The presence or absence of a threshold in carcinogenesis for genotoxic carcinogens was reevaluated. The ED01 study of 2-acetylaminofluorene, performed in the U.S. using more than 24,000 mice, provides us with information about the practical limits of an attainable experimental approach for determining carcinogenesis thresholds. The data indicated that the dose response was highly non-linear and an apparent threshold existed for bladder carcinogenesis, but that it was linear-no-threshold for liver carcinogenesis in the same animals. Despite smaller study sizes, we attempted to evaluate the carcinogenesis dose response to 2-amino-1-methyl-6-phenylimidazo[4,5-b
]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f
]quinoxaline (MeIQx) in rats, using published data. Mammary tumors were induced in female F344 rats by PhIP in a linear-no-threshold dose response, as was lymphocytic leukemia in male and female rats. However, colon tumors were induced in a non-linear dose response, possibly with a threshold, in the same male animals. Liver tumors were induced in male F344 rats by MeIQx, and preneoplastic changes in the liver were induced in non-linear dose response, possibly with a threshold. From these findings, it can be deduced that linear or non-linear dose response with or without thresholds changes depending upon the exposing chemical, species and target organs. Considering heterogeneity of humans there would be no appropriate animal models to evaluate threshold in humans for carcinogenicity of chemicals.
Some types of genotoxic carcinogens, such as methyl methanesulfonate, ethyl methanesulfonate and N
-nitrosoguanidine, show highly non-linear dose response with an apparent threshold in mammalian cells or bacteria in vitro
. Involvement of repair mechanisms strongly supports the presence of a threshold. Although it is necessary to confirm non-linear dose response for animal carcinogenesis of a compound showing a threshold for in vivo
genotoxicity, it is expected that such compounds exhibit thresholds for human carcinogenesis. Dose response studies of genotoxic carcinogens will provide information on using valuable chemicals safely.