The science behind vaping

This special issue examines the science behind electronic nicotine delivery systems (ENDS), also called electronic cigarettes, e-cigarettes, vapour products or vapes. These products have emerged in the last 10–15 years as a potentially less risky alternative to cigarette smoking for those smokers who are struggling to quit smoking. Even though the serious health risks of smoking cigarettes are well understood, smoking remains common around the world. It is well accepted that the health risks from smoking are caused by inhaling toxicants created when tobacco is burned, and, although nicotine is addictive, it does not cause disease. The best way to avoid the health risks of smoking is to never start or to quit.

Tobacco harm reduction (THR) is a pragmatic public health approach that aims to reduce the negative health impacts of tobacco use, by moving smokers from the most dangerous way to consume nicotine (combustible cigarettes) to alternative, less harmful (non-combustible) nicotine delivery products with vastly lower levels of toxicants. These alternative products include e-cigarettes, smokeless tobacco products such as snus or nicotine pouches, heated tobacco products, or nicotine replacement therapy products (NRTs) such as nicotine gums and patches (although these do not work for all smokers). The underlying philosophy of THR is that while complete cessation is ideal, harm reduction measures can significantly improve health outcomes for those who would otherwise continue to smoke.

The concept of harm reduction, however, is controversial and polarised. Those who support it emphasise saved lives and reduced costs on society, while opponents emphasise concerns about ethical principles and potential unintended consequences. In the context of tobacco, some health advocates believe abstinence from nicotine is the only option. Increasingly, the controversy around e-cigarettes is about getting the balance right—these products are clearly reduced risk with respect to cigarettes in terms of chemistry and toxicology and can help some adult smokers to switch from smoking cigarettes, but there are potential risks about attracting nicotine non-users, in particular young people. Drug Testing and Analysis has long been interested in covering controversial topics, to help stimulate robust debate amongst stakeholders, hence the journal's interest in covering this topic.

In our search for articles, we have broadened the scope to include studies that do not focus only on nicotine, but also studies that address detection of other substances such as THC (tetrahydrocannabinol). We have taken a holistic approach to ‘drug testing and analysis’ to include drug delivery and pharmacokinetics of novel products, biomarkers associated with vaping, in vitro and in vivo studies, and the human experience relating to perceptions, behaviour and intentions, which are important when considering population-level effect of these products. In a section dedicated to the regulatory process, we have welcomed several articles from industry to expose our readership to the requirements of the US Food and Drug Administration (FDA) Center for Tobacco Products (CTP).

We begin by exploring subjects that are perhaps familiar to our general readership, with the analysis of compounds in electronic cigarettes by Frinculescu et al.¹ It is unsurprising that the vast majority (87/112; 78%) of the specimens tested contained nicotine, with a smaller proportion containing synthetic cannabinoids (22/112; 20%) and THC (11/112; 10%). Holt et al.² deliver a case report on products containing cannabinoids with a collation of 11 case reports where alarmingly 8/11 individuals reported ‘hallucinogenic or dissociative-like effects’ while 10/11 cases reported use of ‘THC-free’ or off-label presence of Δ-9-THC in concentrations ranging from 0.02 to nearly 500 mg/mL. Haworth-Duff et al.^{3, 4} report on two preliminary analyses of e-cigarette aerosols, one focusing on the analysis and characterisation of a strawberry flavour aerosol using headspace-gas chromatography–mass spectrometry,³ and the other on the analysis of trace metals using inductively coupled plasma-mass spectrometry (ICP-MS),⁴ which show promise for future quantitative characterisation of constituents in vape aerosols.

Reveil et al.⁵ report on the potential of enhanced drug delivery when drugs are combined in e-liquids to form a eutectic mixture. When methadone was combined with nicotine, increased recoveries of both nicotine (from 70% to 97%) and methadone (from 84% to 97%) were obtained. This is the first study to highlight the possibility of a toxicological impact of increased aerosolization resulting from polydrug consumption through e-cigarettes. In another study dealing with nicotine delivery, this time of an in vivo nature, Han et al.⁶ consider the importance of the form of nicotine (which is dependent on pH). In the tobacco leaf, nicotine exists in its salt form, and when it is extracted and purified to create pharmaceutical grade nicotine, it converts to its unprotonated or ‘freebase’ form. Han et al.⁶ examine the pharmacokinetics of freebase nicotine compared with three salts (nicotine lactate, nicotine tartrate and nicotine benzoate). Following subcutaneous administration in rats, the authors found that freebase nicotine can reach higher blood concentrations and nicotine concentrations were sensitive to the pH of the preparations. They suggest that this model can be used to screen for optimal pharmacokinetic properties of nicotine delivery systems. Scherer et al.⁷ describe some of their research to differentiate between users of different types of tobacco and nicotine products. They compared the urinary excretions of 19 different mercapturic acids (MAs; which serve as Biomarkers of Exposure to certain tobacco smoke toxicants) in six groups of volunteers who were exclusively using: combustible cigarettes; e-cigarettes, heated tobacco products; oral tobacco products (predominantly snus); or nicotine replacement therapy (NRT; primarily nicotine gum); plus a group who did not use any tobacco or nicotine products. It is clear that smokers (users of combustible cigarettes) are distinct from all other groups on 13 of these MAs, but that distinction between non-cigarette user groups is not possible with just MAs. This adds to the body of work in this area. In a related Perspective article, Yach and Scherer⁸ describe recent progress in developing biomarkers that distinguish between exposure to tobacco smoke versus a range of nicotine products, including harm reduction products. They also highlight advances in measuring biomarkers that are predictive of future disease outcomes. This progress has implications for conducting more rigorous epidemiological studies and, from a more practical standpoint, for insurance companies approaches to underwriting.

A series of papers look at in vitro testing of electronic cigarettes. In a minireview, Bishop et al.⁹ describe the advances of whole aerosol approaches underpinning in vitro testing and expose readers to the ever-changing landscape of e-cigarette devices and the necessity to adapt traditional exposure studies, providing five examples of optimisation of dosimetry and exposure. The toxicity profile associated with aerosols generated from e-cigarettes is addressed in several original research articles. Caruso et al.¹⁰ use in vitro assays to assess cytotoxicity, reactive oxygen species, cell morphology and mitochondrial function in human bronchial cells in aerosols from four nicotine-containing e-liquids. Xu et al.¹¹ examine four different products available in the Chinese market, first looking at chemistry by assessing the presence of 40 Harmful and Potentially Harmful Constituents in aerosols of e-cigarettes, and comparing with levels found in cigarette smoke. They then report on cytotoxicity and mutagenicity assays, demonstrating that aerosols from e-cigarettes are vastly less mutagenic and cytotoxic than cigarette smoke. Next, Caruso et al.¹² describe a multi-centre approach involving four international laboratories in an effort to standardise and independently verify in vitro studies through the ‘Replica Project’. They demonstrate that aerosols from e-cigarettes and heated tobacco products displayed limited inhibition of endothelial cell migration and wound healing with respect to cigarette smoke in a ‘scratch wound’ assay. Together, these studies help to substantiate the reduced risk nature of e-cigarettes compared with traditional cigarettes. Lastly, Miller-Holt et al.¹³ report the findings of a workshop facilitated by the Institute for In Vitro Sciences (iivs.org), summarising progress in the harmonisation of protocols and provide recommendations for dosimetry, key challenges and areas for future research as an outcome of a working group. Standardising testing methodologies is very important from a regulatory perspective – it is critical for all stakeholders to be using the same methods for testing products.

Guo and Hecht¹⁴ take us to a different aspect of e-cigarette research, with a systematic minireview of the literature that assesses potential DNA damage to oral cells after exposure to e-cigarette vapour (both in vitro and in vivo studies) and evaluates the possible connections between e-cigarette exposure and oral cancer. They conclude that although e-cigarettes may be implicated in DNA damage in human oral cells, in comparison with non-users, the adverse effects on DNA were found to be much less severe compared with what is seen with cigarette smoke. They caution that more thoroughly designed prospective cohort studies with larger sample sizes and longer periods of observation are necessary to establish the safety of e-cigarettes.

While preparing this issue, it has been necessary to discuss e-cigarettes in the context of the regulatory pathways for the products in question. In the United States, successful authorisation of a Pre-Market Tobacco Application (PMTA) allows a company to sell a tobacco or nicotine product whereas a successful outcome of Modified Risk Tobacco Product (MRTP) allows a company to declare a product as having a lower risk than a cigarette. These pathways are comprehensively described in a perspective from Solyst¹⁵ using the experiences of Swedish Match, the first company to be granted the FDA's first authorizations, as an illustration. Patwardhan¹⁶ shares his perspective on the importance of education in bridging the gap between nicotine policy and what healthcare professionals do in practice. Despite decades of research about the relative safety of ‘clean nicotine’, and alternative nicotine products such as NRT and e-cigarettes being endorsed by various healthcare bodies for THR, many healthcare practitioners still bundle tobacco, cigarettes, smoking, cancer and nicotine into one, which prevents them from supporting their patients to make informed choices on safer nicotine alternatives. Patwardhan suggests nicotine confidence based on nicotine literacy starts with reforming medical curricula and myth-busting in the lay media to include factual statements about nicotine and public health policy discussions on the principles of harm reduction.

Fearon¹⁷ provides an overview about human abuse liability (dependence) studies in a review article, including their design and standardisation and highlights the necessity to find the abuse liability ‘sweet spot’ in helping to reduce harm in cigarette smokers, where products have sufficient nicotine to encourage smokers to switch away from cigarette smoking but without posing a risk of initiation or addiction risk among current non-users of nicotine. Wadkin et al.,¹⁸ in their review, highlight the importance of translating human puffing behaviour (topography) to e-cigarette puffing regimes for chemical analyses in order to predict more accurately human exposure to emissions and risk in studies exploring harm reduction potential.

Regulatory authorities (such as the US FDA and the European Union) must also manage risks at the population level, so it is critically important that reduced-risk products such as e-cigarettes only appeal to adults who are current smokers and nicotine users. In the United States, results from studies falling under the category of ‘Perception, Behaviour and Intention to Use’ are part of the supporting evidence for PMTAs, as they model the public health effects of e-cigarettes, by weighing the product's effects on intended users (benefits) versus unintended users (harms) across the whole population. Russell et al.¹⁹ report on one such study involving a disposable e-cigarette in the United States, in which current smokers rate their intentions to use this product to replace smoking partially or completely. Positive intent to use this product was highest among current smokers, much lower among former smokers and non-smokers, and lowest among never smokers. This suggests that the product being studied does not appeal to never smokers. Fearon et al.²⁰ analyse data from two independent surveys about prevalence and perceptions about a pod-based e-cigarette in the United States. They show that curiosity and intention to use this product was 1.6–2.8 times more likely in current smokers than never smokers. Across both surveys, less than 0.1% of participants used this product prior to smoking and going on to become established smokers. So, although a proportion of smokers are likely to try this e-cigarette to substitute or reduce cigarette consumption, non-smokers are unlikely to use this product as a ‘gateway’ into smoking. In addition, Fearon et al.²¹ show that for the same product, higher concentrations of nicotine (which are associated with greater nicotine delivery) are not associated with higher levels of dependence, based on self-reporting amongst 1383 participants. Schiffman and Hannon²² examine a different aspect of consumer behaviour. While it is clear that some smokers use e-cigarettes to switch away from smoking, how this varies with previous quit attempts is unknown. Study participants were established adult smokers who had purchased a particular pod-based e-cigarette starter kit. They were surveyed initially about their prior quit attempts, and then assessed the overall switch rate after 12 months. Two thirds of participants had previously tried to quit, and the overall switch rate to the e-cigarette after 12 months was nearly 60%, suggesting that e-cigarettes may provide an alternate way for smokers with a history of failed quit attempts to stop smoking. Finally, Kumar et al.²³ provide insights into how vaping is framed on online platforms and highlight the need for evidence-based content and better communication to the public to aid with smoking cessation and reducing youth vaping.

We are pleased to have assembled a diverse collection of articles that delve into various aspects of e-cigarette research—the breadth of topics covered underscores the complexity of this emerging field. As vaping and e-cigarettes continue to be controversial, we hope that this collection will serve as a valuable resource for researchers, policymakers, regulators and other stakeholders. It is our intention that insights shared will contribute to the ongoing and robust dialogue on this topic. In closing, we would like to thank all our contributors for their time and expertise in putting together this special issue. We would also like to say a special thank you to our referees, whose expertise and valuable insights have helped to ensure the rigour and quality of articles in the collection.

Sophie Turfus (ST) has no conflicts to declare. Sarah Cooney (SC) is a paid director of Cooney Scientific, an independent science engagement consultancy, whose clients include publishers, the chemicals industry and the nicotine and tobacco industry. Previously SC was employed by British American Tobacco, and before that various Scientific, Technical and Medical (STM) publishers. ST and SC did not receive any funding to guest edit this Special Issue.