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13-Week Nose-Only Inhalation Toxicity Study of NNK in Rats

Principal Investigator: Shu-Chieh Hu and Raymond Yeager

Funding Mechanism: NCTR

ID number: C13038/E0753101

Award Date: 2/3/2014

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-chronic inhalation toxicity of NNK in rats over 90 days of inhalation exposure to NNK aerosols.  In this study, six groups of 46 Sprague-Dawley rats (23 males and 23 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 90 days.  Each study group will contain core toxicology, recovery toxicology, and exposure assessment subgroups.  During the 90-day exposure phase of the study, the rats' mortality, clinical signs, body weights, food consumption, opthalmology, 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 core toxicology subgroup (10 rats/sex/group) for histopathological evaluation. Researchers will maintain the recovery toxicology subgroup (10 rats/sex/group) for six weeks following the exposure phase, at which time they will analyze tissues in order to evaluate post-exposure recovery. Researchers will also evaluate the organ weights, hematology, blood chemistry, and urinalysis on core and recovery toxicology rats in order to determine biological responses. Finally, researchers will collect blood and urine from exposure assessment (3 rats/sex/group) at weeks 1, 5, 9, and 13, and will measure plasma and urine NNK and its metabolites.  This project will yield data indicating the risk associated with exposure to NNK.