Nonlinearities in 2-Acetylaminofluorene Exposure Responses for Genotoxic and Epigenetic Effects Leading to Initiation of

The dose responses for several effects of low-level limited expo-sures to 2-acetylaminofluorene (AAF) in the livers of male Fischer 344 rats were measured and a subsequent phenobarbital tumor promotion regimen was used to manifest initiation of carcinogen-esis. Three doses over a 10-fold range yielding cumulative total exposures of 0.126,0.42, and 1.26 mmol AAF/kg body weight were achieved by daily intragastric instillation for up to 12 weeks with interim terminations. This was followed by 24 weeks administra-tion of 500 ppm phenobarbital (PB) in the diet to promote liver tumor development. At 12 weeks at the end of AAF administra-tion, all exposures produced adducts in liver DNA, measured by 32P postlabeling, and the level of adducts increased with exposure, except that the high exposure did not produce a dose proportional increase. Measurement of arylsutfotransferase activity, a key en-zyme in the metabolic activation of AAF, revealed that in liver