Existence of a Threshold for the Genotoxic Carcinogens: Evidence from Mechanism-based Carcinogenicity Studies

Abstract

The hepatocarcinogenicity of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a carcinogen contained in fried meat and fish, was examined in the medium-term rat liver carcinogenicity bioassay. Induction of DNA-MeIQx adducts occurred with low doses of the chemical, followed by increasing doses by elevation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation in DNA and lacI gene mutations, which might have been related to the initiation of carcinogenesis by MeIQx. Further elevation of the MeIQx dose was shown to cause the formation of glutathione S-transferase placental form (GST-P) positive foci in the liver, a well-known preneoplastic marker in rat hepatocarcinogenesis. In studies with N-nitrosocompounds such as N-nitrosodiethylamine and N-nitrosodimethylamine, no induction of GST-P positive foci was observed after their administration at low doses. When the carcinogenicity of a well-known colon carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was examined, PhIP-DNA adduct formation was observed after treatment with low doses, while only high doses of the chemical were found to induce aberrant crypt foci (ACF), which are a surrogate marker of preneoplastic lesions in the colon. In experiments with potassium bromate, carcinogenicity, mutagenicity, and 8-OHdG formation in the rat kidney were observed only after administration at high dose. From these results, the genotoxic carcinogens were concluded to have a threshold, at least practical, with respect to their carcinogenicity.