Background
Electronic cigarettes (also known as e-cigarettes) are generally recognized as a safer alternative to combusted tobacco products (reviewed in [
1]), but there are conflicting claims about the degree to which these products warrant concern for the health of the vapers (e-cigarette users). A vaper inhales aerosol generated during heating of liquid contained in the e-cigarette. The technology and patterns of use are summarized by Etter [
1], though there is doubt about how current, complete and accurate this information is. Rather conclusive evidence has been amassed to date on comparison of the chemistry of aerosol generated by electronic cigarettes to cigarette smoke [
2‐
8]. However, it is meaningful to consider the question of whether aerosol generated by electronic cigarettes would warrant health concerns on its own, in part because vapers will include persons who would not have been smokers and for whom the question of harm reduction from smoking is therefore not relevant, and perhaps more importantly, simply because there is value in minimizing the harm of those practicing harm reduction.
One way of approaching risk evaluation in this setting is to rely on the practice, common in occupational hygiene, of relating the chemistry of industrial processes and the emissions they generate to the potential worst case of personal exposure and then drawing conclusions about whether there would be interventions in an occupational setting based on comparison to occupational exposure limits, which are designed to ensure safety of unintentionally exposed individuals. In that context, exposed individuals are assumed to be adults, and this assumption appears to be suitable for the intended consumers of electronic cigarettes. “Worst case” refers to the maximum personal exposure that can be achieved given what is known about the process that generates contaminated atmosphere (in the context of airborne exposure considered here) and the pattern of interaction with the contaminated atmosphere. It must be noted that harm reduction notions are embedded in this approach since it recognizes that while elimination of the exposure may be both impossible and undesirable, there nonetheless exists a level of exposure that is associated with negligible risks. To date, a comprehensive review of the chemistry of electronic cigarettes and the aerosols they generate has not been conducted, depriving the public of the important element of a risk-assessment process that is mandatory for environmental and occupational health policy-making.
The present work considers both the contaminants present in liquids and aerosols as well as the declared ingredients in the liquids. The distinction between exposure to declared ingredients and contaminants of a consumer product is important in the context of comparison to occupational or environmental exposure standards. Occupational exposure limits are developed for unintentional exposures that a person does not elect to experience. For example, being a bread baker is a choice that does not involve election to be exposed to substances that cause asthma that are part of the flour dust (most commonly, wheat antigens and fungal enzymes). Therefore, suitable occupational exposure limits are created to attempt to protect individuals from such risk on the job, with no presumption of “assumed risk” inherent in the occupation. Likewise, special regulations are in effect to protect persons from unintentional exposure to nicotine in workplaces (
http://www.cdc.gov/niosh/docs/81-123/pdfs/0446.pdf; accessed July 12, 2013), because in environments where such exposures are possible, it is reasonable to protect individuals who do not wish to experience its effects. In other words, occupational exposure limits are based on protecting people from involuntary and unwanted exposures, and thus can be seen as more stringent than the standards that might be used for hazards that people intentionally choose to accept.
By contrast, a person who elects to lawfully consume a substance is subject to different risk tolerance, as is demonstrated in the case of nicotine by the fact that legally sold cigarettes deliver doses of nicotine that exceed occupational exposure limits [
9]: daily intake of 20 mg of nicotine, assuming nearly 100% absorption in the lungs and inhalation of 4 m
3 of air, corresponds to roughly 10 times the occupational exposure limit of 0.5 mg/m
3 atmosphere over 8 hours [
10]. Thus, whereas there is a clear case for applicability of occupational exposure limits to contaminants in a consumer product (e.g. aerosol of electronic cigarettes), there is no corresponding case for applying occupational exposure limits to declared ingredients desired by the consumer in a lawful product (e.g. nicotine in the aerosol of an electronic cigarette). Clearly, some limits must be set for voluntary exposure to compounds that are known to be a danger at plausible doses (e.g. limits on blood alcohol level while driving), but the regulatory framework should reflect whether the dosage is intentionally determined and whether the risk is assumed by the consumer. In the case of nicotine in electronic cigarettes, if the main reason the products are consumed is as an alternative source of nicotine compared to smoking, then the only relevant question is whether undesirable exposures that accompany nicotine present health risks, and the analogy with occupational exposures holds. In such cases it appears permissible to allow at least as much exposure to nicotine as from smoking before admitting to existence of new risk. It is expected that nicotine dosage will not increase in switching from smoking to electronic cigarettes because there is good evidence that consumers adjust consumption to obtain their desired or usual dose of nicotine [
11]. The situation is different for the vapers who want to use electronic cigarettes without nicotine and who would otherwise not have consumed nicotine. For these individuals, it is defensible to consider total exposure, including that from any nicotine contamination, in comparison to occupational exposure limits. In consideration of vapers who would never have smoked or would have quit entirely, it must be remembered that the exposure is still voluntary and intentional, and comparison to occupational exposure limits is legitimate only for those compounds that the consumer does not elect to inhale.
The specific aims of this review were to:
1.
Synthesize evidence on the chemistry of liquids and aerosols of electronic cigarettes, with particular emphasis on the contaminants.
2.
Evaluate the quality of research on the chemistry of liquids and aerosols produced by electronic cigarettes.
3.
Estimate potential exposures from aerosols produced by electronic cigarettes and compare those potential exposures to occupational exposure standards.
Conclusions
By the standards of occupational hygiene, current data do not indicate that exposures to vapers from contaminants in electronic cigarettes warrant a concern. There are no known toxicological synergies among compounds in the aerosol, and mixture of the contaminants does not pose a risk to health. However, exposure of vapers to propylene glycol and glycerin reaches the levels at which, if one were considering the exposure in connection with a workplace setting, it would be prudent to scrutinize the health of exposed individuals and examine how exposures could be reduced. This is the basis for the recommendation to monitor levels and effects of prolonged exposure to propylene glycol and glycerin that comprise the bulk of emissions from electronic cigarettes other than nicotine and water vapor. From this perspective, and taking the analogy of work on theatrical fogs [
46,
47], it can be speculated that respiratory functions and symptoms (but not cancer of respiratory tract or non-malignant respiratory disease) of the vaper is of primary interest. Monitoring upper airway irritation of vapers and experiences of unpleasant smell would also provide early warning of exposure to compounds like acrolein because of known immediate effects of elevated exposures (
http://www.atsdr.cdc.gov/toxprofiles/tp124-c3.pdf; accessed July 11, 2013). However, it is questionable how much concern should be associated with observed concentrations of acrolein and formaldehyde in the aerosol. Given highly variable assessments, closer scrutiny is probably warranted to understand sources of this variability, although there is no need at present to be alarmed about exceeding even the occupational exposure limits, since occurrence of occasional high values is accounted for in established TLVs. An important clue towards a productive direction for such work is the results reported in [
40,
41] that convincingly demonstrate how heating the liquid to high temperatures generates compounds like acrolein and formaldehyde in the aerosol. A better understanding about the sources of TSNA in the aerosol may be of some interest as well, but all results to date consistently indicate quantities that are of no more concern than TSNA in smokeless tobacco or nicotine replacement therapy (NRT) products. Exposures to nicotine from electronic cigarettes is not expected to exceed that from smoking due to self-titration [
11]; it is only a concern when a vaper does not intend to consume nicotine, a situation that can arise from incorrect labeling of liquids [
25,
44].
The cautions about propylene glycol and glycerin apply only to the exposure experienced by the vapers themselves. Exposure of bystanders to the listed ingredients, let alone the contaminants, does not warrant a concern as the exposure is likely to be orders of magnitude lower than exposure experienced by vapers. Further research employing realistic conditions could help quantify the quantity of exhaled aerosol and its behavior in the environment under realistic worst-case scenarios (i.e., not small sealed chambers), but this is not a priority since the exposure experienced by bystanders is clearly very low compared to the exposure of vapers, and thus there is no reason to expect it would have any health effects.
The key to making the best possible effort to ensure that hazardous exposures from contaminants do not occur is ongoing monitoring of actual exposures and estimation of potential ones. Direct measurement of personal exposures is not possible in vaping due to the fact the aerosol is inhaled directly, unless, of course, suitable biomarkers of exposure can be developed. The current review did not identify any suitable biomarkers, though cotinine is a useful proxy for exposure to nicotine-containing liquids. Monitoring of potential composition of exposures is perhaps best achieved though analysis of aerosol generated in a manner that approximates vaping, for which better insights are needed on how to modify “smoking machines” to mimic vaping given that there are documented differences in inhalation patterns [
52] that depend on features of e-cigarettes [
14]. These smoking machines would have to be operated under a realistic mode of operation of the atomizer to ensure that the process for generation of contaminants is studied under realistic temperatures. To estimate dosage (or exposure in personal breathing zone), information on the chemistry of the aerosol has to be combined with models of the inhalation pattern of vapers, mode of operation of e-cigarettes and quantities of liquid consumed. Assessment of exhaled aerosol appears to be of little use in evaluating risk to vapers due to evidence of qualitative differences in the chemistry of exhaled and inhaled aerosol.
Monitoring of liquid chemistry is easier and cheaper than assessment of aerosols. This can be done systematically as a routine quality control measure by the manufacturers to ensure uniform quality of all production batches. However, we do not know how this relates to aerosol chemistry because previous researchers did not appropriately pair analyses of chemistry of liquids and aerosols. It is standard practice in occupational hygiene to analyze the chemistry of materials generating an exposure, and it is advisable that future studies of the aerosols explicitly pair these analyses with examination of composition of the liquids used to generate the aerosols. Such an approach can lead to the development of predictive models that relate the composition of the aerosol to the chemistry of liquids, the e-cigarette hardware, and the behavior of the vaper, as these, if accurate, can anticipate hazardous exposures before they occur. The current attempt to use available data to develop such relationships was not successful due to studies failing to collect appropriate data. Systematic monitoring of quality of the liquids would also help reassure consumers and is best done by independent laboratories rather than manufactures to remove concerns about impartiality (real or perceived).
Future work in this area would greatly benefit from standardizing laboratory protocols (e.g. methods of extraction of compounds from aerosols and liquids, establishment of “core” compounds that have to be quantified in each analysis (as is done for PAH and metals), development of minimally informative detection limits that are needed for risk assessment, standardization of operation of “vaping machine”, etc.), quality control experiments (e.g. suitable positive and negative controls without comparison to conventional cigarettes, internal standards, estimation of % recovery, etc.), and reporting practices (e.g. in units that can be used to estimate personal exposure, use of uniform definitions of limits of detection and quantification, etc.), all of which would improve on the currently disjointed literature. Detailed recommendations on standardization of such protocols lie outside of scope of this report.
All calculations conducted in this analysis are based on information about patterns of vaping and the content of aerosols and liquids that are highly uncertain in their applicability to “typical” vaping as it is currently practiced and says even less about future exposures due to vaping (e.g. due to development of new technology). However, this is similar to assessments that are routinely performed in occupational hygiene for novel technology as it relied on “worst case” calculations and safety margins that attempt to account for exposure variability. The approach adopted here and informed by some data is certainly superior to some currently accepted practices in the regulatory framework in occupational health that rely purely on description of emission processes to make claims about potential for exposure (e.g. [
53]). Clearly, routine monitoring of potential and actual exposure is required if we were to apply the principles of occupational hygiene to vaping. Detailed suggestions on how to design such exposure surveillance are available in [
54].
While vaping is obvious not an occupational exposure, occupational exposure standards are the best available option to use. If there were a standard for voluntary consumer exposure to aerosols, it would be a better fit, but no such standard exists. The only candidate standard is the occupational standard, which is conservative (more protective) when considered in the context of voluntary exposures, as argued above, and any suggestion that another standard be used needs to be concrete and justified.
In summary, analysis of the current state of knowledge about the chemistry of contaminants in liquids and aerosols associated with electronic cigarettes indicates that there is no evidence that vaping produces inhalable exposures to these contaminants at a level that would prompt measures to reduce exposure by the standards that are used to ensure safety of workplaces. Indeed, there is sufficient evidence to be reassured that there are no such risks from the broad range of the studied products, though the lack of quality control standards means that this cannot be assured for all products on the market. However, aerosol generated during vaping on the whole, when considering the declared ingredients themselves, if it were treated in the same manner as an emission from industrial process, creates personal exposures that would justify surveillance of exposures and health among exposed persons. Due to the uncertainty about the effects of these quantities of propylene glycol and glycerin, this conclusion holds after setting aside concerns about health effects of nicotine. This conclusion holds notwithstanding the benefits of tobacco harm reduction, since there is value in understanding and possibly mitigating risks even when they are known to be far lower than smoking. It must be noted that the proposal for such scrutiny of “total aerosol” is not based on specific health concerns suggested by compounds that resulted in exceedance of occupational exposure limits, but is instead a conservative posture in the face of unknown consequences of inhalation of appreciable quantities of organic compounds that may or may not be harmful at doses that occur during vaping.
Competing interests
Funding for this work was provided by The Consumer Advocates for Smoke-free Alternatives Association (CASAA) Research Fund. CASAA is an all-volunteer, donation-funded, non-profit organization devoted to defending consumer access to and promoting tobacco harm reduction; it is a consumer (not industry) advocacy NGO. For more information, see
http://casaa.org/. CASAA exercised no editorial control over the author’s writing or analysis: the author, not the funder, had full control of the content.