TOXICOGENOMIC TECHNOLOGIES AND RISK ASSESSMENT OF ENVIRONMENTAL CARCINOGENS

A Workshop Summary

Committee on How Toxicogenomics Could Inform Critical Issues in Carcinogenic Risk Assessment of Environmental Chemicals

Committee on Emerging Issues and Data on Environmental Contaminants

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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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary TOXICOGENOMIC TECHNOLOGIES AND RISK ASSESSMENT OF ENVIRONMENTAL CARCINOGENS A Workshop Summary Committee on How Toxicogenomics Could Inform Critical Issues in Carcinogenic Risk Assessment of Environmental Chemicals Committee on Emerging Issues and Data on Environmental Contaminants 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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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary 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 National Institute of Environmental Health Sciences. 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 0-309-09700-2 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 2005 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary 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.

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary COMMITTEE ON HOW TOXICOGENOMICS COULD INFORM CRITICAL ISSUES IN CARCINOGENIC RISK ASSESSMENT OF ENVIRONMENTAL CHEMICALS Members LINDA E. GREER (Chair), Natural Resources Defense Council, Washington, DC JAMES S. BUS, Dow Chemical Company, Midland, MI JOHN D. GROOPMAN, Johns Hopkins University, Baltimore, MD JOHN A. MOORE, Hollyhouse, Inc.,Wicomico Church, VA KENNETH S. RAMOS, University of Louisville, Louisville, KY CHERYL L. WALKER, University of Texas, Smithville TIMOTHY R. ZACHAREWSKI, Michigan State University, East Lansing Staff MARILEE K. SHELTON-DAVENPORT, Project Director ROBERTA M. 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, Program Associate JORDAN P. CRAGO, Senior Program Assistant SAMMY BARDLEY, Librarian Sponsor NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary COMMITTEE ON EMERGING ISSUES AND DATA ON ENVIRONMENTAL CONTAMINANTS Members DAVID L. EATON (Chair), University of Washington, Seattle WILLIAM F. GREENLEE (Vice Chair), CIIT Centers for Health Research, Research Triangle Park, NC N. LEIGH ANDERSON, Plasma Proteome Institute, Washington, DC PATRICIA A. BUFFLER, University of California, Berkeley JAMES S. BUS, Dow Chemical Company, Midland, MI GEORGIA M. DUNSTON, Howard University, Washington, DC LINDA C. FENTIMAN, Pace University School of Law, White Plains, NY 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 SERRINE S. LAU, University of Arizona, Tucson PHILIP LEDER, Harvard Medical School, Boston, MA JOHN A. MOORE, Hollyhouse, Inc., Wicomico Church, VA FREDERICA P. PERERA, Columbia University, New York, NY JOHN QUACKENBUSH, Institute for Genomic Research, Rockville, MD KENNETH S. RAMOS, University of Louisville, Louisville, KY BING REN, University of California, San Diego, La Jolla MARK A. ROTHSTEIN, University of Louisville School of Medicine, Louisville, KY ELLEN K. SILBERGELD, Johns Hopkins University, Baltimore, MD CHERYL L. WALKER, University of Texas, Smithville RUSSELL D. WOLFINGER, SAS Institute, Inc., Cary, NC TIMOTHY R. ZACHAREWSKI, Michigan State University, East Lansing Staff MARILEE K. SHELTON-DAVENPORT, Project Director ROBERTA M. WEDGE, Project Director JENNIFER E. SAUNDERS, Research Associate LUCY V. FUSCO, Senior Project Assistant Sponsor NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary BOARD ON LIFE SCIENCES Members COREY 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 RUTH BERKELMAN, Emory University, Atlanta, GA R. ALTA CHARO, University of Wisconsin, MadisonI DENNIS CHOI, Merck Research Laboratories, West Point, PA JEFFREY L. DANGL, University of North Carolina, Chapel Hill PAUL R. EHRLICH, Stanford University, Stanford, 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 Staff FRANCES E. SHARPLES, Director KERRY A. BRENNER, Senior Program Officer MARILEE K. 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 MATTHEW MCDONOUGH, Program Assistant DENISE GROSSHANS, Financial Associate

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary Preface Toxicogenomics is described as a discipline combining expertise in toxicology, genetics, molecular biology, and environmental health to elucidate the response of living organisms to stressful environments. As this emerging field rapidly develops, it is important to assess how toxicogenomic data can be applied to improve risk assessment, particularly for carcinogens. The Committee on How Toxicogenomics Could Inform Critical Issues in Carcinogenic Risk Assessment of Environmental Chemicals designed a workshop to identify critical knowledge gaps in carcinogenic risk assessment and discuss the potential role of toxicogenomics in addressing these gaps. This summary of the workshop discusses current approaches to cancer risk assessment, the potential use of toxicogenomic data in this process, lessons learned from case studies on two carcinogens (1,3-butadiene and arsenic), and research that may be useful in moving the field forward. This workshop summary 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 summary as sound as possible and to ensure that the summary meets institutional standards of objectivity, evidence, and responsiveness to the study charge.

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary 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 summary: David L. Eaton, University of Washington; James C. Lamb IV, The Weinberg Group; William D. Pennie, Pfizer, Inc.; Edwin P. Przybylowicz, retired; and Rita Schoeny, U.S. Environmental Protection Agency. Although the reviewers listed above have provided many constructive comments and suggestions, they did not see the final draft of the workshop summary before its release. The review of this workshop summary was overseen by David Hoel, Medical University of South Carolina. Appointed by the National Research Council, he was responsible for making certain that an independent examination of the workshop summary was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of the workshop summary rests entirely with the committee and the institution. The committee is grateful for the assistance of the NRC staff in preparing this workshop summary: Marilee Shelton-Davenport and Roberta Wedge, project directors; Fran Sharples, director of the Board on Life Sciences; Jennifer Saunders and Mirsada Karalic-Loncarevic, research associates; Ruth E. Crossgrove and Norman Grossblatt, senior editors; Lucy Fusco, senior project assistant; and Sam Bardley, librarian. I would like to thank David Eaton, University of Washington, and the members of the committee for their presentations during the workshop, as well as workshop participants who provided thoughtful comments that were critical for articulating the issues and focusing the discussion. Finally, I wish to thank the committee members for their dedicated efforts throughout the development of the summary and Ellen Silbergeld, Johns Hopkins University, for her contributions. Linda E. Greer, Chair, Committee on How Toxicogenomics Could Inform Critical Issues in Carcinogenic Risk Assessment of Environmental Chemicals

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Toxicogenomic Technologies and Risk Assessment of Environmental Carcinogens: A Workshop Summary Contents     SUMMARY OF THE WORKSHOP   3      Introduction   3      Cancer Risk Assessment   5      Application of Toxicogenomic Approaches in Risk Assessment   20      Use of “-omics” Experiments to Improve Risk Assessment: Lessons from Case Studies   32      Moving Forward   40      Conclusion   42      References   43     APPENDIXES     A:   Workshop Agenda   48 B:   Biographical Information on Workshop Organizing Committee and Speakers   50 C:   Abbreviations   54

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