A study of tobacco carcinogenesis, LIII: carcinogenicity of N′-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in mink (Mustala vison)

In an earlier study, young male and female mink (Mustela vison) were found to be highly susceptible to the carcinogenic effect of N′-nitrosonornicotine (NNN). In this follow-up study we tested (i) the importance of the age of the animals with regard to the carcinogenic effect of NNN, (ii) the carcinogenic activity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and (iii) the combined carcinogenic effect of NNN plus NNK. (I) In the previous study, the latency of nasal tumor induction by NNN (11.9 mM) averaged 84 ± 40 weeks upon twice weekly applications, starting at the age of 3 weeks and continuing for 38 weeks. In this bioassay, giving NNN in 28 weeks but starting at the age of 3 months, it took, on the average. 97 ± 29 weeks to induce malignant nasal tumors, primarily esthesioneuroepithelioma with invasion of the brain, (ii) NNK (6.3 mM), given by s.c. injection, induced nasal carcinoma with invasion of the forebrain after 77 ± 39 weeks. (iii) NNN (11.9 mM) plus NNK (6.3 mM) led to the same type of carcinoma but at an accelerated pace, namely after 71 ± 57 weeks. This study supports the earlier observation that tobacco-specific N-nitrosamines induce malignant tumors of the nasal cavity with invasion of the brain, dependent to some degree on the age of the mink at first application. NNK appears to be a stronger carcinogen than NNN in mink which follows the observations made with mice, rats and hamsters. It is suggested that combined administration of NNN with NNK induces a stronger carcinogenic effect than NNN or NNK given alone.