Tobacco- specific N- nitrosamine exposures and cancer risk in the Shanghai cohort study: Remarkable coherence with rat tumor sites

The tobacco-specific nitrosamines N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are potent carcinogens for the rat esophagus and lung, respectively. Consistent with the animal carcinogenicity data, we previously reported a remarkably strong association between prospectively measured urinary total NNN, a biomarker of human NNN intake, and the risk of developing esophageal cancer among smokers in the Shanghai Cohort Study. We also demonstrated that urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a biomarker of exposure to the lung carcinogen NNK, is strongly associated with the risk of lung, but not esophageal cancer in smokers. In this study, we investigated the potential relationship between NNN intake and lung cancer risk in the same cohort. The prospectively collected urine samples from lung cancer cases and matching controls selected for this study, all current smokers, have been previously analyzed for total NNAL, cotinine (a biomarker of nicotine intake) and phenanthrene tetraol (PheT) (a biomarker of exposure to polycyclic aromatic hydrocarbons). Urinary levels of total NNN were not associated with the risk of lung cancer: odds ratios (95% confidence intervals) associated with the second and third tertiles of total NNN, relative to the lowest tertile, were 0.82 (0.36-1.88) and 1.02 (0.39-2.89), respectively (p for trend=0.959), after adjustment for self-reported smoking history, urinary cotinine and PheT. The results of this study reaffirm the previously reported specificity of urinary total NNN and total NNAL as predictors of esophageal and lung cancer risks, respectively, in smokers, and demonstrate remarkable coherence between rat target tissues of these carcinogens and susceptibility to cancer in smokers. What's new? Previous laboratory animal data have demonstrated that the tobacco-specific nitrosamines NNN and NNK are highly carcinogenic for the rat esophagus and lung, respectively. The results presented here based on the Shanghai Cohort Study provide strong support for the coherence of the NNN and NNK carcinogenicity data in rats with the effects of exposure to these carcinogens in smokers. This study thus supports the use of F-344 rat studies to elucidate the carcinogenic effects in smokers of tobacco-specific nitrosamines, and possibly other tobacco smoke constituents.