Radon, tobacco-specific nitrosamine and mutagenesis in mammalian cells.

The mutagenicity of 4-methylnitrosamine-1-3-pyridyl-1-butanone (NNK), either alone or in combination with low dose alpha particle irradiation, was examined using the human-hamster hybrid (A(L)) cell assay. NNK induced a dose-dependent toxicity in A(L) cells. In combination with a 25 cGy dose of alpha particles, the induced survival fraction fell within the statistical range of the calculated values assuming an additive interaction of the two agents. In addition, NNK is mutagenic in A(L) cells at the CD59 locus. Furthermore, a low dose of NNK, when combined with radon alpha particles, resulted in a combined mutagenic effect in A(L) cells that was consistent with an additive model but less than additive at higher NNK concentrations. The majority of NNK induced CD59(-) mutants (77.6%) lost at least one additional marker in addition to the CD59 which encodes the cell surface antigen. When combined with alpha particles, the proportion of mutants with additional marker loss increased with increasing dose of NNK. Our study further confirms that NNK is mutagenic in mammalian cells, induces mostly deletions, and provides an in vitro assessment of the combined genotoxic effects of NNK and alpha particles at low environmentally relevant doses. This finding should be helpful in understanding the molecular mechanism of the mutagenic process as a result of multi-agent interaction.