Carcinogenicity of hydroxyalkylnitrosamines in F344 rats: contrasting behavior of beta- and gamma-hydroxylated nitrosamines.

The carcinogenicity of N-nitrosomethyl-(2-hydroxyethyl)amine (NMHEA), N-nitrosomethyl-(3-hydroxypropyl)amine (NMHPA), and the p-toluenesulfonate (tosylate) ester of NMHEA (NMHEATs) was tested in male and female F344 rats. The chemicals (25.6 mumol per application) were administered by twice-weekly gavage in corn oil (0.2 ml) for the lifetime of the animals. NMHEA was found to be an effective carcinogen under those conditions. The median survival time for the females was 9 mo after treatment was initiated, while for the males it was 12 mo. The principal cause of death of the females was hepatocellular carcinoma (14 of 20), while only 6 of 20 male rats exhibited that tumor. A few of the male rats had squamous cell carcinomas of the nasal epithelium (4 of 20), tumors which were not observed in the females. NMHPA was a much weaker carcinogen. Many of these rats survived for 2 yr and most had many age-related cancers. Nevertheless, 10 of the NMHPA-treated males and 2 females had adenocarcinoma of the lung, which was absent in the controls and also induced a significant number of neoplastic nodules in the livers of rats of both sexes. NMHEATs was also a weak carcinogen. However, besides many age-related tumors, it induced some hepatocellular carcinomas as well as hemangiosarcomas of the liver. NMHEATs was at least partially hydrolyzed to NMHEA, which was detected in the blood plasma of treated rats. A hypothesis has been advanced that NMHEA is activated to a proximate carcinogen by sulfate conjugation of the hydroxyl group; the present data do not contradict this hypothesis. The relatively lower carcinogenic potency of NMHPA, the different tumor spectrum induced by this chemical, and particularly the differences in chemical behavior suggest that its mode of activation is not the same as that for NMHEA.