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

Autor: Hu SC; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR, 72079, USA., Min S; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR, 72079, USA., Kang HK; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR, 72079, USA., Yang DJ; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR, 72079, USA., Basavarajappa M; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR, 72079, USA., Lewis SM; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR, 72079, USA., Davis KJ; Toxicologic Pathology Associates, National Center for Toxicological Research, Jefferson, AR, 72079, USA., Patton RE; Toxicologic Pathology Associates, National Center for Toxicological Research, Jefferson, AR, 72079, USA., Bryant MS; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR, 72079, USA., Sepehr E; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR, 72079, USA., Trbojevich R; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR, 72079, USA., Pearce MG; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR, 72079, USA., Bishop ME; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR, 72079, USA., Ding W; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR, 72079, USA., Heflich RH; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR, 72079, USA., Maisha MP; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR, 72079, USA., Felton R; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR, 72079, USA., Chemerynski S; The Center for Tobacco Products (CTP), U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA., Yee SB; The Center for Tobacco Products (CTP), U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA., Coraggio M; The Center for Tobacco Products (CTP), U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA., Rosenfeldt H; The Center for Tobacco Products (CTP), U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA., Yeager RP; The Center for Tobacco Products (CTP), U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA., Howard PC; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR, 72079, USA., Tang Y; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR, 72079, USA. Electronic address: Yunan.Tang@fda.hhs.gov.
Jazyk: angličtina
Zdroj: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association [Food Chem Toxicol] 2022 Feb; Vol. 160, pp. 112780. Date of Electronic Publication: 2021 Dec 26.
DOI: 10.1016/j.fct.2021.112780
Abstrakt: 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 O 6 -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 O 6 -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.
(Published by Elsevier Ltd.)
Databáze: MEDLINE
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