Carcinogenicity of N-nitrosomethyl(2-oxobutyl)amine and N-nitrosomethyl-(3-oxobutyl)amine in Syrian hamsters with special reference to the pancreas.

Studies with oxidized derivatives of N-nitrosodi-n-propylamine suggested a structure-activity relationship between pancreatic cancer induction in Syrian hamsters and position and degree of nitrosamine oxidation. To elucidate the importance of the position of the oxidized substituent relative to the N-nitroso group in pancreatic carcinogenesis, we compared the toxicity and carcinogenicity of two substituted methylbutylnitrosamines. N-Nitrosomethyl(2-oxobutyl)amine (M-2-OB) and N-nitrosomethyl(3-oxobutyl)amine (M-3-OB) were given in equitoxic doses to male and female Syrian hamsters. The 50% lethal doses for M-2-OB and M-3-OB in males and females, respectively, were 92 and 160 and 705 and 810 mg/kg body weight. M-2-OB, although given in significantly smaller doses (minimum dose, 2.3 mg/kg body weight) than was M-3-OB (minimum dose, 17.6 mg/kg body weight), induced a much broader spectrum of neoplasms (in 17 tissues), whereas M-3-OB induced tumors in only 5 tissues and had no carcinogenic effect in the pancreas. M-2-OB, however, produced pancreatic ductular-ductal adenocarcinomas in over 90% of the males and 67% of the females, even at the lowest doses (2.3 and 4.0 mg/kg, respectively). Although both compounds caused a similar incidence of morphologically equivalent neoplasms (mostly adenocarcinomas) in the nasal and paranasal cavities, the remaining distribution of affected tissues differed significantly. M-2-OB predominantly affected the lip (epitheliomas, squamous cell carcinomas), liver (cholangiomas and cholangiocarcinomas), and flank organ (epitheliomas, squamous cell carcinomas). The principal target organs for M-3-OB were the cheek pouch (papillomas, squamous cell carcinomas) and trachea (polyps). In contrast to M-2-OB, M-3-OB did not induce renal and urethral tumors. These findings indicate the importance of the 2-oxo group as a prerequisite for the carcinogenicity of methylalkylnitrosamines in the hamster pancreas; however, a methyl group in one aliphatic chain, alpha to the N-nitroso function, appears to cause the molecule to lose its selectivity for the pancreas.