The impact of toxicity on carcinogenicity studies: implications for risk assessment

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Abstract
Previous results in a number of laboratories have demonstrated that epidermal papillomas and carcinomas induced by the two-stage protocol of initiation and promotion contain a point mutation in the 61st codon of the c-Ha-ras oncogene when the initiating agent used is 7,12-dimethylbenz-[a]anthracene (DMBA). In the present report, we have analyzed DNA purified from ‘spontaneously initiated’ papillomas and carcinomas induced in SENCAR mouse epidermis after repetitive treatments with a tumor-promoting agent. Southern blot hybridization studies of tumor DNA digested with diagnostic restriction endonudeases demonstrated that seven of nine papillomas and carcinomas contained a point mutation in the 61st codon of one allele of the c-Ha-ras oncogene. The implications of our findings with respect to the role which a point-mutated Ha-ras protooncogene plays in initiation of skin tumorigenesis are discussed.