2-amino-1-methyl-6-phenylimidazo[4,5-
b]pyridine (
PhIP), an abundant food-derived heterocyclic
amine (HCA), has attracted particular attention as a human colon
carcinogen. Humans are in fact exposed to continuous low doses of HCAs during lifetime. Therefore, we focused on rat large intestinal carcinogenicity of
PhIP at levels that mimic practical human exposure. A total of 192 6-week-old male F344 rats were subcutaneously injected twice with 15 mg/kg
body weight azoxymethane (AOM), then continuously fed various doses (0, 0.001, 0.01, 0.1, 1, 10, 50 and 200 ppm) of
PhIP in the diet. At week 16,
aberrant crypt foci (ACF) were quantitatively analyzed. At week 36,
tumor occurrence was pathologically analyzed. Then immunohistochemical examinations were performed.
PhIP was found to enhance strongly AOM-initiated rat large intestinal
tumorigenesis at high doses (50 and 200 ppm), while lower doses (0.001-10 ppm) had no apparent effects. High doses also caused variation in
tumor histologic types and their distribution throughout the large intestinal segments. Frequencies of ACF/cm(2) did not meaningfully vary between the groups. Cellular proliferation activity in normal-appearing colonic mucosa was significantly increased at high doses. These novel findings may provide evidence of a low-dose potential for
PhIP, with a no-observed effect level speculated to be 10 ppm in the present initiation-promotion experimental model.