J. $oc. Cosmet. Chem. 29 207-223 (1978) An appraisal of the current state of mutagenicity testing DIANA ANDERSON Imperial Chemical Industries Limited, Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire Presented at the Symposium on Cosmetics and Toiletries - Safety Assessment, 8 November 1977 Birmingham Synopsis Every year many new chemical substances are introduced into our environment. Some of these chemicals may possibly induce genetic damage in populations exposed to them. There is a risk that such damage may accumulate in the gene pool and affect future generations, or even cause cancer in the present gener- ation since a link has now been established between mutagenicity and carcinogenicity. At present the most appropriate way to determine which chemicals may cause genetic damage is to test them in various in vitro or in vivo laboratory test systems capable of detecting damage to DNA, chromosomes or the genome. Some of these methods are discussed, as are the factors which determine a mutagenic response, problems encountered when using the test systems, together with data interpretation and assessment of genetic effects. INTRODUCTION The problem of the possible induction of genetic damage after chemical exposure is worrying both to the scientific community and to the population at large The increase in number of different chemical substances and biological synthesis products in man's environment is due to the rapid strides made by scientific and technical progress. Each year new chemical substances are introduced in the form of medical preparations, pesticides, food additives and industrial compounds and some of these could induce mutations. There is a risk that such mutations may accumulate in the population and affect future generations. In recent years many substances shown to be mutagens have also been shown to be carcinogenic, with 80-90•o correlations between mutagenicity and carcinogenicity with certain organic chemicals 0-8). These data are in conflict with similar studies made in the early 1950s on the mutagenicity of chemical carcinogens which showed little correlation between carcinogenic and mutagenic activity. These early experiments led to the premature demise of the somatic mutation theory of cancer metabolic activation systems were not used and it was not realised that certain strains of bacteria might detect only specific types of genetic alterations (9). Nowadays, with the new-found interest in the somatic mutation theory of cancer, a study of the genetic effect of chemical substances may be useful not only for protecting future generations but also for preventing cancer in present generations. Little is known of the practical use of results obtained from mutagenic studies, how these results might apply in the field of toxicology in general, or how relevant they are to man. Whilst cancer in man has a definitive end-point in the production of a malignant 0037-9832/78/0400-0000 $02.00 ¸ 1978 Society of Cosmetic Chemists of Great Britain 207

208 Diana Anderson tumour and is a very emotive issue, the end-point of genetic damage in man is more obscure. With current techniques we are able to distinguish between molecular changes in the gene and small chromosome aberrations. Most human traits are inherited as Mendelian units which can be divided into autosomal dominant, autosomal recessive and X-linked recessive units. There are also X-linked dominants and there may be a few Y-linked traits but these are numerically insignificant (10). McKusick (11) lists such traits. Th, dominant expression of a mutant gene is sufficient to cause a recognisable abnormality or disease and there are also some well-established recessive traits. However, whilst a change in a dominant trait is immediately evident in the next generation, recessive traits may take very many generations before they are expressed. Therefore, the effect of chemi- cal mutagenesis at this level of the gene may not show immediate results and the data generated by mutagenic tests lose their impact. Chromosome abnormalities may arise by errors in the distribution of chromosomes leading to abnormalities of chromosome numbers such as non-disjunction, where the effect is seen in the next generation, or by the consequence of chromosome breakage. Consequences of chromosome damage are physical or mental abnormalities, sterility or embryonic death. With regard to the last condition, epidemiological evidence suggests that there is an increased incidence in foetal wastage in wives of workers exposed to vinyl chloride (12, 13, 14). There is however, a conflict concerning the statistical interpretation of the data (15), and as yet there is thus no unequivocal epidemiological evidence that vinyl chloride can cause germ cell mutations in man. Married women anaesthetists were claimed to have a higher incidence of spontaneous abortion when they worked than when they did not work and the incidence was also higher by comparison with non- anaesthetist married women doctors (16) but, it is difficult to determine if the abortions were due to genetic events or embryotoxicity because of systemic involvement after exposure of the women. Many constitutional and degenerative diseases such as epilepsy and schizophrenia may be caused by other irregularities of the gene expression or arise from multiple genes (10). The effect of chemical mutagenesis both on multiple gene effects as well as at the level of the cromosome may also not be immediately obvious. Nevertheless, since the world population is rapidly increasing the chance for natural selection in civilised communities is being sharply reduced, and whilst it is recognised that not all mutagens are harmful and some are necessary for evolution, any increase in the mutagenic factors in the environment could cause a potential risk to the population. It is estimated that more than 4•o of the population are affected by genetic anomalies and about 1 •o of children born each year have chromosomal mutations (17). Mutations that cause sterility or early embryonic loss are detrimental in the Darwinian sense but have little impact on society. Mutations that are more fit biologically may be a heavy burden to society if the affected persons require medical or institutional care (18). Thus it is necessary to monitor potential chemical mutagens which could increase the percentage of genetic aberrations in the population, and although a great number of relatively simple and practical methods are available the evaluation of mutagenic effects is a complex and extremely difficult task. FACTORS DETERMINING A MUTAGENIC RESPONSE The mutagenic activity of chemical substances has been studied in a number of organisms, using different methods for calculating both gene and chromosome mutations in somatic