Effects of low dose mixtures of four N-nitroso compounds on hepatic foci development in the rat.
Potential synergism between four N-nitroso compounds (nitrosomorpholine, nitrosodimethylamine, nitrosodiethanolamine, nitroso-oxazolidine) in rat liver carcinogenesis was examined in the medium-term bioassay. Male F344 rats were initially given diethylnitrosamine (DEN, 200 mg/kg, ip) and beginning 2 weeks later received test chemicals for 6 weeks individually at a full or 1/4 dose of that proven to be carcinogenic individually or in combination. All animals were subjected to partial hepatectomy at week 3 and killed at week 8. Induction of immunohistochemically-demonstrated glutathione S-transferase placental form (GST-P) positive foci was evaluated. The numbers and size of GST-P positive foci were significantly higher than the control levels by the treatment with each nitrosamine at full (1/1) and one quarter doses (1/4), excepting nitrosodiethanolamine and by combination of the four chemicals at 1/4 and 1/16. Because the dose-response curves were considered non-linear for most nitrosamines, synergistic effects were not apparent for the 1/4 mixture. Interestingly, however, the values for rats treated with these four chemicals in combination at the 1/4 dose level were almost the same as the average of four individual treatments at the full dose, and those for the 1/16 dose mixture were almost the same as the average of 1/4 individual treatment groups. These results indicate that these nitrosamines worked additively, rather than synergistically, in rat liver carcinogenesis.
Futakuchi
M
M
First Department of Pathology, Nagoya City University Medical School, Japan.
Lijinsky
W
W
Hasegawa
R
R
Hirose
M
M
Ito
N
N
Shirai
T
T
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004052:Diethylnitrosamine / Q000031:analogs & derivatives* / Q000633:toxicity; D004128:Dimethylnitrosamine / Q000633:toxicity*; D005982:Glutathione Transferase / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D009602:Nitrosamines / Q000633:toxicity*; D009603:Nitroso Compounds / Q000633:toxicity*; D011230:Precancerous Conditions / Q000139:chemically induced*; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D009602:Nitrosamines; D009603:Nitroso Compounds; C014129:N-nitrosodiethanolamine; C035920:N-nitroso-1,3-oxazolidine; D004052:Diethylnitrosamine; C002741:N-nitrosomorpholine; D005982:Glutathione Transferase; D004128:Dimethylnitrosamine