No-observed effect levels for carcinogenicity and for in vivo mutagenicity of a genotoxic carcinogen.

To elucidate the relationship between in vivo carcinogenic and mutagenic potentials of genotoxic carcinogens, low doses were tested in the livers of Big Blue transgenic rats with 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx). Male Big Blue rats were fed a diet containing 0.001, 0.01, 0.1, 1, 10, or 100 ppm of MeIQx for 16 weeks, and the frequencies of lacI mutants and glutathione S-transferase placental form (GST-P) positive foci in the liver were determined. The mutation frequencies significantly increased at doses of 10 and 100 ppm, and GST-P positive foci significantly increased at a dose of 100 ppm. However, no statistical increases in both frequencies were observed at lower doses. MeIQx most frequently induced G frameshifts, followed by G to T transversions. Thus, no observed effect level (NOEL) was demonstrated for both carcinogenicity in terms of preneoplastic lesion induction and in vivo mutagenicity of MeIQx, and the NOEL for in vivo mutagenicity was lower than that for carcinogenicity.