Recent efforts by the Centers for Disease Control and Prevention (CDC), the US Food and Drug Administration (FDA), and state authorities have led to the determination that vitamin E acetate (VEA) is strongly associated with e-cigarette or vaping product use-associated lung injury (EVALI) (1). VEA has been found in nearly all patient lung fluid samples analyzed and not observed in lung fluid from healthy cohorts. Despite strong evidence linking VEA to EVALI, its putative role as a causative agent has yet to be determined. To address the key issue of whether VEA is a just marker or a significant mediator of EVALI, Wu and O’Shea (2) report in PNAS that VEA reacts when aerosolized with an e-cigarette to produce the highly toxic gas ketene. Confirmation that VEA-derived ketene is a causative agent of EVALI must await rigorous clinical investigation. However, Wu and O’Shea (2) have in the meantime uncovered a compelling lead

Strongin, Robert

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Portland State University PDXScholar Chemistry Faculty Publications and Presentations Chemistry 3-2020 Toxic Ketene Gas Forms on Vaping Vitamin E Acetate Prompting interest in its ossible Role in the EVALI outbreak Robert Strongin Portland State University, strongin@pdx.edu Follow this and additional works at: https://pdxscholar.library.pdx.edu/chem_fac  Part of the Chemistry Commons Let us know how access to this document benefits you. Citation Details Strongin, R. M. (2020). Toxic ketene gas forms on vaping vitamin E acetate prompting interest in its possible role in the EVALI outbreak. Proceedings of the National Academy of Sciences, 117(14), 7553-7554. This Article is brought to you for free and open access. It has been accepted for inclusion in Chemistry Faculty Publications and Presentations by an authorized administrator of PDXScholar. For more information, please contact pdxscholar@pdx.edu. COMMENTARYToxic ketene gas forms on vaping vitamin E acetateprompting interest in its possible role in theEVALI outbreakRobert M. Strongina,1Recent efforts by the Centers for Disease Control andPrevention (CDC), the US Food and Drug Administra-tion (FDA), and state authorities have led to the de-termination that vitamin E acetate (VEA) is stronglyassociated with e-cigarette or vaping product use-associated lung injury (EVALI) (1). VEA has been foundin nearly all patient lung fluid samples analyzed andnot observed in lung fluid from healthy cohorts. De-spite strong evidence linking VEA to EVALI, its putativerole as a causative agent has yet to be determined. Toaddress the key issue of whether VEA is a just marker ora significant mediator of EVALI, Wu and O’Shea (2) re-port in PNAS that VEA reacts when aerosolized with ane-cigarette to produce the highly toxic gas ketene.Confirmation that VEA-derived ketene is a causativeagent of EVALI must await rigorous clinical investiga-tion. However, Wu and O’Shea (2) have in the mean-time uncovered a compelling lead.One of the most concerning aspects of EVALI is itsaggressive onset. In contrast to the devastating effectsof traditional cigarettes that take decades to manifest,EVALI has afflicted young patients who developedlife-threatening symptoms literally within hours afterexperiencing initial nausea and respiratory discomfort(3). This seems consistent with ketene toxicity, whichhas been reported to cause severe, acute lung damagein animal models at the alveolar level within 24 h afterexposure. The Acute Exposure Guideline Level (lethal)10-min exposure value for ketene is 0.24 ppm (4).Importantly, the finding reported in PNAS that ketenecan be produced from VEA using a commercial vapingdevice (2) highlights the need to investigate the chemicalreactions that take place during vaping to enhance un-derstanding of toxicological pathways. Some vaping pro-ponents have been dismissive of the relevance ofnonclinical chemical investigations of e-cigarette aerosolchemical toxins, positing that vapers can effectively self-regulate any elevated toxin intake simply by sensorialperception (5). Sadly, the EVALI outbreak has shownself-regulation by vapers to be unreliable at best anddeadly at worst. Moreover, without a chemistry-focusedstudy, such as reported by Wu and O’Shea (2), the po-tential relevance of ketene to EVALI would have goneunnoticed. This is largely because ketene’s notorious in-stability renders its direct determination highly impracti-cal in processed patient samples. Challenging indirectdetection strategies may thus be required to link keteneto EVALI patients, such as the determination of biologicalfootprints, including posttranslationally modified proteins(4) and characteristic reaction products.The rationale for the formation of ketene from VEAhas its roots in 1938 reports describing the pyrolysisof organic esters (6, 7). VEA possesses a phenyl ace-tate functional group known to convert smoothly toketene and phenol (Fig. 1) (6). However, the thermalconversion of VEA to ketene has a relatively highFig. 1. The pyrolysis reaction of phenyl acetate toproduce ketene reported in 1938 and the analogoustransformation of vitamin E acetate to ketene recentlyshown to occur on heating and aerosolization in acommercial vaping device.aDepartment of Chemistry, Portland State University, Portland, OR 97207Author contributions: R.M.S. wrote the paper.The author declares no competing interest.Published under the PNAS license.See companion article, “Potential for release of pulmonary toxic ketene from vaping pyrolysis of vitamin E acetate,” 10.1073/pnas.1920925117.1Email: strongin@pdx.edu.First published March 31, 2020.www.pnas.org/cgi/doi/10.1073/pnas.2003384117 PNAS | April 7, 2020 | vol. 117 | no. 14 | 7553–7554COMMENTARYDownloaded at Portland State University Library on April 29, 2020 activation energy (2), prompting the question as to whether sig-nificant levels of ketene can form under vaping temperatures andconditions that are realistic for users (8). Narimani and de Silva (8),for example, recently calculated that the formation of ketene fromVEA is feasible only at temperatures above 500 °C or “dry puff”conditions. Under such conditions, they determined that ketenelung concentrations would attain severe (30-ppm) levels (8).Dry puff is a colloquial term that is used by some vapingproponents as a panacea to reports describing dangerous toxinlevels in e-cigarette aerosols (5). The term implies the conditionwhereby e-cigarette solvent levels are so low as to prevent effectivewicking and cooling of the heating coils, resulting in overheatingand the resultant formation of elevated levels of hazardous partialcombustion products. However, it has been shown that e-cigarettescan emit hazardous levels of aerosol toxins under conditions thatare not associated with dry puff (9). For example, Narimani and deSilva (8) speculate that, as an alternative to dry puff, surface catalysiscould enable the formation of ketene under benign vaping condi-tions. Indeed, it has been conclusively demonstrated by Shihadehand coworkers (10) that e-cigarette filament wires exhibit strongcatalytic effects that modulate aerosol toxin formation at lowtemperatures.While catalysis originating from metal device componentscould lead to ketene formation at relatively low temperatures,one issue not clearly noted in the recent reports focusing onketene is that most EVALI patients vaped cannabis as opposedto tobacco products (1). VEA is used for tetrahydrocannabinol(THC) concentrate (cannabis oil) adulteration. Importantly, THCis highly viscous and will require more heat to aerosolize com-pared with tobacco e-cigarette solvents and ingredients. Forexample, the cotton wick materials used for tobacco productvaping have been known to catch fire when used for cannabisoil vaping (9). Another important consideration is that coun-terfeit THC vape cartridges were used by a large proportion ofEVALI patients (1, 11). Such devices will exhibit overall poorerwicking and heat transfer efficiency compared with authenticlicensed dispensary and medical use vaporizers. Thus, vapinghighly viscous, adulterated materials with cheap, low-quality vap-ing devices will optimize toxic aerosol emissions.In summary, the study by Wu and O’Shea (2) shows that vap-ing VEA can lead to exposure to the poisonous gas ketene. Thisis a significant finding that is already prompting further investi-gations to determine whether ketene produced from VEA playsa causative role in EVALI (1). Additionally, it demonstrates that anunderstanding of the reactions that can lead to toxic aerosolemissions is needed to augment the focus on screening chem-ical ingredients in unvaped samples. Currently, the CDC cannotrule out chemicals of concern other than VEA, including tobaccoproducts, as playing a role in the development of EVALI (1). Forinstance, Rahman and coworkers (11) have shown that numeroushazardous and potentially hazardous compounds are present inthe aerosols derived from vaping products recovered fromEVALI patients. These include solvent-derived hydrocarbons,silicon-conjugated compounds, pesticides, plasticizers, poly-caprolactones, and metals (11). Finally, the study by Wu andO’Shea (2) embodies a stark reminder that flavorings, vitamins,and other additive molecules deemed safe for ingestion shouldnever be assumed safe for vaping without proof in the form ofrigorous evidence-based data.AcknowledgmentsMy research is supported by the US NIH and FDA Award R01 ES025257. Thecontent herein is solely the responsibility of the author and does not necessarilyrepresent the views of the NIH or the FDA.1 B. C. Blount et al.; Lung Injury Response Laboratory Working Group, Vitamin E acetate in bronchoalveolar-lavage fluid associated with EVALI. N. Engl. J. Med.382, 697–705 (2020).2 D. Wu, D. F. O’Shea, Potential for release of pulmonary toxic ketene from vaping pyrolysis of vitamin E acetate. Proc. Natl. Acad. Sci. U.S.A. 117, 6349–6355(2020).3 X. F. Fuentes, et al., VpALI—vaping-related acute lung injury: A new killer around the block. Mayo Clin. Proc. 96, 2534–2545 (2019).4 Committee on Acute Exposure Guideline Levels; Committee on Toxicology; Board on Environmental Studies and Toxicology; Division on Earth and Life Studies;National Research Council, Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 16 (National Academies Press, Washington, DC, 2014).5 K. E. Farsalinos, V. Voudris, A. Spyrou, K. Poulas, E-cigarettes emit very high formaldehyde levels only in conditions that are aversive to users: A replication studyunder verified realistic use conditions. Food Chem. Toxicol. 109, 90–94 (2017).6 C. D. Hurd, F. H. Blunck, The pyrolysis of esters. J. Am. Chem. Soc. 60, 2419–2425 (1938).7 D. J. Loder, “Organic acid synthesis.” US Patent 2,135,451 (1938).8 M. Narimani, G. da Silva, Does “dry hit” vaping of vitamin E acetate contribute to EVALI? Simulating toxic ketene formation during e-cigarette use. ChemRxiv.https://doi.org/10.26434/chemrxiv.11889828.v1 (3 February 2020).9 R. M. Strongin, E-Cigarette chemistry and analytical detection. Annu. Rev. Anal. Chem. (Palo Alto, Calif.) 12, 23–39 (2019).10 N. A. Saliba et al., Surface chemistry of electronic cigarette electrical heating coils: Effects of metal type on propylene glycol thermal decomposition. J. Anal. Appl.Pyrolysis 134, 520–525 (2018).11 T. Muthumalage, M. Friedman, M. McGraw, A. Friedman, I. Rahman, Chemical constituents involved in e-cigarette, or vaping product use-associated lung injury(EVALI). https://www.biorxiv.org/content/10.1101/2020.01.14.905539v1 (15 January 2020).7554 | www.pnas.org/cgi/doi/10.1073/pnas.2003384117 StronginDownloaded at Portland State University Library on April 29, 2020 

Toxic Ketene Gas Forms on Vaping Vitamin E Acetate Prompting interest in its Possible Role in the EVALI outbreak

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Toxic Ketene Gas Forms on Vaping Vitamin E Acetate Prompting interest in its ossible Role in the EVALI outbreak

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