Uptake and Metabolism of Carcinogenic Levels of Tobacco-Specific Nitrosamines by Sudanese Snuff Dippers

It was recently reported that toombak, a type of snuff used in the Sudan, contained unusually high levels of tobacco-specific nitrosamines. To estimate the internal dose of 4-(methylnitrosamino)-1 -(3-pyridyl)-1 -butanone (NNK) received by individuals who use this type of tobacco, urine from a group of users was analyzed for 2 metabolites of NNK, 4-(methylnitrosamino)-1 - (3-pyridyl)-1-butanol (NNAL) and its O-glucuronide, NNAL-Gluc. NNK is a strong lung carcinogen believed to contribute to human lung cancer. NNAL is also a lung carcinogen. NNAL and NNAL-Gluc were analyzed by gas chromatography with a nitrosamine selective detector. The average levels detected were 0.39 ± 0.14 (SD) nmol/ml urine (n = 7) and 0.88 ± 0.50 nmol/ml urine (n = 7), respectively. In a 24-h period, these individuals would excrete from 0.12 to 0.44 mg of these two metabolites (expressed per mg NNAL). Therefore, assuming chronic toombak use, the minimum daily dose of NNK to which these users were exposed was 0.120.44 mg. This is the highest documented uptake of a nonoccupational carcinogen. Two diastereomers of NNAL-Gluc were present in all urine samples analyzed. Previously, these two diastereomers were identified in the urine of an NNK-treated patas monkey but only one was detected in the urine of NNK-treated rats. The level of the 4-hydroxy-1 -(3-pyridyl)-1 -butanone releasing hemoglobin adduct was also quantified in these individuals. This adduct is believed to be a measure of NNK activation. The levels ranged from 68 to 323 fmol/g hemoglobin [mean, 148 ± 104 (SD)]. The wide range of adduct levels which were observed suggests that despite similar levels of NNK exposure, there are significant differences in the ability of individuals in this population to activate NNK, as well as potential differences in their cancer risk.