Effect of age on dose-response relationship in carcinogenesis induced by single administration of N-nitrosomethylurea in female rats.

Female rats aged 3 months and 15 months each received a single i.v. administration of N-nitrosomethylurea (NMU) at one of three doses: 10, 20, and 50 mg/kg. The rats exposed to NMU at the age of 3 months developed neoplasms of all sites examined, including mammary carcinomas and tumors of the kidney, ovaries and colon, the incidence varying with the carcinogen dose. The incidence of malignant neoplasms in old animals did not depend on NMU dose. In contrast to young animals, the old ones showed a higher frequency of tumors of the corpus and cervix uteri following exposure to NMU, and a lower frequency of mammary and intestinal adenocarcinomas and tumors of the ovary and kidney. Comparison of the present experimental results with the data on DNA alkylation, synthesis and O6-methylguanine repair obtained previously on the same model suggests a leading role of age-related proliferative activity changes occurring in the target tissues in the mechanism of age in modifying the effect on carcinogenesis. The analysis of data on the dose dependance of the carcinogenic effect of NMU within the framework of a multistage model suggests age-related accumulation, in different tissues, of cells occasionally lesioned and in the "late" stages of becoming malignant.