SYNERGISTIC ENHANCEMENT OF HEPATIC FOCI DEVELOPMENT BY COMBINED TREATMENT OF RATS WITH 10 HETEROCYCLIC AMINES AT LOW-DOSES

Potential synergism between 10 carcinogenic heterocyclic amines [3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), 2-amino-6 methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1), 2-amino-dipyrido[1,2-a:3',2'-d]imidazole (Glu-P-2), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA alpha C), 2-amino-9H-pyrido[2,3-b]indole (A alpha C) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)] in rat liver carcinogenesis was examined. Male F344 rats were initially given diethylnitrosamine (200 mg/kg, i.p.) and beginning 2 weeks later received heterocyclic amines individually at doses 1/10 of that proven to be carcinogenic or in combination at 1/10 or 1/100 doses for 6 weeks. All animals were subjected to partial hepatectomy at week 3 and killed at week 8. The induction of immunohistochemically demonstrable placental glutathione S-transferase positive foci was significantly increased in rats given all 10 chemicals in combination at the 1/10 dose level while values were almost the same as in controls with the 1/100 dose mixture and the individual chemicals, except for Glu-P-1 which significantly increased foci development and Glu-P-2 and A alpha c which significantly decreased levels of foci at the 1/10 dose level. Thus apparent synergism was observed with the 1/10 dose level combination. When the data are considered together with our previous results obtained with five heterocyclic amines using 1/1, 1/5 and 1/25 dose levels, combined effects were found to be related to the number of chemicals included and the dose levels of each, with a possible isoadditive influence being common. The findings are of particular significance since heterocyclic amines and other carcinogenic agents might be simultaneously generated during cooking.