Flavor-solvent reaction products in electronic cigarette liquids activate respiratory irritant receptors and elicit cytotoxic metabolic responses in airway epithelial cell

Abstract

Manufacturers claim that E-cigarettes are inherently safe since they vaporize a defined set of chemicals. It is assumed that e-liquids vaporized by E-cigarettes are chemically stable, however, potential reaction pathways suggests that reactions may occur during production and storage.

Using a combination of gas chromatography, mass spectrometry and NMR, we observed that flavor aldehydes such as vanillin (vanilla flavor) and benzaldehyde (berry / fruit flavor) rapidly undergo chemical reactions with the E-liquid solvents PG and VG after mixing. The chemical adducts formed, named aldehyde PG/VG acetals, are carried over into the aerosol and are stable at physiological conditions.

Toxicological tests reveal that these compounds activate the sensory irritant receptors TRPV1 and TRPA1, involved in triggering cough, secretions and cardiovascular reflexes to irritant inhalation. The aldehyde acetals activate these receptors more robustly and potently than the parent aldehydes. Comparison of the cytotoxic effects of parent aldehydes and acetals in cultured bronchial epithelial cells demonstrate that acetals induce cell death at lower concentrations. Analysis of mitochondrial respiration and glycolysis reveal that flavor aldehyde acetals suppress mitochondrial oxygen consumption and ATP production.

These findings suggest that electronic cigarettes release unstable chemical mixtures containing a large variety of chemical products with unexpected toxicological properties. Thorough risk assessment is required by regulators to identify and mitigate toxicological threats to e-cigarette users.