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


Authored by  B Phillips, M Esposito, J Verbeeck, S Boue, A Iskandar, G Vuillaume, P Leroy, AS Krishnan *, U Kogel, A Utan, W Schlage, E Veljkovic, M Bera, J Hoeng, M Peitsch, P Vanscheeuwijck

Published in Inhalation Toxicology     
* This author is not affiliated with PMI.

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 mg/l), sodium pyruvate (NaPyr, 33.9 mg/l) or equimolar Nic/Pyr mixtures (18, 25 and 50 mg 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 nonrespiratory 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. 

Our Findings

We are committed to sharing our results as the development and scientific assessment of our products advance. Read our most important findings with supporting peer-reviewed articles, presentations, and registered clinical trials.

What we have learned so far...