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Developing Methods for the Evaluation of Smokeless Tobacco-Associated Carcinogenesis

Principal Investigator: Lei Guo and Frederick Beland / Kimberly Benson

Funding Mechanism: JV

ID number: E0748801

Award Date: 6/5/2012

Institution: National Center for Toxicological Research


Epidemiological studies have shown that smokeless tobacco use is associated with elevated risk of oral cavity cancers, esophageal cancer and pancreatic cancer.  About 30 carcinogens have been identified in smokeless tobacco products, with alkaloid derived tobacco-specific N-nitrosamines (TSNAs) being the most important.  Two major types of TSNAs are found in smokeless tobacco: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N’-nitrosonornicotine (NNN).  NNK and NNN have been detected in saliva samples collected from smokeless tobacco users, and nitrosamine-4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a major metabolite of NNK, has been detected in the saliva, plasma and urine of smokeless tobacco users, indicating that these carcinogens are absorbed and metabolized by the body.  These metabolites could potentially be used as sensitive biomarkers for smokeless tobacco-associated toxicity/carcinogenicity.  The carcinogenic activity of smokeless tobacco has been studied using various animal models; the hamster cheek pouch and the rat artificial lip canal appear to be the best models currently available for studying the effects of smokeless tobacco products. This study will determine the appropriate animal models for long-term carcinogenesis studies, evaluate and compare the carcinogenicity of smokeless tobacco products, and develop biomarkers for the risks associated with smokeless tobacco exposure.