Evaluation of Respiratory Tract Organ Toxicity and Carcinogenicity of E-Vapor Aerosols in an 18-Month Inhalation Study in A/J Mice

      Wong, E.; Luettich, K.; Demenescu, L.; Kondylis, A.; Zhang, J.; Sciuscio, D.; Peitsch, M.; Lee, K.; Vanscheeuwijck, P.

      Conference date
      Mar 10, 2023
      Conference name
      Society of Toxicology (SOT) Annual Meeting and ToxExpo 2023

      There is limited toxicological information on the long-term inhalation exposures of e-vapor aerosols containing various flavors, humectants, and nicotine. Following Organisation for Economic Co-operation and Development (OECD) Test Guideline 453, A/J mice were used to evaluate respiratory tract organ toxicity as well as lung tumor incidence and multiplicity upon life-time exposure to cigarette smoke (CS) or to aerosols from a prototype e-liquid formulation containing 38 selected flavors. Mice were exposed via whole-body inhalation for 6 h/day for 5 days/week for up to 18 months to air; aerosol from propylene glycol (PG) and vegetable glycerol (VG); PG/VG with nicotine (N, 2% [w/w]); PG/VG/N with flavors (F) at low, medium, and high concentrations (1.2 to 18.6% [w/w]); PG/VG/F-High; or CS from the 3R4F reference cigarette. Histopathological evaluation, lung function and morphometric measurements were the key endpoints to evaluate respiratory tract toxicity and carcinogenicity. Plasma nicotine and cotinine were measured to confirm the systemic exposure. Exposure to e-vapor aerosols resulted in minimal or no changes in respiratory rate, lung function, lung inflammatory and emphysema parameters, as well as lung tumor incidence and multiplicity compared to the Sham group. In contrast, exposure to CS suppressed the respiratory rate, altered lung function, led to pulmonary inflammation and emphysematous changes, and―at terminal dissection―increased lung tumor incidence and multiplicity compared to the Sham group. In addition, histopathological evaluation of the respiratory tract showed severe changes and papilloma development in the larynx. In contrast, laryngeal histopathological changes were only observed in the high flavor e-vapor groups and showed significantly lower severity and incidence compared to the CS groups. Nasal and pulmonary changes when present in the e-vapor groups also showed lower severity and incidence compared to the CS groups. In summary, chronic exposure to e-vapor aerosols under the tested conditions showed consistently reduced toxicity and carcinogenicity responses in the respiratory tract compared to CS, supporting its potential role in tobacco harm reduction.