Why Is Vaping Going Up in Flames?

Since their introduction to the United States market in 2007, electronic cigarettes (e-cigarettes) have caused significant controversy among clinicians, the tobacco control community, researchers, smokers and e-cigarette users, and policy makers (1–3). While smokers and e-cigarette users fight for access to these aerosol delivery devices they perceive as safe and healthy, clinicians and researchers urge caution as more and more data demonstrating adverse health effects accumulate. The recent e-cigarette/vaping product use–associated lung injury (EVALI) epidemic highlights the need to better regulate e-cigarette production and sales in the United States. Here we discuss the emergence of vaping devices; the history of e-cigarette regulation (or lack thereof); what is known and unknown about the health effects, including EVALI; and finally what policy changes are desperately needed.

E-cigarettes are designed to deliver inhaled nicotine via a process that mimics smoking. E-cigarette users inhale an aerosol commonly referred to as e-cigarette “vapor,” produced by heating a mix of chemicals, called “e-liquid,” in a tank, cartridge, or pod. Each device is slightly different, but in general e-liquid is drawn across a heating element to facilitate the reaction between humectants and water vapor in the air to produce the aerosol. The majority of e-liquids contain a pharmacologically active agent, either nicotine or cannabinoids such as tetrahydrocannabinol (THC), dissolved in a solution composed of propylene glycol, glycerin, and flavoring agents. Many flavoring agents are generally recognized as safe by the U.S. Food and Drug Administration (FDA) and are widely used in the food industry (4); however, this designation is specifically for consumption via the gastrointestinal tract, not via the pulmonary system by inhalation. Furthermore, many of these flavoring chemicals found in e-liquid are known to cause damage to human cells (5, 6), and at least one of them, diacetyl (a chemical that produces a buttery flavor), is known to cause popcorn workers lung (bronchiolitis obliterans) (7, 8).

The relative simplicity of the device design and readily available ingredients for e-liquids and e-cigarette components (i.e., alloy metals for coil production, lithium batteries, tank reservoirs, and pods) makes it easy for users to easily modify the e-liquid or the device itself. YouTube is now littered with how-to videos for adding active chemicals and flavors to e-liquids. Such readily available materials encourage users to feel comfortable with making these modifications. There is a burgeoning diversity of products available to the individual user, a factor that creates a major challenge for those studying the effects of e-cigarettes on lung health.

E-cigarettes have been marketed illegally by some manufacturers as useful for smoking cessation. They have been promoted for harm reduction, under the premise that smokers who switch to e-cigarettes would be exposed to a lower-risk aerosol than tobacco smoke (3, 9) and hence be at reduced risk for diseases caused by cigarette smoking. These claims are not supported by evidence, as research evaluating the health effects of chronic e-cigarette inhalation has just begun, and so far the best evidence indicates that chronic inhalation of e-cigarette vapor will cause cardiovascular, renal, and lung disease (10–13).

E-cigarette companies have been using the big tobacco playbook of both old and new strategies proven to increase the numbers of consumers of their products. Older tricks now used by e-cigarette companies include: 1) altering the chemistry of e-liquids to optimize nicotine absorption and thus increase nicotine levels reaching the dopamine reward pathways in the brain, and 2) targeting specific populations through the use of flavors like fruit and candy, to attract children (14, 15), and menthol, which is preferred by women and African American smokers (16). Newer strategies include the use of social media targeting younger consumers and the production of sleek e-cigarette devices that mimic commonly used electronics, such as USB memory sticks or devices resembling lipstick and even inhalers, making them easy to conceal. These clever strategies have paid off handsomely for the e-cigarette industry, with vaping of nicotine increasing in adolescents more than any other tracked substance in the history of Monitoring the Future, an ongoing survey (17). Unfortunately, there are now strong data demonstrating that teens who have ever vaped an e-cigarette have much higher rates of initiation of cigarette smoking (18). The prevalence of vaping nicotine among youth and young adults during the previous 30 days doubled between 2017 and 2019 in 10th, 11th, and 12th graders (17, 19, 20). Flavored products are a major factor in the surge in youth vaping, and flavored e-cigarette use has been linked to increased smoking initiation (21). Youth are highly susceptible to nicotine addiction, and the still-developing brain of the adolescent is adversely affected by nicotine and more vulnerable to the effects of addictive substances (1, 22–24). It is likely that it only takes a few vaping sessions for a child or teenager to develop nicotine addiction, because e-cigarettes deliver equivalent or even higher doses of nicotine than conventional cigarettes, and several exposures to that level of nicotine may be sufficient to cause addiction (1, 25, 26).

The scientific community has struggled to keep pace with the ever-changing landscape of e-cigarette devices and e-liquids, with initial studies using devices that had lower capacity to deliver nicotine and some involving exposure of cells and animals to the e-liquid itself in a liquid form. Recently, researchers have developed more sophisticated and physiologically relevant systems to replicate human vaping in animal models (27) and are using multiple combinations of e-liquid chemicals to drill down on toxicities and potential health effects of e-cigarettes. Many of these studies demonstrate that exposure to e-cigarette vapor will lead to significant cellular toxicity, cellular dysfunction, and alterations in cellular metabolism, repair mechanisms, and inflammation by altering both protein function and gene expression pathways (28–30). Furthermore, the toxic effects of e-cigarettes will not be limited to the respiratory system. Systemic effects have been seen, and although they may be similar to the effects of conventional cigarettes, some toxicity may be unique to e-cigarettes (10, 31–33).

In August of 2019, the U.S. Centers for Disease Control and Prevention (CDC) released an advisory on e-cigarettes because of 193 potential cases of EVALI (34). As of December 2019, there have been 2,561 cases of EVALI that required hospitalization and 55 deaths (35). This EVALI epidemic appears to have hit peak levels in September 2019. Vitamin E acetate has been identified in many of the e-liquids used by subjects affected by EVALI (36, 37) and has also been identified in 48 of 51 bronchoalveolar lavage samples (38), such that it is considered a likely causal agent. However, other substances found in e-cigarette vapor have also been implicated (38). Although this outbreak has gained significant recognition by the medical community and has been made renowned by the media, for years before EVALI was recognized as an entity, e-cigarette vaping had already been connected with several pulmonary diseases, including acute respiratory distress syndrome, hypersensitivity pneumonitis (39), organizing pneumonia (40), lipoid pneumonia (41), eosinophilic pneumonia (42, 43), asthma (44–47), and other respiratory illnesses (48–50). There have also been multiple reports of trauma, burns, and deaths from e-cigarette device explosions; seizures; and nicotine overdoses (both accidental and intentional) from e-liquid ingestion (51–53).

The CDC case series describing EVALI found that the majority of cases were in young men, and 30% had asthma (54). A high proportion reported vaping THC, many in combination with nicotine, and some cases were reported in subjects in whom THC exposure was not demonstrated (37). Patients suffering from EVALI had evidence of systemic inflammation, with elevated white cell counts and/or increased erythrocyte sedimentation rates. Unfortunately, beyond the definitional criteria of a history of e-cigarette exposure, diffuse infiltrates on imaging, and no clear evidence of infection, specific markers of EVALI have yet to be identified with biomarkers, findings on bronchoalveolar lavage (BAL), or in pathology specimens (55), and the measurement of vitamin E acetate in BAL or other chemicals requires sophisticated laboratory equipment not readily available in many clinical setting. Although the number of cases appears to be decreasing, many unanswered questions remain about the nature of EVALI. For example, besides vitamin E acetate, what other chemicals present in the e-liquid could quickly lead to acute lung injury? Is there a dose-exposure effect, or is it mainly an idiosyncratic reaction occurring only in susceptible individuals? Is the decline in the cases reported during the last few months the effect of public awareness and reduction in the use of e-cigarettes by the public or by changes made by the manufactures of e-liquid in the United States?

In response to the increasing number of EVALI cases, many cities and some states used their authority to ban sales of e-devices and e-liquids. For example, San Francisco banned the sales of JUUL (56), Michigan and New York State banned sales of flavored e-cigarettes (57, 58), Philadelphia banned minors from entering stores that sell flavored e-cigarettes, and Massachusetts temporarily banned the sale of all e-cigarettes (59). These initiatives will likely face legal challenges from manufacturers, retailers, and other parties with significant financial interests, reflecting the economic power of this multi-billion-dollar industry.

Many of us are asking an obvious question: why were these drug delivery devices not regulated before now? In fact, the FDA attempted to block importation of e-cigarettes as drug delivery devices in 2009, just 2 years after they first entered the country. However, a decision by the District Court of the District of Columbia allowed their importation, because the judge ruled that e-cigarettes can be regulated solely as tobacco products because the intended use of an electronic cigarette is to encourage nicotine use (and thus addiction), rather than prevent or mitigate it (60). At the same time, then-president Obama signed into law the 2009 Tobacco Control Act, which gave the FDA regulatory authority over tobacco products, but it was not until 2016 that the FDA determined that e-cigarettes fell under its authority and produced a set of regulations for these products known as the deeming rule. The deeming rule initially 1) did not allow products to be sold to minors, 2) required ID for purchase, 3) did not allow sales in vending machines (except adult-only facilities), and 4) did not allow the distribution of free samples. Flavors were not banned, and the regulation was rolled out slowly, which led to the rise of popular pod devices like JUUL and Suorin.

These pod devices were developed to optimize the delivery and absorption of the addictive substance through the use of extremely high concentration of nicotine salts, such that one pod contains 40 mg of nicotine (at 59 mg/ml), which is greater than the nicotine inhaled or absorbed when smoking an entire pack of cigarettes (22–36 mg) because of side-stream smoke and combustion of nicotine. Such high levels of nicotine are notable, because the FDA has actively sought to limit the amount of nicotine within conventional cigarettes to decrease their addictive potential. Addiction specialists believe that it only takes one to three vaping sessions for adolescents and young adults to become addicted to nicotine, as their ongoing brain development makes them more susceptible. Even though the United Kingdom has been largely pro–e-cigarette for harm reduction, regulations have limited the amount of nicotine allowed within e-liquids (JUULs are sold with <20 mg of nicotine per pod in the United Kingdom). By allowing these high levels of nicotine within e-cigarettes, the United States has facilitated the explosion of the nicotine addiction/vaping epidemic among adolescents and young adults, many of them whom are unaware of the presence of nicotine in e-cigarettes and are unaware of the high addiction potential.

Since the FDA regulations came into effect, there have been more than 350 warning letters and 1,500 fines to online distributors and e-cigarette retailers, respectively, due to illegal sales to minors (61). However, these actions likely greatly underrepresent the magnitude of sales to minors, because they can easily purchase these products online, which represents 30% of the market share (62, 63). The still-to-be implemented provisions of the deeming rule address various critical issues related to e-cigarettes, including standardization of e-liquids and e-cigarette device production, the use of flavoring agents, and the marketing and sales of these products via the internet. However, the time frame to enact the latter regulations has been a moving target, and it is now the subject of litigation. Professional societies, such as the American Thoracic Society, have led litigation efforts to make the FDA exert its authority in this arena.

Although banning e-devices and/or all flavored e-liquids may be the fastest way to protect public health—by attempting both to shut down the EVALI epidemic and to stop further addiction to nicotine and THC by children, teenagers, and young adults—implementing a ban may have some unintended consequences. For example, nicotine-addicted e-cigarette users may turn to conventional cigarettes with well-known consequences (64, 65). Supporters of e-cigarettes as harm-reduction devices will argue that by banning flavors or by removing e-cigarettes completely from the market, current smokers will be less likely to quit; however, the evidence supporting e-cigarettes for smoking cessation is still shaky at best. The proposition that flavors in e-cigarettes increase smoking cessation comes mainly from user surveys funded by the industry (66), and it has been argued that e-cigarettes may decrease a user’s chances of quitting smoking (67). An e-cigarette ban will come with the costs of enforcement and contending with litigation by e-cigarette companies. Finally, banning e-cigarettes and/or flavors could increase the purchase and use of e-devices and e-liquids through alternatives, such as from companies in other countries or an emerging black market in the United States. This could lead to exposure of users to lower-quality materials and products with higher levels of contaminants. However, balancing the risks of future e-cigarette–related diseases and deaths against these potential negative consequences eases one’s perspective on e-cigarettes.

While we as clinicians continue to work on how to properly assess and manage patients with EVALI and the rising wave of nicotine-addicted young vapers, we as providers in the field of pulmonary, critical care, and sleep medicine must support the regulation of e-cigarette and vaping products. Although an absolute ban of all tobacco products, including e-cigarettes, would be the most powerful action to protect public health, it will never happen. Thus, we support a global ban of all non-tobacco flavors, including menthol as well as fruity and minty flavors, to reduce the appeal of these devices to children, teenagers, and even adults. Professional societies, such as the American Medical Association and California Thoracic Society, have formally endorsed a ban of all e-cigarette flavorings, and many cities and states have introduced legislation to ban flavored e-cigarettes. A second action that we support is limiting the nicotine concentration of e-liquids to <10 mg/ml (<1%) to decrease their addiction potential. Overall, further research on the health effects of vaping nicotine, THC, and all of the added chemicals and contaminants is desperately needed.