DescriptionPrior studies in human and animal models have demonstrated that exposure to aerosolized toxicants can induce lasting olfactory loss and toxicant transportation to the brain via the olfactory nerve. The surge in vaping popularity requires assessment of potential effects of vaping on olfactory function to inform regulation and public health guidance. Vaping using electronic nicotine delivery systems exposes the upper airway, including the olfactory system, to a complex array of potential toxicants. We assessed olfactory ability in a community sample of 113 participants, of whom 47 self-reported as vaping regularly. These participants were far more likely to exhibit clinical impairment of olfactory function (odds ratio 7.2) than non-vaping participants, requiring on average a 3.1-fold higher concentration to detect an odorant at threshold and scoring 1.0 standard deviations worse on an odor discrimination test. However, vape users showed no deficit in verbal odor identification. These effects were not explained by recency of vape use (ruling out sensory adaptation as a mechanism), type of vape device, or methods of inhalation or exhalation. The data further suggested that vape users might be more vulnerable to olfactory loss associated with COVID-19, but the deleterious effect of vaping was statistically significant among the subset of participants with no history of COVID-19. To identify potential mechanisms of injury, we and our collaborators developed a mouse model in which odor-evoked synaptic output from olfactory nerve terminals into the brain’s olfactory bulb was assayed in vivo using optical neurophysiology before and after exposure to aerosols from a consumer vape device. These data demonstrated that acute vape exposure strongly reduced odor-evoked olfactory nerve output, consistent with the loss of sensitivity observed in humans, and reduced the differences in neural response patterns evoked by similar odors, consistent with the loss of discrimination acuity observed in humans. Exposure to nicotine-free vape aerosols induced similar deficits in a dose-dependent manner, demonstrating that the propylene glycol/vegetable glycerin base fluid contributes to olfactory pathophysiology. We then tested the hypothesis that heavy metals might be present in the vape fluid (potentially introduced by the metal filament used to generate the aerosol) and deposited in the nasal epithelium. Mass spectrometry analysis revealed the presence of arsenic, nickel, manganese, cadmium, chromium, and lead in the vape aerosol, of which arsenic, nickel, and manganese were significantly retained in the olfactory epithelium of vape-exposed mice. These results demonstrate substantial olfactory loss in people who vape and suggest that disruption of the peripheral olfactory system by vape aerosols is the likely mechanism of injury.