Mutagenesis in Sub-Mammalian Systems: Status and Significance PDF
Preview Mutagenesis in Sub-Mammalian Systems: Status and Significance
Mutagenesis in Sub-Mammalian Systems Mutagenesis in Sub-Mammalian Systems status and significance Edited by G. E. Paget Director, Inveresk Research International <. MTPPR ~1~lIT[D 11l1t'/'1/( 1/ iOl1ll1 4'vII'c1i((l1 nt ! ~ i~her Published by MTP Press Limited Falcon House Cable Street Lancaster England Copyright © 1979 MTP Press Limited Softcover reprint of the hardcover 1s t ed ition 1979 No part of this book may be reproduced in any form without permission from the publishers except for the quotation of brief passages for review purposes. ISBN-13: 978-94-011-6641-6 e-ISBN-13: 978-94-011-6639-3 001: 10.1007/978-94-011-6639-3 Contents List of Contributors vii Series Preface ix Foreword xi Introduction xiii Lord Ritchie-Calder SECTION ONE General Background to Mutagenesis Studies 1 Mutagenesis - the significance of DNA damage for man 3 B. A. Bridges 2 The role of Drosophila in mutagen testing 13 C. Auerbach Discussion 21 SECTION TWO Bacterial Tests for Mutagenesis 3 A strategy to minimize human exposure to environmental chemicals causing cancer and genetic birth defects 29 Bruce N. Ames 4 Practical experience in testing unknowns in vitro 53 D. B. McGregor 5 Induced mutation in micro-organisms: validity for estimating risk to man 73 L. Ehrenberg Discussion 89 SECTION THREE Other Mutagenesis Test Systems 6 Sub-mammalian tests other than the Ames test for mutagenesis 95 Diana Anderson 7 Cytogenetic aspects of mutagenicity testing 135 B. J. Dean 8 Cell transformation assays 147 J. A. Styles 9 Implications of carcinogenicity 165 John Ashby Discussion 185 SECTION FOUR General Implications of Mutagenesis 10 Extrapolation of mutagenic test results to man 189 P. Oftedal 11 Tests for mutagenesis from a regulatory point of view 195 M. H. Draper Discussion 203 Round Table Discussion 209 Concluding Remarks 223 INDEX 225 Mutagenesis in Sub-Mammalian Systems was sponsored and organized by Inveresk Research International. The meeting was the third in their series "Topics in Toxicology" aimed at producing meetings on subjects of topical impor tance to toxicologists. vi List of Contributors Professor B. N. AMES Biochemistry Department University of California, Berkeley, California, USA D. ANDERSON Central Toxicology Laboratory, Imperial Chemical Industries Ltd Alder/ey Park, Macclesfield, Cheshire J. ASHBY Central Toxicology Laboratory, Imperial Chemical Industries Ltd, Alder/ey Park, Macclesfield, Cheshire Professor (Emeritus) C. AUERBACH 31 Upper Gray Street Edinburgh 9 Professor B. A. BRIDGES MRC Cell Mutation Unit University of Sussex, Falmer, Brighton Sussex B. J. DEAN Shell Research Ltd Tunstall Laboratory, Sittingbourne, Kent M. H. DRAPER Department of Health & Social Security, Alexander Fleming House, Elephant & Castle, London SE1 6BY Professor L. EHRENBERG Stockholm University, Wallenberglaboratoriet Lilla Frescati, S -1 04 05 Stockholm 50, Sweden D. B. McGREGOR Inveresk Research International. Inveresk Gate, Musselburgh Midlothian P. OFTEDAL Institute of General Genetics, University of Oslo, PO Boks 1031, Blindem Oslo 3, Norway J. A. STYLES Central Toxicology Laboratory. Imperial Chemical Industries Ltd Alderley Park, Macclesfield, Cheshire Series Preface Topics in Toxicology Toxicology is a science that stands at the intersection of several interests and disciplines. These intersecting forces are by no means all scientific since some are legal and some are commercial. All have valid things to say about the conduct and interpretation of toxicity experiments. The practising toxicologist must bear all these sometimes conflicting forces in mind as he carries out his duties. This is especially true, of course, of the toxicologist in industry. Toxicology is also a field in which contract research particularly flourishes and a number of major contract research companies have established over the years a reputation for contributing usefully to the practice of this skill. These contract research organisations are particu larly favoured to develop an appreciation of the problems of the industrial toxicologist, since it is very common for such a company to service the toxicological needs of companies in several sectors of industry producing new chemical compounds, and the contract research company, therefore, is aware of a wider diversity of problems than probably affects a single toxicologist in one industry. Among the problems of which all toxicologists in industry are aware and particularly so those in contract research companies, is the relative paucity of fora for adequate toxicological discussion. There are, it is true, at least two major societies concerned with problems of toxicology, the European Society of Toxicology and the Society of Toxicology in America. Although performing a useful function, these societies are now so large, and cater for such a wide spread of interests and contain so many individuals whose interests in toxicology is at most peripheral, that many toxicologists feel they do not provide an adequate platform for discussion of the most immediate and important issues affecting toxicology at anyone time. The very size and complexity of these societies means that the organization of their meetings and the topics for their symposia must be chosen many months, and indeed years, in advance. Thus issues of current importance cannot usually be dealt with while they are still alive. Inveresk Research International, a contract research company oper ating, among other areas of contract research, in the general field of ix x MUTAGENESIS IN SUB-MAMMALIAN SYSTEMS toxicology, feels that there is a need for small, highly specialized and specific, meetings, arranged at relatively short notice to cover important current issues in toxicology and has instituted the series 'Topics in Toxicology' to meet this need. The subjects for these meetings are, as far as possible, ones of immediate concern to practising toxicologists in industry. They bring together, as far as possible, the most authori tative opinions bearing on the particular subject. Subjects chosen within the general constraint of current interest, ones which stand at the inter section of at least two of the several strands of interest that control industrial toxicology. G. E. Paget Foreword In the past few years there has been a steadily increasing awareness among the scientific community generally, and toxicologists particularly, of several important and related facts and propositions. In the first place it has been thought for many years that a high proportion of human cancers may have environmental causes - this probability arises from the widely differing cancer rates for various geographical locations. Second, it is evident that a very large number - perhaps of the order of 105 - of chemical compounds for all sorts of uses has been introduced into the human environment, and that a relatively small proportion of them - perhaps of the order of 103 - have been tested at all for safety and even fewer have been tested in a way that could be regarded as completely adequate. Finally it is clear that the physical, technical and financial resources required to test the untested 99 % adequately in a reasonable length of time simply do not exist, and are unlikely to exist for a very long time to come if they ever do. This complex of facts has caused an intense search for short-term methods for predicting carcinogenicity with some degree of reliability sufficient at the very least to set priorities for longer-term testing, or, as Ames argues persuasively, for decisive actions. It is relevant in this connection that for many years one of the mechanisms proposed for the pathogenesis of cancer is the development of a somatic mutation, that is a change in the DNA of a somatic cell, which allows the development of the highly abnormal clone of cells that constitute a cancer. From this it is but a short step to the development of a number of methods, and pre-eminently of a series of bacterial test systems by Ames, to detect mutations in simple systems in which the results can be obtained in days or weeks rather than years and at a cost of hundreds rather than hundreds of thousands of pounds, and which it is hoped will predict both the carcinogenic and the genetic hazards of human exposure. The growth of such systems and their widespread use has been pheno menal. In 1973 IRI was one of the first commercial laboratories in the world to establish a department in the charge of a distinguished research scientist with the sole purpose of developing methods for the study of mutagens. For 2 years not a single contract for such work was placed by any industrial client. Now the laboratory is growing at a considerable rate because of the demand for its skills, and a great number of major chemical manufacturers have established groups of their own - leI Ltd. and Shell Ltd. merit special mention for the brilliance and commitment of their work in this field. Such work, of course, can only adequately be done by those skilled in the rapidly advancing science of genetic toxicology. The basic knowledge, indeed even the jargon, lies outside the experience of most toxicologists and research managers, yet it is they who must make, or recommend to wholly non-scientific management, decisions often of great moment based upon the work of the specialist geneticists. In a field advancing as rapidly as is that of mutagenic studies currently, it is difficult as a non-specialist to evaluate the sometimes conflicting claims and techniques of different groups, while the specialist is often an enthusiast utterly persuaded of the significant importance of his own work. To shed some light in this area of debate, IRI established its third dis cussion in the series of 'Topics in Toxicology'. The various distinguished contributors were asked to address themselves primarily to the non specialist but informed scientist, and to endeavour to layout for him the present state of methods, and even more of interpretation in this field. The result was highly satisfactory to all who attended the meeting and even in publication the quite unique flavour of scientific presentations of great profundity and clarity comes over. None of the contributors has pulled any punches in presenting the technical facts, but the conscientious reader will be left with a clear impression of a developing field of study that will with some certainty serve as a basis for useful decision and action in years to come, and will become acquainted with the factual basis, and the interpretative insights of this fascinating field of study that we must learn to call 'genetic toxicology'. G. E. Paget xii
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