Labeled Nornicotine in Smokeless Tobacco
| Status: | Not yet recruiting |
|---|---|
| Healthy: | No |
| Age Range: | 18 - 65 |
| Updated: | 4/17/2018 |
| Start Date: | June 2018 |
| End Date: | August 2020 |
| Contact: | Hanna Vanderloo, MSN |
| Email: | hannav@umn.edu |
| Phone: | 612-624-4983 |
Nornicotine in Smokeless Tobacco as a Precursor for Carcinogen Exposure
Smokeless tobacco users who are unable or unwilling to quit tobacco use may be exposed to the
potent oral and esophageal carcinogen NNN not only from tobacco itself, but also via its
endogenous synthesis from nornicotine. The proposed study will lead to an understanding of
the endogenous formation of NNN from nornicotine in humans, and will also investigate the
effect of the reduction of nornicotine content in smokeless tobacco on the extent of
endogenous NNN formation. The knowledge gained in this study will lead to the development of
recommendations for the regulation, or potentially elimination, of nornicotine in smokeless
tobacco products in order to minimize exposure to NNN in the users of these products.
potent oral and esophageal carcinogen NNN not only from tobacco itself, but also via its
endogenous synthesis from nornicotine. The proposed study will lead to an understanding of
the endogenous formation of NNN from nornicotine in humans, and will also investigate the
effect of the reduction of nornicotine content in smokeless tobacco on the extent of
endogenous NNN formation. The knowledge gained in this study will lead to the development of
recommendations for the regulation, or potentially elimination, of nornicotine in smokeless
tobacco products in order to minimize exposure to NNN in the users of these products.
The tobacco alkaloid nornicotine is a precursor to N'-nitrosonornicotine (NNN), a potent
tobacco-specific carcinogen. NNN is believed to play an important role in the induction of
esophageal and oral cavity cancers in tobacco users. Nornicotine contributes to NNN exposure
in tobacco users in two ways. In addition to being a precursor to NNN formation in tobacco,
it may also be nitrosated endogenously. Endogenous nitrosation of nornicotine that is present
in tobacco products can occur in the oral cavity, in the stomach, or elsewhere in the body of
tobacco users. This is particularly relevant to the use smokeless tobacco products - a form
of tobacco that is kept in the oral cavity for prolonged periods of time, creating favorable
conditions for nornicotine nitrosation. Given the high carcinogenic potency of NNN and the
association of smokeless tobacco use with oral and esophageal cancers, regulation of
nornicotine content in smokeless tobacco products is urgently needed. The Food and Drug
Administration (FDA) has authority to regulate harmful and potentially harmful tobacco
constituents under the Family Smoking Prevention and Tobacco Control Act. The information on
the extent of endogenous nitrosation of nornicotine as a function of its content in smokeless
products is crucial for the adequate regulation of this tobacco constituent by the FDA. Aims
of this proposal are: (1) To determine the variation of nornicotine content in smokeless
products currently marketed in the U.S. There is no information on nornicotine content in
individual smokeless brands, and the extent of variation among the currently marketed U.S.
products is unknown. Aim 1 will address this important gap and will also provide critical
information for Aim 2 of this proposal. (2) To investigate the endogenous formation of NNN in
smokeless tobacco users. Smokeless tobacco users will be randomized to a tobacco-free herbal
snuff containing various amounts of stable isotope-labeled nornicotine added to it.
Isotope-labeled urinary total NNN - a biomarker of exposure to NNN - will be measured in
these subjects by using liquid chromatography-tandem mass-spectrometry. This methodology will
allow for specific identification of urinary total NNN from endogenous nitrosation of
nornicotine, versus that resulting from exposure to NNN in tobacco products. The effect of
nornicotine reduction on the extent of endogenous NNN formation will be studied by gradually
decreasing the amount of isotope-labeled nornicotine added to study snuff. The results of
this study will provide extremely important new information on the endogenous formation of
the carcinogenic nitrosamine NNN upon exposure to nornicotine from tobacco use. An
understanding of this process is absolutely necessary for the adequate regulation of
nornicotine in tobacco products with the purpose of minimizing public harm.
tobacco-specific carcinogen. NNN is believed to play an important role in the induction of
esophageal and oral cavity cancers in tobacco users. Nornicotine contributes to NNN exposure
in tobacco users in two ways. In addition to being a precursor to NNN formation in tobacco,
it may also be nitrosated endogenously. Endogenous nitrosation of nornicotine that is present
in tobacco products can occur in the oral cavity, in the stomach, or elsewhere in the body of
tobacco users. This is particularly relevant to the use smokeless tobacco products - a form
of tobacco that is kept in the oral cavity for prolonged periods of time, creating favorable
conditions for nornicotine nitrosation. Given the high carcinogenic potency of NNN and the
association of smokeless tobacco use with oral and esophageal cancers, regulation of
nornicotine content in smokeless tobacco products is urgently needed. The Food and Drug
Administration (FDA) has authority to regulate harmful and potentially harmful tobacco
constituents under the Family Smoking Prevention and Tobacco Control Act. The information on
the extent of endogenous nitrosation of nornicotine as a function of its content in smokeless
products is crucial for the adequate regulation of this tobacco constituent by the FDA. Aims
of this proposal are: (1) To determine the variation of nornicotine content in smokeless
products currently marketed in the U.S. There is no information on nornicotine content in
individual smokeless brands, and the extent of variation among the currently marketed U.S.
products is unknown. Aim 1 will address this important gap and will also provide critical
information for Aim 2 of this proposal. (2) To investigate the endogenous formation of NNN in
smokeless tobacco users. Smokeless tobacco users will be randomized to a tobacco-free herbal
snuff containing various amounts of stable isotope-labeled nornicotine added to it.
Isotope-labeled urinary total NNN - a biomarker of exposure to NNN - will be measured in
these subjects by using liquid chromatography-tandem mass-spectrometry. This methodology will
allow for specific identification of urinary total NNN from endogenous nitrosation of
nornicotine, versus that resulting from exposure to NNN in tobacco products. The effect of
nornicotine reduction on the extent of endogenous NNN formation will be studied by gradually
decreasing the amount of isotope-labeled nornicotine added to study snuff. The results of
this study will provide extremely important new information on the endogenous formation of
the carcinogenic nitrosamine NNN upon exposure to nornicotine from tobacco use. An
understanding of this process is absolutely necessary for the adequate regulation of
nornicotine in tobacco products with the purpose of minimizing public harm.
1. Adults who are regular smokeless tobacco users
2. Subjects are in good physical health and good general oral health;
3. Subjects are in stable, good mental health
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