Mutation and Neoplastic Transformation

Most short-term tests for carcinogens are predicated on the somatic mutation theory of carcinogenesis.l-3 There now exists good experimental data to support this theory based on molecular and cytogenetic analysis of mutational changes in tumor^.^ Examples of specific genetic changes observed in tumors are given in TABLE 1 and discussed in detail e l ~ e w h e r e . ~ . ~ Despite this increasing evidence for a role of mutagenesis in carcinogenesis, certain chemicals (amitrole, asbestos, arsenicals, 5-azacytidine, benzene, diethylstilbestrol, ethionine, phenobarbital, 2,3,7,8-tetrachlorodibenzo-p-dioxin) have been proposed as “non-mutagenic carcinogens,” and it is important to understand the mechanisms of these chemicals in order to define the role of mutagenic events in carcinogenesis. Several possible mechanisms (TABLE 2) can be proposed to explain the lack of detectable mutagenic activity of the carcinogens listed above. One problem that exists with most in vitro assays is the necessity for exogenous metabolic activation, and the lack of a positive response in a mutation assay may relate to this requirement. Even though considerable advances in the development of metabolic activation systems have been made in the last several years, chemicals with unusual metabolic activation pathways will undoubtedly be discovered. One possible example of this problem is amitrole, a widely used herbicide and an animal ~a rc inogen .~ Although amitrole is inactive as a mutagen in bacterial test systems, it is mutagenic in Syrian hamster embryo cell^.^,^ This suggests that these cells are able to metabolize amitrole by an unusual metabolic mechanism. Recent findings have shown a peroxidase-mediated metabolic activation of this ~ h e m i c a l . ~ Both Syrian hamster embryo cells* and thyroid cells7 (the target cells for this carcinogen) have peroxidative activation capabilities. Thus, metabolic activation of this chemical to reactive immediates in combination with a hormone-like action on the thyroid is an attractive hypothesis to explain the organotropism of amitrole.’ Other apparent exceptions to the correlation between carcinogenicity and mutagenicity, including benzene, arsenic, diethylstilbestrol, and asbestos, may involve the ability of certain chemicals to act specifically as chromosome mutagens (i.e., clastogens andlor aneuploid~gens).~ Benzene, a known human carcinogen, produces negative results in most gene mutation assays, although some exceptions exist .9-11 However, benzene has been clearly shown to induce clastogenic effects,I0 indicating that it is primarily an inducer of chromosome damage, and this is possibly its major mechanism of action. Similarly, arsenic and arsenical compounds are known human carcinogens which are inactive or weak gene mutagens, but very potent clastogens. lo Sodium arsenite and sodium arsenate induce morphological transformation of Syrian hamster embryo cells in culture.I2 Under these conditions, gene mutations at two genetic loci cannot be detected, but