Interpretation and Extrapolation of Chemical and Biological Carcinogenicity Data to Establish Human Safety Standards: The Use of Short-Term Tests for Mutagenicity and Carcinogenicity in Chemical Hazard Evaluation PDF
Preview Interpretation and Extrapolation of Chemical and Biological Carcinogenicity Data to Establish Human Safety Standards: The Use of Short-Term Tests for Mutagenicity and Carcinogenicity in Chemical Hazard Evaluation
Current Issues in Toxicology Current Issues in Toxicology Sponsored by the International Life Sciences Institute Edited by H.C. Grice Interpretation and Extrapolation of Chemical and Biological Carcinogenicity Data to Establish Human Safety Standards The Use of Short-Term Tests for Mutagenicity and Carcinogenicity in Chemical Hazard Evaluation I Springer-Verlag New York Berlin Heidelberg Tokyo H.C. Grice, Editor Nepean, Ontario, Canada © 1984 by Springer-Verlag New York Ine. All rights reserved. No part of this book may be translated or reprodueed in any form without written permission from Springer-Verlag, 175 Fifth Avenue, New York, New York 10010, U.S.A. The use of general descriptive names, trade names, trademarks, etc., in this publication, even if the former are not especially identified, is not to be taken as a sign that such names, as understood by the Trade Marks and Merehandise Marks Aet, may aecordingly be used freely by anyone. Media conversion by Ampersand, Rutland, Vermont. 9 8 7 6 543 2 ISBN-13: 978-3-540-13696-5 e-ISBN-13: 978-3-642-49371-3 DOI: 10.1007/978-3-642-49371-3 Foreword The International Life Sciences Institute (lLSI) is a scientific foundation wh ich addresses critical health and safety issues of national and international concern. ILSI promotes international cooperation by pro viding the mechanism for scientists from government, industry and universities to work together on cooperative programs to generate and disseminate scientific data. The members and trustees of the Institute believe that questions regarding health and safety are best resolved when scientists can ex amine and discuss issues, as an independent body, se~arate from the political pressures of individual countries and the economic concerns of individual companies. Frequently, meaningful assessment of the risk of a test substance is hindered by the inherent inconsistencies in the system. The development and refinement of methods and systems to evaluate the safety of chemicals have evolved in a rapid and largely unplanned fashion. Attempts to improve the system have largely been directed toward broad general concerns, with little attention being given to specific problems or issues. A failure to resolve these problems has frequently resulted in increased testing costs and complications in the assessment and extrapolation of the results. Publicity surrounding toxicologic issues has created chronic public apprehension about the ability of science and government to deal effectively with these problems. In response to these difficulties, ILSI has assembled highly qualified and renowned scientists from research institutes, universities, government and industry, with relevant scientific knowledge and expertise regarding the issues that complicate risk assessment procedures. This series, Current Issues in Toxicology, is the result ofthe endeavors of these international scientists in this regard. It also exemplifies the commitment of ILSI to promote a better understanding of critical safety issues. Throughout this series, an attempt is made to not only ex amine the factors which influence the evaluation of the safety of chemicals but also to develop principles, recommend guidelines and define areas requiring additional research. Contents Interpretation and Extrapolation of Chemical and Biological Data on Carcinogens to Establish Human Safety Standards I. Introduction 7 II. Chronic Toxicity/Carcinogenicity Bioassay 9 III. Short-Term Tests 30 IV. Pharmacokinetics and Metabolism 36 V. Synergism and Antagonism 45 VI. Mechanisms of Action 49 VII. Systematic Analysis of the Chemical and Biological Properties of Carcinogens 58 VIII. Establishing Human Exposure Guidelines 65 IX. Appendix: Profiles of Selected Compounds 68 X. References 105 The Use of Short-Term Tests for Mutagenicity and Carcinogenicity in Chemical Hazard Evaluation I. Introduction 159 11. Development of Test Strategies 160 III. Review of Organization Guidelines 166 IV. Future Developments 181 V. Batteries of Short-Term Tests 186 VI. Approaches to the Interpretation of Short-Term Test Results 187 VII. Conclusions 190 VIII. References 190 Current Issues in Toxicology Interpretation and Extrapolation of Chemical and Biological Carcinogenicity Data to Establish Human Safety Standards Editor in Chief Dr. Harold C. Grice, Scientific Coordinator, International Life Sciences Institute, Nepean, Ontario, Canada Associate Editors Dr. Douglas L. Arnold, Bureau of Chemical Safety, Health Protection Branch, Health and Welfare Canada, Ottawa, Ontario, Canada Dr. David B. Clayson, Bureau of Chemical Safety, Health Protection Branch, Health and Welfare Canada, Ottawa, Ontario, Canada Dr. Miles D. Clarke, Bureau of Chemical Safety, Health Protection Branch, Health and Welfare Canada, Ottawa, Ontario, Canada Dr. John L. Emmerson, Director, Toxicology Studies, Lilly Research Laboratories, Eli Lilly and Company, Greenfield, Indiana, U.SA. Dr. Lawrence Fishbein, Director, Office of Scientific Intelligence, National Center for Toxicological Research, Jefferson, Arkansas, U.S.A. Dr. Donald Hughes, Scientific Coordinator, Regulatory Services Division, The Procter and Gamble Company, Cincinnati, Ohio, U.S.A. Dr. Daniel Krewski, Environmental Health Directorate, Health Protection Branch, Health and Welfare Canada, Ottawa, Ontario, Canada Officers-ILSI Alex Malaspina, Atlanta-President Peter B. Dews, Boston-Vice President Ulrich Mohr, Hannover-Vice President Roger D. Middlekauff, Washington-Secretary/Treasurer Contributors RL. Anderson, Ph.D. L. Fishbein, Ph.D. The Procter and Gamble Company National Center for Cincinnati, Ohio, U.S.A. Toxicological Research Jefferson, Arkansas, U.S.A. D.L. Arnold, Ph.D. Health Protection Branch S. Garattini, M.D. Health and Welfare Canada Instituto di Ricerche Ottawa, Ontario, Canada F armacologiche Milan, Italy R.G. Carlson, D.V.M., Ph.D. Upjohn International, Inc. H.C. Grice, D.V.M., M.Sc., V.S. Kalamazoo, Michigan, U.S.A. International Life Sciences Institute Nepean, Ontario, Canada C. Chang, M.D. Department of Pediatrics R. Hess, M.D. and Human Development CIBA GEIGY AB Michigan State University Basel, Switzerland East Lansing, Michigan, U.S.A. J.C. Kirschman, Ph.D. M. D. Clarke, D.V.M., M.Sc. General Foods Corporation Health Protection Branch Tarrytown, New York, U.S.A. Health and Welfare Canada Ottawa, Ontario, Canada D. Krewski, Ph.D. Health Protection Branch D.B. Clayson, Ph.D. Health and Welfare Canada Bureau of Chemical Safety Ottawa, Ontario, Canada Health and Welfare Canada Ottawa, Ontario, Canada R Kroes, D.V.M., Ph.D. Yin Dai, Ph.D. National Institute of Public Institute of Health Health and Environmental Chinese Academy of Medical Hygiene Science Bilthoven, N etherlands Beijing, China C.T. Miller, Ph.D. J.L. Emerson, D.V.M., Ph.D. Priority Issues Directorate The Coca-Cola Company Environment Canada Atlanta, Georgia, U.S.A. Rull, Quebec, Canada 4 Contributors I.C. Munro, Ph.D. J.W. Stanley, Ph.D. Canadian Centre for Toxicology PepsiCo, Inc. University of Guelph Valhalla, New York, U.S.A. Guelph, Ontario, Canada J. Sugar, M.D. Research Institute of P. Olsen, D.V.M., Ph.D. Oncopathology National F 000 Institute Budapest, Hungary Soborg, Denrnark S. Takayama, M.D. D.V. Parke, Ph.D. Cancer Institute Department of Biochemistry Japanese Foundation for Cancer University of Surrey Research Surrey, England Tokyo,Japan H. Tryphonas, M.Sc. J.J. Roberts, Ph.D., D.Sc. Division of Toxicology Research Institute of Cancer Research Health Proteetion Branch Royal Cancer Hospital Health and Welfare Canada Sutton, Surrey, England Ottawa, Ontario, Canada R.A. Squire, Ph.D. G.M. Williams, M.D. The Johns Hopkins University Naylor Dana Institute for School of Medicine Disease Prevention Baltimore, Maryland, U.S.A. Valhalla, New York, U.S.A. Contents 1. Introduction 7 H. Chronic Toxicity/ Carcinogenicity Bioassay 9 2.1. Introduction 9 2.2. Identity, Analytical Purity and Stability of Test Substances 9 2.3. Species and Strain of Test Animals 10 2.4. Route of Administration 11 2.5. Dose Selection and Treatment Groups 11 2.6. Sampie Size 12 2.7. Methods of Randomization 12 2.8. Duration of Studies l3 2.9. Clinical Observations 14 2.10. Animal Husbandry 14 2.11. Diet 15 2.12. Pathology 15 2.13. F actors That May Modulate Tumor Occurrence 17 2.14. Statistical Analysis 25 2.15. Perinatal Exposure-In Utero Exposure 26 2.16. Interpretation of Results 26 2.17. Predictive Value of Chronic Toxicity/Carcinogenicity Bioassays 27 2.18. Overview 29 IH. Short-Term Tests 30 3.1. Introduction 30 3.2. Short-Term Screening Tests 31 3.3. Short-Term Tests to Detect Mutagenicity 31 3.4. DNA Damage Tests 32 3.5. Chromosome Effects 32 3.6. Cell Transformation Tests 32 3.7. Tests for Tumor Promoters 33 3.8. Predictive Value of Short-Term Screening Tests 33 3.9. Predictive Value of Mutagenicity Tests 34 3.10. Predictive Value of DNA Repair Tests 34 3.11. Predictive Value of Chromosome Tests 34 3.12. Predictive Value of Cell Transformation Tests 35 3.13. Predictive Value ofTests for Tumor Promoters 35 3.14. Role of Short-Term Tests 36
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