Carcinogenesis by combinations of N-nitroso compounds in rats

Five N-nitroso compounds were administered individually or in various combinations to groups of 20 female F344 rats to examine possible additive or synergistic effects on mortality rate and the induction of tumours. Combination of the oesophageal carcinogen dinitroso-2,6-dimethylpiperazine with nitrosodiethylamine, which also induces oesophageal tumours, or with nitrosoethylmethylamine, which induces liver tumours, did not appear to increase tumour incidence. Similarly, combination of nitrosodiethylamine with the bladder carcinogen nitrosomethyldodecylamine did not increase the formation of either bladder or oesophageal tumours compared with the effects of either compound alone, although an additive effect was suggested by a higher incidence of liver tumours after the combined treatment than after treatment with either compound alone. Nitrosomethylurethane, which induces tumours of the forestomach in rats, appeared to enhance the effectiveness of nitrosoethylmethylamine and dinitroso-2,6-dimethylpiperazine in inducing tumours of the oesophagus, and increased the rate of death. Nitrosomethylurethane given, at a somewhat higher dose, in combination with both of these compounds increased the incidence of oesophageal tumours even when the treatment lasted only 4 wk. This evidence suggests that additive or synergistic effects of combinations of N-nitroso compounds at low dose rates can be demonstrated in small groups of rats.