SYNERGISM IN HEPATOCARCINOGENESIS INDUCED BY HETEROCYCLIC AMINES IN RATS

Abstract

Effects of simultaneous administration of 5 or 10 heterocyclic amines at low dose levels on rat liver carcinogenesis were investigated using our medium-term bioassay protocol. Male F344 rats were initially given diethylnitrosamine (DEN, 200mg/kg, i.p.) and beginning 2 weeks later received heterocyclic amines for 6 weeks. All animals were subjected to partial hepatectomy at week 3 and killed at week 8. Five carcinogenic heterocyclic amines in each experiment 1 (Trp-P- 1, Glu-P-2, IQ, MeIQ, MeIQx) and experiment 2 (Trp-P-2, Glu-P- 1, McAαC, AαC, PhIP) were administered together or individually in the diet at levels of 1/1, 1/5, or 1/25 carcinogenic doses, and all 10 chemicals of 1/10 or 1/100 levels in experiment 3. Induction of immunohisto-chemically-demonstrated glutathione S-transferase placental form (GST-P) positive foci, reliable preneoplastic lesions, was generally increased in the combination groups over the sum of individual effects. Thus an apparent synergism was observed based on the heteroadditive model, the most obvious effects being found in the group given all 10 chemicals at the 1/10 dose levels. However, the values in groups given chemical mixtures were generally close to means of 5 or 10 individual data in their corresponding higher dose groups, indicating that isoadditivity might occur in those groups. The theoretical basis underlying the concept of synergism is briefly reviewed and a simple method for analysis of isoadditivity is proposed.