title: Toxicity of aerosols of nicotine and pyruvic acid (separate and combined) in Sprague-Dawley rats in a 28-day OECD 412 inhalation study and assessment of systems toxicology.
abstract: Toxicity of nebulized nicotine (Nic) and nicotine/pyruvic acid mixtures (Nic/Pyr) was characterized in a 28-day Organization for Economic Co-operation and Development 412 inhalation study with additional transcriptomic and lipidomic analyses. Sprague-Dawley rats were nose-only exposed, 6 h/day, 5 days/week to filtered air, saline, nicotine (50 µg/l), sodium pyruvate (NaPyr, 33.9 µg/l) or equimolar Nic/Pyr mixtures (18, 25 and 50 µg nicotine/l). Saline and NaPyr caused no health effects, but rats exposed to nicotine-containing aerosols had decreased body weight gains and concentration-dependent increases in liver weight. Blood neutrophil counts were increased and lymphocyte counts decreased in rats exposed to nicotine; activities of alkaline phosphatase and alanine aminotransferase were increased, and levels of cholesterol and glucose decreased. The only histopathologic finding in non-respiratory tract organs was increased liver vacuolation and glycogen content. Respiratory tract findings upon nicotine exposure (but also some phosphate-buffered saline aerosol effects) were observed only in the larynx and were limited to adaptive changes. Gene expression changes in the lung and liver were very weak. Nic and Nic/Pyr caused few significant changes (including Cyp1a1 gene upregulation). Changes were predominantly related to energy metabolism and fatty acid metabolism but did not indicate an obvious toxicity-related response. Nicotine exposure lowered plasma lipids, including cholesteryl ester (CE) and free cholesterol and, in the liver, phospholipids and sphingolipids. Nic, NaPyr and Nic/Pyr decreased hepatic triacylglycerol and CE. In the lung, Nic and Nic/Pyr increased CE levels. These data suggest that only minor biologic effects related to inhalation of Nic or Nic/Pyr aerosols were observed in this 28-day study.
authors: a Philip Morris International Research Laboratories Pte Ltd , Science Park II , Singapore and.
authors: Blaine
authors: B
authors: Phillips
authors: Marco
authors: M
authors: Esposito
authors: Jan
authors: J
authors: Verbeeck
authors: Stéphanie
authors: S
authors: Boué
authors: Anita
authors: A
authors: Iskandar
authors: Gregory
authors: G
authors: Vuillaume
authors: Patrice
authors: P
authors: Leroy
authors: Subash
authors: S
authors: Krishnan
authors: Ulrike
authors: U
authors: Kogel
authors: Aneli
authors: A
authors: Utan
authors: Walter K
authors: WK
authors: Schlage
authors: Monali
authors: M
authors: Bera
authors: Emilija
authors: E
authors: Veljkovic
authors: Julia
authors: J
authors: Hoeng
authors: Manuel C
authors: MC
authors: Peitsch
authors: Patrick
authors: P
authors: Vanscheeuwijck
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D000975:Antioxidants / Q000633:toxicity*; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009538:Nicotine / Q000633:toxicity*; D018722:Nicotinic Agonists / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D019289:Pyruvic Acid / Q000633:toxicity*; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D013047:Specific Pathogen-Free Organisms; D061485:Tobacco Use Cessation Devices / Q000009:adverse effects*; D059550:Toxicity Tests, Subchronic; D015430:Weight Gain / Q000187:drug effects
chemical_list: D000336:Aerosols; D000975:Antioxidants; D015415:Biomarkers; D004338:Drug Combinations; D018722:Nicotinic Agonists; D009538:Nicotine; D019289:Pyruvic Acid
keywords: Nicotine; pyruvic acid; sub-chronic inhalation; systems toxicology