E-Cigarettes: Unstandardized, Under-regulated, Understudied – and Unknown Health and Cancer Risks

Abstract

E-cigarettes have the ability to deliver nicotine in a manner that is similar to, and – theoretically – safer than, combusted tobacco. However, these devices are extremely heterogeneous and regulation has struggled to keep up with their rapid evolution. A compilation of early data suggest that e-cigarettes may contain numerous toxic substances, including known carcinogens. However, there are few data available on the short- and long- term health effects of e-cigarettes, including any potential effect on cancer risk. Until more is known, e-cigarettes should not be considered a safe alternative to combusted tobacco use.

Introduction

The U.S. and the world finds itself at a critical juncture in tobacco control. Although tobacco remains a leading risk factor for disease, disability and early death, its use has steeply declined in much of the world. The age-standardized global prevalence of daily smoking in 2015 was 15.3%, a nearly 30% reduction from 1990.¹ However, in the last decade, declines have slowed or stalled in some countries and U.S. population sub-groups. There remain nearly 1 billion smokers in the world¹ and an estimated 2,000 children younger than age 18 try their first cigarette each day in the U.S. alone.² Therefore, there is an urgent need to re-double efforts in tobacco prevention and cessation to protect the gains made thus far, and to eventually eliminate the use of tobacco – and its tremendous associated health and economic toll - once and for all.

Electronic cigarettes (e-cigarettes) are capable of delivering nicotine to users at levels comparable to traditional cigarettes but in the absence of combusted tobacco. Theoretically, therefore, by attracting current smokers away from combusted tobacco products with their innumerable carcinogens, e-cigarettes have the potential to significantly reduce the enormous tobacco-associated disease burden. However, they could also potentially addict a new generation of non-smokers, particularly adolescents who are uniquely susceptible to the harms of nicotine, and who may then go on to use traditional tobacco products³ – and, hence, threaten 50 years of progress in tobacco control. While it is still too early to determine if these devices will result in a net public health benefit or harm, we argue that, at the present time, they should: 1) not be considered a safe alternative to traditional tobacco products, 2) not be recommended for use as an effective smoking cessation tool, and 3) not be used by non-smokers.

E-cigarettes - Unstandardized, Under-regulated and Understudied

E-cigarettes is a single term that is often used to describe hundreds of products that are marketed to deliver inhaled nicotine in a manner that is similar to traditional cigarettes. They are hand-held, battery-powered devices, often resembling pens or USB drives, that heat e-liquids containing nicotine, flavorings (e.g., chocolate, bubble gum - added to e-cigarettes to make them more palatable) and humectants, such as propylene glycol (PG) and vegetable glycerin (glycerol), that retain moisture. While most humectants and flavors are classified by the FDA as “GRAS” (i.e., generally regarded as safe) when consumed as food additives, it is unclear what, if any, risks might be posed by their inhalation over the long-term. Complicating e-cigarettes’ potential to be subjected to rigorous and systematic study, tremendous variability in the levels of all e-liquid constituents has been documented within and between devices and brands. Consequently, exposure to these chemicals is highly dependent upon the characteristics of the particular product in use (e.g., battery power), as well as those of the user (e.g. puff topography).^{4, 5} Further, there are no current federal regulations in place to ensure quality and standardization of e-liquid ingredients, or even to ensure the accuracy of products’ labeling. In 2016, the FDA extended its authority to regulate e-cigarettes under the “deeming rule”, but implementation of many of the proposed regulations, including pre-market review of e-liquids, has been delayed. (Although e-cigarettes do not contain tobacco, they are considered a tobacco product for regulatory purposes due to their nicotine content, as nicotine is a potent addictive derivative of tobacco).

Because e-cigarettes have only been on the U.S. market since about 2006, and because of the relative absence of product standards as well as the inability of regulation to keep up with the rapid manufacture, distribution, marketing, and sale of e-cigarettes, there are still very few high-quality data regarding the long-term potential health effects of these devices and how they might compare to traditional combusted tobacco products. Nevertheless, recent reviews^{6, 7} of early data provide some insights into e-cigarette constituents, their short-term health effects, their initial impact on combusted tobacco initiation and cessation, and their potential for harm reduction.

We must keep in mind that e-cigarettes represent an attempt to more safely deliver nicotine, a highly addictive stimulant with well-described adverse cardiovascular, cognitive and reproductive health effects. While nicotine content varies widely among e-cigarette products, and exposure to nicotine depends upon both device characteristics and user behaviors, there is strong evidence that nicotine intake from e-cigarettes is comparable to, or may even commonly exceed, nicotine intake from combusted tobacco products. But, at present, we do not know if the aerosolization of nicotine versus its delivery as a constituent of tobacco smoke or other FDA-approved nicotine replacement products might affect its health consequences. Indeed, a recent study published in PNAS shows that 22.5% of mice exposed to e-cigarette smoke generated from a nicotine-filled e-liquid for 54 weeks developed lung adenocarcinoma in comparison to no mice who were exposed to e-cigarette smoke generated from an e-liquid without nicotine.⁸ However, based on data from users of long-term nicotine-replacement therapy and of smokeless tobacco, nicotine from e-cigarettes may pose minimal direct cancer risk.⁶

Aside from nicotine, the health effects of PG and glycerin must also be considered, as they are the primary constituents of e-liquids by volume. Most e-liquids contain 30–50% glycerol, with the remainder being PG. These substances have a long history of use in the food, cosmetics and pharmaceutical industries, where exposure is typically through an oral/dietary or dermal route. There is a wealth of data supporting their non-toxicity when administered via these routes, and as such, they have each been designated as GRAS by the FDA. However, the data on inhalational exposure to PG and glycerin, as occurs with e-cigarettes, are extremely limited. Similarly, many flavorings are deemed as GRAS, but again, all data are based on oral/dietary exposures. Without data from rigorous studies designed to assess inhalational exposures, it is difficult to estimate what the short- or long- term health effects might be, if any, of the humectants and flavors currently found in e-liquids.

In addition to these known components of the e-liquid, e-cigarettes have been shown to contain and emit numerous other potentially toxic substances that are either contaminants introduced through the manufacturing process or occur as a result on the vaporization process itself, as chemical reactions resulting from heating of the e-liquid may result in the formation of new compounds. Table 1 lists substances identified to date in e-cigarettes along with their current IARC classification or other potential effects on health as determined by the relevant government agency or the recent evidence compilation by the National Academies of Science, Engineering and Medicine (NASEM).⁶ Although these compiled data are early and not without limitations, it is clear that a number of toxic substances, including known carcinogens, from combusted tobacco products may also be present in e-cigarettes. However, it is unclear if the delivered concentrations of these toxins are sufficient to cause health harms, but at least in the short-term, there is substantial evidence that e-cigarette aerosols can induce acute endothelial cell dysfunction, promote formation of reactive oxygen species, increase heart rate, and possibly increase diastolic blood pressure.⁶ And although carcinogens have been detected in e-cigarettes, there is no available evidence to determine if their use is associated with intermediate cancer endpoints (e.g., pre-malignant lesions), let alone cancer itself, in humans.

Table 1:

Selected Identified Harmful and Potentially Harmful Substances in E-liquids and / or E-cigarette Aerosols

Substance	IARC Carcinogen Classification / Other Health Effects
Nicotine	Addictive; Long-term exposure implicated in adverse cardiovascular, cognitive, reproductive/developmental outcomes; plausibility that it can act as a tumor promoter (U.S Department of Health and Human Services, U.S. Surgeon General: The Health Consequences of Smoking—50 Years of Progress, 2014; and The Health Consequences of Smoking: Nicotine Addiction, 1988 )
Propylene Glycol	GRAS for dietary/dermal exposures; Unknown health effects from inhalation (FDA)
Glycerol	GRAS for dietary/dermal exposures; Unknown health effects from inhalation (FDA)
Minor Tobacco Alkaloids	Less toxic than nicotine, but unknown health effects to E-cigarette users6
Free Radicals / Reactive Oxygen Species	Cause oxidative stress, stimulates cellular proliferation and alters metabolism; Implicated in some cancers, atherosclerosis, diabetes, and respiratory and neurodegenerative diseases6
Carbonyl Compounds
Formaldehyde	Group 1
Acetaldehyde	Group 2B
Acrolein	Group 3
Tobacco-Specific Nitrosamines
NNN	Group 1
NNK	Group 1
NAB	Group 3
NAT	Group 3
Volatile Organic Compounds
Benzene	Group 1
Styrene	Group 2A
Catechol	Group 2B
Ethylbenzene	Group 2B
Pyridine	Group 2B
Toluene	Group 3
Xylenes	Group 3
Phthalates
Diethylhexyl phthalate	Group 2B
Diethyl phthalate	Unknown health effects (ATSDR)
Metals
Arsenic	Group 1
Cadmium	Group 1
Chromium (unknown valance state)	Chromium VI – Group 1 Chromium III – Group 3
Lead	Group 2B
Nickel	Nickel compounds – Group 1 Nickel, metallic and alloys –Group 2B
Residual Solvents
1,3-butadiene	Group 1
Ethylene Glycol	Acutely toxic; throat and upper respiratory tract irritation at low levels of inhalation (ATSDR)
Other
Pulegone	Group 2B

GRAS, generally regarded as safe; E-cigarette, electronic cigarette; Group 1, carcinogenic to humans; Group 2A, probably carcinogenic to humans; Group 2B, possibly carcinogenic to humans; Group 3, unclassifiable with regard to carcinogenicity in humans; ATSDR, Agency for Toxic Substances and Disease Registry. IARC, International Agency for Research on Cancer.

The need to determine the absolute risks associated with e-cigarette use is highlighted by the recent outbreak of over 1,000 cases of “severe lung illness associated with e-cigarette use” resulting in more than 20 deaths (as of October 8; https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html).^9,10 No particular e-cigarette product or constituent has been identified or conclusively linked to the cluster, although, based on preliminary data from certain states, most - but not all - patients have reported a history of using e-cigarette products that contain THC (the active ingredient in marijuana).^10,11 The CDC and affected states are investigating and have released interim guidance on the use of e-cigarettes in the meantime.⁹ Determining the source of this outbreak is critical to gain a better understanding of the absolute risks posed by e-cigarettes, which will likely have implications for their future use, particularly as a component of a harm reduction strategy.

E-Cigarette Use for Harm Reduction

A harm reduction strategy is one in which the focus of an intervention or policy is to lessen the damaging effects of a particular behavior, rather than eradicating the behavior itself.⁶ Applied to tobacco use, a harm reduction strategy aims to reduce the adverse health effects of combusted tobacco use without necessarily addressing the underlying behavior of nicotine use or addiction. Because e-cigarettes are comparable to traditional tobacco products in terms of their nicotine content and other behavioral and sensory characteristics, they offer a potentially promising approach to transition current smokers away from combusted tobacco use and most, if not all, of its associated harms. However, the evidence needed to support the use of e-cigarettes as an effective harm reduction strategy in tobacco control is still quite limited, although rapidly evolving.

Several laboratory studies suggest that the levels of toxicants in e-cigarettes, including carcinogens, are substantially lower than in combusted tobacco products. One such study comparing levels of the known carcinogens formaldehyde, acetaldehyde, NNN, and NNK in tobacco smoke to e-cigarettes showed that the levels of these carcinogens were 9–450 times lower in e-cigarette aerosols than in tobacco smoke.¹² Another study comparing e-cigarette aerosol to tobacco smoke concluded that, on a per-puff basis, the known toxicants emitted from e-cigarettes were 82% - 99% lower than in combusted tobacco smoke.¹³ In general, laboratory studies suggest that the aerosol generated by e-cigarettes is much less complex and toxic than the smoke generated by traditional tobacco products. Furthermore, short-term human studies assessing metabolites and biomarkers of toxicant exposure, as well as disease biomarkers, among smokers who switched to e-cigarettes suggest that the use of these devices results in reduced exposure to toxicants and carcinogens, as well as significant improvements in short-term respiratory (e.g., forced expiratory volume), cardiovascular (e.g., systolic and diastolic blood pressure), and oral (e.g. bleeding index) health outcomes.⁶ The clinical significance, if any, of these short-term improvements remains unknown, but is promising and warrants further investigation. Assessing any long-term health improvements attributable to substituting combusted tobacco with e-cigarettes has not been possible due to the limited amount of time that they have been widely available and in use, as well as their substantial heterogeneity and difficulty in securing relevant investigational new drug (IND) applications to conduct independent, academic assessments of marketed products.

There is also some evidence from a handful of studies to suggest that secondhand exposure to nicotine and particulate matter is lower from e-cigarettes than from combusted tobacco products. In one such study, airborne markers of secondhand exposure, including nicotine and particulate matter (PM_2.5), were measured in an exposure chamber and compared between e-cigarette aerosols and tobacco smoke generated by volunteers experienced in the use of both types of products.¹⁴ Air concentrations of nicotine generated by tobacco smoking were 10 times the nicotine air concentrations generated by e-cigarettes; and levels of PM_2.5 were seven times higher than from e-cigarettes.¹⁴

The use of e-cigarettes as an effective harm reduction tool depends not only on the relative harms of these devices in comparison to traditional tobacco products, but also on how they are used and any potential effects on patterns of combustible tobacco use, including cessation. Currently, an estimated 3.8% of U.S. adults (5.5 million) report using e-cigarettes every day or some days; although the rate is much higher among current smokers, who have the highest rate of e-cigarette use at 16.2%.¹⁵ And data from the Population Assessment of Tobacco and Health (PATH) study show that 84% of e-cigarette users are current (69.7%) or former (> 1 year; 5.7%) smokers, or recent quitters (≤1 year; 8.6%).¹⁶ These data suggest a high-rate of using e-cigarettes in conjunction with combustible tobacco (i.e., dual use). Obviously, the extent of harm reduction in a current smoker will depend upon the extent to which that smoker replaces combusted tobacco with e-cigarettes. Theoretically, harm reduction would be maximized in those who completely transition to e-cigarettes. Currently, there is insufficient evidence to determine if dual users experience reduced exposure to toxicants and improved short-term health outcomes as compared to those who completely switch. Going forward, it will be critical to determine if dual use eventually leads to complete replacement of combusted tobacco with e-cigarettes, leads to relapse of using only combusted tobacco, or if combined use simply continues indefinitely. There are presently very few data to suggest the most likely path of dual users. And the larger question of whether or not e-cigarettes can help smokers quit, particularly in comparison to the several evidence-based, widely available, FDA-approved, and recommended cessation aids, has yet to be answered. Several systematic reviews on the topic have been undertaken, and while some have found suggestive evidence for a beneficial effect of e-cigarettes on cessation, all conclude that the number, size and quality of studies conducted to date is far too limited to draw any definitive conclusions.⁶ A very recent publication of a randomized, controlled trial in the United Kingdom (UK) comparing the use of e-cigarettes with nicotine replacement therapies (NRT) in 886 adults attending the National Health Services’ stop-smoking services documented an 18% one-year abstinence rate among those assigned to the e-cigarette group versus a 9.9% abstinence rate among those assigned to NRT (RR, 1.83; 95% CI: 1.30–2.58, P<0.001).¹⁷ However, among those who were abstinent at 1 year, 80% of those in the e-cigarette arm continued to use e-cigarettes, while 91% of those in the NRT arm were off all forms of nicotine.¹⁷ This trial represents the largest and most definitive trial to date, yet it remains to be seen if the results can be replicated outside the UK and the setting of a national health care system providing comprehensive tobacco cessation support.

While e-cigarettes appear to significantly reduce exposure to toxicants and known carcinogens and even improve some short-term health outcomes in those who completely transition from combusted tobacco, the prevalence of dual use is high and it is not known how this type of use affects health or eventual abstinence from combusted tobacco. Further, it is far from clear if e-cigarettes help current smokers successfully quit more often than established cessation methods, or if they might lead to relapse. Given how much currently remains unknown about both the use of e-cigarettes as a harm reduction aid and their long-term safety, and given the availability of seven proven and FDA-approved smoking cessation aids, the promotion of e-cigarettes as either a cessation tool or as simply a way to reduce exposure to combusted tobacco through dual use among current smokers is premature.

E-cigarette Use Among Youth

The salient issues and concerns surrounding the use of e-cigarettes among youth are quite different than among established smokers and different standards for assessing potential harms apply. The relative difference in harms between combusted tobacco and e-cigarettes is irrelevant in this demographic. The primary concerns in youth are the absolute risks posed by exposure to nicotine and e-cigarette aerosol, as well as the potential for these devices to lead to nicotine addiction and combusted tobacco use in the longer term. Unlike in adult e-cigarette users, up to half of adolescent and young adult users report no previous exposure to combusted tobacco^{6, 18, 19} and e-cigarettes have been the most commonly used tobacco product among teens since 2014.²⁰ Use of e-cigarettes is rising dramatically in this group, increasing from 11.7% to 20.8% among high school students between 2017 and 2018;²¹ and preliminary 2019 data from the National Youth Tobacco Survey show that 27.5% of high school students report past 30-day use of an e-cigarette.²² These data highlight the urgent need for stricter regulation and enhanced implementation of comprehensive evidence-based tobacco control strategies to protect all youth.

According to the 2012 report from the Surgeon General on tobacco use among youth, adolescents are more sensitive to nicotine than adults and can become addicted much more quickly than adults.²³ There is “substantial evidence” that nicotine intake from e-cigarettes can be comparable to combustible tobacco cigarettes, and that e-cigarettes can induce dependence in a similar manner.⁶ Adolescence represents a critical window for brain development and exposure to nicotine during this time period has been shown to result in lasting deficits in cognitive function and development.²⁴ Further, observational and animal data support the notion that nicotine can act as a “gateway” to the abuse of other recreational drugs in teens. Several epidemiological studies document an association between the use of e-cigarettes and the use of alcohol, marijuana and amphetamines. But perhaps most concerning about the use of e-cigarettes among teens is the potential for the re-normalization of smoking at the population level. Strong and consistent data from 10 observational studies conducted within and outside of the U.S. suggest that e-cigarette use increases the risk of ever smoking combustible tobacco cigarettes, and they may even do so among youth with few traditional risk factors for smoking.⁶ There is also “moderate evidence” that e-cigarette increases the frequency and intensity of subsequent combusted tobacco use.⁶ Contrary to the notion that e-cigarettes may divert teens from using combusted tobacco, these data suggest that these devices may drive teens towards it. Ecological data also suggest this, as the rate of reduction in smoking among U.S. youth has not accelerated in recent years as e-cigarettes have increased in popularity.⁶ The use of e-cigarettes by teens may have serious detrimental implications for the use of combusted tobacco in a group in which such use has been declining.

Call to Action

There is an urgent need to standardize the manufacture of e-cigarettes, document the contents of each marketed product (or similar classes of products), and study them to establish both their relative and absolute safety and efficacy as cessation aides. This will require regulation by the FDA, which is long overdue in our estimation. Unfortunately, we are still learning of the health consequences of combusted tobacco 55 years after the publication of the first Surgeon General’s report linking smoking to lung cancer. In the meantime, youth access to e-cigarettes must be prevented by implementing similarly serious and comprehensive measures that were employed to prevent youth access to combusted tobacco. While many of these regulations went into effect on the effective date of the FDA deeming rule (Aug. 23, 2016), such as prohibiting sales to anyone younger than age 18, more needs to be done. The recent outbreak of severe respiratory illnesses, which includes many teens, underscores the urgency with which parents, youth peers, policymakers, physicians, and others must act to keep youth from accessing e-cigarettes. State-based Tobacco21 legislation, which seeks to raise the minimum legal age to purchase tobacco, including e-cigarettes, from 18 to 21 years of age, represents one key approach in which states can restrict e-cigarette use by teens, if federal action continues to lag.

In conclusion, e-cigarettes should not be assumed to be harmless or a totally safe alternative to tobacco use, as often implied by marketers of these products. They may contain well-known carcinogens and other toxins, although likely at much lower levels than combusted tobacco. The long-term absolute risks of e-cigarettes, including any potential increased cancer risks, are poorly defined, and while there is some evidence to suggest that harm reduction among smokers is possible with e-cigarettes, it is not yet clear just how much harm reduction can be achieved.⁶ Continued high-rates of dual use may challenge harm reduction efforts. Further, there is not yet sufficiently compelling evidence to support the use of e-cigarettes as a safe and effective smoking cessation aid. Numerous FDA-approved cessation therapies and highly effective cessation strategies exist,²⁵ and smokers who have already made the switch to e-cigarettes should work with their healthcare providers to establish a quit plan. E-cigarettes are harmful to adolescents as they pose risks of nicotine addiction, adverse respiratory and cognitive outcomes, and eventual use of combusted tobacco.