Table Of ContentCurrent Issues in Toxicology
Current Issues in Toxicology
Sponsored by the
International Life Sciences Institute
Edited by H.C. Grice
The Selection of Doses in Chronic
Toxicity ICarcinogenicity Studies
Age-Associated (Geriatric) Pathology:
Its Impact on Long-Term Toxicity Studies
I
Springer-Verlag
New York Berlin Heidelberg Tokyo
H.C. Grice, Editor
Nepean, Ontario, Canada
Library of Congress Cataloging in Publication Data
Main entry under title:
The selection of doses in chronic toxicity/carcincr
genicity studies; Age associated (geriatric)
pathology, its impact on long-tenn toxicity studies.
(Current issues in toxicology)
Includes bibliographies.
1. Toxicity testing-Addresses, essays, lectures.
2. Poisons-Dose-response relationship-Addresses.
essays, lectures. 3. Carcinogenicity testing-Addresses,
essays, lectures. 4. Carcinogens-Dose-response re
lationship-Addresses, essays, lectures. 5. Xencr
biotics-Metabolism-Age factors-Addresses, essays,
lectures. 6. Rodems-Diseases-Age factors-Addresses,
essays, lectures. I. Age associated (geriatric) path-
ology, its impact on long-tenn toxicity studies. 1983.
n.
Series. (DNLM: I. Toxicology. 2. Carcinogens,
Environmental-Administration and dosage. 3. Aging
Drug effects. QV 600 S464]
RAIl99.S44 1983 615.9'07 83-10445
With 3 Figures
C> 1984 by Springer-Verlag New York Inc.
All rights reserved. No part of this book may be translated or reproduced in any
fonn without written pennission 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 fonner are not especially identified, is not to be taken as a
sign that such names, as understood by the Trade Marks and Merchandise Marks
Act, may accordingly be used freely by anyone.
9 8 7 6 5 4 3 2
ISBN 978-3-540-12845-8 ISBN 978-3-642-49293-8 (eBook)
DOl 10.1007/978-3-642-49293-8
Foreword
The International Life Sciences Institute (ILSI) is a scientific foundation which
addresses critical health and safety issues of national and international concern.
ILSI promotes international cooperation by providing the mechanism for sci
entists from government, industry and universities to work together on co
operative 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 examine and discuss issues, as an in
dependent body, separate 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 evalute 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.
In response to these difficulties, ILSI has assembled highly qualified and
renowned scientists from research institutes, universities, government and in
dustry, with relevant scientific knowledge and expertise regarding the issues
that complicate risk assessment procedures.
This series, Current Issues in Toxicology, is the result of the 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 examine the factors which influence
the evaluation of the safety of chemicals but also to develop principles, rec
ommend guidelines and define areas requiring additional research.
Contents
The Selection of Doses in Chronic Toxicity!
Carcinogenicity Studies
I. Introduction 9
IT. Factors Relating to the Dose Selection 21
m. Principles for Dose Selection 35
N. Evaluation and Interpretation of Experimental Findings 37
V. Recommendations for Future Research on Dose
Selection 38
VI. Summary 39
VII. Glossary of Terms - As They Pertain to Toxicology 40
vm. References 41
Age-Associated (Geriatric) Pathology:
Its Impact on Long-Term Toxicity Studies
I. Introduction 57
II. Types of Long-Term Tests 58
ITI. Factors Related to the Aging Process that Influence the
Design and Conduct of Long-Term Rodent Studies 59
IV. Age-Associated Diseases: How They Complicate
Long-Term Toxicity Studies 66
V. Effect of Aging on Drug Metabolism 71
VI. Duration of Long-Term Studies 86
VIT. Cost of Conducting Toxicity Studies with Durations of
18, 24, or 30 Months 89
VIII. Conclusions 92
IX. Areas in Need of Future Research 93
X. Summary 94
XI. References 95
Current Issues in Toxicology
The Selection of Doses in
Chronic Toxicity/Carcinogenicity Studies
Editor in Chief
Dr. H.C. Grice, Scientific Coordinator, International Life Sciences Insti
tute, Nepean, Ontario, Canada
Associate Editors
Dr. D.L. Arnold, Bureau of Chemical Safety, Health and Welfare Canada,
Ottawa, Ontario, Canada
Dr. H. Blumenthal, Bureau of Foods, Department of Health and Human
Services, Food and Drug Administration, Washington, D.C., U.S.A.
Dr. J.L. Emmerson, Director, Toxicology Studies, Lilly Research Labora
tories, Eli Lilly and Company, Greenfield, Indiana, U.S.A.
Dr. D. Krewski, Environmental Health Directorate, Health and Welfare
Canada, Ottawa, Ontario, Canada
Contributors
D.L. Arnold, Ph.D. D. Krewski, Ph.D.
HPB, Health and Welfare Canada HPB, Health and Welfare Canada
Ottawa, Canada Ottawa, Canada
R.G. Carlson, D.V.M., Ph.D. R. Kroes, D.V.M., Ph.D.
Upjohn International, Inc. Institute CIVO Toxicology and
Kalamazoo, Michigan, U.S.A. Nutrition TNO
Zeist, Netherlands
Yin Dai, Ph.D.
Chinese Academy of Medical Science I.C. Munro, Ph.D.
Beijing, China HPB, Health and Welfare Canada
Ottawa, Canada
J.L. Emerson, D.V.M., Ph.D.
The Coca-Cola Company F.W. Oehme, D.V.M., Ph.D.
Atlanta, Georgia, U.S.A. Kansas State University
Manhattan, Kansas, U.S.A.
L. Fishbein, Ph.D.
National Center for D. V. Parke, Ph.D.
Toxicology Research University of Surrey
Jefferson, Arkansas, U.S.A. Surrey, England
S. Garattini, M.D. J.R. Schenken, M.D.
Instituto di Ricerche Farmacologiche University of Nebraska
Milan, Italy Omaha, Nebraska, U.S.A.
H.C. Grice, D. V.M., M.Sc., V.S. J.W. Stanley, Ph.D.
International Life Sciences Institute PepsiCo, Inc.
Ottawa, Canada Valhalla, New York, U.S.A.
R. Hess, M.D. R.C. Truhaut, D.Sc.
CIBA Geigy AB Universite Rene Descarte
Basel, Switzerland Paris, France
J.C. Kirschman, Ph.D.
General Foods Corporation
Tarrytown, New York, U.S.A.
Contents
I. Introduction 9
1. Objectives of Chronic Toxicity Testing 9
2. Review of Existing Guidelines 9
3. Overview of Problems Involved in Dose Selection. 20
II. Factors Relating to the Dose Selection 21
1. Physical and Chemical Properties of the Test Compound 21
2. Human Exposure 23
3. Acute Toxicity Studies 23
4. Subchronic Toxicity Studies 24
5. Metabolism and Pharmacokinetics 25
6. Pharmacology and Biochemistry 27
7. Toxicology 28
8. Nutrition 29
9. Statistics 31
10. In Utero Exposure 33
III. Principles for Dose Selection 35
IV. Evaluation and Interpretation of Experimental Findings 37
V. Recommendations for Future Research on Dose Selection 38
VI. Summary 39
VII. Glossary of Terms-As They Pertain to Toxicology 40
VIII. References 41
I. Introduction
1. Objectives of Chronic Toxicity Testing
Increasing public demand for greater assurance of safety regarding chemicals
found in the human environment has led, in recent years, to a tremendous
increase in research and regulatory activity in the field of toxicology. While
the ultimate goal is human health, information for use in the safety evaluation
of chemicals is derived primarily from various types of bioassay studies using
animal models. The objective of long-term tests in rodents is to assess poten
tial chronic toxicity, including carcinogenicity, which would not be evident
in tests of shorter duration.
Of paramount importance in the design of any toxicological study is the selec
tion of appropriate exposure levels. Care in the selection of the dosages will
maximize the value of the information obtained and greatly facilitate the
interpretation of the study results.
In designing a chronic toxicity/carcinogenicity study, it is important to
distinguish between a study intended to defme the shape and nature of the dose
response curve for the toxicological endpoint of interest and a study in which
the primary objective is simply to evaluate the presence or absence of a par
ticular toxicological effect such as carcinogenicity. Because of the limited
amount of information provided by the latter type of study (which typically
involves the use of only one or two very high dose levels), it is difficult to
estimate potential hazards to man at low levels of exposure. The purpose of
this monograph, therefore, is to consider strategies to approach the problem
of dose selection, with emphasis on the selection of the dose levels to be used
in multi-dose, dose-response studies.
2. Review of Existing Guidelines
Existing guidelines for the selection of dosages to be used in chronic toxici
ty/carcinogenicity studies have been established largely on empirical grounds.
These guidelines are often presented in a pragmatic manner without adequate
rationale. Practical constraints imposed by the limited availability of adequate
testing facilities and the large number of compounds to be tested have
frequently resulted in the use of a limited number of relatively high dose levels.
A summary of the published guidelines on dose selection is given in Table
I, "Summary of Existing Guidelines for Dose Selection in Chronic Toxicity
