AGE AND DOSE-DEPENDENT CARCINOGENIC EFFECTS OF N-NITROSOMETHYLUREA ADMINISTERED INTRAPERITONEALLY IN A SINGLE-DOSE TO YOUNG AND ADULT FEMALE MICE

Female Swiss-derived SHR mice aged 3 (''young'') and 12 months (''adult'') were exposed to a single i.p. administration of N-nitrosomethylurea (NMU) at one of four doses: 0, 10, 20, or 50 mg/kg. The mean survival time of the young mice so treated was 440, 325, 398 and 182 days, and of the adult mice 221, 249, 191, and 168 days respectively. The incidence of all kinds of tumours in young mice was 40%, 64%, 77%, and 40%, of malignant tumours 33%, 43%, 57% and 20% of lung adenomas 7%, 14%, 40%, and 20% and of papillomas of the forestomach 0%, 14%, 23%, and 3% respectively. In adult mice these figures were for all kinds of tumours 52%, 52%, 56%, and 50%, for malignant tumours 44%, 52%, 52%, and 40%, for lung adenomas 7%, 0%, 8%, and 20%, for papillomas of the forestomach 0%, 0%, 12%, and 0% respectively. The exposure of adult female mice to various doses of NMU did not significantly increase the incidence of tumours or of malignant tumour incidence in comparison to age-matched controls. At the same time the latency of fatal tumours was shorter in the adult groups than in the young groups. Histoautoradiography of tissues of intact young and adult mice showed that there are no statistically significant age-related differences in the labelling index of forestomach epithelium, endometrium and lung alveolar wall epithelium. Only the labelling index of hepatocytes was decreased in the liver of adult mice in comparison to young ones. Comparison of the present experimental results with the data available on DNA synthesis and on O6-methylguanine repair in target tissues suggests a requirement for individual monitoring of age-related changes of biomarkers in exposure to carcinogenic agents. The analysis of data on the dose dependence of the carcinogenic effect of NMU against the background of a multistage model suggests an age-related accumulation of stochastically damaged cells for some tissues.