Cardiovascular Research

Flavoring Agents in E-cigarette Liquids: A Comprehensive Analysis of Multiple Health Risks.

Authors: Jaspreet Sachdeva|||Anisha Karunananthan|||Jianru Shi|||Wangde Dai|||Michael T Kleinman|||David Herman|||Robert A Kloner

Affiliations: + Expand

Abstract

The availability of a wide range of flavored e-cigarettes is one of the primary reasons for vaping initiation and persistent use among adolescents and young people. This plethora of flavors available on the market are crafted using different flavoring agents such as cinnamaldehyde, vanillin, benzaldehyde, ethyl maltol, menthol, and dimethylpyrazine. Recent studies have brought to light the potential risks associated with e-cigarette flavoring agents and their effects on various organ systems, both with and without nicotine. Research has demonstrated that flavoring agents can induce inflammation, endothelial dysfunction, epithelial barrier disruption, oxidative stress, DNA damage, electrophysiological alterations, immunomodulatory effects, and behavioral changes, even independently of nicotine. Notably, these negative outcomes adversely affect cardiovascular system by reducing cell viability, decreasing endothelial nitric oxide synthase, nitric oxide bioavailability, soluble guanylyl cyclase activity and cyclic guanosine monophosphate accumulation, impairing endothelial proliferation and tube formation, and altering vasoreactivity resulting in vascular dysfunction. In the heart, these agents decrease parasympathetic activity, induce depolarization of resting membrane potential, loss of rhythmicity, increase isovolumic relaxation time, and change in ventricular repolarization and ventricular tachyarrhythmias. It is found that the specific response elicited by flavoring agents in different organ systems varies depending on the flavor used, the concentration of the flavoring agent, and the duration of exposure. However, the literature on the effects of flavoring agents is currently limited, emphasizing the need for more preclinical and randomized clinical trials to gain a deeper understanding and provide further evidence of the harmful effects of flavored e-cigarette use. In summary, recent research suggests that flavoring agents themselves can have detrimental effects on the body. To fully comprehend these effects, additional preclinical and clinical studies are needed to explore the risks associated with flavored e-cigarette usage.

---

Reference List

Atlanta, GA: Centers for Disease Control and Prevention; 2016. E-Cigarette Use Among Youth and Young Adults: A Report of the Surgeon General.|||Sales of nicotine-containing electronic cigarette products: United States, 2015. Marynak KL, Gammon DG, Rogers T, Coats EM, Singh T, King BA. Am J Public Health. 2017;107:702–705.|||Patterns of nicotine concentrations in electronic cigarettes sold in the United States, 2013-2018. Romberg AR, Miller Lo EJ, Cuccia AF, et al. Drug Alcohol Depend. 2019;203:1–7.|||Effect of exposure to e-cigarettes with salt vs free-base nicotine on the appeal and sensory experience of vaping: a randomized clinical trial. Leventhal AM, Madden DR, Peraza N, et al. JAMA Netw Open. 2021;4|||Notes from the field: E-cigarette use among middle and high school students - United States, 2022. Cooper M, Park-Lee E, Ren C, Cornelius M, Jamal A, Cullen KA. MMWR Morb Mortal Wkly Rep. 2022;71:1283–1285.|||E-cigarette unit sales, by product and flavor type - United States, 2014-2020. Ali FR, Diaz MC, Vallone D, et al. MMWR Morb Mortal Wkly Rep. 2020;69:1313–1318.|||The role of flavors in vaping initiation and satisfaction among U.S. adults. Landry RL, Groom AL, Vu TH, et al. Addict Behav. 2019;99|||Age differences in electronic nicotine delivery systems (ENDS) usage motivations and behaviors, perceived health benefit, and intention to quit. Vu TH, Hart JL, Groom A, et al. Addict Behav. 2019;98|||Adolescents’ interest in trying flavoured e-cigarettes. Pepper JK, Ribisl KM, Brewer NT. Tob Control. 2016;25:0–6.|||Disposable E-cigarette use prevalence, correlates, and associations with previous tobacco product use in young adults. Leventhal AM, Dai H, Barrington-Trimis JL, Tackett AP, Pedersen ER, Tran DD. Nicotine Tob Res. 2022;24:372–379.|||Electronic nicotine delivery systems (ENDS) flavours and devices used by adults before and after the 2020 US FDA ENDS enforcement priority: findings from the 2018 and 2020 US ITC Smoking and Vaping Surveys. Gravely S, Meng G, Hammond D, et al. Tob Control. 2022;31:0–75.|||Assessing toxicant emissions from e-liquids with DIY additives used in response to a potential flavour ban in e-cigarettes. El-Hellani A, Soule EK, Daoud M, et al. Tob Control. 2022;31:0–8.|||Ethyl maltol, vanillin, corylone and other conventional confectionery-related flavour chemicals dominate in some e-cigarette liquids labelled 'tobacco' flavoured. Omaiye EE, Luo W, Mcwhirter KJ, Pankow JF, Talbot P. Tob Control. 2022;31:0–44.|||E-cigarette flavored pods induce inflammation, epithelial barrier dysfunction, and DNA damage in lung epithelial cells and monocytes. Muthumalage T, Lamb T, Friedman MR, Rahman I. Sci Rep. 2019;9|||Flavourings significantly affect inhalation toxicity of aerosol generated from electronic nicotine delivery systems (ENDS) Leigh NJ, Lawton RI, Hershberger PA, Goniewicz ML. Tob Control. 2016;25:0–7.|||In vitro consequences of electronic-cigarette flavoring exposure on the immature lung. Berkelhamer SK, Helman JM, Gugino SF, Leigh NJ, Lakshminrusimha S, Goniewicz ML. Int J Environ Res Public Health. 2019;16|||Assessing the hazard of E-cigarette flavor mixtures using zebrafish. Holden LL, Truong L, Simonich MT, Tanguay RL. Food Chem Toxicol. 2020;136|||Flavorings in tobacco products induce endothelial cell dysfunction. Fetterman JL, Weisbrod RM, Feng B, et al. Arterioscler Thromb Vasc Biol. 2018;38:1607–1615.|||Cherry-flavoured electronic cigarettes expose users to the inhalation irritant, benzaldehyde. Kosmider L, Sobczak A, Prokopowicz A, et al. Thorax. 2016;71:376–377.|||In vitro and in vivo cardiac toxicity of flavored electronic nicotine delivery systems. Abouassali O, Chang M, Chidipi B, et al. Am J Physiol Heart Circ Physiol. 2021;320:0–43.|||Airway epithelial cell exposure to distinct e-cigarette liquid flavorings reveals toxicity thresholds and activation of CFTR by the chocolate flavoring 2,5-dimethypyrazine. Sherwood CL, Boitano S. Respir Res. 2016;17|||Lung toxicity of condensed aerosol from E-CIG liquids: Influence of the flavor and the in vitro model used. Bengalli R, Ferri E, Labra M, Mantecca P. Int J Environ Res Public Health. 2017;14|||Why flavored vape products may be attractive: green apple tobacco flavor elicits reward-related behavior, upregulates nAChRs on VTA dopamine neurons, and alters midbrain dopamine and GABA neuron function. Avelar AJ, Akers AT, Baumgard ZJ, Cooper SY, Casinelli GP, Henderson BJ. Neuropharmacology. 2019;158|||Green apple e-cigarette flavorant farnesene triggers reward-related behavior by promoting high-sensitivity nAChRs in the ventral tegmental area. Cooper SY, Akers AT, Henderson BJ. eNeuro. 2020;7|||Flavors enhance nicotine vapor self-administration in male mice. Cooper SY, Akers AT, Henderson BJ. Nicotine Tob Res. 2021;23:566–572.|||Toxicology of flavoring- and cannabis-containing e-liquids used in electronic delivery systems. Stefaniak AB, Lebouf RF, Ranpara AC, Leonard SS. Pharmacol Ther. 2021;224|||Formation of flavorant-propylene glycol adducts with novel toxicological properties in chemically unstable E-cigarette liquids. Erythropel HC, Jabba SV, DeWinter TM, Mendizabal M, Anastas PT, Jordt SE, Zimmerman JB. Nicotine Tob Res. 2019;21:1248–1258.|||Chemical adducts of reactive flavor aldehydes formed in E-cigarette liquids are cytotoxic and inhibit mitochondrial function in respiratory epithelial cells. Jabba SV, Diaz AN, Erythropel HC, Zimmerman JB, Jordt SE. Nicotine Tob Res. 2020;22:0–34.|||Modeling cardiovascular risks of e-cigarettes with human-induced pluripotent stem cell-derived endothelial cells. Lee WH, Ong SG, Zhou Y, et al. J Am Coll Cardiol. 2019;73:2722–2737.|||Effects of flavoring compounds used in electronic cigarette refill liquids on endothelial and vascular function. Wölkart G, Kollau A, Stessel H, et al. PLoS One. 2019;14|||Flavored and nicotine-containing E-cigarettes induce impaired angiogenesis and diabetic wound healing via increased endothelial oxidative stress and reduced NO bioavailability. Liu Z, Zhang Y, Youn JY, Zhang Y, Makino A, Yuan JX, Cai H. Antioxidants (Basel) 2022;11|||Comparative effects of parent and heated cinnamaldehyde on the function of human iPSC-derived cardiac myocytes. Nystoriak MA, Kilfoil PJ, Lorkiewicz PK, et al. Toxicol In Vitro. 2019;61|||A 6-month systems toxicology inhalation study in ApoE-/- mice demonstrates reduced cardiovascular effects of E-vapor aerosols compared with cigarette smoke. Szostak J, Wong ET, Titz B, et al. Am J Physiol Heart Circ Physiol. 2020;318:0–31.|||Effects of mango and mint pod-based e-cigarette aerosol inhalation on inflammatory states of the brain, lung, heart, and colon in mice. Moshensky A, Brand CS, Alhaddad H, et al. Elife. 2022;11|||Vapors produced by electronic cigarettes and e-juices with flavorings induce toxicity, oxidative stress, and inflammatory response in lung epithelial cells and in mouse lung. Lerner CA, Sundar IK, Yao H, et al. PLoS One. 2015;10|||Comparison between in vitro toxicities of tobacco- and menthol-flavored electronic cigarette liquids on human middle ear epithelial cells. Go YY, Mun JY, Chae SW, Chang J, Song JJ. Sci Rep. 2020;10|||Cardiovascular function during early development is suppressed by cinnamon flavored, nicotine-free, electronic cigarette vapor. Piechowski JM, Bagatto B. Birth Defects Res. 2021;113:1215–1223.|||In utero exposures to electronic-cigarette aerosols impair the Wnt signaling during mouse lung development. Noël A, Hansen S, Zaman A, et al. Am J Physiol Lung Cell Mol Physiol. 2020;318:0–22.|||Flavored e-cigarette liquids and cinnamaldehyde impair respiratory innate immune cell function. Clapp PW, Pawlak EA, Lackey JT, Keating JE, Reeber SL, Glish GL, Jaspers I. Am J Physiol Lung Cell Mol Physiol. 2017;313:0–92.|||Common E-cigarette flavoring chemicals impair neutrophil phagocytosis and oxidative burst. Hickman E, Herrera CA, Jaspers I. Chem Res Toxicol. 2019;32:982–985.|||Electronic-cigarette vehicles and flavoring affect lung function and immune responses in a murine model. Szafran BN, Pinkston R, Perveen Z, et al. Int J Mol Sci. 2020;21|||Flavor-specific enhancement of electronic cigarette liquid consumption and preference in mice. Wong AL, McElroy SM, Robinson JM, et al. Drug Alcohol Depend. 2020;211|||Menthol enhances nicotine reward-related behavior by potentiating nicotine-induced changes in nAChR function, nAChR upregulation, and DA neuron excitability. Henderson BJ, Wall TR, Henley BM, Kim CH, McKinney S, Lester HA. Neuropsychopharmacology. 2017;42:2285–2291.|||Impacts of nicotine and flavoring on the sensory perception of e-cigarette aerosol. Pullicin AJ, Kim H, Brinkman MC, Buehler SS, Clark PI, Lim J. Nicotine Tob Res. 2020;22:806–813.|||Impact of e-liquid flavors on e-cigarette vaping behavior. St. Helen G, Shahid M, Chu S, Benowitz NL. Drug Alcohol Depend. 2018;189:42–48.