A STUDY OF TOBACCO CARCINOGENESIS .53. 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 f ound to be highly susceptible to the carcinogenic effect of N'-nitroso nornicotine (NNN). In this follow-up study we tested (i) the importanc e of the age of the animals with regard to the carcinogenic effect of NNN, (ii) the carcinogenic activity of 4-(methylnitrosamino)-1-(3-pyri dyl)-1-butanone (NNK), and (iii) the combined carcinogenic effect of N NN plus NNK. (I) In the previous study, the latency of nasal tumor ind uction by NNN (11.9 mM) averaged 84+/-40 weeks upon twice weekly appli cations, starting at the age of 3 weeks and continuing for 38 weeks. I n this bioassay, giving NNN in 28 weeks but starting at the age of 3 m onths, it took, on the average, 97+/-29 weeks to induce malignant nasa l tumors, primarily esthesioneuroepithelioma with invasion of the brai n. (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 m M) plus NNK (6.3 mM) led to the same type of carcinoma but al an accel erated pace, namely after 71+/-57 weeks. This study supports the earli er observation that tobacco-specific N-nitrosamines induce malignant t umors of the nasal cavity with invasion of the brain, dependent to som e degree on the age of the mink at first application. NNK appears to b e a stronger carcinogen than NNN in mink which follows the observation s made with mice, rats and hamsters. It is suggested that combined adm inistration of NNN with NNK induces a stronger carcinogenic effect tha t NNN or NNK given alone. (C) 1997 Elsevier Science Ireland Ltd.