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COMPLEX MIXIU1tES Methods for ~ Vivo Toxicity Testing Committee on Methods for the In Vivo Toxicity Testing of Complex Mixtures Board on Environmental Studies and Toxicology Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington, D.C. 1988

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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 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. Frank Press 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 spon- sors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Robert M. White 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. Samuel O. Thier 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 Na- tional 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. Frank Press and Dr. Robert M. White are chairman and vice chairman, respectively, of the National Research Council. This project has been funded by the National Institute of Environmental Health Sciences under Contract NO1-ES45058 with the National Academy of Sciences. The contents of this document do not necessarily reflect the views and policies of the National Institute of Environmental Health Sciences, and an official endorsement should not be inferred. Library of Congress Catalog Card Number 87-28178 International Standard Book Number 0-309-03778-6 Printed in the United States of America

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Committee on Methods for the In Vivo Toxicity Testing of Complex Mixtures JOHN Dough, University of Kansas Medical Center, Kansas City, Kansas (Ch~airman) Eu~A BINGHAM? University of Cincinnati, Cincinnati, Ohio (Vice-Chairman) KENNETH CANTOR, National Cancer Institute, Bethesda, Maryland DoNA~D Ecos~cHoN, McGill University, Montreal, Quebec, Canada MICHAEL A. GALLO, University of Medicine and Dentistry of New Jersey- Robert Wood Johnson Medical School, Piscataway, New Jersey JEROME KEEINERMAN, Cleveland Metropolitan General Hospital, Cleveland, Ohio BARBARA C. LEVIN, National Bureau of Standards, Gaithersburg, Maryland JoE~EN LEWTAS, Environmental Protection Agency, Research Triangle Park, North Carolina MORTON LIPPMANN, New York University, Tuxedo, New York HAROLD N. MAcFAR~AND, Victoria, British Columbia, Canada EDO D. PE~uzzAR~, Research Triangle Institute, Research Triangle Park, North Carolina GABRIEL L. PLAA, University of Montreal, Montreal, Quebec, Canada ROBERT A. SCALA, Exxon Corporation, East Millstone, New Jersey RITA S. SCHOENY, Environmental Protection Agency, Cincinnati, Ohio DAv~D WARSHAWSKY, University of Cincinnati College of Medicine, Cincinnati, Ohio BERNARD WE~ss,~ University of Rochester Medical Center, Rochester, New York HANSPETER WITSCHI, Oak Ridge National Laboratory, Oak Ridge, Tennessee RONALD WYZGA, Electric Power Research Institute, Palo Alto, California v

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Subcommittee on Modeling and Biostatistics RoNA~D E. WYZGA, Electric Power Research Institute, Palo Alto, California (Chairman) PAu~ FEDER, Battelle Columbus Laboratories, Columbus, Ohio DANIEL KREwsK~, Health and Welfare Canada, Ottawa, Ontario, Canada STEPHEN LAGAKOS, Harvard University, Boston, Massachusetts HAROLD N. MAcFARLAND, Toxicology Consultant, Victoria, British Columbia, Canada ELIZABETH H. MARGOSCHES, Environmental Protection Agency, Washington, D.C. FINBARR O'Su~uvAN, University of California, Berkeley, California TODD THoRs~uND, ICF/Clement Associates, Washington, D.C. MARVIN SCHNEIDERMAN, National Research Council, Washington, D.C. JOHN VAN RYZIN, Columbia University, New York, New York BERNARD Weiss, University of Rochester Medical Center, Rochester, New York Advisors, Consultants, and Contributors R~cHARD Burn, Washington State University, Pullman, Washington GAIL CHARNLEY, ICF/Clement Associates, Washington, D.C. CHRISTOPHER Cox, University of Rochester, Rochester, New York DAVID GROTH, Robert A. Taft Laboratory, Cincinnati, Ohio National Research Council Staff RICHARD D. THOMAS, Study Director BRUCE K. BERNARD, Project Director EVELYN E. SIMEON, Project Secretary KATH! CocHRAN-REDMoND, Assistant Project Secretary ALISON KAMAT, Bibliographer Technical Contract Monitor, National Institute of Environmental Health S. clences BERNARD A. SCHWETZ, Systemic Toxicology Branch, Toxicology Research and Testing Program, National Toxicology Program, Research Triangle Park, North Carolina Vl

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Board on Environmental Studies and Tox: icology DONALD F. HORNIG, School of Public Health, Harvard University, Boston, Massachusetts (Chairman) ALVIN L. ALM, President, Alliance Technologies Corp., Bedford, Massachusetts RICHARD N. L. ANDREWS, UNC Institute for Environmental Studies, Chapel Hill, North Carolina DAv~D BATES, Department of Medicine, UBC Health Science Center Hospital, Vancouver, British Columbia R~cHARD A. CONWAY, Engineering Department, Union Carbide Corp., South Charleston, West Virginia WILUAM E. COOPER, Department of Zoology, Michigan State University? Lansing BENJAMIN G. FERRIS, Department of Environmental Science and Physiology, Harvard School of Public Health, Boston, Massachusetts SHErDoN K. FRIEDLANDER, National Center Intermedia Transport Research, University of California, Los Angeles BERNARD GOLDSTEIN, Department of Environmental and Community Medicine, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey DoNA~D MATT~soN, Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock PHIMP A. PALMER, Engineering Department, E.I. du Pont de Nemours & Co., Wilmington, Delaware DUNCAN T. PATTEN, Center for Environmental Studies, Arizona State University, Tempe EMIL PFITZER, Department of Toxicology and Pathology, Hoffmann- La Roche Inc., Nutley, New Jersey PAUL PORTNEY, Resources for the Future, Washington, D.C. PAUL RISSER, University of New Mexico, Albuquerque WILOAM H. RODGERS, Schoo} of Law, University of Washington, Seattle F. SHERWOOD ROWLAND, Department of Chemistry, University of California, Irvine LIANE B. RUSSELL, Biology Division, Oak Ridge National Laborato~y, Oak Ridge, Tennessee ELLEN SILBERGELD, Toxics Program, Environmental Defense Fund, Washington, D.C. GLENN I. SIPES, Department of Toxicology and Pharmacology, University of Arizona School of Medicine, Tucson ~ Vl!

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~ V111 BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY National Research Council Staff DEVRA LEE Davis, Director, Board on Environmental Studies and Toxicology JACQUELINE PRINCE, Staff Assistant

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Preface The National Institute of Environmental Health Sciences asked the National Research Council to evaluate the toxicity testing of mixtures and make recom- mendations for improving that testing. The National Research Council re- sponded to the request by appointing 16 scientists to serve on the Committee on Methods for the In Vivo Toxicity Testing of Complex Mixtures, in the Board on Environmental Studies and Toxicology of the National Research Council's Commission on Life Sciences. The committee membership represented the disciplines of toxicology, pathology, biochemistry, analytic chemistry, envi- ronmental sciences, biostatistics, and epidemiology. Toxicity testing is a subject of major current concern to both the scientific and regulatory communities and has been the subject of several recent work- shops, reports, and discussions. Consequently, many of the committee mem- bers were concerned about our ability to "break new ground" or to provide significant new insights for either the toxicologic methods for testing mixtures or the use of resulting data to protect human and environmental health. After reviewing both the toxicologic and epidemiologic data on the adverse health effects of mixtures, the committee concluded that a new approach, rasher then new methods, is the primary need. This report describes ourration- ale for this conclusion and presents a series of recommended strategies for testing mixtures. As the chairman and vice-chairman of this committee, we want to thank Drs. Morton Lippmann, Robert A. Scala, Edo D. Pellizzari, and Ronald Wyzga for chairing task groups that focused on concepts for analyzing human exposure to complex mixtures, testing strategies and methods, sampling and chemical characterization, and interpretation and modeling of toxicity-test results, re- spectively. Working with this distinguished committee was an honor and a IX

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x PREFACE pleasure, and we thank the members for their contributions and hard work in completing this report. Dr. Devra Davis deserves special thanks for the con- stant encouragement and insight that she communicated to a diverse and large committee. On behalf of the committee, we would also like to thank Drs. Bruce K. Bernard and Richard D. Thomas for~cheir sustained and patient staff effort in support of the committee. JOHN Dough, Chairman EULA BINGHAM, Vice-Chairman Committee on Methods for the In Vivo Toxicity Testing of Complex Mixtures

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Contents EXECUTIVE SUMMARY 1 INTRODUCTION 2 CONCEPTS FOR ANALYZING HUMAN EXPOSURE TO COMPLEX CHEMICAL MIXTURES TESTING STRATEGIES AND METHODS 4 SAMPLING AND CHEMICAL CHARACTERIZATION INTERPRETATION AND MODELING OF TOXICITY-TEST RESU LTS APPENDIXES A. ORIGINS OF COMPLEX MIXTURES B. CASE STUDIES ESTABLISHING ACTIVE AGENTS AND/OR INTERACTIONS IN COMPLEX MIXTURES .................. 5 10 39 65 99 127 133 C. CASE STUDIES ON STRATEGIES FOR TESTING THE TOXICITY OF COMPLEX MIXTURES . . . . . . . . . . . . .. .... .. . .. .. .. . . . 1 68 D. PREDICTING THE JOINT RISK OF A MIXTURE IN TERMS OF THE COMPONENT RISKS .............................. E. CANCER MODELS ..................................... F. DEVELOPMENTAL TOXICOLOGY G. EMPIRICAL MODELING OF THE TOXICITY OF MIXTURES Xl 179 185 202 209 221

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