90-day nose-only inhalation toxicity study of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in Sprague-Dawley rats

• Published in: Food and chemical toxicology 2022-02, Vol.160, p.112780, Article 112780
• Main Authors: Hu, Shu-Chieh, Min, Seonggi, Kang, Hyun-Ki, Yang, Dong-Jin, Basavarajappa, Mallikarjuna, Lewis, Sherry M., Davis, Kelly J., Patton, Ralph E., Bryant, Matthew S., Sepehr, Estatira, Trbojevich, Raul, Pearce, Mason G., Bishop, Michelle E., Ding, Wei, Heflich, Robert H., Maisha, MacKean P., Felton, Robert, Chemerynski, Susan, Yee, Steven B., Coraggio, Melis, Rosenfeldt, Hans, Yeager, R. Philip, Howard, Paul C., Tang, Yunan
• Format: Article
• Language: English
• Subjects: Animals; Cigarette Smoking - adverse effects; DNA Adducts - genetics; DNA Damage - drug effects; Female; Humans; Inhalation Exposure - adverse effects; Male; Micronucleus Tests; Nitrosamines - toxicity; NNK; No-Observed-Adverse-Effect Level; Nose - drug effects; Nose - pathology; Nose-only inhalation; Rats; Rats, Sprague-Dawley; Smoke - adverse effects; Subchronic toxicity; Tobacco Products
• ISSN: 0278-6915; 1873-6351; 1873-6351
• DOI: 10.1016/j.fct.2021.112780

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the key tobacco-specific nitrosamines that plays an important role in human lung carcinogenesis. Repeated dose inhalation toxicity data on NNK, particularly relevant to cigarette smoking, however, is surprisingly limited. Hence, there is a lack of direct information available on the carcinogenic and potential non-carcinogenic effects of NNK via inhalational route exposure. In the present study, the subchronic inhalation toxicity of NNK was evaluated in Sprague Dawley rats. Both sexes (9–10 weeks age; 23 rats/sex/group) were exposed by nose-only inhalation to air, vehicle control (75% propylene glycol), or 0.2, 0.8, 3.2, or 7.8 mg/kg body weight (BW)/day of NNK (NNK aerosol concentrations: 0, 0, 0.0066, 0.026, 0.11, or 0.26 mg/L air) for 1 h/day for 90 consecutive days. Toxicity was evaluated by assessing body weights; food consumption; clinical pathology; histopathology; organ weights; blood, urine, and tissue levels of NNK, its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and their glucuronides (reported as total NNK, tNNK, and total NNAL, tNNAL, respectively); tissue levels of the DNA adduct O6-methylguanine; blood and bone marrow micronucleus (MN) frequency; and bone marrow DNA strand breaks (comet assay). The results showed that NNK exposure caused multiple significant adverse effects, with the most sensitive endpoint being non-neoplastic lesions in the nose. Although the genotoxic biomarker O6-methylguanine was detected, genotoxicity from NNK exposure was negative in the MN and comet assays. The Lowest-Observed-Adverse-Effect-Level (LOAEL) was 0.8 mg/kg BW/day or 0.026 mg/L air of NNK for 1 h/day for both sexes. The No-Observed-Adverse-Effect-Level (NOAEL) was 0.2 mg/kg BW/day or 0.0066 mg/L air of NNK for 1 h/day for both sexes. The results of this study provide new information relevant to assessing the human exposure hazard of NNK.