Fate of inhaled electronic nicotine delivery systems (ENDS) puff constituents in the human respiratory tract

Published research on the fate of a puff from electronic nicotine delivery systems (ENDS) in the lungs is limited; more information would better inform human exposure and potential adverse outcomes from ENDS use. An ENDS puff is a mixture of multiple constituents in droplet and vapor form, including propylene glycol, vegetable glycerin, nicotine, water, and flavor chemicals. Understanding the complexity of the puff aids in developing mechanistic models that can account for the physical, physiological, and thermodynamic processes of the puff while traveling and depositing in lung airways. Previously, we developed a mathematical model to predict deposition and uptake of ENDS constituents in the oral cavity. In this study, we formulated the model for lung airways to extend to the entire respiratory tract and made adjustments to mechanisms such as phase change and nicotine protonation to study effects on droplet pH and nicotine evaporation. We conducted model simulations for two representative inhalation profiles relevant to ENDS users: mouth-to-lung and direct-to-lung inhalation. Simulation results showed that vapor uptake during ENDS use was the primary mechanism of the overall tissue dose for higher vapor pressure constituents. Nicotine protonation was unaffected by the ratio of propylene glycol to vegetable glycerin but changes to vanillin molarity impacted droplet pH and free nicotine fraction. The largest uptake and deposition occurred in the deep lung, where constituents more efficiently reach the arterial blood. Predicted total respiratory tract retention of higher vapor pressure constituents such as nicotine, propylene glycol, and benzaldehyde were 94–95%, whereas retention of lower volatility constituents such as vegetable glycerin and vanillin was 82–83%. Results also indicated regional uptake differences for the constituents evaluated in the two inhalation scenarios. Predictions from the ENDS deposition model can be linked to physiologically based pharmacokinetic (PBPK) models to determine the fate of puff constituents such as nicotine in other tissues and organs of the body and provides further basis for evaluating flavor chemicals and puff constituents based on user-specific exposure characteristics as well as internal dose to inform risk assessment of ENDS.