The molecular basis for induction of human cancers by tobacco specific nitrosamines.

Cellular DNA damage that is misrepaired or not repaired, constitutes a necessary, although not sufficient prerequisite for induction of cancer. For carcinogenic oral snuffs with extremely high concentrations of tobacco specific nitrosamines (TSNA) the DNA adduct levels predicted from animal experiments exceed those found in "unexposed" individuals. On the other hand, and supported by extensive Swedish epidemiological data, no significant increase of TSNA-induced DNA damages can be anticipated in humans from the use of low-nitrosamine oral snuffs. The extrapolated adduct concentrations are orders of magnitude lower than those found in the corresponding human tissues, a discrepancy that is difficult to account for by species differences. Furthermore, in exposed subjects the observed increment in the background levels of pyridyloxobutyl(POB)-hemoglobin adducts - a relevant indicator for TSNA activation - lie in a range predicted by rodent data. When based on the same type of tissues this provides justification for extrapolating rates of TSNA induced adduct formation from animals to humans. A TSNA exposure that does not affect the background level of pro-mutagenic DNA lesions should be considered as "virtually safe". The high background concentrations of methylated and POB-DNA adducts in "unexposed" humans must be ascribed to other sources than tobacco.