Threshold in Carcinogenicity of Genotoxic Carcinogens

Abstract

Nowadays the idea of threshold in the carcinogenicity of chemical carcinogens has attracted interest in the field of carcinogenesis. With genotoxic agents there is considerable experimental evidence in support of the idea. Here, we report on the low dose carcinogenicity in rats observed with heterocyclic amines contained in cooked food, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP), and contaminants of natural and manufactured food products, N-nitrosocompounds such as N-nitrosodiethylamine (DEN) and N-nitrosodimethylamine (DMN). The existence of a no-effect level for MeIQx carcinogenicity was confirmed in a medium-term rat liver bioassay. Treatment with increasing doses of MeIQx caused sequence of events to occur in the liver tissue: first, the induction of DNA-MeIQx adducts at low doses, then an increase of DNA 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation and lacI gene mutations, following by the development of preneoplastic lesions, glutathione S-transferase placental form positive (GST-P +) foci, at high doses. In another study, IQ was found to induce preneoplastic lesions in the rat liver at high doses, but lack any effect at low doses. Similarly, examination of carcinogenicity of a well-known colon genotoxic carcinogen PhIP have shown that application at low doses caused the formation of PhIP-DNA adducts, however, a surrogate marker of preneoplastic lesions in the colon, aberrant crypt foci, were detected only at high doses. In studies with N-nitrosocompounds, no GST-P+ foci in the rat livers was detected after the treatment at low doses, on the contrary, at high doses DEN and DMN induced their development. In conclusion, DNA-reactive genotoxic agents such as heterocyclic amines MeIQx, IQ and PhIP, and N-nitrosocompounds DEN and DMN were concluded to exert a threshold, at least practical, with respect to their carcinogenicity.