Carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rats: dose-response studies.

The carcinogenic potential of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), identified as the most abundant mutagenic heterocyclic amine in cooked meat and fish, was investigated in dose-response studies. Six-week-old F344 rats of both sexes were administered PhIP in the diet at concentrations of 0, 25, 100, or 400 ppm for up to 104 weeks. Animals receiving the highest dose were killed at week 52 due to marked retardation in body weight gain. PhIP was demonstrably carcinogenic for the colon in males and for the mammary glands in females, in a clear dose-dependent manner for both cases. Mammary carcinogenicity of PhIP was also confirmed in female SD rats with a clear dose-response relationship. In rat two-stage carcinogenicity models, PhIP exerted tumor-promoting activity in the small intestine as well as in the large intestine, but no promoting effects were apparent in the liver, although DNA adducts were formed dose dependently. The virtually safe dose (VSD) at the 10(-6) risk level calculated from the long-term carcinogenicity test was 0.023-0.52 ppm in the diet. This range of values is very close to or lower than human intake in daily life. Since PhIP is a most abundant heterocyclic amine and its carcinogenic organotropism overlaps with the types of neoplasias most commonly observed in western countries, the compound is likely to be extremely important with respect to human cancer development.