It has been proposed that the tobacco-specific N-nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) may be involved in the causation of human lung cancer (Hecht and Hoffmann, 1988), but direct evidence for the involvement of NNK in human lung cancer is lacking (Hecht and Tricker, 1999). In the A/J mouse lung tumor model, a single intraperitoneal (i.p.) injection of 10 μmole [2.07 mg] NNK/mouse results in 7–12 lung tumors per mouse after 16 weeks (Hecht et al., 1989). The initial events in NNK-induced A/J mouse lung tumorigenesis are believed to be metabolism of NNK to biological reactive intermediates (BRI) with the potential to react (via methylation of DNA) to produce O6-methylguanine (O6MeG), GC→AT transitional mispairing, and subsequent activation of the K-ras proto-oncogene (Ronai et al., 1993). α-Hydroxylation of the methylene carbon atoms adjacent to the N-nitroso group in NNK and NNAL yields unstable BM which spontaneously decompose to methanediazohydroxide with the potential to react with DNA to produce 7-methylguanine (7-MeG), O4-methylthymidine (O4MeT) and O6MeG adducts. α-Hydroxylation of the NNK methyl group yields a BM with the potential to pyridyloxobutylate DNA, while α-methyl hydroxylation of NNAL is not known to result in DNA adduct formation. Other metabolic transformations represent detoxification pathways for NNK and NNAL.