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Toxicity Testing Strategies to Determine Needs and Priorities Steering Committee on identification of Toxic and Potentially Toxic Chemicals for Consicleration by the National Toxicology Program Board on Toxicology and Environmental Health Hazarcis Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington, D. C. 1984 /

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NATIONAL ACADEMY PRESS 2101 CONSTITUTION AVE., NW WASHINGTON, DC 20418 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 report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The National Research Council was established 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 of advising the federal government. The Council operates in accordance with general policies determined by the Academy under the authority of its congressional charter of 1863, which establishes the Academy as a private, nonprofit, self-governing membership corporation. The Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in the conduct of their services to the government, the public, and the scientific and engineering communities. It is administered jointly by both Academies and the Institute of Medicine. The National Academy of Engineering and the Institute of Medicine were established in 1964 and 1970, respectively, under the charter of the National Academy of Sciences. The work on which this publication is based was performed pursuant to Contract NO1-ES-0-0008 with the National Toxicology Program. Library of Congress Catalog Card Number 84-60095 International Standard Book Number 0-309-03433-7 Printed in the United States of America

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STEERING COMMITTEE ON IDENTIFICATION OF TOXIC AND POTENTIALLY TOXIC CHEMICALS FOR CONSIDERATION BY THE NATIONAL TOXICOLOGY PROGRAM James L. Whittenberger, Chairman Southern Occupational Health Center University of California Irvine, California John C. Bailar School of Public Health Harvard University Boston, Massachusetts John Doull Department of Pharmacology University of Kansas Medical Center Kansas City, Kansas Emil A. Pfitzer Department of Toxicology and Experimental Pathology Hoffman-LaRoche, Inc. Nutley, New Jersey Arthur C. Upton Institute of Environmental Medicine New York University Medical Center New York, New York Staff Robert G. Tardiff Project Director (until July 1983) Alvin G. Lazen Project Director (from July 1983) Norman Grossblatt Editor Jacqueline K. Prince Staff Assistant ~ 111

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COMMITTEE ON STATISTICAL SAMPLING METHODS (Conunittee on Sampling Strategies) John C. Bailar, Chairman Department of Biostatistics Harvard School of Public Health Boston, Massachusetts William W. Carlton Department of Veterinary Microbiology Purdue University Lafayette, Indiana Bernard D. Goldstein Department of Environmental and Community Medicine University of Medicine and Dentistry of New Jersey/Rutgers Medical School Piscataway, New Jersey William D. Kalsbeek Population Laboratories University of North Carolina Chapel Hill, North Carolina Richard D. Remington Office of the Vice President for Academic Affairs University of Iowa Iowa City, Iowa Benjamin Tepping Silver Spring, Maryland William L. Wagner Rocky Mountain Center for Occupational and Environmental Health University of Utah Salt Lake City, Utah Joseph Waksberg Westat, Inc. Rockville, Maryland Staff Scott R. Baker Project Director Resha M. Putzrath Staff Officer (until September 1983) iv Michele W. Zinn Administrative Assistant Shirley A. Perry Secretary

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COMMITTEE ON CHARACTERI ZATION OF STATUS OF TOXICITY DATA ELEMENTS E OR A SELECT UNIVERSE OF COMPOUNDS (Committee on Toxicity Data Elements) John Doull, Co-Chairman Department of Pharmacology University of Kansas Medical Center Kansas City, Kansas Emil A. Pfitzer, Co-Chairman Department of Toxicology and Pathology Hoffmann-LaRoche, Inc. Nutley, New Jersey Eula gingham Kettering Laboratory University of Cincinnati Medical Center Cincinnati, Ohio David J. Brusick Department of Genetics Litton Bionetics Research Laboratory Kensington, Maryland George T. Bryan Department of Human Oncology Clinical Science Center Madison, Wisconsin Robert T. Drew Medical Department Brookhaven National Laboratory Upton, New York E. Marshall Johnson College of Medicine Comas Jefferson University Philadelphia, Pennsylvania Morton Lippmann Aerosol and Inhalation Research Laboratory. New York University New York, New York Stat f Scott R. Baker Project Director Gordon W. Newell Project Director ( until October 1981) Barbara B. Jaf fe Senior Staff Officer (until July 1983) Resha M. Putzzath Staff Officer (until September 1983) Comas Mack Cancer Surveillance Program University of Southern California School of Medicine Los Angeles, California Gilbert J. Mannering Department of Pharmacology University of Minnesota Minneapolis, Minnesota Donald E. McHillan Department of Pharmacology University of Arkansas Little Rock, Arkansas Robert A. Neal Chemical Industry Institute of Toxicology Research Triangle Park, North Carolina Edward O. Oswald Department of Environmental Health Sciences University of South Carolina Columbia, South Carolina Marvin A. Schneiderman Clement Associates Washington, D.C. Carrol S. Well Carnegie-Mellon Institute of Research Carnegie-Mellon University Pittsburgh, Pennsylvania Hanspeter R. Witschi Biology Division Oak Ridge National Laboratory Oak Ridge, Tennessee Leslye B. Giese Research Assistant Ronnie M. Good Bibliographic Assistant Michele W. Zinn Administrative Assistant Shirley A. Perry Secretary

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COMMITTEE ON RESEARCH OF AGENTS POTENTIALLY HAZARDOUS TO HUMAN HEALTH (Committee on Priority Mechanisms) Arthur C. Upton, Chairman Institute of Environmental Medicine New York University Medical Center New York, New York Bernard D. Astill Health, Safety and Human Factors Laboratory Eastman Kodak Company Rochester, New York Stephen L. Brown Center for Health and Environmental Research SRI International Menlo Park, California Patricia A. Buffler School of Public Health University of Texas Houston, Texas Richard M. Cooper Williams and Connolly Washington, D.C. Baruch Fischhoff Decision Research, Inc. Eugene, Oregon Corwin H. Hansch Department of Chemistry Pomona College Claremont, California Sheldon D. Murphy Department of Pharmacology University of Texas Medical School Houston, Texas Michael R. Overcash Department of Chemical Engineering North Carolina State University Raleigh, North Carolina Talbot R. Page Environmental Quality Laboratory California Institute of Technology Pasadena, California V1 Verne A. Ray Medical Research Laboratory Pfizer, Inc. Groton, Connecticut Harold R. Ward Center for Environmental Studies Brown University Providence, Rhode Island Staff Samuel B. McKee Project Director Walter G. Rosen Project Director (until July 1983) Azora L. Irby Secretary

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BOARD ON TOXICOLOGY AND ENVIRONMENTAL HEALTH HAZARDS Gerald N. Wogan, Chairman Department of Nutrition and Food Science Massachusetts Institute of Technology Cambridge, Massachusetts Philip J. Landrigan, Co-Vice-Chairman National Institute for Occupational Safety and Health Cincinnati, Ohio Donald F. Hornig, Co-Vice-Chairman School of Public Health Harvard University Boston, Massachusetts Edward Bresnick Eppley Institute for Cancer Research University of Nebraska Medical Center Omaha, Nebraska Herman N. Eisen Department of Biology Massachusetts Institute of Technology Cambridge, Massachusetts Ronald W. Estabrook Department of Biochemistry University of Texas Medical School Dallas, Texas Emmanuel Farber Department of Pathology University of Toronto Toronto, Ontario David G. Hoel Biometry and Risk Assessment Program National Institute of Environmental Health Sciences Research Triangle Park, North Carolina Michael W. Lieberman Deparment of Pathology Washington University St. Louis, Missouri vii Abraham M. Lilienfeld School of Hygiene and Public Health The Johns Hopkins University Baltimore, Maryland Richard Merrill School of Law University of Virginia Charlottesville, Virginia Vaun A. Newill Medicine and Environmental Health Department Exxon Corporation New York, New York John Peters Department of Preventive Medicine University of Southern California Los Angeles, California Joseph V. Rodricks Environ Corporation Washington, D.C. Liane B. Russell Biology Division Oak Ridge National Laboratory Oak Ridge, Tennessee Ellen Silbergeld Environmental Defense Fund Washington, D.C. Ex Officio Gary P. Carlson Department of Pharmacology and Toxicology Purdue University Lafayette, Indiana Maureen M. Henderson Department of Epidemiology University of Washington Seattle, Washington

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Roger 0. McClellan Lovelace Inhalation Toxicology Research Institute Albuquerque, New Mexico Daniel Menzel Departments of Pharmacology and Medicine Duke University Medical Center Durham, North Carolina Norton Nelson Institute of Environmental Medicine New York University Medical Center New York, New York Staff Devra Lee Davis, Executive Director Jacqueline K. Prince, Staff Assistant Shirley A. Ash, Administrative Secretary mini

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PREFACE In September 1980, the National Toxicology Program (NTP), through the National Institute of Environmental Health Sciences, contracted with the National Research Council (NRC) and the National Academy of Sciences for study with two principal charges: (1) To characterize the toxicity-testing needs for substances to which there is known or anticipated human exposure' so that federal agencies responsible for the protection of public health will have the appropriate information needed to assess the toxicity of such substances. (2) To develop and validate uniformly applicable and w~de-ranging criteria by which to set priorities for research on substances with potentially adverse public-heath impact. me study, titled "Identification of Toxic and Potentially Toxic Chemicals for Consideration by the National Toxicology Program," was established in the Board on Toxicology and Environmental Health Hazards of the NRC's Commission on Life Sciences. A Steering Committee was formed to address the charges and coordinate the efforts of three operating committees. The Committee on Statistical Sampling Methods ("Committee on Sampling Strategies") and the Committee on Characterization of the Status of Toxicity Data Elements ("Committee on Toxicity Data Elements") addressed the first charge. The Committee on Research of Agents Potentially Hazardous to Human Health ("Committee on Priority Mechanisms") addressed the second charge. m e two charges of the study involved concepts with many similarities, but they also required different approaches. The first charge--to characterize the status of toxicity-testing information on substances--required a detailed examination of existing toxicity data based on available criteria for qualitative and quantitative characteristics of adequacy. The approach required judgments on the adequacy of testing of specific substances, independently of whether the substances were potent agents or relatively inert substances with low toxicity. The second charge--to develop criteria for setting research priorities--required a detailed examination of methods of selecting potentially toxic substances from a large universe of substances on which there was little or no toxicity information. The approach required judgments on the predictability of testing procedures, the nature and severity of potential toxic effects, and the systemic modeling of steps in decision-making. This is the final report of the four committees. It represents the work of their members, NRC staff, a large number of consultants, ano others who provided invaluable assistance to the committees. This report is designed to be a stand-alone document, summarizing and synthesizing 1X

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the full scope of work first described at two interim stages of evolution in documents entitled Strategies to Determine Needs and Priorities for Toxicity Testing--Volume 1: Design and Volume 2: Development. These earlier reports were published at the end of the first and second years of the study. The activities to address the two charges were conducted with substantial interchange of concepts and practices, but they were recognized to be sufficiently different in approach to warrant presentation as two distinct parts. The specific differences are presented in a final appendix to Part 2. The reader should be aware of this intent when reading Parts 1 and 2 of this report. We of the Steering Committee thank all the participants, who have contributed so much to this study. The amount of work performed indicates the magnitude of the task that faces NTP. In particular, we wish to recognize the enormous effort dedicated to this study by the three operating committees and the NRC staff. The dossiers containing the analyses of all toxicity data that were available on a subsample of 100 substances constitute approximately 2 cubic meters of decision-making information. me collection, analysis, and interpretation of information on just this small number of substances in general use required thousands of hours of the time of volunteer committee members, the staff, and other participants over a 3-year period. The thoughtfulness and computer work needed to select the study samples and model the criteria for priority-setting required no less intensive an effort. The large scope of work addressed by the committees could not have been accomplished without the assistance of the skilled and dedicated staff of the Board on Toxicology and Environmental Health Hazards. We wish to thank Robert G. Tardiff, who was project director for this study during his tenure with the Board, and Alvin G. Lazen, who was associated with the study in its last stages. We also thank Scott R. Baker for his important contributions to the "needs" section of this report and Samuel B. McKee and Walter G. Rosen for their work on the "priorities" section; Lamar B. Dale, Leslye R. Giese, Ronnie M. Good, Norman Grossblatt, Cheryl J. Haily, Veronica C. Harris, Azora L. Irby, Barbara B. Jaffe, Paula H. Morris, Gordon W. Newell, Shirley A. Perry, Frances M. Peter, Jacqueline K. Prince, Resha M. Putzrath, Joyce A. Russell, Patricia A. Sterling, Robert J. Comas, and Michele W. Zinn for their professional and administrative contributions; and Andrew M. Pope, Gerald M. Rosen, and Jeannee K. Yermakoff for their contributions while they were serving as National Research Council Fellows. We are particularly grateful for the assistance provided by Raymond E. Shapiro, who served as the study's project officer for NTP. 1 James L. Whittenberyer' Chairman John C. Bailar John Doul1 Emil A. Pfitzer Arthur C. Upton x

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ACKNOWLEDGMENTS Valuable contributions to this study were made by Steven Wilhelm and Yvonne Hales, who served as technical consultants, and by Lynn Jones, Nora Riley, and Janice Miller, who assisted in the acquisition of documents. The following colleagues in both the public and private sectors generously shared information, resource material, and expertise: Wellman Bachtel, Susan Bloodworth, Miles Bogle, Keith Booman, Edward Brooks, Dorothy Canter, Michael Conners, Paul Craig, Sonia Crisp, Denny Daniels, Karen Dickerson, David Disbennett, Ronald Dunn, Donald Dunnom, Robert Elder, Curt Enslein, Norman Estrin, Theodore Farber, Kenneth Fisher, Gary Flamm, Richard Ford, Vasilios Frankos, John Froines, Vera Glocklin, John Gordon, Martin Greif, Allen Heim, Joseph Highland, Louis Hades, David Hoel, Maurice Hubert, Vera Hudson, Julius Johnson, Judy Jones, Henry Kissman, Mary Rose Kornreich, Raymona Kukol, Ann McCann, Arthur McCreesch, Jerald McEwan, Carolyn McHale, Joseph Merenda, Mary Lou Miller, William Milne, Victor Morgenroth, Therese Murtaugh, Ian Nisbet, William Olson, Donald Opdyke, Norbert Page, William Payne, Alan Rulis, Andrew Sage, Virginia Salzman, Phillip Sartwell, Takashi Sugimura, John Tinker, Justine Welch, and Karen Wetterhahn. xi

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CONTENTS EXECUTIVE SUMMARY INTRODUCTION PART 1: TOXICITY-TESTING NEEDS IN THE SELECT UNIVERSE Contents to Part 1 PART 2: SETTING PRIORITIES FOR TOXICITY TESTING Contents to Part 2 xiii Page 1 19 23 199

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