N'-Nitrosonornicotine (NNN) and
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are tobacco-specific
nitrosamines. NNN and NNK can induce
cancers of the esophagus and lung, respectively, in laboratory animals, but data on human
esophageal cancer are lacking. The association between levels of NNN and
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), an NNK metabolite, in urine samples collected before diagnosis and risk of
esophageal cancer was examined in 77 patients with
esophageal cancer and 223 individually matched controls, all current smokers, from a cohort of 18244 Chinese men in Shanghai, China, followed from 1986 to 2008. Urinary total NNN (free NNN plus NNN-N-
glucuronide) was significantly higher, whereas the percentage of its detoxification product NNN-N-
glucuronide was significantly lower in cases than controls. Odds ratios (95% confidence intervals) of
esophageal cancer for the second and third tertiles of total NNN were 3.99 (1.25-12.7) and 17.0 (3.99-72.8), respectively, compared with the first tertile after adjustment for urinary total NNAL and total
cotinine and smoking intensity and duration (P(trend) < 0.001). The corresponding figures for the percentage of NNN-N-
glucuronides were 0.37 (0.17-0.80) and 0.27 (0.11-0.62) (P(trend) = 0.001). Urinary total NNN and the percentage of NNN-N-
glucuronides almost completely accounted for the observed association for urinary total NNAL (free NNAL plus its
glucuronides), urinary total
cotinine and smoking intensity with
esophageal cancer risk. These findings along with results of previous studies in laboratory animals support a significant and unique role of NNN in esophageal
carcinogenesis in humans.