Analysis of synergism in hepatocarcinogenesis based on preneoplastic foci induction by 10 heterocyclic amines in the rat.
The effects of simultaneous treatment with 5 or 10 heterocyclic amines at low dose levels on hepatocarcinogenesis in rats were investigated using a medium-term liver bioassay protocol based on the two-stage carcinogenesis hypothesis with diethylnitrosamine initiation (200 mg/kg, i.p.). Five carcinogenic heterocyclic amines in experiment 1 (Trp-P-1, Glu-P-2, IQ, MeIQ, MeIQx) and experiment 2 (Trp-P-2, Glu-P-1, MeAalphaC, AalphaC, 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 were given at 1/10 or 1/100 levels in experiment 3. Induction of preneoplastic glutathione S-transferase placental form (GST-P)-positive foci in the liver was generally increased in the combination groups over the sums of the 5 or 10 individual effects. Thus, based on the heteroadditive concept, synergism was observed for each combination, being most obvious in the group given all 10 chemicals at the 1/10 dose levels. However, the values for the combined groups were generally close to the averages of the 5 or 10 data gained for the heterocyclic amines alone at the corresponding higher doses, indicating the possibility of isoadditivity. Based on these findings, we propose here a new statistical method for analysis of combined effects of multiple chemicals, and, using this, we demonstrated (true) synergism with some heterocyclic amine combinations. The importance of dose-response curves for evaluation of combination effects is discussed.
Hasegawa
R
R
First Department of Pathology, Nagoya City University Medical School, Mizuho-ku.
Yoshimura
I
I
Imaida
K
K
Ito
N
N
Shirai
T
T
D000588:Amines / Q000633:toxicity*; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D003043:Cocarcinogenesis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005982:Glutathione Transferase / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000633:toxicity*; D007093:Imidazoles / Q000633:toxicity; D007211:Indoles / Q000633:toxicity; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000201:enzymology; D008297:Male; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000201:enzymology; D011804:Quinolines / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344
D000588:Amines; D002273:Carcinogens; D006571:Heterocyclic Compounds; D007093:Imidazoles; D007211:Indoles; D011804:Quinolines; D005982:Glutathione Transferase