Principles of Genetic Toxicology

292 Pages·1987·24.419 MB·English

by  David Brusick (auth.)

Principles of
Genetic Toxicology
Second Edition
Principles of
Genetic Toxicology
Second Edition
David Brusick
Hazleton Laboratories
Kensington, Maryland
SPRINGER SCIENCE+BUSINESS MEDIA, LLC
Library of Congress Cataloging in Publication Data
Brusick, David.
Principles of genetic toxicology.
Bibliography: p.
Includes index.
1. Genetic toxicology. I. Title. [DNLM: 1. Environmental Pollutants. 2. Mutagens.
3. Mutation. QH 465.C5 B912p)
RAI224.3.B78 1987 575.2'9 87-17169
ISBN 978-1-4899-1982-3 ISBN 978-1-4899-1980-9 (eBook)
DOI 10.1007/978-1-4899-1980-9
© 1987 Springer Science+Business Media New York
Originally published by Plenum Press, New York in 1987
Softcover reprint of the hardcover 2nd edition 1987
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted
in any form or by any means, electronic, mechanical, photocopying, microfilming,
recording, or otherwise, without written permission from the Publisher
This book is dedicated to
Dr. Alexander Hollaender
(1899-1986)
Foreword
The field of genetic toxicology has gone through remarkable development
in the seven years since the appearance of the first edition of Principles
of Genetic Toxicology.
One branch of toxicology research, chemical mutagenesis, has been
elucidated and expanded as a result of increased effort, testing, and the
sharing of data. This expansion has occurred not only in the industrialized
countries, but also in countries that are comparatively less advanced in
scientific implementation. These developing countries have taken advan
tage of the basic practical methods that were so well described in the first
edition of this work. It is significant to note how many centers have been
established throughout the world and are now studying the basic concepts
and applying them to practical problems such as the detection of genetic
effects caused by exposure to chemicals. In fact, there are now toxicology
training centers in twelve countries. Genetic toxicology, in addition to
being investigated as a science unto itself, has been taught to people in
the applied fields so that these techniques may be put to use in solving
other biological problems.
For these reasons, it is most useful to have an update of the basic
methods and their development. Dr. Brusick should be congratulated for
doing such an excellent job of assembling a text that will be worthwhile
to any researcher who is interested in the principles of genetic toxicology.
Alexander Hollaender
Council for Research Planning in
Biological Sciences, Inc.
Washington, D.C. 20036
vii
Preface
The present generation is only a caretaker of
the human genome offuture generations.
MALLING AND V ALCOVIC (1978)
The above quotation from MaIling and Valcovic was used in the first
edition of this work. It is so accurate and states so clearly the task placed
before genetic toxicologists that it is used again to set the tone of this
edition.
Since the first edition of this book was published in 1980, genetic
toxicology has encountered numerous challenges and has participated in
several scientific breakthroughs, which will affect the course of this dis
cipline for many years to come. Yet at the same time some of the fun
damental problems that faced genetic toxicologists in 1980 remain in 1987
with no appearance of forward progress.
The objectives of this edition remain essentially the same as those
of the first edition. It strives to provide a synthesis and perspective on
genetic toxicology that might in some way help practitioners and indi
viduals just entering this area of toxicology to make real progress toward
solving some of the difficult problems, and to help assure that our gen
eration will be a responsible caretaker of the gene pool.
David J. Brusick
Kensington, Maryland
ix
Contents
FOREWORD BY ALEXANDER HOLLAENDER ................ Vll
PREFACE ............................................................. ix
Chapter 1
ORIGINS OF GENETIC TOXICOLOGY 1
Introduction ............................................................ 1
The Role of Genetic Toxicology in Health Effects Testing ........ 3
History of Genetic Toxicology ....................................... 4
Technology Transfer and Applied Genetics ......................... 5
The Components of Genetic Toxicology ............................ 6
References ............................................................. 9
Chapter 2
FUNDAMENTALS OF GENETIC TOXICITY 13
Introduction............................................................ 13
Basic Genetics for Toxicologists ..................................... 13
Gene Structure...................................................... 13
Gene Function ...................................................... 16
xi
xii CONTENTS
The Cell Cycle and Chromosome Mechanics in Somatic
and Germ Cells ................................................... 22
Somatic versus Germ Cells ........................................ 22
The Chromosome ................................................... 23
The Mitotic Cell Cycle ............................................. 26
Meiosis and Chromosome Mechanics ............................. 29
DNA Alterations Resulting in Genotoxic Effects in Cells:
Mechanisms and Categorization ................................. 33
A Classification Scheme for Genotoxic Effects .................. 33
Significance of the Classes of Genotoxic Effects ................. 44
Repair of DNA Damage .............................................. 47
References ............................................................. 50
ChapterS
THE CONSEQUENCES OF GENOTOXIC EFFECTS IN
HUMANS AND OTHER MAMMALS ................................. 53
Introduction ............................................................ 53
Gene Pool Consequences ............................................. 54
Genomic Target in Human Cells ..................................... 58
The Direct Effect of Mutagens on the Transmissible
Gene Pool ......................................................... 58
The Relationship of Genotoxic Effects to Other
Toxicologic Phenomena .......................................... 67
False-Negative and -Positive Responses............................. 71
Promoting Agents as False Negatives ...... .............. ......... 73
Relationship of Potency between Mutagenicity A&says
and in Vivo Oncogenicity ........................................ 75
References ............................................................. 76
Chapter 4
SCREENING CHEMICALS FOR GENOTOXIC PROPERTIES .... 79
Introduction and Background ........................................ 79
Definitions of Terms .................................................. 81
Screening Tests ..................................................... 82
Hazard Assessment Tests .......................................... 83
Risk Analysis Tests ................................................. 83
Characteristics of Adequate Screening Test Methods .............. 84
The Type(s) and Number(s) of Endpoints Detected .............. 85
CONTENTS xiii
The Metabolic Capability of the Test or Associated Activating
System ............................................................ 85
Test ReliabilitylReproducibility .................................... 89
Test Transferability ................................................. 90
Strategies for Building a Test Battery ............................... 90
General Philosophy ................................................. 90
Specific Approaches ................................................ 91
Conducting the Tests .................................................. 93
General Criteria for Dose Selection ............................... 93
The Use of Controls in in Vitro and in Vivo Testing ............. 99
Use of in Vivo Genetic Toxicology Assays ....................... 103
Stand-Alone Techniques............................................ 104
Expansion of Standard Toxicology Assays ....................... 105
Regulations Affecting Testing...................................... 107
Data Analysis and Interpretation ..................................... 107
Primary Evaluation ofIndividual Tests ........................... 107
Evaluation Approaches for Batteries .............................. 108
The Ideal Test Battery ............ .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. . 108
Interpretation of Results from Test Batteries..................... 110
Summary ............................................................... 115
References ............................................................. 117
Chapter 5
GENETIC RISK ESTIMATION 121
Introduction............................................................ 121
Definition of Risk Estimation......................................... 122
Estimates of Current Genetic Burdens in Humans ............... 123
Secondary Factors Influencing Risk Analyses ...................... 124
Genotype ............................................................. 124
DNA Repair Capacity.............................................. 124
Sex.... .... .......... ... ........ ... ... ..... ........ ..... ... ..... ...... 125
Cell Type ............................................................ 125
Diet . .... ..... ..... ... ......... ..................... ..... ... ... ....... 126
Theoretical and Practical Considerations Important
to Risk Analysis .................................................. 127
Risk Estimation Method for Somatic and Germ Cells .............. 129
Somatic Cell Risk................................................... 129
Germ Cell Risk ...................................................... 133
Indirect Measurement Approach to Risk Estimation ............. 133
Direct Measurement Approach to Risk Estimation .............. 134
Alternative Indirect Methods ....................................... 135