Mechanistic basis for nonlinearities and thresholds in rat liver carcinogenesis by the DNA-reactive carcinogens 2-acetylaminofluorene and diethylnitrosamine

To explore differences in mechanisms of carcinogenicity at tow and high exp osures. we have conducted a series of exposure response studies of hepatoca rcinogenesis in rats using 2 well-studied DNA-reactive carcinogens, 2-acety laminofluorene and diethylnitrasamine. In these studies, we have used intra peritoneal injection or intragastric instillation to deliver exact doses du ring an initiation segment followed by phenobarbital as a liver tumor promo ter to enhance manifestation of initiation. This protocol results in carcin ogenicity comparable to that produced by lifetime exposure to the carcinoge ns. Our findings in these experiments provide evidence for the following: ( a) formation of DNA adducts can be nonlinear. with a plateau at higher expo sures: (b) cytotoxicity shows no-effect Levels and is related to exposure; (c) compensatory hepatocyte proliferation shows no-effect levels and can be supralinear at high exposures: (d) formation of preneoplastic hepatocellul ar altered foci can show no-effect levels and appears supralinear at high e xposures; (e) no-effect levels can exist for tumor development, and the exp osure response can be supralinear. We interpret these findings to reflect t hresholds for hepatocellular initiating effects of these carcinogens and ex aggerated responses at high exposures attributable to cytotoxicity and comp ensatory hepatocyte proliferation. Such enhanced proliferation of hepatocyt es harboring DNA damage likely results in an exaggerated yield of mutations in critical genes, Leading to supralinear initiation of carcinogenesis. Th us, mechanisms differ between low and high exposures. Based on these observ ations. we suggest that linear extrapolation from high toxic exposures to p ostulated low-exposure effects of DNA-reactive carcinogens can yield overes timates. Such extrapolation must be supported by mechanistic information. T he finding of no-effect levels provides a basis for understanding why low-l evel environmental exposures of humans to even DNA-reactive carcinogens may convey no cancer risk.