Dear Editor, Electronic cigarettes (ECIGs) are a class of products that generate inhalable aerosols by heating a liquid with an electrically powered metallic/ceramic coil. Since their introduction, ECIGs frequently have been compared to combustible cigarettes in terms of the two products’ purported differences or similarities in nicotine delivery, abuse liability, or toxicant emission. Results of such comparisons encouraged ECIG proponents and some public health authorities to promote ECIGs as less lethal relative to their combustible counterparts. Furthermore, the fact that ECIGs operate at lower temperatures and emit fewer smoke toxicants compared to combustible cigarettes suggested to proponents that ECIGs should be described using toxicity-neutral terms like “nicotine vaporizers”, “vaporized nicotine products”, “electronic vapor products”, “vapes”, and “vape pens”. In this communication, we argue, based on the mechanisms of formation of toxicants, that ECIGs are described more accurately as chemical reactors: devices where mass transfer, diffusion, and heat transfer along with chemical reactions may occur. The fact that ECIGs involve mass transfer, diffusion, and heat transfer is indisputable,(1) so here we focus on chemical reactions such as pyrolysis and pyrosynthesis. Regardless of being a heterogeneous product class, ECIGs are generally similar in the composition of their liquid that is composed of mainly propylene glycol (PG) or vegetable glycerol (VG), nicotine, and flavorants. Despite this relatively simple set of constituents, other toxicants have been found in ECIG aerosol, including carbonyls, reactive oxygen species (ROS), radicals, and volatile organic compounds (VOCs), with some studies also reporting the detection of trace amounts of tobacco-specific nitrosamines (TSNAs) and polycyclic aromatic hydrocarbons (PAHs). The source of these toxicants in ECIG aerosols is both the direct distillation of contaminants from ECIG liquids and chemical transformations of PG/VG and other constituents leading to the formation of new chemical compounds. Although recently challenged, PG and VG remain a major source of toxicants in ECIG aerosols, suggesting that toxicant emission is intrinsic to the product class. The most discussed chemical transformation mechanism of PG and VG is the pyrolysis type of reactions that include oxidation, dehydration, and thermal degradation. These reactions can explain the formation of smaller molecules from PG and VG (carbonyls, ROS, radicals, and some VOCs)(2) but are unable to describe the formation of molecules that have more atoms than PG and VG (some VOCs and PAHs). The formation of these larger molecules may be due to a pyrosynthesis mechanism. As reviewed below, published evidence suggests that both pyrolysis and pyrosynthesis occur within an ECIG, supporting the contention that these products are best characterized as chemical reactors. We and others have presented evidence demonstrating conclusively that pyrolysis can occur when an ECIG is activated. This evidence included a pyrolytic simulation study of carbonyl formation from PG thermal degradation in a quartz pyrolysis chamber,(3) and the detection of pyrolysis products like CO and small hydrocarbon gases including acetylene and ethylene in the gas phase of ECIG aerosols generated by heating PG and VG.(4) Also, physical determinants of the degradation reactions were identified to be dependent on the coil geometry and its impact on heat dissipation(5) and the heat flux that determines toxicant emissions from ECIG. Indeed, we are currently working to propose a certain upper bound of heat flux as a potential regulatory approach to reduce ECIG toxicant emissions. Similar studies were reported by other groups with one report giving a very detailed account of solvent chemistry in the ECIG reaction vessel.(2) The observation that pyrolysis can occur within an ECIG upon activation is consistent with the notion that these products are chemical reactors. Moreover, we showed that, like a chemical reactor, the more the feed, the greater the products, as illustrated by the high correlation between aldehyde emissions from ECIGs and the amount of liquid consumed (Figure 2 in ref (5)). These observations are vital to a comprehensive understanding of the toxicity profile of ECIG aerosols. In addition, we reported evidence of pyrosynthesis taking place upon ECIG activation. The formation of phenolic compounds in ECIG aerosols generated from liquids made of PG/VG recently was shown to be significantly associated with power, puff duration, and mass of generated aerosols.(6) Hence, the formation of phenols is attributed to thermally driven synthesis from smaller molecules or intermediates (i.e., PG, VG, and their degradation products). In contrast, phenol formation in the smoke of combustible tobacco products is attributed to the pyrolysis of larger molecules like quinic acid, chlorogenic acid, and quercetin. Other ECIG-specific examples of pyrosynthesis include the formation of chloropropanols from the degradation of the sucralose additive in ECIG. The hydrochloric acid generated from the thermal degradation of sucralose reacts with PG and VG to give chloropropanols.(7) Overall, the observation of pyrosynthesis upon ECIG activation, in addition to pyrolysis, supports characterizing these products as chemical reactors that may yield the formation of ECIG-specific toxicants or common toxicants with combustible cigarettes but via unique mechanistic routes. This critical analysis of ECIG toxicant formation calls for considering any ECIG as a chemical reactor. In this reactor, pyrolysis and pyrosynthesis mechanisms follow unique pathways that may produce unique toxicants. The understanding of the formation of ECIG toxicants is necessary for a successful determination of ECIG-specific biomarkers of exposure. More work is needed to elucidate the various mechanisms of toxicant formation in ECIG aerosols, mainly using isotopic labeling, additive-toxicant correlations, and chemical kinetic modeling. Highlighting the conditions and mechanisms of toxicant formation is of high importance for predicting the toxicity of ECIGs and thus implementing evidence-based regulations that minimize toxic emissions from these devices. This research is supported by Grant No. U54DA036105 from the National Institute on Drug Abuse of the National Institutes of Health and the Center for Tobacco Products of the U.S. Food and Drug Administration. The content is solely the responsibility of the authors and does not necessarily represent the views of the NIH or the FDA. Drs. Eissenberg and Shihadeh are paid consultants in litigation against the tobacco industry and the electronic cigarette industry. They are named on a patent for a device that measures the puffing behavior of electronic cigarette users. Also, Dr. Eissenberg is named on another patent for a smartphone app that determines electronic cigarette device and liquid characteristics. The other authors have no competing interests to declare. This article references 7 other publications.

中文翻译：

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电子烟是化学反应器：对毒性的影响


尊敬的编辑，电子烟（ECIG）是一类通过用电动金属/陶瓷线圈加热液体来产生可吸入气溶胶的产品。自推出以来，人们经常将 ECIG 与可燃卷烟进行比较，以比较这两种产品在尼古丁释放、滥用倾向或有毒物质排放方面据称的差异或相似之处。此类比较的结果鼓励 ECIG 支持者和一些公共卫生当局宣传 ECIG 相对于可燃同类产品的致命性较低。此外，与可燃香烟相比，ECIG 的工作温度较低，释放的烟雾毒物较少，这一事实向支持者建议，ECIG 应该使用毒性中性术语来描述，如“尼古丁蒸发器”、“蒸发尼古丁产品”、“电子蒸汽产品”、 “vapes”和“vape pen”。在本次交流中，我们认为，根据有毒物质的形成机制，ECIG 更准确地描述为化学反应器：可能发生传质、扩散和传热以及化学反应的装置。 ECIG 涉及传质、扩散和传热的事实是无可争议的，(1) 因此这里我们重点关注热解和热合成等化学反应。尽管是异质产品类别，ECIG 的液体成分通常相似，主要由丙二醇 (PG) 或植物甘油 (VG)、尼古丁和调味剂组成。 尽管成分相对简单，但 ECIG 气溶胶中还发现了其他有毒物质，包括羰基化合物、活性氧 (ROS)、自由基和挥发性有机化合物 (VOC)，一些研究还报告检测到痕量烟草 -特定亚硝胺 (TSNA) 和多环芳烃 (PAH)。 ECIG 气溶胶中这些有毒物质的来源既是 ECIG 液体中污染物的直接蒸馏，也是 PG/VG 和其他成分的化学转化，导致新化合物的形成。尽管最近受到挑战，PG 和 VG 仍然是 ECIG 气溶胶中有毒物质的主要来源，这表明有毒物质排放是该产品类别固有的。 PG 和 VG 讨论最多的化学转化机制是热解类型的反应，包括氧化、脱水和热降解。这些反应可以解释 PG 和 VG（羰基、ROS、自由基和一些 VOC）较小分子的形成(2)，但无法描述比 PG 和 VG 原子数更多的分子（一些 VOC 和 PAH）的形成。这些较大分子的形成可能是由于热合成机制。如下所述，已发表的证据表明热解和热合成都发生在 ECIG 内，支持了这些产品最适合作为化学反应器的论点。我们和其他人已经提供了证据，最终证明当 ECIG 激活时会发生热解。 该证据包括在石英热解室中对 PG 热降解形成羰基的热解模拟研究，(3) 以及在加热 PG 产生的 ECIG 气溶胶气相中检测热解产物，如 CO 和小烃气体（包括乙炔和乙烯） (4) 此外，降解反应的物理决定因素被确定为取决于线圈的几何形状及其对散热的影响(5) 以及决定 ECIG 有毒物质排放的热通量。事实上，我们目前正在努力提出一定的热通量上限，作为减少 ECIG 有毒物质排放的潜在监管方法。其他小组也报告了类似的研究，其中一份报告非常详细地描述了 ECIG 反应容器中的溶剂化学。(2) 观察到 ECIG 激活后会发生热解，这与这些产品是化学反应器的概念是一致的。此外，我们表明，就像化学反应器一样，进料越多，产物就越大，正如 ECIG 的醛排放量与消耗的液体量之间的高度相关性所示（参考文献 (5) 中的图 2）。这些观察结果对于全面了解 ECIG 气溶胶的毒性特征至关重要。此外，我们报告了 ECIG 激活时发生热合成的证据。最近表明，由 PG/VG 制成的液体产生的 ECIG 气溶胶中酚类化合物的形成与功率、抽吸持续时间和所产生气溶胶的质量显着相关。(6) 因此，酚类的形成归因于热驱动合成来自较小的分子或中间体（即 PG、VG 及其降解产物）。 相比之下，可燃烟草产品烟雾中苯酚的形成归因于奎尼酸、绿原酸和槲皮素等较大分子的热解。热合成的其他 ECIG 特定示例包括通过 ECIG 中三氯蔗糖添加剂的降解形成氯丙醇。三氯蔗糖热降解产生的盐酸与 PG 和 VG 反应生成氯丙醇。 (7) 总体而言，除热解外，ECIG 活化后热解反应的观察结果支持将这些产物表征为化学反应器，可能会形成ECIG 特定毒物或可燃香烟常见毒物，但通过独特的机制途径。对 ECIG 毒物形成的批判性分析要求将任何 ECIG 视为化学反应器。在该反应器中，热解和热合成机制遵循独特的途径，可能产生独特的有毒物质。了解 ECIG 毒物的形成对于成功确定 ECIG 特异性暴露生物标志物是必要的。需要开展更多工作来阐明 ECIG 气溶胶中毒物形成的各种机制，主要是使用同位素标记、添加剂-毒物相关性和化学动力学模型。强调有毒物形成的条件和机制对于预测 ECIG 的毒性非常重要，从而实施基于证据的法规，最大限度地减少这些设备的有毒排放。这项研究得到了美国国立卫生研究院国家药物滥用研究所和美国食品和药物管理局烟草产品中心的资助号 U54DA036105 的支持。 内容完全由作者负责，并不一定代表 NIH 或 FDA 的观点。博士。艾森伯格和施哈德在针对烟草业和电子烟行业的诉讼中担任付费顾问。它们以一项测量电子烟使用者吸烟行为的设备专利命名。此外，艾森伯格博士的名字还出现在另一项智能手机应用程序专利上，该应用程序可以确定电子烟装置和液体特性。其他作者没有需要声明的竞争利益。本文参考了其他 7 篇出版物。