Effects of low dose mixtures of four N-nitroso compounds on hepatic foci development in the rat

• Published in: Cancer letters Vol. 106; no. 2; pp. 263 - 269
• Main Authors: Futakuchi, Mitsuru, Lijinsky, William, Hasegawa, Ryohei, Hirose, Masao, Ito, Nobuyuki, Shirai, Tomoyuki
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 10.09.1996; Elsevier
• Subjects: Animal tumors. Experimental tumors; Animals; Biological and medical sciences; Carcinogenesis; Carcinogens - toxicity; Diethylnitrosamine - analogs & derivatives; Diethylnitrosamine - toxicity; Dimethylnitrosamine - toxicity; Experimental digestive system and abdominal tumors; Glutathione Transferase - metabolism; Liver; Liver Neoplasms, Experimental - chemically induced; Male; Medical sciences; Nitrosamine; Nitrosamines - toxicity; Nitroso Compounds - toxicity; Precancerous Conditions - chemically induced; Rat; Rats; Rats, Inbred F344; Tumors; Rat; Carcinogenesis; Nitrosamine; Liver; Poison interaction; Premalignant lesion; Enzyme; Toxicity; Transferases; Low dose; Rodentia; Hepatic disease; Carcinogen; Vertebrata; Mammalia; Glutathione transferase; Animal; Digestive diseases
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/0304-3835(96)04326-1

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.