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14-Day Nose-Only Inhalation Toxicity Study of NNK in Rats

Principal Investigator: Shu-Chieh Hu and Raymond Yeager

Funding Mechanism: NCTR

ID number: C13036/E0753401

Award Date: 2/14/2014

Institution: National Center for Toxicological Research

Human exposure to 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific nitrosamine that has been classified as a human lung carcinogen, occurs through smoking tobacco products, using oral smokeless tobacco products, or being exposed to environmental tobacco smoke. The goal of this study is to determine the sub-acute inhalation toxicity of NNK in rats over 14 days of inhalation exposure to NNK aerosols.  In this study, six groups of 32 Sprague-Dawley rats (16 males and 16 females per group) will be exposed by nose-only inhalation to one of four dose levels of NNK aerosols or one of two control conditions (vehicle or air) for one hour per day, seven days per week for 14 days.  Each study group will contain toxicology (10 rats/sex/group) and exposure assessment (6 rats/sex/group) subgroups. Moreover, three additional groups of toxicology animals (7 rats/sex/group) will be exposed to NNK aerosols by nose-only inhalation for four hours per day, seven days per week for 14 days, and their biological responses will be compared to the one-hour exposure group animals who receive the same exposure doses (i.e., the product of NNK concentration and exposure time will be constant).  During the 14-day exposure phase of the study, the rats' mortality, clinical signs, body weights, food consumption, and pulmonary physiology (breathing rate and minute volume) will be evaluated periodically.  One day after the last inhalation dose, researchers will collect tissues from the rats in the toxicology subgroups for histopathological evaluation. Researchers will also evaluate the organ weights, hematology, and blood chemistry of the rats in the toxicology subgroups in order to determine biological responses. Finally, researchers will collect blood and urine from rats in the exposure assessment subgroups at days 1, 8, and 14, and will measure plasma and urine NNK and its metabolites.  This project will yield data indicating the risk associated with exposure to NNK.

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