An In Vitro Systems Toxicology Assessment of Novel Electronic Vapor Device by Using Air–Liquid Interface Buccal, Bronchial, Small Airway, and Alveolar Culture Models

      Iskandar, A.; Zanetti, F.; Giralt, A.; Kondylis, A.; Sewer, A.; Ortega-Torres, L.; Majeed, S.; Acali, S.; Marescotti, D.; Guedj, E.; Merg, C.; Trivedi, K.; Frentzel, S.; Ivanov, N.; Martin, F.; Peitsch, M. C.; Hoeng, J.

      Conference date
      Mar 3, 2021
      Conference name
      6th German Pharm-Tox Summit

      Aerosols of electronic vapor (e-vapor) products have a different composition than cigarette smoke (CS). Most studies rely on testing the effects of the liquid formulations applied directly to cell cultures. But, this setup does not mimic real-life aerosol exposure to evapor product (EVP) users. Using advanced cellular models (air–liquid interface human organotypic buccal, bronchial, small airway, and alveolar cultures), we examined the biological effects of acute exposure to the whole aerosol generated by the EVP P4M3 with "Classic Tobacco" flavor (Philip Morris International). The concentrations of nicotine and carbonyls deposited in the exposure chamber were measured as exposure markers. The effects of EVP exposure were compared with those of CS exposure at similar concentrations of deposited nicotine. Using a systems toxicology approach, we complemented histological and cytotoxicity endpoints with analysis of molecular changes (profiles of mRNA and secretory proteins). The results showed that CS exposure caused culture damage and reduced ciliary beating frequency (in ciliated epithelial cultures), while the EVP aerosol exposure induced minimal changes despite resulting in higher concentrations of deposited nicotine than CS exposure. Carbonyl concentrations increased with an increasing dose of CS; however, of their concentrations following EVP aerosol exposure were below the detection limits. The magnitude of alterations in gene expression and secreted mediator were greater following CS exposure than EVP aerosol exposure at all tested doses. We consistently detected increased concentrations of secreted matrix metalloproteinase 1 (MMP-1) following CS exposure in all culture types. MMP-1 concentrations following EVP aerosol exposure were comparable with those following air exposure. Using a network perturbation amplitude methodology, greater biological impacts were detected at the earlier than at the later post-exposure time points for all exposure conditions tested. In all culture models, the biological impacts following EVP aerosol exposure were generally less than those following CS exposure at comparable concentrations of deposited nicotine. In conclusion, the studies showed that the effects of exposure to aerosol from P4M3 were lower than those of CS exposure in epithelial cultures of the aerodigestive tract. These studies demonstrated the suitability of air–liquid interface aerodigestive culture models for toxicity testing of inhalation products.