Ketene is one of the most toxic vaping emissions identified to date. However, its high reactivity renders it relatively challenging to identify. In addition, certain theoretical studies have shown that realistic vaping temperature settings may betoo low to produce ketene.
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Each of these issues is addressed herein. First, an isotopically labeled acetate precursor is used for the identification of ketene with enhanced rigor in vaped aerosols. Second, discrepancies between theoretical and experimental findings are explained by accounting for the effects of aerobic (experimental) versus anaerobic (simulated and theoretical) pyrolysis conditions. This finding is also relevant to explaining the relatively low-temperature production of aerosol toxicants beyond ketene. Moreover, the study presented herein shows that ketene formation during vaping is not limited to molecules possessing a phenyl acetate substructure. This means that ketene emission during vaping, including from popular flavorants such as ethyl acetate, may be more prevalent than is currently known.
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1. Introduction
Ketenes comprise a unique class of cumulene molecules with the general formula RR′C═C═O. Initially described by Wedekind as a reactive intermediate in 1901, (1) Staudinger reported the first synthesis and characterization of a ketene molecule, diphenyl ketene (R═ R′═Ph), in 1905. (2) Since that time, despite their relative instability, ketenes have served as valuable reagents and intermediates in organic synthesis. (3,4) Currently, however, the smallest homologue (R═R′═H, ketene, ethenone) of the series is receiving attention as a potentially significant public health hazard, (5) since it has been identified in aerosols generated by commercial vaping products. (6,7)
The chemical and toxicological properties of ketene mirror those of phosgene (Cl2C═O), a WW-I chemical warfare agent, as a reactive acylating agent and respiratory poison. (8) There is a lack of human toxicity data for ketene exposure. The available animal data was obtained mainly prior to 1950. Exposure to animals causes alveolar damage and a delayed onset of pulmonary toxicity leading to death by pulmonary edema. (8) Similar to phosgene, the delayed effects result from the nonenzymatic acylation of lung proteins, as opposed to direct irritation. The Acute Exposure Guideline Levels (AEGL)-3 (life-threatening levels) for ketene are 0.24 ppm for 10 min and 0.088 ppm for 8 h. (8)
Vitamin E acetate (VEA) has been linked to the 2019–2020 e-cigarette or vaping product use–associated lung injury (EVALI) epidemic, in large part due to VEA’s prevalence in patient samples. (9) In 2020, Wu and O’Shea reported the formation of ketene when heating and vaping VEA, (6) indicating an additional possible link between ketene and EVALI. There is general agreement that EVALI is caused by chemical toxicant inhalation. (10) However, to date, neither ketene, VEA, nor any other specific chemical has been conclusively proven to be the causative agent of EVALI. Moreover, although there has been a significant decline since 2020, cases continue to be observed throughout the US. (10)
Regardless of whether VEA-derived ketene is a primary cause of EVALI, any source of exposure to ketene may put one at risk for a significant lung injury. Recently, we reported that four acetylated cannabinoids [acetylated Δ8- and Δ9-THC (tetrahydrocannabinol), CBN (cannabinol), and CBD (cannabidiol); Figure 1] produce ketene emissions under real-world vaping conditions from either a vape pen or dab platform, including at levels in range of National Institute for Occupational Safety and Health (NIOSH) thresholds. (7) Interestingly, aerosolized THC products had been reported to cause acute respiratory syndromes prior to the EVALI outbreak. (11)
Figure 1
Figure 1. Cannabinoid acetates were previously shown to produce ketene emissions under vaping conditions. The study described herein focuses on CBN-acetate because it produces the relatively cleanest aerosol analytical data due to the added stability of its second aryl ring.
The strong experimental evidence of ketene emissions arising from vaping cannabinoid acetates or VEA raises two issues. First, since ketene is too reactive and short-lived to be characterized as an intact molecule under common laboratory conditions, vaping studies to date have employed the well-known method of trapping ketene with a nucleophile (i.e., benzylamine) for characterization as the corresponding N-benzylacetamide. Since amines are relatively nonselective reagents, their use for ketene trapping and determination should ideally be limited to relatively well-defined systems that do not contain molecules that can react to form the same N-benzylacetamide product as ketene. However, manufacturers are not required to disclose most vaping product ingredients, and moreover, heating and vaping produce aerosols containing complex chemical mixtures.
To address this issue, herein, we describe the use of isotopically labeled CBN-acetate to rigorously identify ketene formation during vaping. All experiments were performed by using a commercially available device set at temperature settings consistent with normal user practices. The main hypothesis addressed via isotopic labeling is illustrated in Scheme 1: (Top) A characteristic dideuterated N-benzylacetamide product (N-benzylacetamide-D2) would result if a ketene intermediate is formed from the trideuterated acetate methyl (i.e., CBN-OAc-D3). (Bottom) Conversely, if ketene is not formed as a reaction intermediate, an alternative addition–elimination or related reaction would result in trideuterated N- benzylacetamide (N-benzylacetamide-D3).
Scheme 1
Scheme 1. Top: Ketene Possesses a Methylene Carbon; Its Formation from a Trideuterated Acetate Will Therefore Result in N-Benzylacetamide-D2; Bottom: Alternatively, N-Benzylacetamide-D3 Will Form if a Different (e.g., Addition–Elimination) Mechanism Not Involving a Ketene Intermediate Is Relevanta
aThe addition–elimination transformation is a common method of amide formation. It is a potentially competing mechanism for other compounds (e.g., even the acetate precursors to ketene) besides ketene to form N-benzylamide. Control experiments (ref (7)) showed that the reaction of acetates directly with benzylamine was too slow in the impinger to have occurred on the time-scale of our experiments and subsequent analyses. In the current paper, we have obtained additional rigorous evidence to distinguish between the addition–elimination mechanism and the ketene acetylation mechanism via the use of deuterium labeling.
The second issue centers on concerns that real-world vaping power settings do not provide enough energy to produce ketene. Recent theoretical studies show that unrealistically high vaping temperatures, in excess of at least 700 °C, are required for any significant levels of ketene to form from VEA or other acetates. (5,12,13) To address this issue, some have proposed that ineffective wicking (resulting in dry, overheated vaporizer coils, colloquially termed “dry puff”) or catalysis are potential causes of ketene production at relatively low power settings. (12) Alternatively, herein, we hypothesize that ketene formation at real-world vaping temperatures can be explained if one accounts for the impact of oxygen. This hypothesis is based on prior studies reported by our group in 2017, (14) as well as in subsequent reports by us (15) and by others. (16,17)
