Cell studies show short-term endothelial disruption with exposure Short-term exposure to certain flavorings used in electronic cigarettes and other tobacco products proved toxic to endothelial cell function in laboratory studies, suggesting that the flavor additives could impair blood vessel function over time and contribute to heart damage. When researchers examined the impact of nine flavorings commonly added to e-cigarettes, little cigars, hookahs, and other tobacco products to the cells that line and regulate blood vessel function, there was evidence that all nine induced acute alterations in endothelial function. All nine flavorings were found to impair nitric oxide production, which inhibits inflammation and clotting and regulates blood vessel enlargement in response to blood flow. The flavorings vanillin (vanilla), cinnamaldehyde (cinnamon), eugenol (clove), and acetylpyridine (burnt flavor) impaired A23187-induced nitric oxide production and increased expression of the proinflammatory mediator interleukin(IL)-6 across all concentrations tested, "suggesting that the endothelium is particularly sensitive to these flavors," Jessica Fetterman, PhD, of Boston University School of Medicine, and colleagues wrote in the American Heart Association journal Arteriosclerosis, Thrombosis and Vascular Biology. There are currently more than 7,000 different flavors of e-cigarettes on the market, with e-liquids in menthol, sweet, and fruity flavors among the most popular. Although many of the flavorings used to produce the flavors have been determined to be safe in food products, the long-term safety for inhalation into the lungs is not known. "When we eat something, the stomach has a lot of mechanisms to detoxify, but the lungs and blood vessels are largely unprotected," Fetterman told MedPage Today. "People aren't meant to inhale a lot of stuff into their lungs other than air." In addition to examining vanillin, cinnamaldehyde, eugenol, and acetylpyridine, the researchers also investigated the impact of the flavorings dacetyl (butter), dimethylpyrazine (strawberry), isoamyl acetate (banana), and eucalyptol (spicy cooling) on endothelial cell function. Freshly isolated endothelial cells from participants who use non-menthol- or menthol-flavored tobacco cigarettes showed impaired A23187-stimulated nitric oxide production compared with endothelial cells from nonsmoking participants. Treatment of endothelial cells isolated from nonsmoking participants with either menthol (0.01 mmol/L) or eugenol (0.01 mmol/L) decreased A23187-stimulated nitric oxide production. To further evaluate the effects of flavoring compounds on endothelial cell phenotype, the researchers incubated commercially available human aortic endothelial cells with vanillin, menthol, cinnamaldehyde, eugenol, dimethylpyrazine, diacetyl, isoamyl acetate, eucalyptol, and acetylpyrazine (0.1–100 mmol/L) for 90 minutes. The team then measured cell death, reactive oxygen species production, expression of IL-6, and nitric oxide production. "Cell death and reactive oxygen species production were induced only at high concentrations unlikely to be achieved in vivo. Lower concentrations of selected flavors (vanillin, menthol, cinnamaldehyde, eugenol, and acetylpyridine) induced both inflammation and impaired A23187-stimulated nitric oxide production consistent with endothelial dysfunction." Tobacco flavoring additives were found to impair stimulated nitric oxide production and inflammation, "suggestive of endothelial dysfunction across a range of concentrations likely to be achieved in vivo." Fetterman said that in vivo studies are needed to better understand the short-term and long-term cardiovascular impact of exposure to inhaled tobacco product flavorings. Study limitations, the researchers noted, included that the flavoring compounds were suspended in media without heating or the addition of other typical electronic liquid constituents, such as the solvents propylene glycol and glycerol. "Heating or combustion of the flavoring compounds likely alters the compounds, making them more or less toxic." Still, the study findings overall "provide quantitative support for the regulatory prohibition or the establishment of limitations on allowable levels of these flavorings in electronic liquids and other tobacco products," the authors wrote. The U.S. Food and Drug Administration is currently considering a ban on flavors in e-cigarettes and other tobacco products. In March, FDA officials formally asked for public input on banning or restricting menthol and other flavorings in some or all tobacco products. "Our work and prior research have provided evidence that flavorings induce toxicity in the lung and cardiovascular systems," Fetterman said. "Flavorings are also a driver of youth tobacco use and sustained tobacco use among smokers." Source
