Electronic cigarettes and health outcomes: epidemiological and public health challenges

Abstract

Electronic cigarettes (e-cigarettes) are battery-powered devices that heat and aerosolize an ‘e-liquid’. The aerosol is then inhaled by the user. Since their first introduction to broad global markets in 2006–7, use has become increasingly common, particularly among youth.1 The population and individual health impacts of e-cigarettes relate to patterns of use, their direct effects on health and their indirect effects, through impacts on smoking behaviour, as well as background disease risks and tobacco control.2 Based on the current worldwide evidence summarized in our recent systematic review, use of nicotine e-cigarettes increases the risks of addiction, poisoning, toxicity from inhalation (including seizures) and trauma and burns.3 Applying the National Academies of Science, Engineering and Medicine framework for rating the strength of conclusions based on evidence,4 the review found strong evidence that, among young non-smokers, uptake of conventional smoking is increased by an average of 3-fold in e-cigarette users versus non-users.5 Use of e-cigarettes can cause e-cigarette- or vaping-associated lung injury (EVALI), largely attributable to e-liquids containing tetrahydrocannabinol/vitamin E acetate, although one in eight cases in the largest case series to date were reported to be related to use of nicotine e-cigarettes.6 The review found that the effects of e-cigarettes on most important clinical outcomes are not known, due to insufficient or absent evidence. This includes outcomes related to cancer, cardiovascular disease,7 respiratory conditions other than lung injury, mental health, development, reproductive health, sleep, neurological conditions other than seizures, and endocrine, olfactory, optical, allergic and haematological conditions.3 There was conclusive or substantial evidence that e-cigarettes can cause indoor air pollution, waste and fires.3 There was less direct evidence that e-cigarette use can adversely affect cardiovascular health markers, such as blood pressure and heart rate, lung function and adolescent brain development and function.3 The review also found limited evidence that freebase nicotine e-cigarettes used in the clinical setting are efficacious smoking cessation aids.3 Evidence was also limited that former smokers who use e-cigarettes are around twice as likely to take up smoking again than those not using e-cigarettes.3,5 Based on the systematic review findings, there is currently strong evidence that use of e-cigarettes by non-smokers is harmful to health overall, with multiple health harms and no health benefits identified in this population.3 Ex-smokers would be likely to reduce e-cigarette-related health effects if they avoid ongoing e-cigarette use. Dual tobacco smoking and e-cigarette use is the commonest pattern of e-cigarette use in most settings where evidence is available.3,8–10 The direct health effects of combining smoking and e-cigarette use are unknown.3 Dual use may facilitate prolongation of smoking, which would be likely to increase risks.11 E-cigarette use in smokers may offset the pressure of many effective tobacco control measures, as evidenced by common reported reasons for use including that, compared with tobacco cigarettes, e-cigarettes are cheaper, more socially acceptable, able to be consumed in settings where tobacco smoking is prohibited and considered less hazardous to health.3,8 Most smokers who quit successfully do so without specific smoking cessation aids.12,13 Therapeutic products must demonstrate an acceptable balance of benefits and risks to be approved by regulatory authorities14–16 and a range of approved smoking cessation aids are available.17 Internationally, at the time of writing, e-cigarettes are not approved as therapeutic goods. The United States Preventive Services Task Force concluded recently that ‘the current evidence is insufficient to assess the balance of benefits and harms of electronic cigarettes (e-cigarettes) for tobacco cessation in adults, including pregnant persons’ and ‘recommends that clinicians direct patients who use tobacco to other tobacco cessation interventions with proven effectiveness and established safety’.18 In England, e-cigarettes combined with behavioural support are recommended as an option for smoking cessation, particularly for smokers who have tried other methods without success,19 and in Australia current guidelines list them as an option following use of approved products.17 Smoking is extremely harmful and our systematic review findings indicate that the balance of probabilities may be that e-cigarettes benefit smokers who have tried other measures unsuccessfully and who use e-cigarettes to quit tobacco smoking completely and promptly. However, the ultimate balance of safety and efficacy of the use of e-cigarettes for smoking cessation remains unclear; most of their effects on health outcomes are unknown, a number of risks have been identified, evidence on their efficacy for smoking cessation is limited and most smokers using e-cigarettes continue to smoke.18 It is important that evidence regarding e-cigarettes is appropriately contextualized and issues are considered in perspective. This includes noting that in many countries, >80–90% of the population are non-smokers and the main driver of decreasing prevalence of smoking is declining smoking initiation in youth, rather than smoking cessation.20 As noted above, smokers seeking medical assistance to quit and using medications are in the minority.12,13 For example, in Australia in 2019, 11% of the population aged 14 and over were current daily smokers (Figure 1).8 Among current smokers, recent data indicate 36.3% make at least one quit attempt in a given year and, of these, 33.2% report use of (approved) nicotine replacement therapy.21 In Australia, this amounts to around 1.3% of the population aged 14 and over being a current daily smoker who makes a quit attempt using nicotine replacement therapy; an example of a group that could use e-cigarettes. In many countries, potential benefits to smokers—an important minority—are used to justify widespread exposure to e-cigarettes, with risks to young people and the much larger population who are non-smokers. Perspective on contemporary population smoking and quitting patterns in Australia, among people aged 14 and over, including estimated proportions and numbers of smokers making quit attempts and using approved nicotine replacement therapy (data sources: National Drug Strategy Household Survey 20198 and Dono et al.21) Evaluation of health impacts focuses primarily on evidence regarding the causal relationship of use of e-cigarettes to health outcomes. In terms of establishing the safety of an exposure, it is also important to consider the extent to which adverse effects can be excluded, which relates to the statistical limits around risk estimates. The context of use is also important. E-cigarette exposure in the general population is increasingly common, which means that moderate elevations in relative risk—around 20% to 30% (i.e. relative risks of 1.2 to 1.3) — would have important implications for public health. Hence, evidence is needed that is capable of both detecting and excluding such elevations in risk. It is therefore necessary to focus on study designs able to provide evidence regarding causality, with sufficient statistical power and quality. Alongside standard issues relating to reliably establishing and excluding exposure-outcome effects, there are some e-cigarette-specific challenges, outlined below. A major underlying issue in establishing the health impacts of e-cigarettes is the massive ongoing and extremely well resourced efforts of the closely-related and overlapping tobacco and e-cigarette industries22,23 to promote their products and further their interests. These are well documented in the World Health Organization taxonomy of tobacco industry tactics and include efforts to distort and undermine science, influence outcomes and interpretation of findings, influence political and community priorities and divide the tobacco control community.24,25 The e-cigarette industry markets aggressively to children and adolescents, at the same time as claiming that its sole intention is to provide a ‘safer alternative to tobacco’ and to support smokers to quit. Industry funding of scientists and studies provides an important potential source of bias and should be carefully documented and considered when reviewing the evidence.26,27 The health effects of e-cigarettes relate chiefly to: (i) the chemicals emitted by the e-cigarette, which originate from the e-liquid, chemical reactions in the heating element and the device itself28; (ii) the device; and (iii) aspects impacting on smoking behaviour. There may also be summative and/or synergistic effects of the combination of these exposures. E-liquids generally contain chemical solvents propylene glycol and vegetable glycerine, and the vast bulk of e-cigarette use is of those delivering nicotine29; these commonalities underpin investigation of health effects. Bearing this in mind, there are many thousands of e-cigarette devices and e-liquids, with >17 000 flavours available currently and hundreds being introduced to the market on a monthly basis. Hence, e-cigarette use in the population results in exposure to many thousands of different chemical combinations, and varying doses of these chemicals.28 Certain health effects may relate to specific chemical constituents or device properties, and risk may therefore vary between e-cigarettes. Currently, a major division is between use of freebase nicotine and nicotine salt products. Nicotine salt preparations make high concentrations of nicotine more palatable by reducing throat irritation, and are the main form of nicotine used in disposable and pod e-cigarettes.28 These e-cigarette types are small and easily concealed and are heavily marketed to children and adolescents, including through their design. They have been identified as key drivers of widespread youth use of e-cigarettes, including in Canada and the USA.3,30 Many commonly used disposable nicotine salt products deliver high concentrations of nicotine, which would increase the risk of nicotine toxicity via inhalation, including seizures. Evidence also suggests that nicotine salt products confer higher risks of dependency than other types.31 EVALI has largely—but not exclusively—been attributed to e-liquids containing tetrahydrocannabinol/vitamin E acetate. ‘Popcorn lung’ is bronchiolitis obliterans attributed to inhalation of diacetyl used as a flavouring in microwave popcorn; concerns have been raised about use of diacetyl in e-liquids.32,33 Users of ‘open’ e-cigarettes fill a reservoir in the device with the e-liquid. Such e-liquids are either premixed or involve the mixing of the different components, often including the dilution of more concentrated liquid nicotine. Concentrated liquid nicotine is highly toxic and at-home dilution of high-concentration nicotine increases the risk of accidental and intentional poisoning, including in children.3 It also increases the risk of e-liquid adulteration. The risk of injuries related to exploding batteries varies according to the construction of the device and the quality of the batteries within it. It is often difficult to know with accuracy what the components of an e-liquid are, as labelling is variable and often absent or inaccurate. Many studies do not report on the types of e-cigarettes used by participants and/or many participants are unable to report on the specific type of e-cigarette or combinations of e-cigarettes that they have used. There can also be issues generalizing between e-liquid types, and rapid change creates a ‘moving target’ for monitoring and research. For example although much contemporary use is of nicotine salt products,34 most of the studies to date, including randomized trials of smoking cessation and observational studies of smoking uptake, are of e-cigarettes delivering freebase nicotine. A major related factor influencing e-cigarette exposure and risks is user behaviour: use confined to smoking cessation would lead to very different population risks compared with use primarily among youth who are not established smokers.35 Population exposure to e-cigarette use has only become substantial since around 2010. Certain immediate or short-term outcomes are already discernible, particularly those where cause and effect are able to be ascertained at an individual level and where appropriate surveillance systems are in place. For example, the addictive effects of e-cigarettes are well established, as is their ability to cause poisoning, trauma, burns and toxicity through inhalation. The EVALI outbreak was detected and addressed rapidly. Effects on the uptake of smoking in young people have also been able to be assessed fairly quickly, with >25 studies available in our recent meta-analysis.5 For some e-cigarette components and e-liquid constituents, toxicological and other data on their impacts is informative—for example, many effects of nicotine are well established. It will be some time before it is possible to reliably ascertain many important effects of e-cigarettes on health, due to the time needed to conduct research and because some conditions take many years to develop. This, along with the other issues outlined in this article, means that evidence on major clinical conditions such as cancer, cardiovascular disease, mental illness, respiratory conditions other than EVALI and adverse reproductive outcomes is very limited. Evidence should focus on clinically meaningful health outcomes including disease endpoints such as invasive cancer, cardiovascular disease events (e.g. myocardial infarction and stroke), respiratory diseases (e.g. asthma, infections and chronic obstructive pulmonary disease) and addiction and dependency-related outcomes. In the absence of this type of evidence, it is tempting to focus on biomarkers, so-called ‘intermediate’ outcomes (such as arterial wall thickness) and pathophysiological parameters (e.g. heart rate, blood pressure). Whereas these may be informative, they are not reliable substitutes for clinical outcomes and there are many examples of the risks relating to relying on this type of evidence for making decisions on safety. In epidemiological studies, a comparator has two major related but distinct functions: (i) as a group reliable of the effect of an and (ii) as a in the likely of an For e-cigarettes, the comparator to factor in smoking for reasons further in the below. The most appropriate group for the distinct health effects and safety of e-cigarettes is people who have used e-cigarettes of people who in the group major direct e-cigarette effects smoking using e-cigarettes is the most appropriate to using e-cigarettes for the of the population who are non-smokers in countries, particularly for young people (Figure are as harmful as smoking, and quitting tobacco smoking is highly to health, compared with the of to For people who currently multiple e-cigarette-related For ongoing there is the with people who continue to and who do not use e-cigarettes. Since it is smokers who use e-cigarettes may smoking, the of quitting by means other than e-cigarettes may also For who have used e-cigarettes to quit there are of to and of quitting smoking by other There are efforts to to smoking as the comparator for use of use by smokers and non-smokers, and use for smoking cessation and for other This is a of the tobacco and e-cigarette by use of along the that e-cigarettes are ‘safer than for the broad of these including to non-smokers. with smoking are also in the of e-cigarettes as a The of tobacco smoking means that such are highly to and be used as evidence of safety in E-cigarette effects on disease risk in smokers but they must be as distinct from population impacts and impacts in non-smokers. In of e-cigarettes with smoking should be in to use in non-smokers should be with potential in one population should not be considered at a population level and the World Health Organization is that use of alternative tobacco as non-smokers be considered the health impacts of e-cigarettes of their likely effects from those of other that use is related include reproductive other use, tobacco and and mental health as well as issues in to tobacco Smoking increases the risk of a very range of health data from Australia demonstrate that lung in current smokers is that of with a risk in former disease risk in current versus is and the risk of of chronic obstructive pulmonary disease is more than In risk increases with of smoking and there are elevations in risk with number of cigarettes For example, compared with the for lung is for current smokers of cigarettes and with cigarettes also vary according to and background risk of disease and among disease risk with time since The of current smokers to quit when they become is well established and further to smoking In the where an exposure is related to smoking and smoking has a strong relationship to the reliable of exposure-outcome of smoking is difficult if not if smokers are in the of for smoking generally can only for broad of and smoking, with limited ability to for of and other smoking to major issues with the often the evidence from to people who have of where this is used include studies of the relationship of lung to tobacco and risk other than E-cigarette use relates to E-cigarette use is more common in current or compared with and use of both e-cigarettes and tobacco cigarettes is a pattern of use in many There are in tobacco smoking between users and tobacco smokers, including in tobacco smoking and as well as other In smokers who become may take up e-cigarette use, to reduce or quit smoking These issues are likely to on effect when who use e-cigarettes with those who do will when users with the group is then with e-cigarette users who are current or are particularly the safety of e-cigarettes studies able to and relative risk increases from e-cigarette exposure of However, this of in disease risk is small in with that from in the number of cigarettes among for diseases such as lung and chronic obstructive pulmonary for many with tobacco smoking is likely to the ability to reliably effects of e-cigarettes, following This means that who use e-cigarettes and who do not on to are the most reliable population in which to the direct health effects of e-cigarette The that some who e-cigarette use smoking further limits evidence about health outcomes attributable to e-cigarette relative risks to in between which vary in of For example, cardiovascular disease vary by in cardiovascular are with blood in and the of this effect varies with relative risk are in and risk are in of disease between and if it was possible to reliably ascertain relative risks in that smokers, the relative effect of e-cigarettes would be likely to between the combined effects of smoking and e-cigarettes may from their effects. This the of including the effects of e-cigarettes in people who currently and in the issues with and bias outlined reliable of an exposure-outcome relationship sufficient numbers of events among the and to the parameters of with of such as and of the issues noted in the have a on statistical In important health such as addiction, mental health issues and the most of the major clinical disease outcomes of in the effects of as cancer, cardiovascular disease and chronic obstructive pulmonary at Use of e-cigarettes at (e.g. those aged is among people who currently or have in the there is very use among E-cigarette use among and people who are not established smokers is a common pattern in youth and, since smoking are generally not established people are in their use this is chiefly not at smoking Hence, at the where the vast of disease events use of e-cigarettes is in smokers, making it very difficult to the effects of e-cigarettes from those of in smoking where e-cigarette use among is more common, chronic disease from those generally For example, in a major study of e-cigarettes and respiratory of e-cigarette users were either current or former in studies, the necessary to be of effects of smoking may limited power to effects in particularly as disease events will to in people who the and other issues identified, evidence regarding the health impacts of e-cigarettes is rapidly. The risks that have been identified are sufficient to that use in non-smokers, particularly youth, is harmful to health. For most major health the effects of e-cigarettes are A key ongoing for and public health is not only the of reliable evidence on e-cigarettes, but also its interpretation and use as well as its public health of evidence, the of risks and benefits and to multiple population and effective measures to risk. and it is not about a on that or that measures will In it is not about that up that to for an individual or group would be for the population as a in public health of and health also to as the tobacco to at the of the health and of the health on e-cigarettes, including regulatory must their identified risks as well as The the of exposure to an when there is combined with evidence of risks to health, those It that the is on by the of an widespread exposure, and the to take to rather than is are important and of e-cigarettes varies with at least them that do not include a and no in at the time of the evidence is of efforts in many to avoid e-cigarette use in the general particularly in non-smokers and It is also of the World Health Organization that smokers who completely and to an appropriately e-cigarette may in the of evidence on impacts It is important that evidence regarding the health impacts of e-cigarettes is and of industry Industry from and widespread e-cigarette use, and research to and efforts to control e-cigarette use are by its Industry to evidence of potential efficacy for smoking cessation in some or with the that such use is in smokers and that widespread e-cigarette use would public health. the tobacco and e-cigarette industry would in its and only smokers who to use their products to would be very It is a to consider what this would no to children and no flavours to to children (such as and use primarily for smoking and of e-cigarette products for regulatory for smoking The issues outlined in this the of in research to and ongoing issues regarding e-cigarettes, including but not limited to: data to e-cigarette and tobacco use, including tobacco smoking, particularly among studies of health able to e-cigarette and smoking evidence the balance of safety and efficacy of e-cigarettes as aids for smoking research on tobacco and e-cigarette industry and research on effective measures to identified risks related to e-cigarettes, including e-cigarette use in non-smokers, Evidence on to control to children and youth, particularly via is a It is also important to and to the to on evidence, in where evidence is should make the most of in the to e-cigarettes, to effective regulatory to the health of current and including through tobacco was as this is based on available This is based on available the and the first statistical important and approved the This on an report by the of is by an from the National Health and of of the people their data to studies on tobacco control and e-cigarettes.

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