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Nornicotine in Smokeless Tobacco as a Precursor for Carcinogen Exposure

Principal Investigator: Irina Stepanov

Funding Mechanism:  National Institutes of Health- Grant

ID Number: 1R01CA180880-01

Award Date:  4/30/14

Institution:  University of Minnesota 

N'-nitrosonornicotine (NNN), a tobacco-specific carcinogen, is believed to play an important role in causing esophageal and oral cavity cancer in tobacco users.  NNN is formed from the nitrosation of tobacco alkaloids such as nornicotine. Nornicotine in tobacco products is nitrosated during tobacco processing, but it may also be nitrosated endogenously (i.e., within the body) in the oral cavity, the stomach, or elsewhere.  This is particularly relevant to smokeless tobacco product use, given that keeping smokeless tobacco in the oral cavity for prolonged time periods creates favorable conditions for nitrosation. Information on nornicotine content in individual smokeless tobacco brands does not exist, and the extent of variation among products is unknown. The goal of this study is to generate information on endogenous nitrosation of nornicotine as a function of its content in smokeless products. Specific aims are: (1) to determine the variation of nornicotine content in smokeless products currently marketed in the U.S.; and (2) to investigate the endogenous formation of NNN in smokeless tobacco users. To investigate Aim 1, researchers will analyze a variety of smokeless products (e.g., moist snuff, snus, lozenges, sticks, strips) for nornicotine, nitrate, and nitrite content using liquid chromatography tandem mass spectrometry (LC-MS/MS).  To investigate Aim 2, researchers will randomize 130 smokeless tobacco users aged 18-65 to use a tobacco-free herbal snuff containing various added amounts of stable isotope-labeled nornicotine. Isotope-labeled urinary total NNN will be measured in these subjects by using LC-MS/MS, allowing researchers to differentiate the amount of NNN from endogenous nitrosation of nornicotine versus that from exposure to NNN in tobacco products. The results of this study will provide new information on endogenous NNN formation that may inform regulatory decisions related to nornicotine in tobacco products.

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