Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment

Committee on Applications of Toxicogenomic Technologies to Predictive Toxicology

Board on Environmental Studies and Toxicology

Board on Life Sciences

Division on Earth and Life Studies

NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

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Committee on Applications of Toxicogenomic Technologies to Predictive Toxicology Board on Environmental Studies and Toxicology Board on Life Sciences Division on Earth and Life Studies

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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. N01-OD-4-2139 between the National Academy of Sciences and the U.S. Department of Health and Human Services. Any opinions, findings, conclu- sions, or recommendations expressed in this publication are those of the author(s) and do not neces- sarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-11298-7 International Standard Book Number-10: 0-309-1129802 Cover design by Liza R. Hamilton. 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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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 Na- tional 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 further- ing 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 adminis- tered 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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COMMITTEE ON APPLICATIONS OF TOXICOGENOMIC TECHNOLOGIES TO PREDICTIVE TOXICOLOGY Members DAVID C. CHRISTIANI (Chair), Harvard School of Public Health, Boston, MA CYNTHIA A. AFSHARI, Amgen, Inc.,Thousand Oaks, CA JOHN M. BALBUS, Environmental Defense, Washington, DC JAMES S. BUS, The Dow Chemical Company, Midland, MI BRUCE F. DEMPLE, Harvard School of Public Health, Boston, MA LINDA E. GREER, Natural Resources Defense Council, Washington, DC SHARON L.R. KARDIA, University of Michigan, Ann Arbor GEORGE D. LEIKAUF, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA DANIEL C. LIEBLER, Vanderbilt University School of Medicine, Nashville, TN GARY E. MARCHANT, Arizona State University College of Law, Tempe JOHN QUACKENBUSH, Harvard School of Public Health, Boston, MA KENNETH S. RAMOS, University of Louisville, Louisville, KY MARK A. ROTHSTEIN, University of Louisville School of Medicine, Louisville, KY RAYMOND E. STOLL, Stoll & Associates, LLC, Storrs-Mansfield, CT ROGER G. ULRICH, Calistoga Pharmaceuticals Inc., Seattle, WA HELMUT ZARBL, University of Medicine and Dentistry of New Jersey, Piscataway Staff MARILEE SHELTON-DAVENPORT, Project Director SUZANNE VAN DRUNICK, Senior Program Officer KARL GUSTAVSON, Senior Program Officer EILEEN ABT, Senior Program Officer CAY BUTLER, Editor MIRSADA KARALIC-LONCAREVIC, Manager, Toxicology Information Center LIZA R. HAMILTON, Senior Program Assistant MORGAN R. MOTTO, Senior Program Assistant Sponsor U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES v

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BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Members JONATHAN M. SAMET (Chair), Johns Hopkins University, Baltimore, MD RAMON 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 RUTH DEFRIES, University of Maryland, College Park COSTEL D. DENSON, University of Delaware, Newark E. DONALD ELLIOTT, Willkie Farr & Gallagher LLP, Washington, DC MARY R. ENGLISH, University of Tennessee, Knoxville 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 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 vi

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BOARD ON LIFE SCIENCES Members KEITH YAMAMOTO (Chair), University of California, San Francisco ANN M. ARVIN, Stanford University School of Medicine, Stanford, CA RUTH BERKELMAN, Emory University, Atlanta, GA DEBORAH BLUM, University of Wisconsin, Madison VICKI I. CHANDLER, University of Arizona, Tucson JEFFERY L. DANGL, University of North Carolina, Chapel Hill PAUL R. EHRLICH, Stanford University, Stanford, CA MARK D. FITZSIMMONS, John D. and Catherine T. MacArthur Foundation, Chicago, IL JO HANDELSMAN, University of Wisconsin, Madison KENNETH H. KELLER, Johns Hopkins University School of Advanced International Studies, Bologna, Italy JONATHAN D. MORENO, University of Pennsylvania, Philadelphia RANDALL MURCH, Virginia Polytechinc Institute and State University, Alexandria MURIEL E. POSTON, Skidmore College, Saratoga Springs, NY JAMES REICHMAN, University of California, Santa Barbara BRUCE W. STILLMAN, Cold Spring Harbor Laboratory, Cold Springs Harbor, NY MARC T. TESSIER-LAVIGNE, Genentech, Inc., South San Francisco, CA JAMES TIEDJE, Michigan State University, East Lansing CYNTHIA WOLBERGER, Johns Hopkins University School of Medicine, Baltimore, MD TERRY L. YATES, University of New Mexico, Albuquerque Senior Staff FRANCES E. SHARPLES, Director KERRY A. BRENNER, Senior Program Officer ANN H. REID, Senior Program Officer MARILEE K. SHELTON-DAVENPORT, Senior Program Officer EVONNE P.Y. TANG, Senior Program Officer ROBERT T. YUAN, Senior Program Officer ADAM P. FAGEN, Program Officer ANNA FARRAR, Financial Associate MERCURY FOX, Program Assistant REBECCA L. WALTER, Program Assistant vii

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OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Models in Environmental Regulatory Decision Making (2007) Toxicity Testing in the Twenty-first Century: A Vision and a Strategy (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) 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 viii

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OTHER REPORTS OF THE BOARD ON LIFE SCIENCES Recognizing the Role of Theory in Biology (2007) 2007 Amendments to the National Academies’ Guidelines for Human Embryonic Stem Cell Research (2007) Assessing the Medical Risks of Human Oocyte Donation for Stem Cell Research: A Workshop Report (2007) The New Science of Metagenomics: Revealing the Secrets of Our Microbial Planet (2007) Validation of Toxicogenomic Technologies: A Workshop Summary (2007) Protecting Building Occupants and Operations from Biological and Chemical Airborne Threats (2007) Understanding Interventions That Encourage Minorities to Pursue Research Careers: Summary of a Workshop (2007) Exploring the Role of Antiviral Drugs in the Eradication of Polio: Workshop Report (2006) Path to Effective Recovering of DNA from Formalin-Fixed Biological Samples in Natural History Collections: Workshop Summary (2006) Application of Toxicogenomics to Cross-Species Extrapolation (2006) Review of the Department of Energy’s Genomics: GTL Program (2006) Overcoming Challenges to Develop Countermeasures Against Aerosolized Bioterrorism Agents: Appropriate Use of Animal Models (2006) Status of Pollinators in North America (2006) Treating Infectious Diseases in a Microbial World: Report of Two Workshops on Novel Antimicrobial Therapeutics (2005) Guidelines for Human Embryonic Stem Cell Research (2005) Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary (2005) Reopening Public Facilities After a Biological Attack: A Decision-Making Framework (2005) Bridges to Independence: Fostering the Independence of New Investigators in Biomedical Research (2005) Smallpox: Transforming Biological Information into New Therapies (2004) Dietary Supplements: A Framework for Evaluating Safety (2004) Communicating Toxicogenomics Information to Nonexperts: A Workshop Summary (2004) Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects (2004) Biological Confinement of Genetically Engineered Organisms (2004) Seeking Security: Pathogens, Open Access, and Genome Databases (2004) Indicators for Waterborne Pathogens (2004) Enhancing the Vitality of the National Institutes of Health: Organizational Change to Meet New Challenges (2003) Sharing Publication-Related Data and Materials: Responsibilities of Authorship in the Life Sciences (2003) Bio2010: Transforming Undergraduate Education for Future Research Biologists (2003) The National Ecological Observatory Network (NEON): Addressing the Nation’s Environmental Challenges (2003) Scientific and Medical Aspects of Human Reproductive Cloning (2002) The National Plant Genome Initiative: Objectives for 2003-2008 (2002) Exploring Horizons for Domestic Animal Genomics (2002) Animal Biotechnology: Science-Based Concerns (2002) Environmental Effects of Transgenic Plants (2002) Countering Agricultural Bioterrorism (2002) Predicting Invasions of Nonindigenous Plants and Plant Pests (2002) Funding Smithsonian Scientific Research (2002) Stem Cells and the Future of Regenerative Medicine (2001) Environmental Contamination, Biotechnology, and the Law: The Impact of Emerging Genomic Information (2001) ix

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Ecological Monitoring of Genetically Modified Crops (2001) Bioinformatics: Converting Data to Knowledge (2000) Environmental Issues in Pacific Northwest Forest Management (2000) Copies of these reports may be ordered from the National Academies Press (800) 624-6242 or (202) 334-3313 www.nap.edu x

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Preface In recent years, completion of the sequencing of the human genome as well as the genomes of dozens of other organisms and subsequent development of tools for compre- hensive analysis of other cellular constituents have revolutionized biology. These new technologies, referred to broadly as “genomics,” have integrated biologic sciences with information sciences and engineering. The application of these new technologies to toxicology has opened a new era in which genetic variation and expression signatures might be used to screen compounds for hazard identification, to assess cellular responses to different doses, to classify toxicants on the basis of mechanisms of action, to monitor exposure of individuals to toxicants, and to predict individual variability in sensitivity to toxicants. In pharmacology, these tech- nologies have been used both to detect desired cellular responses to drugs and to monitor potential toxicity. Although the combination of genomic technologies with toxicology has the poten- tial to alter risk assessment by improving the predictive capabilities of toxicology for human health, it is equally clear that significant challenges remain to be overcome, and realistic limitations must be acknowledged. An issue well highlighted by the development of toxicogenomic technologies is the wide impact of these technologies. The applications of these technologies affect two broad areas: assessment of risk from exposure to chemicals in the environment and as- sessment of pharmaceutical safety. The National Institutes of Health, regulatory agencies (Environmental Protection Agency, Occupational Safety and Health Administration, Food and Drug Administration), the chemical and pharmaceutical industries, health pro- fessionals, attorneys, and the entire public are affected by the applications that toxicoge- nomics brings to environmental health risk assessment as well as drug efficacy and toxicity. Recognizing the challenges of dealing with these new types of scientific informa- tion, the director of the National Institute of Environmental Health Sciences (NIEHS) of the U.S. Department of Health and Human Services, Dr. Kenneth Olden, asked the Na- tional Academies in 2002 to convene a committee of experts to facilitate discussion and communication among stakeholders on technical, regulatory, and ethical issues that need to be considered when deciding how data from this rapidly evolving technology can be used most appropriately to inform public policy and promote human health. The National Academies’ standing Committee on Emerging Issues and Data on Environmental Con- taminants was established to facilitate exchanges of information among the academic community, government, industry, environmental advocates, and public interest groups about these new approaches. xi

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Acknowledgment of Review Participants 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 Na- tional Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the delib- erative process. We thank the following individuals for their review of this report: Christopher Amos, University of Texas Wylie Burke, University of Washington C. Thomas Caskey, University of Texas George Daston, Procter & Gamble Company Lutz Edler, German Cancer Research Center David Goodlett, University of Washington William Mattes, Critical Path Institute Roger McClellan, Chemical Industry Institute of Toxicology Stephen Roberts, University of Florida Martha Sandy, California Environmental Protection Agency Gerald Wogan, Massachusetts Institute of Technology Timothy Zacharewski, Michigan State University Lauren Zeise, California Environmental Protection Agency 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 Robert A. Goyer, University of Western Ontario, and Gilbert S. Omenn, University of Michigan Medical School. Appointed by the National Research Council, 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 authoring committee and the institution. xv

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Abbreviations ALL acute lympboblastic leukemia AML acute myeloblastic leukemia ANNs artificial neural networks ANOVA analysis of variance CART classification and regression trees CERCLA Comprehensive Environmental Remediation, Compensation and Liability Act CNS central nervous system CPSC Consumer Product Safety Commission EPA U.S. Environmental Protection Agency FDA Food and Drug Administration FDR false discovery rate FQPA Food Quality Protection Act HHS U.S. Department of Health and Human Services HIPAA Health Insurance Portability and Accountability Act of 1996 HPV high production volume 5-HT6 5-hydroxytryptamine ICCA International Council of Chemical Associations kNN k-nearest neighbors LOAEL lowest-observed-adverse-effect level MOA monoamine oxidase NCI National Cancer Institute NOAEL no-observed-adverse-effect level OHRP Office for Human Research Protections OPPT Office of Pollution Prevention and Toxics OSHA Occupational Safety and Health Administration PKU phenylketonuria PMNs Pre-Manufacturing Notices QSAR quantitative structure-activity relationship RfC reference concentration SAM significance analysis of microarrays SDWA Safe Drinking Water Act SOMs self-organizing maps SVM support vector machines TRI Toxic Release Inventory TSCA Toxic Substances Control Act xvii

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Contents SUMMARY ......................................................................................................................1 1 INTRODUCTION..................................................................................................11 Background, 11 Committee Charge and Response, 17 2 TOXICOGENOMIC TECHNOLOGIES .............................................................22 Genomic Technologies, 24 Transcriptomic Technologies, 27 Proteomic Technologies, 34 Metabolomic Technologies, 41 Technology Advancement and Economy of Scale, 43 3 EXPERIMENTAL DESIGN AND DATA ANALYSIS ......................................45 Experimental Design, 45 Types of Experiments, 47 Toxicogenomics and Biomarker Discovery, 54 Conclusions, 56 Recommendations, 57 4 APPLICATION TO EXPOSURE ASSESSMENT .............................................59 Conventional Biomarkers of Exposure and Response, 60 State of the Art: Toxicogenomic Approaches to the Development of Exposure Biomarkers, 61 Evaluation of Exposure in Risk Assessment, 67 Scientific Challenges, 68 Conclusions, 71 Recommendations, 72 5 APPLICATION TO HAZARD SCREENING ....................................................73 Description and Properties of Current Hazard Screening Methods, 73 In Vitro Versus In Vivo Testing, 76 Development of Predicitve Algorithms for Screening Purposes, 77 State of the Art, 77 Potential Applications, 83 xix

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xx Contents Challenges and Limitations, 86 Conclusions, 89 Recommendations, 90 6 APPLICATION TO ANALYZING VARIATION IN HUMAN SUSCEPTIBILITY ................................................................................92 State of the Art in Assessment of Individual Variation, 93 Risk Assessment, 100 Challenges, 102 Conclusions, 103 Recommendations, 105 7 APPLICATION TO THE STUDY OF MECHANISMS OF ACTION ...........107 State of the Art in Transcriptomics Analyses, 108 Conclusions, 118 Recommendations, 119 8 OTHER POTENTIAL APPLICATIONS OF TOXICOGENOMIC TECHNOLOGIES TO RISK ASSESSMENT...................................................121 Potential Applications to Risk Assessment, 121 Implications for Better Use and Potential Reduction in the Use of Experimental Animals, 131 Implications of Toxicogenomics for Risk Assessment Infrastructure Needs, 132 Conclusions, 133 Recommendations, 133 9 VALIDATION......................................................................................................135 Levels of Validation, 135 Conclusions, 149 Recommendations, 151 10 SAMPLE AND DATA COLLECTION AND ANALYSIS ...............................152 Leveraging Samples and Information in Population-Based Studies and Clinical Trials for Toxicogenomic Studies, 152 Existing Toxicogenomic Data Repositories: Standardization, Availability and Transparency, 161 Conclusions, 166 Recommendations, 169 11 ETHICAL, LEGAL, AND SOCIAL ISSUES ....................................................172 Research Issues, 172 Ethical and Social Issues, 178 Regulatory Implications, 186 Litigation, 191 Communication and Education, 195 Conclusions and Recommendations, 197 12 CONCLUSIONS AND RECOMMENDATIONS..............................................201 A New Human Toxicogenomics Initiative, 202 Data Analysis Tools, 203

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xxi Contents Exposure Assessment, 204 Hazard Screening, 205 Variability in Susceptibility, 206 Mechanistic Information, 207 Dose-response Relationships, 208 Cross-species Extrapolation, 209 Developmental Exposures, 209 Mixtures, 209 Validation, 210 Ethical, Legal, and Social Issues, 210 Education and Training in Toxicogenomics, 212 REFERENCES.............................................................................................................213 APPENDIXES A BIOGRAPHIC INFORMATION ON THE COMMITTEE ON APPLICATIONS OF TOXICOGENOMIC TECHNOLOGIES TO PREDICTIVE TOXICOLOGY ..........................................................................255 B MINIMUM INFORMATION ABOUT A MICROARRAY EXPERIMENT FOR TOXICOGENOMICS ....................................................262 C OVERVIEW OF RISK ASSESSMENT .............................................................270 BOXES, FIGURES, AND TABLES BOXES S-1 Human Toxicogenomics Initiative, 6 1-1 Toxicogenomics Definition, 12 1-2 Typical Information Gaps and Inconsistencies That Limit Conventional Risk Assessment, 14 1-3 Statement of Task, 18 1-4 Selected Examples of the Use of Toxicogenomic Technologies in Predictive Toxicology, 19 2-1 Experimental Details of Transcriptome Profiling with Microarrays, 29 3-1 Supervised and Unsupervised Analysis, 52 3-2 Defining Biomarkers, 55 6-1 Paraoxonase 1 Gene Polymorphisms and Occupational Exposure to Pesticide, 94 6-2 Multiple Genetic Factors Influence Response to Cigarette Smoke, 95 6-3 Summary of Research Issues and Potential Applications, 104 7-1 Types of Experimental Approaches in Toxicogenomics Studies to Evaluate Mechanisms of Toxicity, 109 9-1 Validation of Toxicogenomic Applications, 136

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xxii Contents 9-2 Microarray Gene Expression Data Society Workshop, September 2005, Bergen, Norway, 140 9-3 Clinical Validation of Transcriptome Profiling in Breast Cancer, 145 10-1 Possible Steps for Developing an Initial Database, 170 11-1 Toxicogenomic Research on Workers, 182 11-2 Genetic Screening for Susceptibility to Chronic Beryllium Disease, 184 11-3 BiDil and Race-Linked Pharmaceuticals, 186 11-4 Regulatory Agency Guidance Documents, 188 FIGURES 2-1 Hierarchical relationships of DNA, RNA, proteins, and metabolites, 23 2-2 Overview of commonly used methods and technologies for gene expression analysis, 28 2-3 An overview of DNA microarray analysis, 32 2-4 Schematic representation of 2D gel-based proteome analysis (upper) and shotgun proteome analysis (lower), 35 2-5 A hierarchy of proteomic data, 38 3-1 Overview of the workflow in a toxicogenomic experiment, 46 9-1 Human plasma proteome, 138 TABLES 3-1 Data Analysis Approaches, 48 3-2 Phases of Cancer Biomarker Development As Defined by Pepe et al. (2001), 57 5-1 Elements of the OECD SIDS, 75 9-1 Worldwide Regulatory Policies and Guidelines Relations to Toxicogenomics and Pharmacogenomics, 147

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