APPLICATION OF TOXICOGENOMICS TO CROSS-SPECIES EXTRAPOLATION

Committee on Applications of Toxicogenomics to Cross-Species Extrapolation

Committee on Emerging Issues and Data on Environmental Contaminants

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
Washington, D.C.
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Application of Toxicogenomics to Cross-Species Extrapolation APPLICATION OF TOXICOGENOMICS TO CROSS-SPECIES EXTRAPOLATION Committee on Applications of Toxicogenomics to Cross-Species Extrapolation Committee on Emerging Issues and Data on Environmental Contaminants 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 Washington, D.C. www.nap.edu

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Application of Toxicogenomics to Cross-Species Extrapolation 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 National Institute of Environmental Health 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 0-309-10084-4 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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Application of Toxicogenomics to Cross-Species Extrapolation 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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Application of Toxicogenomics to Cross-Species Extrapolation COMMITTEE ON APPLICATIONS OF TOXICOGENOMICS TO CROSS-SPECIES EXTRAPOLATION: A WORKSHOP Members N. LEIGH ANDERSON (Chair), Plasma Proteome Institute, Washington, DC JAMES S. BUS, Dow Chemical Company, Midland, MI DAVID L. EATON, University of Washington, Seattle SERRINE S. LAU, University of Arizona, Tucson JOHN A. MOORE, Hollyhouse, Inc., Wicomico Church, VA JOHN QUACKENBUSH, Harvard School of Public Health, Boston, MA KENNETH S. RAMOS, University of Louisville, Louisville, KY Staff MARILEE SHELTON-DAVENPORT, Project Director ROBERTA WEDGE, Project Director NORMAN GROSSBLATT, Senior Editor JENNIFER E. SAUNDERS, Research Associate MIRSADA KARALIC-LONCAREVIC, Research Associate ALEXANDRA STUPPLE, Senior Editorial Assistant LUCY V. FUSCO, Senior Program Assistant JORDAN CRAGO, Senior Program Assistant SAMMY BARDLEY, Librarian Sponsor NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

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Application of Toxicogenomics to Cross-Species Extrapolation COMMITTEE ON EMERGING ISSUES AND DATA ON ENVIRONMENTAL CONTAMINANTS Members KENNETH S. RAMOS (Chair), University of Louisville, Louisville, KY N. LEIGH ANDERSON, Plasma Proteome Institute, Washington, DC PATRICIA A. BUFFLER, University of California, Berkeley JAMES S. BUS, Dow Chemical Company, Midland, MI JOSEPH DEGEORGE, Merck Pharmaceuticals, West Point, PA GEORGIA M. DUNSTON, Howard University, Washington, DC LINDA E. GREER, Natural Resources Defense Council, Washington, DC ROBERT J. GRIFFIN, Marquette University, Milwaukee, WI JOHN D. GROOPMAN, Johns Hopkins University, Baltimore, MD CASIMIR A. KULIKOWSKI, Rutgers University, New Brunswick, NJ AMY D. KYLE, University of California, Berkeley PHILIP LEDER, Harvard Medical School, Boston, MA PETER LORD, Johnson & Johnson, Raritan, NJ WILLIAM B. MATTES, Gene Logic, LLC, Gaithersburg, MD GEORGE ORPHANIDES, Syngenta, LLC, Cheshire, UK FREDERICA P. PERERA, Columbia University, New York, NY JOHN QUACKENBUSH, Harvard School of Public Health, Boston, MA MARK A. ROTHSTEIN, University of Louisville School of Medicine, Louisville, KY LEONA D. SAMSON, Massachusetts Institute of Technology, Cambridge PETER S. SPENCER, Oregon Health Sciences Institute, Portland LAWRENCE SUNG, University of Maryland, Baltimore CHERYL L. WALKER, University of Texas, Smithville RUSSELL D. WOLFINGER, SAS Institute, Inc., Cary, NC Staff MARILEE SHELTON-DAVENPORT, Project Director KARL GUSTAVSON, Project Director EILEEN ABT, Program Director NORMAN GROSSBLATT, Senior Editor JENNIFER E. SAUNDERS, Research Associate LUCY V. FUSCO, Senior Program Assistant JORDAN CRAGO, Senior Program Assistant

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Application of Toxicogenomics to Cross-Species Extrapolation BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Members JONATHAN M. SAMET (Chair), The Johns Hopkins University, Baltimore, MD RAMÓN ALVAREZ, Environmental Defense, Austin, TX THOMAS BURKE, The Johns Hopkins University, Baltimore, MD JUDITH C. CHOW, Desert Research Institute, Reno, NV COSTEL D. DENSON, University of Delaware, Newark E. DONALD ELLIOTT, Willkie Farr & Gallagher LLP, Washington, DC CHRISTOPHER B. FIELD, Carnegie Institution of Washington, Stanford, CA 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 ROBERT HUGGETT, Michigan State University, East Lansing BARRY L. JOHNSON, Emory University, Atlanta, GA JAMES H. JOHNSON, 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 JOSEPH V. RODRICKS, ENVIRON Corporation, Arlington, VA ARMISTEAD G. RUSSELL, Georgia Institute of Technology, Atlanta LISA SPEER, Natural Resources Defense Council, New York, NY KIMBERLY M. THOMPSON, Harvard School of Public Health, Boston, MA G. DAVID TILMAN, University of Minnesota, St. Paul CHRIS G. WHIPPLE, ENVIRON Corporation, Emeryville, CA LAUREN A. 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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Application of Toxicogenomics to Cross-Species Extrapolation BOARD ON LIFE SCIENCES Members CORY S. GOODMAN (Chair), Renovis Inc., South San Francisco, CA ANN M. ARVIN, Stanford University School of Medicine, Stanford, CA JEFFREY L. BENNETZEN, University of Georgia, Athens, GA RUTH BERKELMAN, Emory University, Atlanta, GA R. ALTA CHARO, University of Wisconsin, Madison DENNIS CHOI, Merck Research Laboratories, West Point, PA JEFFREY L. DANGL, University of North Carolina, Chapel Hill PAUL R. EHRLICH, Stanford University, Palo Alto, CA JAMES M. GENTILE, Hope College, Holland, MI ED HARLOW, Harvard Medical School, Boston, MA DAVID HILLIS, University of Texas, Austin KENNETH F. KELLER, University of Minnesota, Minneapolis RANDALL MURCH, Institute for Defense Analyses, Alexandria, VA GREGORY A. PETSKO, Brandeis University, Waltham, MA STUART L. PIMM, Duke University, Durham, NC BARBARA A. SCHAAL, Washington University, St. Louis, MO JAMES TIEDJE, Michigan State University, East Lansing KEITH YAMAMOTO, University of California, San Francisco Senior Staff FRANCES E. SHARPLES, Director KERRY A. BRENNER, Senior Program Officer ROBIN A. SCHOEN, Senior Program Officer MARILEE SHELTON-DAVENPORT, Senior Program Officer ROBERT T. YUAN, Senior Program Officer ADAM P. FAGEN, Program Officer ANN REID, Program Officer EVONNE P.Y. TANG, Program Officer SETH STRONGIN, Senior Program Assistant DENISE GROSSHANS, Financial Associate

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Application of Toxicogenomics to Cross-Species Extrapolation Preface Toxicogenomics has been described as a discipline combining expertise in toxicology, genetics, molecular biology, and environmental health to elucidate the response of living organisms to stressful environments. It includes, but is not limited to, the study of how genomes respond to toxicant exposures and how genotype affects responses to toxicant exposures. As the technology rapidly develops, it is critical that scientists and the public communicate about the promises and limitations of this new field. Despite the dependence on animal models in toxicologic research for predicting human health effects in the regulatory arena, there can be important differences between how animals and humans respond to different chemicals. The Committee on Applications of Toxicogenomics to Cross-Species Extrapolation designed a workshop to consider using toxicogenomics in cross-species extrapolation from animals to humans. The workshop reflected on the promises and limitations of emerging data-rich approaches—such as genotyping (genomics), mRNA analysis (transcriptomics), protein analysis (proteomics), and metabolite analysis (metabolomics)—to inform cross-species extrapolation. Specifically, the workshop considered whether the data-rich technologies offer new ways of determining whether the effects of chemicals in test animals can be used to predict human responses. This workshop report has been reviewed in draft form by persons chosen for their diverse perspectives and technical expertise in accordance with procedures approved by the National 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 workshop report as sound as possible and to ensure

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Application of Toxicogenomics to Cross-Species Extrapolation 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 people for their review of this workshop report: Susan Sumner, RTI International; Jonathan H. Freedman, Duke University; Kevin W. Gaido, CIIT Centers for Integrated Genomics; and Frank A. Witzmann, Indiana University School of Medicine. 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 workshop report before its release. The review of the workshop report was overseen by Rogene Henderson, of the Lovelace Respiratory Research Institute. Appointed by the National Research Council, she was responsible for making certain that an independent examination of the workshop report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of the workshop report rests entirely with the committee and the institution. The committee gratefully acknowledges the following for making presentations at the workshop: John L. Butenhoff, 3M Company; Frank A. Witzmann, Indiana University School of Medicine; William H. Benson, Stephen Nesnow, and Kerry L. Dearfield, U.S. Environmental Protection Agency; Richard T. Di Giulio, Duke University; Donna Mendrick, Gene Logic Inc.; Susan Sumner, RTI International; and Russell Thomas, CIIT Centers for Health Research. The committee is grateful for the assistance of the National Research Council staff in preparing this workshop summary: Marilee Shelton-Davenport, Roberta Wedge, and Karl Gustavson, project directors; James Reisa, director of the Board on Environmental Studies and Toxicology; Fran Sharples, director of the Board on Life Sciences; Jennifer Saunders and Mirsada Karalic-Loncarevic, research associates; Jennifer Roberts, postdoctoral research associate; Norman Grossblatt, senior editor; Lucy Fusco and Jordan Crago, senior program assistants; and Sammy Bardley, librarian. Finally, I thank the members of the committee for their dedicated efforts throughout the development of this workshop summary. N. Leigh Anderson Chair, Committee on Application of Toxicogenomics to Cross-Species Extrapolation

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Application of Toxicogenomics to Cross-Species Extrapolation Contents     SUMMARY OF THE WORKSHOP   1      Introduction,   1      Emerging Molecular and Computational Approaches for Cross-Species Extrapolation,   4      Potential Implications of Genomics for Risk Assessment,   5      Technological Challenges of Cross-Species Extraploation Using Proteomics,   8      Modeling Gene-Expression Data to Predict Human Hepatotoxicity After Inconsistent Animal Responses,   9      Using Metabolomics to Explore Species Differences in Metabolism and Distribution,   11      A Systems-Biology Approach to Cross-Species Extrapolation,   14      Combining Transcriptional and Toxicologic Approaches to Understanding the Basis of Species Differences in Conazole Carcinogenesis,   17      Species Differences in Response to Perfluorooctanoic Acid,   20      Summary of Roundtable Discussion,   22      Conclusion,   28     REFERENCES   30

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Application of Toxicogenomics to Cross-Species Extrapolation     APPENDIXES     A.   Workshop Agenda   33 B.   Biographical Information on Workship Speakers   36 C.   Biographical Information on Workshop Planning Committee   41

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Application of Toxicogenomics to Cross-Species Extrapolation APPLICATION OF TOXICOGENOMICS TO CROSS-SPECIES EXTRAPOLATION

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