Inhalation of smoke from burning tobacco remains the most deadly risky behavior in the United States. For years, corporations have sought alternative methods to administer nicotine to the brain without the harms of combustion while retaining the immediate rewarding aspects of cigarettes that make them so profitable, pleasurable, and addictive. The latest attempt at reduced harm products is a heterogeneous collection of battery-driven inhalers termed by the World Health Organization (WHO) as electronic nicotine delivery systems (ENDS)1 or more popularly as electronic cigarettes or e-cigarettes. These devices pose significant challenges to the public health community because their distribution and use has become widespread in the United States while simultaneously evading most regulatory structures. Ultimately, these devices force a close consideration of how the health and regulatory system evaluates claims of safety and harm reduction in a dynamic, consumer driven environment to ensure the broad protection of public health.
No standard definition of ENDS exists; different manufacturers use differing designs and incorporate a range of ingredients. Thus, a challenge to consumers, researchers, regulators, and policymakers is that specific attributes identified for any given ENDS brand may not apply to other brands. Three characteristics, however, appear common: (1) a cartridge containing a humectant carrier, such as propylene glycol, and often with nicotine in solution in different concentrations but no tobacco per se; (2) a tube into which the cartridge is inserted and through which the user inhales; and (3) a battery powered heating element across which the solution is drawn, causing the humectant to vaporize, forming a mist. Distributors also sell bottles of “juice” to refill cartridges with solutions that can contain high concentrations of nicotine and other substances.
Currently, the regulatory status of these devices remains in limbo in the United States. The Family Smoking and Tobacco Control Act of 2009 (HR 1256), provides for a new regulatory pathway for reduced harm products through the Food and Drug Administration (FDA) Center for Tobacco Products (CTP), but medicinal nicotine products remain regulated through the FDA Center for Drug Evaluation and Research (CDER). The CTP has a mandate to evaluate health claims provided by manufacturers, but inherent in the concept of harm reduction is a process of premarket evaluation and the demonstrable absence of unintended consequences on both health and behavior at individual and population levels.2 Historically, tobacco companies have marketed oral and other noncombustible tobacco products purporting to reduce harm without actually providing evidence of such. In March 2010, RJ Reynolds was found liable for falsely claiming harm reduction for the Eclipse cigarette—a predecessor of ENDS that delivered nicotine in a heated glycol solution drawn through a tobacco plug.3
Until recently, attempts to market nicotine products outside of medicinal nicotine replacement therapy (NRT) were subject to regulatory hurdles. Products were either regulated (i.e., FDA approved) cessation aids, such as the nicotine patch, or clearly tobacco industry–based and unregulated, such as Eclipse. Nonpharmaceutical products containing nicotine (such as lollipops and water) have been rapidly removed from the market with little controversy. In general, addiction liability and physiological harm are greatest with inhaled tobacco smoke, and least with medicinal NRT products.2 In cigarettes and other tobacco products, the maximum dose of nicotine is limited by concentrations available in a fixed amount of tobacco. Although a cigarette may contain a highly toxic dose of 10–15mg of nicotine, serious poisoning is rare because presystemic metabolism and spontaneous vomiting limits the systemic absorption of nicotine in swallowed tobacco.4 These upper limits may not apply to nicotine in high concentrations in ENDS or refill “juice” bottles if inhaled, swallowed, or spilled on the skin. Thus ENDS may introduce a new set of risks similar to those in nicotine-based pesticides and not normally present in leaf tobacco products.
Cigarettes remain a major source of preventable mortality; an alternative to smoking that reduces exposure to toxins from tobacco combustion may be an acceptable strategy for harm reduction, provided it is evaluated on a premarket basis and introduces no new deleterious effects on either health or unintended changes in patterns of tobacco use behavior in the broader context of public health.2,5 In adopting a harm-reduction language, manufacturers have promoted ENDS as an alternative to cigarettes rather than as a cessation aid, although ENDS are presumably used for cessation despite the absence of efficacy data. One manufacturer's lawyer stated: “we don't want people weaned off the e-cigarette, we want them smoking it as long as they smoked regular cigarettes.”6 Proponents have claimed that ENDS are logically safer than cigarettes since they avoid or reduce most of the carcinogens from tobacco, particularly its combustion.5,7 Despite claims, the novel construction of ENDS has raised new challenging concerns of other potential risks, including appeal to and addiction of children (especially when flavors like strawberry or chocolate are added), displacement of effective cessation, long-term inhalation of propylene glycol, chemical contamination, uncontrolled levels of nicotine, misleading advertising of contents, variable nicotine delivery leading to unclear absorption mechanics or even potentially lethal systemic delivery, and accidental ingestion by young children because ENDS and “juice” are generally not sold in child resistant containers, are readily obtained via the Internet, and, for some refill kits, even come with a syringe.
Based on FDA testing8 and independent tseting of 2 ENDS brands by our group (full report available on request), we know that despite claims, nicotine varies across manufacturers, devices, cartridges, and, even, puff to puff. Such variations make generalizations of any testing results difficult; nonetheless we found the nicotine in the tested ENDS cartridges was 3- to 5-fold less than claimed (Table 1). Ultimately, the nicotine in the delivered vapor in the products tested is a fraction of that in the cartridge, and plasma testing suggests that current designs produce little systemic delivery of nicotine.8–10 This may stem from any number of reasons; our testing of one device demonstrated an abrupt fall-off in delivery after the first 10 puffs, possibly from a rectifiable manufacturing defect, such as inconsistent current delivery. Triggering lag time from the pressure sensor or heating element may produce a nonlinear delivery curve per puff, causing shorter test puffs to have low nicotine delivery and deeper inhalations to have much more. The pH of the delivered solution may result in an ionized form of nicotine that is slowly absorbed through the tissue membranes, delaying uptake. At minimum, the variability in tested ENDS indicates poor quality control, so their addiction liability remains unclear.
TABLE 1 Summary of ENDS (E-Cigarette) Nicotine Testing
| Nicotine/Cartridgea (mg) | Nicotine/Puff (μcg) | |||||
| Product | Claim | FDA Report8 | GU/SIa | Claim | FDA Report, per 100-mL Puff | GU/SI, per 35-mL Puff |
| Smoking Everywhereb | 16 | 5.98 | 3.23 ±0.5 | NA | 31.5 | Not tested |
| Njoyc | 18 | 6.76 | 4.07 ±0.54 | NA | 26.8–43.2 | 1.0 for puffs 1–10< 0.3 for puffs 11–50 |
| Nicotrol Inhalerd | 10 | Not tested | Not tested | 50 | 15.2 | Not tested |
Note. ENDS = electronic nicotine delivery system; FDA = US Food and Drug Administration; GU = Georgetown University SI = Schroeder Institute.
a We tested 3 cartridges from each manufacturer under ISO (International Organization for Standards) smoking conditions; extracts were analyzed by gas chromatography by Arista Labs Inc. (Richmond, VA).
b Smoking Everywhere Inc, Sunrise, FL.
c Njoy Inc, Scottsdale, AZ.
d Pfizer Inc, New York, NY.
Based on products tested, our results and the FDA's8 confirm a manufacturer-sponsored study11 demonstrating tobacco specific impurities and nitrosamines in cartridges at much lower levels than those found in cigarette smoke. Potentially concerning, and consistent with poor quality control, was the presence of humectants other than propylene glycol—in our case, glycerin, and for the FDA8 diethylene glycol. The latter has a history of mass poisonings and deaths when inadvertently substituted for propylene glycol in consumer products.12 The additional presence of irritants, solvents, genotoxins, and animal carcinogens (e.g., butyl acetate, diethyl carbonate, benzoic acid, quinoline, dioctyl phthalate 2,6-dimethyl phenol) is of unclear significance but needs further consideration.
Although the tested ENDS delivered lower nicotine levels than advertised, without regulatory oversight there are no limits on increasing the dose or probability of accidental ingestion. Aftermarket selling of concentrated “juice” is worrisome—one supplier touts a solution containing 54mg of nicotine per mL (over 1.5 g per 30 mL bottle).13 Propylene glycol is common in some oral and topical products but has not been studied rigorously for long-term inhalational safety in humans. Poor quality control raises additional concerns about other possibly lethal ingredients. Despite these concerns, the regulatory status of ENDS in the United States remains unclear. After asserting that ENDS are drug delivery systems, the FDA was met with a lawsuit.14 The court ruling that ENDS are not drug delivery devices is under appeal, but the ruling is unclear about whether ENDS should be regulated by the FDA's traditional CEDR or the new CTP. Critically, despite the FDA action, ENDS remain widely available in the United States,14 although through regulation they have been effectively banned in many other countries such as Australia, Canada, Singapore and Brazil owing to lack of safety or efficacy data.5
The ENDS tested so far have demonstrated poor quality control; toxic contaminants, albeit at low levels; misrepresentation of the nicotine delivered; and insufficient evidence of overall public health benefit. Ongoing, rigorous safety testing is needed, including determining real-world use patterns and further laboratory testing across device constructions to determine actual systemic nicotine delivery and exposure to harmful constituents. We recognize a manufacturer's desire to market their product and advocates who say ENDS are logically safer than cigarettes. However, to allow their unregulated sale on presumption is not protecting public health. ENDS should be removed from the market and permitted back only if and when it has been demonstrated that they are safe, that their benefits outweigh their harms to overall public health, and that a comprehensive regulatory structure has been established under an appropriate FDA division. It is possible that ENDS-like devices will eventually provide safer alternatives to smoking that do not increase uptake among youths, that foster cessation, and that are less harmful or addictive than cigarettes. Until then, health and safety claims based on assumptions are unacceptable.
Acknowledgments
The study was funded in part by a grant from the National Cancer Institute (5R01CA114377; Laboratory-Based Evaluation of Tobacco Harm Reduction) and the American Legacy Foundation.
