De minimus non curat lex--virtual thresholds for cancer initiation by tobacco specific nitrosamines--prospects for harm reduction by smokeless tobacco.

Whereas the impact of tobacco specific nitrosamines in smokers is obscured by the presence of numerous other carcinogens and promoters, for smokeless tobacco virtually all the carcinogenic potential is associated with 4-(nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN). In some countries exposure to smokeless tobacco with extremely high nitrosamine concentrations have been found to induce cancers in the head-neck region, whereas three recent large epidemiological studies failed to detect any such risk with respect to Swedish low-nitrosamine snuff. This review deals with quantitative aspects of DNA adduct formation from NNN and NNK in relation to the background levels ubiquitously found in healthy humans without known exposures to either tobacco or alkylating agents. The lack of significant increases of pro-mutagenic O6-methylations and DNA pyridyloxobutylations seen in smokers, as well as the negative outcome of the Swedish epidemiological studies, can be expected on basis of extrapolation of the dose response relationships found in rodents to actual exposures to NNK and NNN in Swedish snuff or from smoking. Sweden has the lowest prevalence of male smokers and smoking related diseases in the Western World, which has been ascribed to the fact that more than 20% of the grown up male population uses snuff. Smokeless tobacco represents an inexpensive and effective alternative to nicotine delivering products like nicotine patch, spray or gum. Considering that all other tobacco products are freely marketed, the ban on low-nitrosamine snuff in all countries in EU except Sweden is difficult to defend on either medical or ethical grounds.