions in Developing Tests and Methods   128 5-3   Some Science and Technology Milestones in Developing Toxicity-Pathway Tests As the Cornerstone of Future Toxicity-Testing Strategies   134 FIGURES S-1   The committee’s vision for toxicity testing is a process that includes chemical characterization, toxicity testing, and dose-response and extrapolation modeling   5 S-2   Biologic responses viewed as results of an intersection of exposure and biologic function   7 2-1   The exposure-response continuum underlying the current paradigm for toxicity testing   39 2-2   Biologic responses viewed as results of an intersection of exposure and biologic function   49

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Toxicity Testing in the 21st Century: A Vision and a Strategy 2-3   The committee’s vision is a process that includes chemical characterization, toxicity testing, and dose-response and extrapolation modeling   50 3-1   Overview of chemical characterization component   58 3-2   Toxicity-testing component, which includes toxicity-pathway testing in cells and cell lines and targeted testing in whole animals   61 3-3   Overview of dose-response and extrapolation modeling component   69 3-4   Nrf2 antioxidant-response pathway schematic   73 3-5   Overview of population-based and human exposure data component   76 3-6   Overview of risk contexts component   81 3-7   Risk-assessment components   91 5-1   Progression of some important science and technology activities during assay development   136 5-2   Screening of chemicals that would not otherwise be tested or be subject to only limited testing   149 TABLES 2-1   Options for Future Toxicity-Testing Strategies   44 6-1   Definitions of Adverse Effect   178

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Toxicity Testing in the 21st Century: A Vision and a Strategy TOXICITY TESTING IN THE 21ST CENTURY A VISION AND A STRATEGY

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