Radon, tobacco-specific nitrosamine and mutagenesis in mammalian cells

The mutagenicity of 4-methylnitrosamine-1-3-pyridyl-1-butanone (NNK), eithe r alone or in combination with low dose alpha particle irradiation, was exa mined 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 alph a particles, the induced survival fraction fell within the statistical rang e of the calculated values assuming an additive interaction of the two agen ts. In addition, NNK is mutagenic in A(L) cells at the CD59 locus. Furtherm ore, 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 ad ditive model but less than additive at higher NNK concentrations. The major ity of NNK induced CD59(-) mutants (77.6%) lost at least one additional mar ker in addition to the CD59 which encodes the cell surface antigen. When co mbined with alpha particles, the proportion of mutants with additional mark er loss increased with increasing dose of NNK. Our study further confirms t hat NNK is mutagenic in mammalian cells, induces mostly deletions, and prov ides an in vitro assessment of the combined genotoxic effects of NNK and al pha 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. (C) 1999 Elsevier Science B.V. All rights reserved.