Mammalian Cell Mutagenesis

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.

There is general agreement that increased environmental pollution poses a potential health hazard to humans and that effective control of such genetic injury requires monitoring the exposed individuals for genetic damage and identifying chemicals that may cause mutation or cancer. Tests available for identifying mutagens or carcinogens range from relatively simple, rapid assays in prokaryotes and test systems utilizing mammalian cells in tissue culture to highly elaborate tests in intact animals. No single test can provide data for an unequivocal assessment of the mutagenicity of a given chemical and the risk it might pose to human health. A tier approach, therefore, was suggested for mutagenicity testing in which the suspected agents would be initially evaluated with simple, inexpensive tests that would give qualitative results. Chemicals found to be positive in the first-tier testing would then be evaluated with more complex tests, including those based on mammalian cells in culture. Testing in the final tier requires whole-animal studies, and is expensive and time-consum ing, and even the results from these studies need to be extrapolated for human risk assessment. The mutation systems based on whole animals require scoring large num bers of animals, and therefore are not practical for the routine testing of muta gens. As an alternative to monitoring the pedigree, cells from exposed individ uals may be considered for screening for point mutations through the use of an appropriate marker protein.

This TG includes two distinct in vitro mammalian gene mutation assays requiring two specific tk heterozygous cells lines: L5178Y tk+/-3.7.2C cells for the mouse lymphoma assay (MLA) and TK6 tk+/- cells for the TK6 assay.

Concern is often expressed that our environment may include an increasingly large variety of mutagens, but the extent of the potential hazard they pose has yet to be fully evaluated. A variety of empirical procedures has been devised with which to estimate the mutagenic potency of suspect agents, and the relative merits of different tests are currently under debate. Although such tests are of great value, and are indeed indispensable, they are not, nevertheless, sufficient. In the long term, accurate estimation of hazard will also require a better understanding of the various mechanisms of mutagenesis, and in many instances these remain remarkably elusive. Our knowledge and appreciation of the problem has increased substantially over the last few years, but the precise way in which many mutagens cause mutations is not yet known. The aims of this conference were therefore two-fold. The first was to survey present information about mutagenic mechanisms, drawing together data from work with various experimental approaches and organisms, in order to discern the principles governing the action of different mutagens. The second was to examine the implications of such principles for the execution and evaluation of test procedures, and critically assess the research areas that need further attention in order to improve the interpretation of test results. Chris Lawrence v ACKNOWLEDGEMENT We gratefully acknowledge the support provided for this Conference by the U.,S. Department of Energy, The Foundation for Microbiology, Exxon Corporation and the University of Rochester.