Table Of ContentCurrent 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
