- Journal Details
- Format
- Journal
- eISSN
- 2719-9509
- First Published
- 01 Jan 1992
- Publication timeframe
- 4 times per year
- Languages
- English
Smoking remains an important cause of preventable morbidity and mortality (1). The World Health Organization (WHO) currently estimates that worldwide, around 1.3 billion adults smoke (2). The overwhelming majority of the disease risk is acknowledged to come from compounds formed during combustion of tobacco at very high temperatures (~950 °C) (3, 4). Of roughly 6,500 compounds (5), about 150 are known toxicants (6) that contribute to smoking-related diseases, such as cardiovascular and respiratory diseases, and cancers. These toxicants also increase the risk of disability and death by other diseases; risks rising with increasing duration of regular smoking. However, excess risks are substantially reversible with smoking cessation (7). Nevertheless, not all nicotine users want to quit, and others find it difficult to do so.
In 2010, the WHO published its Framework Convention on Tobacco Control (FCTC) treaty (8), creating aspirational policy goals for the 181 member states that ratified it. Traditionally, WHO has taken an absolute tobacco control approach to smoking, despite article 1(d) in the FCTC advocating for harm reduction strategies. Since its publication, many countries have implemented the associated guidelines to varying degrees. Since these goals were published, various alternative nicotine products have become commercially available (e.g., electronic cigarettes (ECs), tobacco-free nicotine pouches, and other vapour products), which has led to increasing consideration of the concept of tobacco harm reduction. Harm reduction initiatives involving alternatives to smoking must aim to protect youth and non-smokers from uptake, including by regulation of products, advertising, promotion, and sponsorship (9). This principle involves reducing the risk to smokers by offering satisfactory alternative products with lower risk profiles (10,11,12,13). For example, in Sweden, where there is high prevalence of snus use, daily smoking prevalence is one of the lowest in Europe. Only 7% of the adult population were daily smokers in 2020 (14). Snus is less harmful to health than smoking (15), and Swedish men, who are the predominant snus users, have among the lowest rates of lung cancer incidence and tobacco-related mortality worldwide (16). The potential role of snus in a tobacco harm reduction strategy has been recognised by the US Food and Drug Administration (FDA), granting modified risk orders for eight snus products in 2019 (17, 18).
A widely available alternative nicotine product is ECs. Use of ECs is commonly known as vaping and users are known as vapers. These products heat a liquid (termed e-liquid) containing ingredients that function as carriers (e.g., propylene glycol (PG) and vegetable glycerin (VG)) and may contain flavours and/or nicotine. Compared with tobacco combustion, e-liquids are heated to only around 250 °C and release an aerosol that is much less complex than cigarette smoke, having substantially fewer and lower concentrations of compounds (19,20,21,22). Systematic reviews indicate substantially decreased disease risk compared with smoking through greatly reduced exposure to toxicants and carcinogens (23,24,25,26,27,28), although the risks are not wholly eliminated nor yet fully characterised. Several governments, including those in the UK (24, 29), Canada (30), and New Zealand (31) support use of ECs as reduced-risk alternatives to smoking.
Where manufacturing is actively regulated and monitoring systems are in place, EC quality tends to be high (32) and numbers of reported adverse and serious adverse events leading to morbidity or mortality are low (33). By contrast, if poorly made or illegal products are allowed to enter markets, they substantially increase the risks of adverse events. In the electronic vapour acute lung injury (EVALI) crisis in the USA in 2019, non-regulated e-liquid containing vitamin E acetate and medium-chain triglycerides that are often used in consumption of cannabis and tetrahydrocannabidiol were illegally used as additives, causing severe lung injury in some users (34, 35). This tragedy killed 68 people and injured over 2,000.
This review paper considers the role of ECs in tobacco harm reduction. It provides a high-level account of the evolution of EC design, safety and performance, and methods of testing. Scientific evidence is assessed in relation to acute and long-term health risks associated with EC use. Finally, it discusses how ECs perceptions and use behaviours could impact a harm reduction strategy as well as how available evidence can be used to evaluate health outcomes at population level.
ECs were introduced to the market in 2004 and came to prominence around 2010. Despite this short period, the types of devices have cycled through several generations (Figure 1) (28), in each of which many different devices are available (36). From simple closed, low-power ‘cig-a-like’ devices (generation one), they transformed to refillable long-term use (generation two) and modifiable (generation three) systems, and further to discreet closed system devices with many safety features and improved nicotine delivery (generation four; Figure 1).
Figure 1
Schematic illustration of e-cigarette devices showing disposable 1st generation (cig-a-like) e-cigarettes, 2nd generation with refillable system, 3rd generation customizable ECs, and 4th generation e-cigarettes closed systems.
The basic elements of ECs are a battery connected to a heating element and an e-liquid reservoir. In first generation, single-piece cig-a-like products, all parts are encased into one (usually disposable) unit. The three-piece open systems of generations two and three consist of a separate battery, e-liquid cartridge, and atomizer (vaporizes the e-liquid), and parts and components may be swapped to customize the vaping experience (e.g., by increasing voltage, tank size, and/or e-liquid strength and flavour). Fourth-generation two-piece products consist of a battery and a cartomizer (a combined e-liquid cartridge and atomizer), which is the only exchangeable part. EC emissions may differ by product characteristics and operation and user behaviour (28). Many manufacturers’ design changes have been based on feedback from users searching for products that can meet their nicotine preference with sufficient satisfaction to enable them to replace cigarettes while favouring safety and flexibility (21, 36). In most countries, cig-a-like devices account for only 15% of the EC market, except in the USA, where they are used by around 50% of vapers (37).
The most common reasons for smokers rejecting ECs relate to performance (mimicking smoking and effectiveness at lessening cravings for smoking), but other common reasons are ease of use. In a survey published by Action on Smoking and Health (ASH) (38), 7% of users stopped using ECs because of difficulties in replacing components, refilling e-liquid, or due to leaking. W
An unpleasant problem is so-called dry wicking, more commonly known as “dry puff”, which is caused when the wick in the atomizer is not saturated, leading to the coil becoming overheated and thermal breakdown of solvents in e-liquid (41,42,43,44,45,46,47). The dry wick effect can occur when the e-liquid runs out and the user puffs deeply or if the voltage on modifiable devices is too high for the heating system. While this phenomenon is thought to increase the emission of toxicants (42), it causes a very unpleasant acrid taste (48) that is generally viewed as sufficiently arresting to prevent harm (24). In generation four products, some manufacturers have introduced pre-set power settings to help users to vary their vaping experience while avoiding dry wicking. For example, a distiller-plate heating system, which heats the e-liquid directly and replaces the coil and wick system, has increased nicotine delivery while minimizing the risk of dry puffs (21).
Thousands of flavours are available for ECs, and even within individual flavours, many variations in formulations exist. Sensorial aspects, such as sweetness, coolness, and vapour visibility or smoothness, play important parts in product acceptability (49,50,51). A systematic review by Z
In many countries, ECs are regulated (in around 100 countries) (61), but the regulations are inconsistent and generally cover marketing, labelling, ingredients, and/or taxation, leading to highly variable product standards globally. However, only six countries have no regulations beyond minimum age for purchase (61). Marketing authorizations or product notifications/marketing applications may be required before products can enter the market. Pre-market authorizations involve the regulator giving permission for marketing after review of an application, placing some of the responsibility for a product on the regulator. By contrast, with product notifications/marketing applications, while the regulator may act on information provided, responsibility for the product remains with the submitter. The European Parliament, the US Food and Drug Administration (FDA), and various other national authorities request data on ingredients and various compounds in emissions, including types, quantities, and origins. Forty-two countries have banned ECs, most frequently based on the perceived risk of youth nicotine addiction or the potential that yet unknown long-term effects of vaping might outweigh any health benefits (61,62,63,64).
In the USA, regulation of ECs was introduced in 2016 (65). All new tobacco products, including ECs despite their lack of tobacco leaves, are subject to approval via Pre-Market Tobacco Product Applications (PMTA) (66). Manufacturers that wish to be able to claim that an individual tobacco product (but not a product class) reduces risk to health compared with smoking must also make a Modified Risk Tobacco Product Application (67, 68). Each submission requires a dossier with description and formulation of the product, description of non-clinical and clinical research findings relating to the effects of the product on tobacco-related diseases and other health-related conditions, how it will be used, as well as, examples of labelling and a description of how the product would be marketed. So far, numerous Pre-Market Tobacco Product Applications have been made for ECs but no Modified Risk Tobacco Product Application submission for ECs has yet been approved by the FDA. Dossier review times are expected to run into several years, making it likely the market will not easily benefit from product improvements as the category develops. In the EU, the Tobacco Products Directive 2014/40/EU (TPD2) regulates the manufacture, sale, and marketing of tobacco products (69). It incorporates a product notification system and aims “
In most countries, advertising and marketing of ECs is highly controlled in terms of where and what information may be displayed and how. In the UK, the Committee of Advertising Practice does not allow advertising of ECs to make medicinal claims (e.g., can help with smoking cessation) unless they have marketing authorization from the Medicines and Healthcare Products Regulatory Agency, and messages must not appeal to youth or encourage non-smokers or non-nicotine-users to use ECs (72). In the US, modified risk claims can be made only for products authorized by the FDA via the Modified Risk Tobacco Product Application process (73). A few countries, like Canada and New Zealand, allow promotion of the use of ECs as less harmful alternatives to tobacco smoking by providing balanced risk information for consumers (74, 31).
As well as top-line requirements, further detail on interpretation and compliance are provided by regulatory guidance documents, national, regional, and international technical product standards, and voluntary industry codes. Technical committees creating standardised safety and quality guidance for ECs have been set up at the International Organization for Standardization (ISO) and the European Committee for Standardization (CEN), involving experts from industry, regulators, consumers, and other relevant stakeholders. Each has published two technical standards on generating emissions for measurements, what to measure in emissions, device safety, and analytical methods for measuring the main components in e-liquids (75,76,77,78). Further guidelines are being developed on electrical safety, manufacturing, ingredients, additional emissions and e-liquid measurement methods, consumer information, and labelling. Adoption of product standards is important to consumers to inform them about the quality of ECs, and to regulators and industry to clarify methodologies and data generated for marketing applications. Specifically, a framework of testing standards for ECs has been proposed, as many methods used had simply been adapted from cigarette testing methods. This will enable clearer comparison of aerosol yields within and across different product categories, including cigarettes (79).
When ECs were first introduced, concerns were expressed about e-liquid after the number of calls to poison centres reporting exposure and irritation of skin or eyes with contact rose (80,81,82), but the risk of incidents has been reduced by changes in product design and labelling, e.g., non-spill e-liquid cartridges in closed ECs, improved information for use of open, refillable ECs and measures to take when accidental spills do occur, and testing of appropriate concentration ranges for ingredients. Nevertheless, some of the measures that could increase the safety are, for example, by developing child-resistant mechanisms for puff-activated products. For open products, the tanks should be child resistant and refilling could be leak-free, such as with a dock-and-lock mechanism.
Exploding devices and batteries occur infrequently but have led to severe burns and projectile injuries. These events are generally related to use of inappropriate chargers not supplied with the product that deliver too much current to the battery, leading to thermal runaway and generation of flammable and explosive gases (83). Well-designed products should meet international standards for protection against overcharging (76) and ensure sufficient venting capacity of the battery compartment. Likewise, battery quality should comply with existing international standards. EC products in Europe are covered directly by Electromagnetic Compatibility (EMC) Directive (2014/30/EU) (84) and Restriction of the Use of Certain Hazardous Substances (RoHS) Directive (2011/65/EU) (85), as indicated by the CE marking. Additionally, aspects of the General Product Safety (GPS) Directive (2001/95/EC) apply (86). The GPS sets out safety requirements for all consumer products being placed on the European market (and allows the use of adjacent standards, such as within the low-voltage-device safety standards, to control failure modes and risks), but is not itself associated with CE marking. Occasionally, battery explosions have been caused by improper storage or modification by users (28), and this issue requires further user education.
The European Committee for Standardization provides practical and enforceable requirements related to electrical safety, leakage and breakage, child resistance and some high-level device material considerations (76). ECs continue to be a developing product category and best practice guidance will thus require regular updating.
Product stewardship for ECs has been developed by several EC manufacturers to address materials and ingredients, interactions of the e-liquid and the device (e.g., aerosol laboratory and clinical testing), and post-marketing surveillance (e.g., customer feedback or complaints, product sustainability, etc.). A potential approach for toxicological stewardship of ECs is summarised in Panel 1 (87,88,89). The need for purity requirements and exclusion of ingredients with certain toxicological properties has gained widespread recognition (90). However, the basic principle that the dose determines the level of toxicological risk seems often to be forgotten, leading to purported adverse effects in the literature based on
Nicotine and humectants should be of pharmaceutical grade purity
Flavourings should be food grade purity
Protect consumers from ingredients identified as carcinogens, mutagens, reprotoxicants, and respiratory allergens
Manufacturers should maintain an additional negative list of ingredients that have been proven to be unsuitable for use in vaping products (e.g., diacetyl, vitamin E acetate, triglycerides) and follow regulatory guidance about any other substance
Toxicological risk assessments should be performed for each e-liquid to demonstrate ingredients and concentrations in e-liquid are supportable
Conduct chemical and toxicological assessments of aerosol for every device and e-liquid variant (can benefit from a bridging approach)
Besides addressing ingredient selection, an e-liquid toxicological risk assessment should determine whether the levels of the ingredients are suitable for the intended use (92, 93).
Additionally, a robust stewardship process should monitor consumer complaints and analyse them to ensure safety and engagement with the product continuous improvement process.
Multiple scientific frameworks for risk assessment have been presented that outline the approach for investigating the risk profile of non-combustible tobacco and nicotine products (13, 94,95,96). Broadly, all frameworks are underpinned by investigation of acute and long-term risk from using ECs in studies assessing chemistry, toxicology and clinical outcomes, and also by the perceptions and behaviours of users and non-users of ECs. In this section, we present published data from multi-disciplinary scientific studies of ECs generated within product assessment frameworks and investigating acute and long-term risks from using ECs.
Compounds of interest in ECs have often been based on smoking toxicant emissions (97) and many studies use smoking as a comparator, meaning that smoke toxicants have been the focus of most assessments so far (98,99,100,101,102). Investigational approaches are, therefore, evolving in response to emerging evidence and growing understanding of EC aerosol composition.
The EU TPD2 stipulates chemical emissions testing for multiple priority compounds, including acetaldehyde, acrolein, and formaldehyde (84). The US FDA has identified 92 harmful or potentially harmful constituents (HPHCs) in addition to nicotine (103) and public comment was recently sought on the proposal to add a further 19 compounds to the list (104). However, to our knowledge, only one study has investigated the emissions of these additional HPHCs (22). In practice, it has been suggested that Pre-Market Tobacco Product Applications should report at least 32 compounds (66). ECs generally do not reach temperatures higher than 250 °C during normal use or more than 350 °C under dry wicking conditions (105). However, a huge variety of devices and e-liquids exist (106) and many different puffing conditions and analytical techniques have been used to assess them (42, 107,108,109), but, overall, results indicate significantly lower levels of toxicants in EC aerosols than in cigarette smoke (20, 22, 43, 44, 102, 110, 111).
Despite the relative simplicity of EC aerosol, consideration must be given to aerosol collection methods and measurement of specific analytes. For example, a review of papers that measured carbonyl emissions from ECs showed many variations in the measurement techniques, including puffing regime, aerosol collection, and analytical methodology, making data comparisons difficult (41, 42). Reducing variability would maximize sensitivity of reported values (43). The CORESTA Recommended Method No 81 (112) includes standardised puffing conditions for ECs that have now been used in multiple emissions testing studies (20,21,22, 113,114,115).
Potential contamination from the testing environment (e.g., the presence of volatile organic species in occupational and residential room air) is a well-documented phenomenon. Indoor air quality reference values have been established for several species (20). The presence of an analyte in a laboratory reagent used for testing, for example carbonyls in 2,4-dinitrophenylhydrazine, is also well recognized (43). Given the low levels of most compounds in EC emissions, use of air and blank controls and management of the chemical background of the testing environment are crucial to provide context (e.g., contribution of non-product-related compounds of interest) and minimize errors in the analytical data (20, 116). Reporting control data as standard will improve interpretability of results.
The number of components in e-liquids is estimated to be around 113 (28) compared with around 600 in tobacco cigarettes (109). In high-quality manufactured ECs, the main sources of toxicants in aerosol are attributed to impurities in liquid, degradation of the e-liquid ingredients, and device components. Most compounds associated with e-liquid formulation are either not detected or are very close to the limit of quantification (113, 117).
Carbonyl compound levels can increase with increasing flavour content. Retail flavours were added to a 1:1 PG-VG mixture at 5–50% (
Comparison of metal levels in e-cigarette vapour
| Category | Device/Cigarette | Regime | No. of puffs | Metals | Units | Source | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mercury | Cadmium | Lead | Chromium | Nickel | Arsenic | Selenium | ||||||
| Cigarette | 1R6F | HCI | 4.68 | 76.1 | BLQ | BLD | BLD | BLQ | BLD | ng/cig | J | |
| Cigarette | 3R4F | HCI | 4.92 | 93.2 | BLQ | BLD | BLD | BLQ | BLD | ng/cig | J | |
| EC Gen 1 | Various | 70 / 1.8 / 10c | 150 | N/A | 0.01–0.22 | 0.03–0.57 | N/A | 0.11–0.29 | N/A | N/A | μg/150 puffs a | G |
| Cig-a-like | 10 | N/A | N/A | 0.017 | 0.007 | 0.05 | N/A | N/A | μg/10 puffs a | W | ||
| EC Gen 2/3 | Open tank | N/A | 0.05–0.16 | 6.88–541 | 0.39–15.6 | 1.32–2148 | 0.1–1.59 | N/A | μg/kga | Z | ||
| EC Gen 3 | Liquids in reference | CRM81 | N/A | < 0.06 | < 0.05–0.12 | < 0.09–1.58 | < 1.08–1.54 | < 0.12–1.33 | N/A | ng/puffa | B | |
| EC Gen 4 | Closed system | N/A | 0.04–0.05 | 0.88–6.88 | 0.39–0.41 | 1.32–11.9 | 0.09–0.10 | N/A | μg/kga | Z | ||
| CRM81 | 150 | BLQ | BLD | BLD | BLD | BLQ | BLQ | 0.00024 | μg/puff | O'C | ||
Median
tobacco flavour, 1.6% nicotine
puff volume / duration / interval
Abbreviations:
below limit of detection below limit of quantification CORESTA recommended method number 81 electronic cigarette Gen electronic cigarette generation Health Canada intense machine smoking regime not analyzed
K
Aldehyde formation may be influenced by e-liquid ingredients, overheating and dry wicking (41,42,43,44,45,46,47) and e-liquid oxidation through direct contact with the nickel-chromium heater coil (133,134) are the dominant causes. Improved coil designs and wicking materials that enhance e-liquid flow to the heaters can reduce the risk of these phenomena (135,136,137). In fourth-generation ECs, the levels of the key carbonyls of concern – formaldehyde, acetaldehyde, and acrolein – are greatly reduced compared to those in cigarette smoke (22). Table 2 illustrates the complexity of comparisons due to the differences in methodological and reporting approaches.
Comparison of carbonyl levels in e-cigarette vapour versus cigarette smoke from published studies.
| Category | Device/Cigarette | Regime | No. of puffs | Carbonyls | Units | Reference | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Formaldehyde | Acetaldehyde | Acetone | Acrolein | Propionaldehyde Crotonald | ehyde | MEK | Butyraldehyde | ||||||
| Cigarette | 1R6F | HCI | 9.1 | 4.879 | 158.9 | 62.31 | 14.51 | 13.74 | 4.484 | 15.93 | 3.08 | μg/puff | (22) |
| Cigarette | Benson & Hedges Sky Blue | HCI | 8.1 | 5.235 | 177.4 | 65.68 | 15.93 | 15.43 | 5.321 | 17.41 | 4.469 | μg/puff | (22) |
| EC Gen1 | Various | 70 / 1.8 / 10* | 150 | 3.2–56.1 | 2.0–13.6 | N/A | 0–41.9 | N/A | N/A | N/A | N/A | μg/150 puffs | (44) |
| EC Gen 2 | Various open tank | 55 / 4 / 30* | 10 | 0.9–2.7 | 0.3–1.7 | N/A | 0.7–1.9 | N/A | N/A | N/A | N/A | μg/10 puffs | (344) |
| EC Gen 2/3 | Open tank/NHOSS “Lounge” model (no nic./16 mg/mL nic.) | CRM81 | 96 | 0.37–1.48 | 0.16–0.96 | N/A | 0.05–2.1 1 | N/A | N/A | N/A | N/A | ng/mL puff | (113) |
| EC Gen 3/4 | ePen | CRM81 | 122 | 106 | 73 | 70 | LOQ | N/A | N/A | 8 | ng/puff | (20) | |
| EC Gen 4 | JUUL rich tobacco (20 mg/mL) | CRM81 | 112 | 76 | 3 | 13 | N/A | N/A | N/A | N/A | ng/puff | (114) | |
| JUUL rich tobacco (18 mg/mL) | CRM81 | 11 | 12 | 36 | 7 | N/A | N/A | N/A | N/A | ng/puff | (114) | ||
| CRM81 | 150 | < 2.63 | < 17.5 | < 8.75 | < 4.38 | < 4.38 | < 4.38 | < 4.38 | < 4.38 | μg/150 puffs | (115) | ||
| Vype ePen 2 (18 mg/mL nic.) | CRM81 | 268 | 230 | 135.8 | 346 | 96.2 | BLD | BLD | BLD | ng/puff | (22) | ||
| Vype ePen 3 (BAT 18 mg/mL nic.) | CRM81 | 52.8 | NQ | 111 | BLD | NQ | BLD | BDL | BLD | ng/puff | (22) | ||
Puff volume / duration / interval
Abbreviations:
below limit of detection Limit of quantitation CORESTA Recommended Method No81 electronic cigarette electronic cigarette generation Health Canada intense machine smoking regime methyl ethyl ketone not analysed nicotine not quantified
Nicotine salts in e-liquids have lower volatility than free-base nicotine, enabling enhanced nicotine delivery without increased irritation during vaping (138). Pharmacokinetic assessments indicate that the concentration of nicotine delivered is close to that in cigarette smoke, and the efficiency of delivery is improved compared with e-liquids containing free-base nicotine (139,140,141). At least six different acids have been identified in e-liquid formulations, alone or in combination, but the most common are lactic, benzoic, and levulinic acids (142). Nicotine benzoate is one of the most thermally stable organic acids but can decarboxylate under high temperatures to form benzene or phenol (143). Only one study has shown such degradation in ECs, and this effect was limited to high-powered open systems (144).
Harmful health effects from secondhand smoke exposure have been widely reported (145). Although EC aerosol is much simpler than cigarette smoke and does not generate side-stream smoke, bystanders are still exposed to exhaled compounds, especially in indoor conditions.
Studies investigating the extent and nature of this exposure have tended to measure volatile organic compounds, CO2, particulate matter (generally PM2.5 or PM10.0), ultrafine particles, and nicotine. Some studies have found increased concentrations of particulate matter after vaping in indoor settings (146,147,148), but generally conclude that exposure is lower compared to cigarette smoke (149, 150) and is less likely to be harmful to bystanders than second hand smoke (28, 29, 151,152,153). The absolute risk from passive exposure to EC aerosol specially in vulnerable populations, like children, pregnant women and people with impaired respiratory and cardiovascular systems, requires further assessment (151).
As explained in the product stewardship section (see p. 66–67), robust toxicological approaches guided by regulation are essential to screen ingredients and complex mixtures (92, 154). In the screening phase,
Substances of potential concern identified through
Traditional toxicological tests yield complex results and are affected by variability found between and within cell lines, limited translatability to the
Broader toxicological approaches, such as systems toxicology, may be applied. Systems toxicology employs data from techniques like transcriptomics or proteomics from exposed cells to investigate pathways involved in oxidative stress, inflammation, cell proliferation, or DNA damage, and may highlight previously unidentified potential risks (180,181,182,183).
Computational risk assessment methodologies have been proposed to compare cancer potencies across tobacco products (47, 184). Cancer potency can be calculated from EC chemical emissions data and enable comparisons between products by factoring consumer exposure to different products. S
Smoking increases health risks to cardiovascular, respiratory, and other systems soon after the onset of smoking, with the risks of death, disease, and disability rising with increasing duration of use. However, these excess risks are largely reversible with smoking cessation (7). Acute measurements of circulation and lung function may improve within 3–9 months of quitting, and coronary heart disease excess risk due to smoking is halved after 1 year and completely reversed by around 15 years (2, 185). The aim of assessing clinical effects of smoking, therefore, is not only to investigate damage caused but also to assess whether changing behaviour can reduce these excess risks and/or lead to functional benefits.
Satisfactory nicotine delivery is critical to the acceptability of ECs. Despite the popularity of later-generation ECs, many users relapse to smoking alone or alongside EC use (dual use) raising concerns about the viability of ECs as a long-term alternative to cigarettes (186,187,188,189). Data from 1,489 current adult smokers reported they discontinued using ECs mostly because the experience was not close enough to smoking and cravings were not reduced (189). Later-generation EC designs have attempted to address these issues through use of higher power, improved coil heating elements, and nicotine delivery without irritation (190).
Pharmacokinetic clinical trials are often used to investigate safety, nicotine delivery, and acceptability of ECs. These studies assess the likelihood of product-related adverse effects, describe the concentration-time profile for nicotine, and provide insights into the relationship between nicotine concentration and specific responses (e.g., urge for product, craving, and product liking/satisfaction). Pharmacokinetic endpoints estimated from these studies can be used to make comparisons between different EC products and with other product classes (e.g., combustible cigarettes and nicotine replacement therapies (NRTs)).
The average maximum concentration (Cmax) of nicotine with smoking is 10–21 ng/mL, depending on the “tar” and nicotine yield of the cigarette (191,192,193,194,195,196,197). For NRT, Cmax is generally in the range 2–18 ng/mL, depending on the nicotine concentration, type of device, and usage (198,199,200). Early pharmacokinetic studies using first-generation (cig-a-like) ECs with similar nicotine concentrations to NRT and a fixed puffing protocol for 5 min reported Cmax of 1.3–17 ng/mL (201,202,203). Second- and third-generation ECs improved nicotine delivery under similar conditions (Cmax 4–12.8 ng/mL) (100, 201, 204,205,206). Fourth-generation ECs using protonated nicotine have substantially lessened or even closed the nicotine bioavailability gap between cigarette smoke and EC vapour (139, 207, 208). For instance, E
Product use also has an impact on nicotine delivery, with more experienced users achieving greater nicotine concentrations (209, 210). Finally, satisfaction with e-liquid formulations containing nicotine might be limited by sensorial aspects, as nicotine content and flavour strength seem to correlate with harshness or throat irritation and perception of bitterness (51). Together, these findings could explain the results from some studies suggesting that ECs are more successful than NRT in providing smokers a satisfactory alternative to cigarettes (211, 212). Table 3 summarises some of the findings from Pharmacokinetic studies according to EC type/generation.
Summary of pharmacokinetic, pharmacodynamic, vital signs profiles of combustible cigarettes, e-cigarettes (first to fourth generation), and nicotine-replacement therapy.
| Reference | Product type (nicotine concentration) | Pharmacokinetic parameters | Pharmacodynamic parameters | Vital signs | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Cmax (ng/mL) | Tmax (min) | AUC (ng•min/mL) | Cravings | Urge to smoke | Sensory evaluation/satisfaction | Heart rate (bpm) | Systolic BP (mm Hg) | Diastolic BP (mm Hg) | ||
| D | Lucky Strike Red (14.6 mg) | 12.8 | 7.20 | 14.8 | N/A | N/A | N/A | N/A | N/A | N/A |
| Y | Marlboro Gold King Size (0.8 mg) | 15.84S29.23 | N/A | N/A | N/A | N/A | N/A | 4.26 increase in heart rate | 5.74 change in systolic BP | 6.78 change in diastolic BP |
| E | Benson & Hedges Sky | 14.5 (ad libitum) | 5.00 | 660.0 | N/A | N/A | Increased product satisfaction compared to e-cigarettes | Heart rate increased and decreased in similar trends to PK profiles | N/A | N/A |
| Blue (7 mg ISO tar) | 13.7 (fixed puff) | 7.00 | 631.0 | |||||||
| H | Vuse (48 mg/mL); | 13.6 | 4.0 | 244.9 | N/A | N/A | N/A | N/A | N/A | N/A |
| Gamucci (16 mg/mL); | 9.7 | 6.0 | 169.9 | |||||||
| Blu (18 mg/mL); | 9.1 | 6.0 | 173.1 | |||||||
| Vype (16.8 mg/mL); | 8.5 | 6.0 | 161.0 | |||||||
| E-lites (24 mg/mL); | 7.8 | 6.0 | 157.6 | |||||||
| Puritane (20 mg/mL) | 7.5 | 4.0 | 144.4 | |||||||
| B | Ruyan V8 (16 mg/mL) | 1.3 | 19.6 | N/A | No difference in withdrawal symptoms between the e-cigarette and inhalator | Greater decrease in desire to smoke compared to 0 mg placebo (not significant when adjusted for multiple comparisons) | N/A | N/A | N/A | N/A |
| V | NJOY NPRO (18 mg/mL); Hydro (16 mg/mL) | N/A | N/A | N/A | Some abstinence symptoms suppressed | Decrease in urge to smoke compared to sham condition | No effect on sensory evaluation | No significant change was reported between study products | N/A | N/A |
| N | NJOY King Bold (26 mg/mL) | 3.5–5.1 | 30 s–30 min | 0.67–0.57 | Reduction in craving with the highest decrease immediately after product use, followed by steady incremental increases in craving | N/A | N/A | Heart rate increased through the 10-min mark after the beginning first puffs, then gradually declined towards baseline. Mean increases in heart rate 5 and 10 min after the first series of puffs were 2.4 and 5.3 bpm | N/A | N/A |
| Y | Blu (16 mg/mL, two formulations); Blu (24 mg/mL, three formulations) | 10–17 | N/A | N/A | N/A | N/A | N/A | 1.87–4.09 bpm increase in heart rate following product use | 1.13–3.78 | 3.17–6.783 |
| F | V2 (18 mg/mL) | 2.0 (fixed puff) and ( | N/A | N/A | Similar levels to craving reduction observed compared to third-generation EC | N/A | Burning throat sensation was significantly lower compared to third-generation EC | N/A | N/A | N/A |
| V | V2 (11.7 mg/mL) Green smoke (19.4 mg/mL) | 4.07 | 13 | 88.60 | N/A | Low ratings on perceived smoking urge relief | Low satisfaction and sensory ratings | N/A | N/A | N/A |
| 4.16 | 10 | 121.9 | ||||||||
| V | Mod iTazte (29.9 mg/mL) | 6.6 | 10 | 272.3 | N/A | Provided perceived smoking urge relief | High satisfactionrating, taste, pleasantness, harshness (“throat hit”), and speed of effect | N/A | N/A | N/A |
| H | KangerTech EVOD (20 mg/mL) | 9.9 | 6.0 | 200.6 | N/A | N/A | N/A | N/A | N/A | N/A |
| F | EVIC device with EVOD cartomizer (18 mg/mL) | 4.00 (defined) 21.0 ( | N/A | N/A | Similar levels of craving reduction observed compared to first-generation EC | N/A | Burning throat sensation was significantly higher compared to first-generation EC | N/A | N/A | N/A |
| H | Innokin (20 mg/mL) | 11.9 | 6 | 232.1 | N/A | N/A | N/A | N/A | N/A | N/A |
| V | eGO V2 Pro (29.9 mg/mL) | 5.52 | 10 | 121.9 | N/A | Provided fastest perceived urge relief compared to first- and second-generation EC | High satisfaction rating, taste, pleasantness, harshness (“throat hit”), and speed of effect. | N/A | N/A | N/A |
| E | Vype ePen (18 mg/mL) | 4.79 | 7.0 | 267.0 | N/A | N/A | Poor satisfaction compared to fourth-generation EC | Heart rate increased and decreased in similar trends to PK profiles | N/A | N/A |
| O’C | 5.05 | 8.03 | 99.99 | N/A | Higher Cmax was associated with greater relief on urge to smoke | Similar sensorial perception was reported across all products | N/A | N/A | N/A | |
| 6.51 | 6.97 | 118.5 | ||||||||
| 7.58 | 6.03 | 125.2 | ||||||||
| 10.27 | 7.90 | 190.7 | ||||||||
| blu PRO 48 mg/mL (salt) | 4.85 | 6.91 | 84.84 | |||||||
| E | Vype ePen3 18 mg/mL (freebase; | 6.38 | 7.0 | 325 | N/A | N/A | Higher Cmax was linked to increased satisfaction, except for the 30-mg/mL product | Heart rate increased and decreased in similar trends to pharmaco-kinetic profiles | N/A | N/A |
| Vype ePen3 18 mg/mL (med salt; | 10.8 | 5.0 | 429 | |||||||
| Vype ePen3 30 mg/mL (high salt; | 14.1 | 5.0 | 533 | |||||||
| Vype ePen3 18 mg/mL (med salt; fixed puff); | 5.64 | 5.0 | 326 | |||||||
| Vype ePen3 12 mg/mL (low salt; | 5.97 | 7.0 | 284 | |||||||
| D | Nicotine gum (4.2 mg) | 9.10 | 45.0 | 13.1* | N/A | N/A | All products had little effect on the sensory parameter assessed | N/A | N/A | N/A |
| L | Nicotine Polarilex gum (4 mg) | 12.8 | N/A | 3190 | Craving decreased similarly to snus | Urges to smoke decreased similarly with snus | Salivation and throat burn were rated higher for the 4 mg gum | Mean 20 min increase of heart rate 9.3 (± 9.6), 8.9 (± 6.4), and 9.9 (± 5.1) bpm for 9.9 mg snus, 8.7 mg snus, and nicotine gum, respectively | N/A | N/A |
| D | 1 mg Nicotinell lozenges | 2.30 | 66.0 | 8.30 * | N/A | N/A | N/A | N/A | N/A | N/A |
| 2 mg Nicotinell lozenges | 4.80 | 48.0 | 15.8 * | |||||||
| 2 mg Nicorette gum | 2.90 | 48.0 | 10.6 * | |||||||
| C | 4 mg nicotine lozenges | 10.8 | 66.0 | 44.0 * | N/A | N/A | N/A | N/A | N/A | N/A |
| 4 mg nicotine gum | 10.0 | 54.0 | 34.6 * | |||||||
| H | 6 mg nicotine gum | 13.8 | 30.0 | 46.2 * | N/A | N/A | N/A | N/A | N/A | N/A |
| 4 mg nicotine gum | 10.1 | 30.0 | 30.2 * | |||||||
| 2 mg nicotine gum | 5.90 | 30.0 | 17.1 * | |||||||
| 4 mg nicotine lozenge | 9.30 | 45.0 | 35.3 * | |||||||
| K | 1 mg nicotine mouth spray | 3.30 | 10.0 | 6.60 | N/A | N/A | N/A | N/A | N/A | N/A |
| 2 mg nicotine mouth spray | 5.30 | 12.5 | 12.2 | |||||||
| 4 mg nicotine mouth spray | 9.10 | 10.0 | 23.7 | |||||||
| 4 mg nicotine lozenge | 7.00 | 45.0 | 24.3 | |||||||
| 4 mg nicotine gum | 7.80 | 30.0 | 21.1 | |||||||
| S | 4 mg lozenges prototype I | 18.18 | 66.0 | 87.13 * | N/A | N/A | N/A | N/A | N/A | N/A |
| 4 mg lozenges prototype II | 18.11 | 66.0 | 85.69 * | |||||||
| 4 mg lozenges prototype III (I, II, III had different dissolutions) | 17.11 | 66.0 | 84.59 * | |||||||
| 4 mg Nicorette lozenges | 18.67 | 66.0 | 90.03 * | |||||||
| M | 2 mg nicotine sublingual tablet | 13.2 | 20 | 12.4 * | N/A | N/A | N/A | N/A | N/A | N/A |
| 2 mg Nicorette gum | 14.4 | 20 | 13.5 | |||||||
| L | 4 mg Nicorette gum | 12.8 | 46.0 | 52.1 | N/A | N/A | N/A | N/A | N/A | N/A |
| B | Nicorette inhalator (10 mg) | 2.10 | 32.0 | N/A | No significant decrease in craving compared to placebo or first-generation EC | No significant decrease in craving compared to placebo or first-generation EC | N/A | N/A | N/A | N/A |
| G | N/A | N/A | 59 mg/mL silica wick provided highest level of satisfaction followed by 18 mg/mL silica wick, 18 mg/mL coil wick and 9 mg/mL coil wick | N/A | N/A | N/A | ||||
| JUUL 59 mg/mL with silica wick | 9.3 | 6.2 | 5.0 * | |||||||
| JUUL 18 mg/mL with silica wick | 3.2 | 6.3 | 1.7 * | |||||||
| JUUL 18 mg/mL with cotton wick | 3.3 | 5.8 | 1.8 * | |||||||
| JUUL 9 mg/mL with cotton wick | 2.1 | 6.6 | 1.2 * | |||||||
| JUUL 59 mg/mL with silica wick | 8.3 | 6.4 | 4.6 * | |||||||
| JUUL 18 mg/mL with silica wick | 3.5 | 6.5 | 1.8 * | |||||||
| JUUL 18 mg/mL with cotton wick | 3.3 | 7.1 | 2.1 * | |||||||
| JUUL 9 mg/mL with cotton wick | 2.3 | 6.7 | 1.2 * | |||||||
Abbreviations:
= blood pressure = maximum concentration = electronic cigarette = time to maximum concentration = beats per minute = pharmacokinetic = area under the curve = not analyzed
Reported in ng@h/mL
Biomarkers of exposure (BoEs) to cigarette smoke have long been used to assess the effects of tobacco consumption. Exposure to nicotine and aerosol toxicants is assessed by measurement of nicotine metabolites and toxicant concentrations in biological samples, most often in urine. In most EC studies, reductions in toxicant exposure are benchmarked against cigarette smoke and, therefore, the panels of BoEs are based on compounds known to be present in cigarette smoke. The FDA workshop identified the measurement of BoE for nicotine and 19 HPHCs, including nicotine and tobacco alkaloids, carbon monoxide, tobacco-specific nitrosamines, polycyclic aromatic hydrocarbons, volatile organic compounds, carcinogenic aromatic amines, and metals (213).
Multiple studies have assessed changes in BoEs after study participants’ exposure to EC aerosol (Table 4). In interventional studies, which are generally randomised studies, participants are assigned to use a small number of products or different categories of products (214,215,216,217). Observational studies are often larger and assess products chosen or already used by the consumers (218,219,220,221). Interpretation and extrapolation of results from some randomised studies has been hindered by lack of appropriate descriptions of products used in the study (222), exclusion of appropriate controls to provide context (215, 217), and small sample sizes that limit generalizability (216, 222).
Clinical studies of e-cigarettes.
| Reference | Study design/product | Study arms (subgroups) | Conclusions |
|---|---|---|---|
| S | Cross-sectional study, using unspecified EC or NRT products for ≥ 6 months | Smokers (n = 37) | NNAL, 3HPMA, AAMA, CYMA, MHBMA3, HEMA were expressed as proportions of levels in the smoker arm. Significantly lower levels of all biomarkers were observed for EC only users (2.9–43.5% decrease) that were similar to those in NRT only users. NRT and EC dual users presented similar biomarker levels to the smoking group |
| L | Cross-sectional study, using unspecified ECs or smokeless products | No tobacco (n = 12) | The EC users showed higher levels of xylene, cyanide, styrene, ethylbenzene, and acrolein metabolites than non-tobacco users, but lower levels for toluene and acrolein metabolites. Levels of VOC metabolites in the smokeless tobacco group were similar to those in the non-tobacco group |
| C | Three-period crossover design where dual users (smoked ≥ 5 cigarettes per day and used an EC at least once a day for the past 7 days) to either EC > smoking > no tobacco or smoking > EC > no tobacco, with each condition lasting for 7 days | Dual users (n = 48) | 1-HOP was significantly higher during the smoking period than during dual use but was lower during EC use. NNAL levels decreased significantly from dual use, by 30% during EC use and by 35% during cessation but did not change during smoking |
| H | Cross-sectional study comparing biomarker levels in smoker to ECs switchers (≥ 2 months) with those in smokers from three previously published studies (C | EC users (n = 28) | All biomarkers (1-HOP, total NNAL, 3HPMA, 2HPMA, HMPMA, and SPMA) were significantly lower in EC users than in smokers |
| M | Switching study in which smokers switched to ECs or dual use | EC users (n = 16) | 3HPMA in urine showed significant reductions at 4 weeks after switching compared with baseline (ECs 79%, dual use 60%) |
| G | Switching study in which smokers switched to ECs dual use for 2 weeks then ECs only for 2 weeks | Smokers switching to ECs (n = 20) | Significant reductions were seen after 2 weeks in urine biomarkers of exposure to NNAL and eight VOC metabolite levels (50–69%) and fluorene (42–82%), butnot in those for pyrene, phenanthrene, and naphthalene |
| C | Parallel study in which smokers were randomly assigned in a ratio of 3:1 to switch to an EC (tobacco or menthol flavour) or continue smoking for 12 weeks | Switch to EC (n = 306) | After 12 weeks, 3-HPMA, S-PMA and total NNAL in urine were reduced by around 30% compared with baseline in those who switched to ECs, whereas noreductions were among those who continued smoking |
| O’C | Parallel study of smokers switching to ECs or dual use during 6 days in clinic | Rechargeable EC tobacco flavour (n = 15) | Biomarkers: all urine biomarker measures (total NNAL, 3-HPMA, HMPMA, CEMA, 1-OHP, NNN, MHBMA, S-PMA) were significantly reduced compared to baseline in all groups, except MHBMA in the cherry disposable dual use group; levels in dual users were significantly higher than those in the cessation group |
| S | Cross-sectional study of age and gender matched participants, assessing spot urine samples from EC users, smokers and non-smokers for metals (antimony, cadmium, copper, indium, lead, nickel, rubidium, selenium, silver, titanium, and zinc), metal exposure, and BOPH | EC users (n = 20) | Metals: biomarkers for seleniumwere significantly higher in ECusers than in non-smokers or smokers with means 54.0, 41.8, and 39.7 μg/g creatinine, respectively, and were significantly increased for zinc in EC userscompared to non-smokers (584.5 |
| C | Longitudinal study (52 weeks) of smokers switching to ECs with different concentrations of nicotine | 2.4% nicotine (n = 49) | 82 participants continued smoking, 34 significantly reduced thenumber of cigarettes smoked, and 18 quit smoking after switching |
| P | Retrospective chart review study of changes in respiratory outcomes over 2 years in patients with COPD who were daily EC users (without combustible cigarettes) or smokers, matched for age and sex | Baseline COPD GOLD | FEV1, FVC and ratio FEV1/FVC ratio did not change from baseline values in either EC users or smokers, whereas COPD exacerbations were reduced and 6-min walking test scores increased compared with baseline in the EC users group but not the smoking group |
| P | Switch study of smokers switching to an EC for 30 days with choice of seven flavours and two nicotine concentrations (12 or 24 mg/mL) | Smokers (n = 37) | Cigarette consumption: decreased significantly from mean 24.8 days to 14.0 days per month and mean 8.7 to 4.4 cigarettes per day, with six participants quitting, 21 becoming dual users and the remaining 10 sporadic EC only users |
| A | Cross sectional study of nickel and chromium concentrations in EC users | EC users (n = 59) | Concentrations in urine, saliva, and breath: were below the limit of detection for nickel in 4.7%, 3.2% and 3.1% of samples, respectively, and for chromium in 7.8%, 1.6% and 56.3% of samples |
| W | Symptoms study after experimental exposure of healthy non-asthmatic volunteers to propylene glycol mist for 1 min | Healthy volunteers (n = 27) | Symptom VAS ratings: showed significant increase of ocular irritation, throat irritation, and dyspnoea but no effects on solvent smell or other symptoms |
| G | Cross-sectional analysis of population in longitudinal Population Assessment of Tobacco and Health (PATH) study for biomarker concentrations | Smokers (n = 2411) | NNAL: concentrations were significantly lower in never-smokers than in EC users and in both groups compared with smokers (geometric mean 0.921 |
| O | Cross-sectional observational study comparing biomarkers of exposure and BOPH in ex-smoker (≥10 cigarettes per day for ≥10 years) EC users (≥6 months) with current smokers | Smokers (n = 62) | Biomarkers of exposure: concentrations of total NNAL, nicotine equivalents, 3HPMA, and COHb were lower in EC users than smokers |
| P | Baseline assessments for longitudinal observational cohort study (2 years) of smokers | Smokers (n = 166) | In dual users, lower mean valueswere seen than in smokers for smoking duration (22.1 |
| R | Randomized, controlled, open-label, forced switch parallel group study in smokers of menthol and non-menthol cigarettes who switched to an EC or nicotine gum, to measure biomarkers of exposure after 5 days | Smoker to EC (n = 38) | In all switching groups, total nicotine equivalents in urine, cotinine in plasma, and all biomarkers of tobacco smoke exposure decreased except for 3-OH-B[ |
| S | Cross-sectional study of lung inflammation, measured by cell counts, cytokines, genome-wide gene expression and DNA methylation in bronchoalveolar lavage and brushings, in never smokers, EC users and smokers | Never-smokers (n = 42) | Most inflammatory cell counts and cytokine concentrations in EC users were intermediate between those of smokers and never-smokers, while most biomarkers were similar to those for never smokers, as were differential gene expression and DNA methylation |
Abbreviations:
biomarkers of potential harm chronic obstructive pulmonary disease electronic cigarette mid-expiratory flow rate forced expiratory volume in 1 s forced vital capacity Global Initiative for Chronic Obstructive Lung Disease polycyclic aromatic hydrocarbons peak expiratory flow rate visual analogue scale volatile organic compound 1-hydroxypyrene 2-hydroxypropylmercapturic acid 3-hydroxypropyl mercapturic acid 2-cyanoethylmercapturic acid N-acetyl-S-(N-methylcarbamoyl)-L-cysteine S-benzylmercapturic acid 2-cyanoethylmercapturic acid 2-cyanoethylmercapturic acid carboxyhemoglobin N-acetyl-S-(1-cyano-2-hydroxyethyl)-L-cysteine N-acetyl-S-(2-cyanoethyl)-L-cysteine 2-hydroxyethylmercapturic acid 3-hydroxy-1-methylpropylmercapturic acid N-acetyl-S-(3-hydroxypropyl-1-methyl)-L-cysteine monohydroxy-3-butenyl mercapturic acid methylmercapturic acid N-nitrosoanabasine N-nitrosoanatabine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol N-nitrosonornicotine nicotine replacement therapy phenylmercapturic acid S-phenylmercapturic acid
Biomarkers of exposure to
Some of the larger and longer-term studies provide a clearer picture. In a switching study of 153 smokers who switched from cigarettes to a cig-a-like EC or nicotine gum, R
Large observational studies are more representative in terms of demographics and the EC category (219, 227). However, assessment of usage patterns can be complex in ambulatory studies yet not reflect real-world use in confinement settings where product use can be controlled. In all studies, especially large observational studies, the numbers of BoEs that may be assessed might be hampered by resource availability.
Overall, measurement of BoEs appears to reflect toxicant delivery differences observed in chemistry assessments.
Disease-associated biomarkers known as biomarkers of potential harm (BoPHs) could provide valuable information characterising the risk of tobacco products. BoPHs were defined by the Institute of Medicine as the “
Usability of BoPHs to characterize risk associated with ECs is underpinned by reversibility of smoking harm achieved through complete cessation of tobacco products. Most clinical studies compare disease-associated BoPHs in vapers against those in smokers and a cessation group used as a reference. Many BoPHs are not smoking specific or even disease specific, so contextualization against effects observed in cessation groups is crucial to evaluate validity and biological relevance.
The same shortcomings observed in BoE studies are often found in BoPH studies but are often accentuated due to the non-specific nature of the biomarkers, leading to smaller effect sizes, i.e. requiring larger sample sizes. Other important factors to consider when designing these types of studies is to ensure their time frame is long enough for assessment of biomarker reversibility, as many BoPHs may take months to reveal significant changes.
Few BoPH studies have been done in EC users, and most are cross-sectional and compare self-reported vapers with smokers. No standard panel of BoPHs has been established, but most studies focus on end points related to cancer, cardiovascular disease, the respiratory system, oxidative stress, and inflammation.
Spirometry measurements of lung function, like forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), have been used as surrogate end points for COPD. Most studies comparing FEV1, FVC, or ratio of FEV1 to FVC in healthy vapers and smokers have shown no significant differences (229,230,231). C
For cancer, besides BoEs like NNAL and volatile organic compounds, studies overwhelmingly present lower levels of BoPHs in vapers than in smokers but higher than in cessation groups. Other BoPHs, such as the inflammation biomaker 8-
Improvements in vascular health markers have been reported in smokers who switched to ECs for 1 month, particularly among women (237). Various BoPHs, such as 8-isoprostane (238) and 11-dehydro-thromboxane B2 (239), have been associated with cardiovascular disease. Differences have been reported between smokers and vapers for 11-dehydro-thromboxane B2 (234) but not for 8-isoprostane (222). Some reports have pointed to EC use as a potential cause of endothelial dysfunction (240) and heart rate variability (241, 242). In the PATH study, the association between vaping and heart failure was investigated, and the researchers concluded that respondents suffering heart failure had higher odds of being dual users than exclusive EC users (243). A comparison of vapers and/or dual users’ odds of suffering heart failure against those in smokers or never smokers would be of interest.
Most clinical studies assessing ECs have been small and with designs that limit interpretation and generalizability of conclusions. Studies should include appropriate controls, such as a cessation group (including people using NRT), as recommended by the Institute of Medicine (11), to provide context and determine the relevance of changes in relation to the time frame of the study. Much larger and longer-term studies assessing real-world behaviours are needed to fully understand the effects of switching to ECs, as the changes to health might take much longer to manifest than those traceable by other biomarkers in the short term (244).
Whether dual use of combustible cigarettes and ECs provides beneficial changes to the harmful effects of smoking remains unclear. For instance, 5 days after switching half of cigarette consumption to ECs, slight decreases (7–38%) were seen in eight of nine urinary BoE, but concentrations of nicotine equivalents increased by 1–20% (245). In a 7-day switching study, only small reductions in BoEs were found in dual users, with much more substantial reductions seen in exclusive vapers or non-users of any tobacco product (214). In long-term dual users, S
Animal studies have suggested that nicotine has potential teratogenic effects, although the evidence for harmful effects on fetal development and birth outcomes in humans remains unclear (246). NRT is recommended for consideration in pregnant women who have been unable to quit smoking by behavioural changes (247, 248), but increased metabolism of nicotine during pregnancy might affect adherence to nicotine therapy (246, 249, 250). The relative risks of vaping during pregnancy are untested in randomised trials (246), and most data are descriptive and derived from surveys.
Physicians are an important source of information about the risks of nicotine and pregnancy, and women are likely to view them as being able to provide similarly reliable information about vaping. However, without objective data and with developments in devices likely outstripping published evidence, providing objective advice can be difficult (251). Women who use ECs while pregnant seem most commonly to believe that they are less harmful to mothers and babies than combustible cigarettes (although not completely harmless) and that use will help with quitting smoking (26, 252, 253). However, social stigma is viewed as a barrier to EC use in public (252).
Some argue that as the toxicology of ECs is similar to that of NRT (223, 254) it is likely to be a safer alternative to smoking in pregnant women. However, the amount of nicotine consumed via ECs could be as high as that consumed via combustible cigarettes (139, 207, 208, 255) and higher than received from NRT products and dose-effect data are unavailable.
Much more formal and standardised research is needed in this area, particularly on the safety of different nicotine levels, the risks of nicotine dependence among pregnant women who want to quit smoking but have been unable to, and adherence to prevent a return to smoking.
Smoking prevalence is higher among people with mental health illnesses and conditions than in the general population, particularly those with severe mental illness or distress (256, 257). Rates of ever having tried vaping also seem to be higher (258), particularly among people with schizo-affective disorders and bipolar disorder (26). Among smokers with severe mental illness, strong associations were found with EC use, education level, and wish to quit smoking (quit attempt in the previous 6 months) (259).
Misconceptions among health professionals that smokers with severe mental illness are either not willing to quit or will suffer worsening symptoms as a result of doing so is hindering provision of adequate quitting options (260, 261). As well as NRT and supportive behavioural counselling, ASH (262) suggests that ECs could be considered for this subgroup of the population.
Formal studies are needed in this area to clarify the role that ECs could play in tobacco harm reduction.
Tobacco consumption is associated with oral diseases (263), but whether ECs lessen or contribute to the burden is unclear. A study investigating numerous end points (plaque index, bleeding on probing, probing depth, clinical attachment loss, number of missing teeth, and gingival crevicular fluid levels of pro-inflammatory cytokine) found consistent significant differences between smokers and never-smokers, whereas there was no difference between the vapers and never smokers (264). However, in a pilot study, some biomarkers associated with antimicrobial activity and inflammation were increased in EC users compared with in never smokers (265). The findings from these two studies appear to synthesize the conclusion from a systematic review, in which 99 publications investigating ECs and oral health (mouth, throat, periodontal, dental, cytotoxic/genotoxic/oncological, oral microbiome, and traumatic/accidental injury) were assessed (266). Cosmetically, ECs lead to less tooth enamel staining than cigarette smoke. This difference might have social benefits to former smokers who have switched to ECs (267, 268).
Overall, the evidence suggested that while switching from smoking to ECs mitigates some smoking-induced symptoms, a wide range of oral issues could be associated with vaping. However, most of the evidence in the area is weak, with studies so far not specifically designed to assess oral health outcomes.
Perception of risks associated with ECs can be an important determinant of product use (269). Misconceptions about the harmfulness of ECs versus combustible cigarettes seems to be a growing reason among smokers to reject them (38, 59). In this section we review studies investigating perceptions about ECs and nicotine use behaviours associated with those perceptions.
A survey conducted in six European countries suggested that among respondents who were aware of ECs in 2016, 58.5% perceived them to be as risky or of higher risk than cigarettes, increasing to 61.8% in 2018 (270). Only around a quarter of respondents perceived reduced risk with ECs (28.6% and 28.4% in 2016 and 2018, respectively). A similar increasing trend in perceived high risk of ECs was seen in a US survey, where 11.5% (95% CI 10.0–13.2%) of adults viewed them to be as harmful as smoking in 2012 but 36.4% (35.1–37.7%) did so in 2017 (271). The importance of risk perception amongst vapers is clear, as shown in another study where dual users who perceived ECs as being less harmful than smoking were more likely to be exclusive vapers after 1 year than those who did not perceive them as less harmful (7.5%
One criticism of ECs is their inefficacy for sustaining exclusive vaping and propensity to facilitate dual usage (277). These views, in part at least, were based on early studies of products providing low nicotine delivery and hence low user satisfaction (278). While ECs are not marketed as smoking cessation products, a large 1-year study in the UK showed that the smoking abstinence rate among people who switched to later-generation ECs was roughly double that among those who switched completely to NRT (212).
For smokers attempting to quit smoking, higher reward from ECs could help them to completely transition away from combustible cigarettes, as frequency of use of vaping products has been positively associated with becoming a former smoker with quit durations of 2–6 years (188, 279). However, increases in nicotine exposure could raise concerns about the abuse liability of ECs.
Abuse liability is the likelihood of engaging in persistent and problematic use of a substance that will lead to undesirable consequences (280). High nicotine delivery via ECs could increase the risk of abuse liability. However, if ECs can provide a viable alternative to cigarettes, they might have a public health benefit (24, 281, 282) and some degree of abuse liability might be acceptable (283, 284). A standard methodology has been established to assess the abuse liability of pharmaceuticals (285) and is largely adaptable for tobacco products (280, 286). This type of study is likely to be most relevant in countries where high concentrations of nicotine are allowed in e-liquids, such as the USA (287). In a prospective direct comparison of ECs with smoking and NRT (nicotine gum), S
Vaping products have experienced an increase in popularity all around the World. In Europe estimated vaping prevalence increased from 1.5% in 2014 to 1.8% in 2017 (292). Ever use ranged widely from 5.5% to 56.5% and was highest in younger age groups, with studies reporting consumption from respondents ranging from 10–24 years old. In the USA a larger study with 158,626 participants (293) reported ever use of vaping products of 14.8%, 12.8%, 9.4%, 7.0%, 2.3% in the age groups 18–24, 25–34, 35–44, 45–64, ≥65 years, respectively, while regular use (use in ≥20 of the previous 30 days) was more comparable across the same age groups (1.3%, 1.3%, 1.2%, 1.0%, 0.4%, respectively). In the UK, where uptake of ECs has been high, ever use in 2019 was estimated to be 16.5%, 20.1%, 12.3%, 10.8%, 5.2% in the age groups 16–24, 25–34, 35–49, 50–59, ≥60 years and 3.3%, 9.2%, 7.3%, 7.1%, 3.0%, respectively were regular users (294). Prevalence of vaping is generally lower among women than men, as for smoking (292, 295). Most vapers smoke or have smoked in the past. Vapers without smoking history account for a very small proportion of all vapers (26, 292, 294, 296,297,298).
Youth EC initiation has taken centre stage in the EC scientific world since the US Surgeon General declared EC use among youth “
Gateway theory originates in the use of a psychoactive drug being viewed as increasing the likelihood of using further drugs. When applied to vaping, it describes changes in a biological and/or behavioural pathway seen with use of a lower-risk product, such as an EC, increasing the risk of smoking combustible cigarettes for a higher reward (308). This theory has been cited to support the banning or restriction of access to EC products and liquids containing nicotine, for instance in Australia (309), but it is not backed up by reliable evidence (29, 310, 311). Application of such policies risk denying adult smokers the opportunity to switch to ECs and might increase relapse to smoking or smoking initiation (312). K
Consumer use behaviour studies can provide an understanding of puffing topography, potential nicotine uptake, and variability in patterns of usage between different EC types and users (37, 320). The data are crucial for understanding how consumers use products and play a key part in setting the scientific framework for assessing risk potential. EC use differs significantly from cigarette smoking, although more information is needed on topography, perceptions, and behaviours. The US FDA recommends conducting “actual use” studies in “real-world conditions” within their Modified Risk Tobacco Product Application guidelines (73).
Consumer use behaviour studies should adhere to the principles of good clinical research practice, which aim to protect the wellbeing of participants and ensure appropriate study execution and data traceability. Attempts are being made to establish independent ethics committees that can weigh risks against (participant and society) benefits of use behaviour studies conducted with consumer products. Such committees would ensure that the rights, safety, and wellbeing of trial participants prevail over the interests of researchers, science, and society by providing participants with adequate information on study products; details of the study in a scientifically sound protocol; obtaining informed consent from every participant prior to participation; ensuring that the data generated are stored, recorded, handled, and accurately interpreted, verified, and reported by implementing quality systems and procedures.
In a typical EC use behaviour study, volunteers who have given informed consent are trained in the use of the products where necessary to ensure familiarity and are provided with the test product for use at home over a fixed period. Consumption patterns at home are self-reported while periodic attendance at a study site might also be required to assess puffing behaviour with a topography device (320, 321). Questionnaires might be used to obtain feedback about the sensory experience of vaping, satisfaction with selected attributes, and overall acceptability (322). Results from typical topography studies have been summarised in Table 5.
Mouthpiece-based
| Reference | Electronic cigarette type | Mode of activation | Topography device | Mean (± SD) puff characteristics | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| No. of pieces | Components | Rechargeable device | Refillable cartridge | Description | No. of puffs per session | Puff volume (mL) | Puff duration (s) | Puff interval (s) | |||
| B | 1 | All-in-one | No | No | Blu | Puff actuated | CReSSmicro | 33 (± 8) | 56 (± 22) | 2.75 (± 0.96) | 16.9 (± 8.2) |
| C | 1 | All-in-one | Yes | No | Cig-a-like | Puff actuated | Modified SA7 | 21.1 (± 14.9) | 52.2 (± 21.6) | 2.0 (± 0.7) | 23.2 (± 10.6) |
| N | 2 | Battery & cartomizer | Yes | No | Cig-a-like | Puff actuated | CReSSmicro | 8.7 (± 1.6) | 118.2 (± 13.3) | 3.0 (± 1.6) | 29.6 (± 11.7) |
| L | 2 | Battery & cartomizer | Yes | No | Cig-a-like | Puff actuated | CReSSmicro | 21.3 (± 2.4) | 63.3 (± 23.4) | 2.9 (± 0.9) | 22.1 (± 22.0) |
| B | 2 | Battery & cartomizer | Yes | No | V2 | Puff actuated | CReSSmicro | 31 (± 8) | 45 (± 22) | 2.54 (± 1.04) | 18.9 (± 7.3) |
| C | 2 | Battery & cartomizer | Yes | No | Vype ePen | Button activated | Modified SA7 | 16.1 (± 8.0) | 83.0 (± 44.3) | 2.2 (± 0.9) | 29.3 (± 19.2) |
| J | 2 | Battery & cartomizer | Yes | No | IS1.0(T) | Button activated | Modified SA7 | 63.6 (± 36.2) | 41.2 (± 17.0) | 1.5 (± 0.6) | 23.3 (± 17.3) |
H
Connected e-cigarette-based
| Reference | Electronic cigarette type | Mode of activation | Topography device | Mean (± SD) puff characteristics | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| No. of pieces | Components | Rechargeable device | Refillable cartridge | Description | No. of puffs per session | Puff volume (mL) | Puff duration (s) | Puff interval (s) | |||
| R | 2 | Battery & cartomizer | Yes | No | Closed | Puff actuated | Wireless personal use monitor | 225 ± 59 | 133 ± 90 | 3.5 ± 1.8 | 42.7 ± 12.1 |
| R | 2 | Battery & cartomizer | Yes | No | Closed | Puff actuated | Wireless personal use monitor | 78 ± 162 | 65.4 ± 24.8 | 2.0 ± 0.6 | NR |
| D | 3 | Battery, cartridge & atomizer | Yes | Yes | Mod | Puff actuated | Connected e-cigarette | 70.7 ± 34.4 | NR | 5.2 ± 1.4 | NR |
| F | 3 | Battery, cartridge & atomizer | Yes | Yes | Mod | Puff actuated | Connected e-cigarette | 57 ± 14.9 | NR | 4.6 ± 1.0 | NR |
| L | 2 | Battery & cartomizer | Yes | No | Closed | Puff actuated | Wireless personal use monitor | 13.7 | 110.3 | 13.7 | 38.1 |
Topography data can be used to improve understanding of baseline characteristics related to EC use, which can then be used to establish representative vaping machine protocols. While standardization of regimes would be valuable to industry, academics, and regulators, no single regime is likely to represent true human behaviour or produce emissions linked closely enough to human exposure given the wide range of puffing behaviours. CORESTA Recommended Method No 81 lays out the essential requirements necessary to generate and collect EC aerosol for analytical testing purposes (112), but the parameters do not reflect intense use.
Rather than using maximum settings for intense regimes, parameters for puff duration, volume, frequency, profile, and number, battery charge status, coil or atomiser age, voltage setting, ventilation setting, and device orientation should be based on representative human usage data. These parameters are not all independent and improved understanding of how different combinations affect the amount of aerosol generated will be central to defining protocols for testing and regulating ECs.
Given the pace of EC innovation, providing the amount of data required for regulatory decisions while a product remains relevant is not always possible. Borrowed from the pharmaceutical industry, the concept of bridging applies the best practice data from an existing product to the design of a similar product and updates only data pertinent to modifications (95). For example, for ‘biosimilars’ in Europe, data from a reference drug are supplied and the only new data are those which show that the new variant does not diverge in safety or efficacy from the reference (325). In ECs this can be translated to maintaining product safety while ensuring the new variant does not increase health risks to users and non-users. Regulatory bodies, such as the FDA, recognize the potential of this approach for ECs as long as it is supported by a rationale and justification (66).
Thus, for an EC variant of an existing product, if the changes do not affect factors like age, gender, race of users or cultural environmental factors, data could be reused from studies using earlier models of the product and new bridging data should be only required only for those aspects which could potentially be affected by the changes.
Modelling has become important to support risk-benefit assessments and policy decisions in tobacco control because it provides projections based on credible simplifications of complex mechanisms underlying nicotine use. The strength of modelling resides in the capability of processing many parameters with complex interactions rather than looking at one aspect of an issue at a time. Additionally, the impact of inputs’ uncertainty may be assessed. A wide range of topics in relation to tobacco control and harm reduction has been assessed, from the impact of taxation of cigarettes (326) to banning menthol cigarettes in the USA (327). In assessment of potential health benefits or burdens from commercialization of ECs, models have been used to consider morbidity or mortality at the population level, including EC use
There are two main types of nicotine population models. First, microsimulation models aggregate changes at the individual level (328). Various parameters can be set to reflect individual characteristics and interactions between the units (people). Macrosimulations involve groups of people considered to be homogenous individuals with respect to the main factors affecting the outcome (329). Macrosimulations can be further separated into two main categories: birth cohort models (330) and system models (331). In birth cohort models, a group of homogenous individuals born in a specific year (e.g., smokers born in 1960) is followed up until death or a timepoint. The potential impact of introducing different scenarios involving ECs is projected, and effects are compared to the counterfactual scenario of no change (i.e., the
Population modelling studies.
| Reference | Focus and assumptions | Conclusions |
|---|---|---|
| L | Projections show that a strategy of replacing cigarette smokingwith vaping would yield substantial life-year gains, even under pessimistic assumptionsregarding cessation, initiation and relative harm | |
| L | Alteration in smoking patterns caused by transitions from trialof e-cigarettes to established vaping (exclusive or dual use) and effects of cessation at later ages in a 1997 birth cohort; measured by estimated public health impact on deaths and life-years lost incorporating evidence-informed parameter estimates | Conservative assumptions indicated reductions of 21% in smoking-attributable deaths and of 20% in life-years lost with established vaping compared to no vaping. Health gains from vaping were especially sensitive to vaping risks and use rates among those who were otherwise likely to smoke cigarettes |
| L | Cohort-specific simulation model of the impact of e-cigarettes containing nicotine on smoking cessation by adult smokers and premature deaths and life-years lost, by gender in two US birth cohorts aged 30 or 50 years in 2012 | Vaping was projected to have a net positive impact on population health over a wide range of plausible levels of use (transitions to dual, exclusive, andno e-cigarette use) and vaping risks, although net impact wassensitive to parameter estimates |
| W | Dynamic model that tracked smoking status in the US adult population and smoking-related deaths over time and the effects of vaping-induced smoking initiation and cessation on life-years saved or lost to the year 2070 | Health benefits were strongly suggested for e-cigarette use, interms of their potential to increase adult smoking cessation, that exceeded risks to healthresulting from increasing the number of youthful smoking initiators |
| P | Multistate life-table model of 16 tobacco-related diseases thatsimulated lifetime quality-adjusted life-years and health-system costs at a 0% discount rate, incorporating transitions from never, former, and current smoker states to and fromregular vaping and based on literature estimates for relative risk of disease incidence for vaping | A regulatory environment permissive of vaping achieved net health-gain and cost savings, although uncertainty intervals were wide |
| C | Agent-based model examining hypothetical scenarios of e-cigarette use by smoking status and e-cigarette effects on smoking initiation and smoking cessation | With current patterns of e-cigarette use by smoking status and the heavy concentration of e-cigarette use among current smokers, simulated effects of e-cigarettes on smoking cessation generated substantiallylarger changes to smoking prevalence than on smoking initiation |
| S | Monte Carlo stochastic simulation model of expected years of life gained or lost due to effects of e-cigarette use on smoking cessation among current smokers and transition to long-term cigarette smoking among never smokers in 2014US population, with model parameters drawn from census counts, national healthand tobacco use surveys, and published literature | The existing evidence and optimistic assumptions about the relative harm of e-cigarette use compared to cigarette smoking, suggest that e-cigarette usecurrently represents more population-level harm than benefit |
| K | A base case model using data on reported cigarette and e-cigarette use patterns in the US and UK to quantify transitionsfrom no cigarette or e-cigarette use to never use of either, cigarette use, e-cigarette use, dual use, or quit | If e-cigarette use increased only among smokers interested in quitting |
| H | System Dynamics Model representing UK population. Assumes the risk of dual users is the same as smokers and any benefit obtained from quitting is lost if there is a relapse to smoking. Provide projections to 2050. | The results suggest that by 2050, smoking prevalence in adults could be as low as 12.4% in the core model and 9.7% (including dual users) in the counterfactual. Smoking-related mortality would be 8.4% and 8.1%, respectively. |
Most studies are based on data from the US adult population. W
L
A model used by B
Not all model projections based on US data have been favourable to ECs. S
Beyond the USA, H
In summary, a wide range of models have been used to assess the potential impact of commercialization of ECs and, when credible inputs are considered, these models have pointed to an overall health benefit at the population level.
Despite extensive variation in EC devices and e-liquid formulations (106), in the absence of tobacco combustion, EC aerosol is much simpler than cigarette smoke and the numbers and concentrations of compounds present are substantially lower (19,20,21,22). To promote comparability and interpretability, testing of ECs should be performed using appropriate puffing parameters (42, 75,76,77,78, 112) and always with the measurement of air blanks to contextualize contamination by laboratory-based toxicants (20).
Frequently, flavouring ingredients are not fully listed on packaging. To maximize safety, manufacturers should restrict flavours to ingredients that are food grade or generally recognised as safe (339), and perform appropriate testing when the toxicological profile is not well characterised (87). Of note, many ingredients have not been tested for safety when consumed by aerosolization and inhalation and/or when heated, and effects might not transfer reliably from ingestion. For example, diacetyl, which gives a butterscotch flavour, is safe to eat but when inhaled in large amounts in popcorn factories was associated with bronchiolitis obliterans, also known as popcorn lung. As a result, this flavouring is banned in ECs in many countries, although testing at the very low levels that would be required has not been performed (93). Such safety aspects of EC design and ingredients continue to evolve through manufacturers product stewardship, and are being reflected in regulatory guidance (106). A wide range of assessment methods, including toxicological assays (88), three-dimensional organotypic models (161, 169, 181), and
The gold standard to investigate EC-associated health risks are clinical and epidemiological studies. However, clinical studies are expensive and, therefore, primarily conducted through sponsorship by large manufacturers, which could bias studies towards well-designed and highly stewarded products. While epidemiological outcomes can be difficult to unveil, as it might take many years to observe significant changes, reversibility of harm from smoking as well as epidemiological effects might be further complicated by the fluidity between products among nicotine users. For exposure to toxicants, reduced levels of BoEs in exclusive vapers have been confirmed at population level, even with heterogeneity in products and how they are used (219), and BoPH and biomarkers of biological effect studies suggest a reduction of risk of acute health effects caused by smoking (340). Further work is required, particularly on endothelial dysfunction, oxidative stress, and cancer.
In conclusion, the harm reduction potential of ECs will be maximized by complete displacement of cigarettes. Two aspects will have a critical impact on the effectiveness of ECs to displace smoking.
First will be the manufacture of robust, high-quality products that compete with conventional cigarettes by satisfying consumers through product performance, sensorial characteristics, and nicotine delivery, while striking a balance against abuse liability. Manufacturers must use these and all other tools they have, including flavours, to make ECs a more attractive proposition to adults than smoking.
Second, public health institutions must unambiguously and accurately inform smokers about the likely reduced risk character of ECs compared with cigarettes. The UK has seen some public health institutions openly supporting ECs as lower risk alternatives to smoking. In 2019, more than 50% of all vapers in the UK used ECs exclusively (294) and smoking prevalence reached a record minimum of 15.8%, down from 16.6% in 2018 (341). Consolidating this trend, the proportion of former smokers in 2019 was the highest recorded at 62.5% (341).
Despite all evidence supporting ECs as reduced risk products as part of a smoking harm reduction framework, outright bans and restrictions of ECs or flavoured e-liquids continue in many countries, and others are introducing restrictions, for example on flavours, that are not supported by scientific evidence. The main reasons being used to ban or legislate against ECs are underage usage and the hypothesis of a gateway effect. However, irresponsible marketing of vaping products has led to a situation of distrust between governments and the vaping industry and is an area that needs to be addressed. As this topic is highly controversial, it may deviate from the scientific focus of this review. It is mentioned as it clearly can have an impact on initiation, but it deserves a publication of its own.
At population level, national surveys do not suggest any gateway effect, and smoking initiation rates among youth in the US also indicate the absence of such an effect and the lowest rates of smoking initiation on record in 2018 (2.29%) (302). Similar patterns have been observed across European countries where ECs are widely available (303) and are also suggested by a study commissioned by H
Regulatory strategies must promote quality in product development led by robust stewardship which is essential to identify and eliminate, or minimize potential hazards
Vapour products have been soundly demonstrated to be able to reduce exposure to toxicants found in conventional cigarette smoke among smokers who transition completely to vapour products
Emerging evidence in biomarkers of effect point to lower risk for most smoking-related disease endpoints, with further research required particularly for cardio-vascular endpoints, where there are conflicting data.
Vapour products must offer a compelling alternative to smoking to attract smokers, including flavours while mitigating products’ youth appeal
Research suggests lower abuse liability from vaping products in comparison with conventional cigarettes
Gateway effect claims are generally not sustained by public data which show lowest levels of smoking initiation ever recorded in key markets such as the US and UK.
Figure 1
Comparison of carbonyl levels in e-cigarette vapour versus cigarette smoke from published studies.
| Category | Device/Cigarette | Regime | No. of puffs | Carbonyls | Units | Reference | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Formaldehyde | Acetaldehyde | Acetone | Acrolein | Propionaldehyde Crotonald | ehyde | MEK | Butyraldehyde | ||||||
| Cigarette | 1R6F | HCI | 9.1 | 4.879 | 158.9 | 62.31 | 14.51 | 13.74 | 4.484 | 15.93 | 3.08 | μg/puff | ( |
| Cigarette | Benson & Hedges Sky Blue | HCI | 8.1 | 5.235 | 177.4 | 65.68 | 15.93 | 15.43 | 5.321 | 17.41 | 4.469 | μg/puff | ( |
| EC Gen1 | Various | 70 / 1.8 / 10 |
150 | 3.2–56.1 | 2.0–13.6 | N/A | 0–41.9 | N/A | N/A | N/A | N/A | μg/150 puffs | ( |
| EC Gen 2 | Various open tank | 55 / 4 / 30 |
10 | 0.9–2.7 | 0.3–1.7 | N/A | 0.7–1.9 | N/A | N/A | N/A | N/A | μg/10 puffs | ( |
| EC Gen 2/3 | Open tank/NHOSS “Lounge” model (no nic./16 mg/mL nic.) | CRM81 | 96 | 0.37–1.48 | 0.16–0.96 | N/A | 0.05–2.1 1 | N/A | N/A | N/A | N/A | ng/mL puff | ( |
| EC Gen 3/4 | ePen | CRM81 | 122 | 106 | 73 | 70 | LOQ | N/A | N/A | 8 | ng/puff | ( |
|
| EC Gen 4 | JUUL rich tobacco (20 mg/mL) | CRM81 | 112 | 76 | 3 | 13 | N/A | N/A | N/A | N/A | ng/puff | ( |
|
| JUUL rich tobacco (18 mg/mL) | CRM81 | 11 | 12 | 36 | 7 | N/A | N/A | N/A | N/A | ng/puff | ( |
||
| CRM81 | 150 | < 2.63 | < 17.5 | < 8.75 | < 4.38 | < 4.38 | < 4.38 | < 4.38 | < 4.38 | μg/150 puffs | ( |
||
| Vype ePen 2 (18 mg/mL nic.) | CRM81 | 268 | 230 | 135.8 | 346 | 96.2 | BLD | BLD | BLD | ng/puff | ( |
||
| Vype ePen 3 (BAT 18 mg/mL nic.) | CRM81 | 52.8 | NQ | 111 | BLD | NQ | BLD | BDL | BLD | ng/puff | ( |
||
Population modelling studies.
| Reference | Focus and assumptions | Conclusions |
|---|---|---|
| L |
Projections show that a strategy of replacing cigarette smokingwith vaping would yield substantial life-year gains, even under pessimistic assumptionsregarding cessation, initiation and relative harm | |
| L |
Alteration in smoking patterns caused by transitions from trialof e-cigarettes to established vaping (exclusive or dual use) and effects of cessation at later ages in a 1997 birth cohort; measured by estimated public health impact on deaths and life-years lost incorporating evidence-informed parameter estimates | Conservative assumptions indicated reductions of 21% in smoking-attributable deaths and of 20% in life-years lost with established vaping compared to no vaping. Health gains from vaping were especially sensitive to vaping risks and use rates among those who were otherwise likely to smoke cigarettes |
| L |
Cohort-specific simulation model of the impact of e-cigarettes containing nicotine on smoking cessation by adult smokers and premature deaths and life-years lost, by gender in two US birth cohorts aged 30 or 50 years in 2012 | Vaping was projected to have a net positive impact on population health over a wide range of plausible levels of use (transitions to dual, exclusive, andno e-cigarette use) and vaping risks, although net impact wassensitive to parameter estimates |
| W |
Dynamic model that tracked smoking status in the US adult population and smoking-related deaths over time and the effects of vaping-induced smoking initiation and cessation on life-years saved or lost to the year 2070 | Health benefits were strongly suggested for e-cigarette use, interms of their potential to increase adult smoking cessation, that exceeded risks to healthresulting from increasing the number of youthful smoking initiators |
| P |
Multistate life-table model of 16 tobacco-related diseases thatsimulated lifetime quality-adjusted life-years and health-system costs at a 0% discount rate, incorporating transitions from never, former, and current smoker states to and fromregular vaping and based on literature estimates for relative risk of disease incidence for vaping |
A regulatory environment permissive of vaping achieved net health-gain and cost savings, although uncertainty intervals were wide |
| C |
Agent-based model examining hypothetical scenarios of e-cigarette use by smoking status and e-cigarette effects on smoking initiation and smoking cessation | With current patterns of e-cigarette use by smoking status and the heavy concentration of e-cigarette use among current smokers, simulated effects of e-cigarettes on smoking cessation generated substantiallylarger changes to smoking prevalence than on smoking initiation |
| S |
Monte Carlo stochastic simulation model of expected years of life gained or lost due to effects of e-cigarette use on smoking cessation among current smokers and transition to long-term cigarette smoking among never smokers in 2014US population, with model parameters drawn from census counts, national healthand tobacco use surveys, and published literature | The existing evidence and optimistic assumptions about the relative harm of e-cigarette use compared to cigarette smoking, suggest that e-cigarette usecurrently represents more population-level harm than benefit |
| K |
A base case model using data on reported cigarette and e-cigarette use patterns in the US and UK to quantify transitionsfrom no cigarette or e-cigarette use to never use of either, cigarette use, e-cigarette use, dual use, or quit | If e-cigarette use increased only among smokers interested in quitting |
| H |
System Dynamics Model representing UK population. Assumes the risk of dual users is the same as smokers and any benefit obtained from quitting is lost if there is a relapse to smoking. Provide projections to 2050. | The results suggest that by 2050, smoking prevalence in adults could be as low as 12.4% in the core model and 9.7% (including dual users) in the counterfactual. Smoking-related mortality would be 8.4% and 8.1%, respectively. |
Clinical studies of e-cigarettes.
| Reference | Study design/product | Study arms (subgroups) | Conclusions |
|---|---|---|---|
| S |
Cross-sectional study, using unspecified EC or NRT products for ≥ 6 months | Smokers (n = 37) |
NNAL, 3HPMA, AAMA, CYMA, MHBMA3, HEMA were expressed as proportions of levels in the smoker arm. Significantly lower levels of all biomarkers were observed for EC only users (2.9–43.5% decrease) that were similar to those in NRT only users. NRT and EC dual users presented similar biomarker levels to the smoking group |
| L |
Cross-sectional study, using unspecified ECs or smokeless products | No tobacco (n = 12) |
The EC users showed higher levels of xylene, cyanide, styrene, ethylbenzene, and acrolein metabolites than non-tobacco users, but lower levels for toluene and acrolein metabolites. Levels of VOC metabolites in the smokeless tobacco group were similar to those in the non-tobacco group |
| C |
Three-period crossover design where dual users (smoked ≥ 5 cigarettes per day and used an EC at least once a day for the past 7 days) to either EC > smoking > no tobacco or smoking > EC > no tobacco, with each condition lasting for 7 days | Dual users (n = 48) | 1-HOP was significantly higher during the smoking period than during dual use but was lower during EC use. NNAL levels decreased significantly from dual use, by 30% during EC use and by 35% during cessation but did not change during smoking |
| H |
Cross-sectional study comparing biomarker levels in smoker to ECs switchers (≥ 2 months) with those in smokers from three previously published studies (C |
EC users (n = 28) | All biomarkers (1-HOP, total NNAL, 3HPMA, 2HPMA, HMPMA, and SPMA) were significantly lower in EC users than in smokers |
| M |
Switching study in which smokers switched to ECs or dual use | EC users (n = 16) |
3HPMA in urine showed significant reductions at 4 weeks after switching compared with baseline (ECs 79%, dual use 60%) |
| G |
Switching study in which smokers switched to ECs dual use for 2 weeks then ECs only for 2 weeks | Smokers switching to ECs (n = 20) | Significant reductions were seen after 2 weeks in urine biomarkers of exposure to NNAL and eight VOC metabolite levels (50–69%) and fluorene (42–82%), butnot in those for pyrene, phenanthrene, and naphthalene |
| C |
Parallel study in which smokers were randomly assigned in a ratio of 3:1 to switch to an EC (tobacco or menthol flavour) or continue smoking for 12 weeks | Switch to EC (n = 306) |
After 12 weeks, 3-HPMA, S-PMA and total NNAL in urine were reduced by around 30% compared with baseline in those who switched to ECs, whereas noreductions were among those who continued smoking |
| O’C |
Parallel study of smokers switching to ECs or dual use during 6 days in clinic | Rechargeable EC tobacco flavour (n = 15) |
Biomarkers: all urine biomarker measures (total NNAL, 3-HPMA, HMPMA, CEMA, 1-OHP, NNN, MHBMA, S-PMA) were significantly reduced compared to baseline in all groups, except MHBMA in the cherry disposable dual use group; levels in dual users were significantly higher than those in the cessation group |
| S |
Cross-sectional study of age and gender matched participants, assessing spot urine samples from EC users, smokers and non-smokers for metals (antimony, cadmium, copper, indium, lead, nickel, rubidium, selenium, silver, titanium, and zinc), metal exposure, and BOPH | EC users (n = 20) |
Metals: biomarkers for seleniumwere significantly higher in ECusers than in non-smokers or smokers with means 54.0, 41.8, and 39.7 μg/g creatinine, respectively, and were significantly increased for zinc in EC userscompared to non-smokers (584.5 |
| C |
Longitudinal study (52 weeks) of smokers switching to ECs with different concentrations of nicotine | 2.4% nicotine (n = 49) |
82 participants continued smoking, 34 significantly reduced thenumber of cigarettes smoked, and 18 quit smoking after switching |
| P |
Retrospective chart review study of changes in respiratory outcomes over 2 years in patients with COPD who were daily EC users (without combustible cigarettes) or smokers, matched for age and sex | Baseline COPD GOLD |
FEV1, FVC and ratio FEV1/FVC ratio did not change from baseline values in either EC users or smokers, whereas COPD exacerbations were reduced and 6-min walking test scores increased compared with baseline in the EC users group but not the smoking group |
| P |
Switch study of smokers switching to an EC for 30 days with choice of seven flavours and two nicotine concentrations (12 or 24 mg/mL) | Smokers (n = 37) | Cigarette consumption: decreased significantly from mean 24.8 days to 14.0 days per month and mean 8.7 to 4.4 cigarettes per day, with six participants quitting, 21 becoming dual users and the remaining 10 sporadic EC only users |
| A |
Cross sectional study of nickel and chromium concentrations in EC users | EC users (n = 59) | Concentrations in urine, saliva, and breath: were below the limit of detection for nickel in 4.7%, 3.2% and 3.1% of samples, respectively, and for chromium in 7.8%, 1.6% and 56.3% of samples |
| W |
Symptoms study after experimental exposure of healthy non-asthmatic volunteers to propylene glycol mist for 1 min | Healthy volunteers (n = 27) | Symptom VAS ratings: showed significant increase of ocular irritation, throat irritation, and dyspnoea but no effects on solvent smell or other symptoms |
| G |
Cross-sectional analysis of population in longitudinal Population Assessment of Tobacco and Health (PATH) study for biomarker concentrations | Smokers (n = 2411) |
NNAL: concentrations were significantly lower in never-smokers than in EC users and in both groups compared with smokers (geometric mean 0.921 |
| O |
Cross-sectional observational study comparing biomarkers of exposure and BOPH in ex-smoker (≥10 cigarettes per day for ≥10 years) EC users (≥6 months) with current smokers | Smokers (n = 62) |
Biomarkers of exposure: concentrations of total NNAL, nicotine equivalents, 3HPMA, and COHb were lower in EC users than smokers |
| P |
Baseline assessments for longitudinal observational cohort study (2 years) of smokers |
Smokers (n = 166) |
In dual users, lower mean valueswere seen than in smokers for smoking duration (22.1 |
| R |
Randomized, controlled, open-label, forced switch parallel group study in smokers of menthol and non-menthol cigarettes who switched to an EC or nicotine gum, to measure biomarkers of exposure after 5 days | Smoker to EC (n = 38) |
In all switching groups, total nicotine equivalents in urine, cotinine in plasma, and all biomarkers of tobacco smoke exposure decreased except for 3-OH-B[ |
| S |
Cross-sectional study of lung inflammation, measured by cell counts, cytokines, genome-wide gene expression and DNA methylation in bronchoalveolar lavage and brushings, in never smokers, EC users and smokers | Never-smokers (n = 42) |
Most inflammatory cell counts and cytokine concentrations in EC users were intermediate between those of smokers and never-smokers, while most biomarkers were similar to those for never smokers, as were differential gene expression and DNA methylation |
Comparison of metal levels in e-cigarette vapour versus cigarette smoke from published studies analysed.
| Category | Device/Cigarette | Regime | No. of puffs | Metals | Units | Source | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mercury | Cadmium | Lead | Chromium | Nickel | Arsenic | Selenium | ||||||
| Cigarette | 1R6F | HCI | 4.68 | 76.1 | BLQ | BLD | BLD | BLQ | BLD | ng/cig | J |
|
| Cigarette | 3R4F | HCI | 4.92 | 93.2 | BLQ | BLD | BLD | BLQ | BLD | ng/cig | J |
|
| EC Gen 1 | Various | 70 / 1.8 / 10 |
150 | N/A | 0.01–0.22 | 0.03–0.57 | N/A | 0.11–0.29 | N/A | N/A | μg/150 puffs |
G |
| Cig-a-like | 10 | N/A | N/A | 0.017 | 0.007 | 0.05 | N/A | N/A | μg/10 puffs |
W |
||
| EC Gen 2/3 | Open tank | N/A | 0.05–0.16 | 6.88–541 | 0.39–15.6 | 1.32–2148 | 0.1–1.59 | N/A | μg/kg |
Z |
||
| EC Gen 3 | Liquids in reference | CRM81 | N/A | < 0.06 | < 0.05–0.12 | < 0.09–1.58 | < 1.08–1.54 | < 0.12–1.33 | N/A | ng/puff |
B |
|
| EC Gen 4 | Closed system | N/A | 0.04–0.05 | 0.88–6.88 | 0.39–0.41 | 1.32–11.9 | 0.09–0.10 | N/A | μg/kg |
Z |
||
| CRM81 | 150 | BLQ | BLD | BLD | BLD | BLQ | BLQ | 0.00024 | μg/puff | O'C |
||
Summary of pharmacokinetic, pharmacodynamic, vital signs profiles of combustible cigarettes, e-cigarettes (first to fourth generation), and nicotine-replacement therapy.
| Reference | Product type (nicotine concentration) | Pharmacokinetic parameters | Pharmacodynamic parameters | Vital signs | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Cmax (ng/mL) | Tmax (min) | AUC (ng•min/mL) | Cravings | Urge to smoke | Sensory evaluation/satisfaction | Heart rate (bpm) | Systolic BP (mm Hg) | Diastolic BP (mm Hg) | ||
| D |
Lucky Strike Red (14.6 mg) | 12.8 | 7.20 | 14.8 | N/A | N/A | N/A | N/A | N/A | N/A |
| Y |
Marlboro Gold King Size (0.8 mg) | 15.84S29.23 | N/A | N/A | N/A | N/A | N/A | 4.26 increase in heart rate | 5.74 change in systolic BP | 6.78 change in diastolic BP |
| E |
Benson & Hedges Sky | 14.5 (ad libitum) | 5.00 | 660.0 | N/A | N/A | Increased product satisfaction compared to e-cigarettes | Heart rate increased and decreased in similar trends to PK profiles | N/A | N/A |
| Blue (7 mg ISO tar) | 13.7 (fixed puff) | 7.00 | 631.0 | |||||||
| H |
Vuse (48 mg/mL); | 13.6 | 4.0 | 244.9 | N/A | N/A | N/A | N/A | N/A | N/A |
| Gamucci (16 mg/mL); | 9.7 | 6.0 | 169.9 | |||||||
| Blu (18 mg/mL); | 9.1 | 6.0 | 173.1 | |||||||
| Vype (16.8 mg/mL); | 8.5 | 6.0 | 161.0 | |||||||
| E-lites (24 mg/mL); | 7.8 | 6.0 | 157.6 | |||||||
| Puritane (20 mg/mL) | 7.5 | 4.0 | 144.4 | |||||||
| B |
Ruyan V8 (16 mg/mL) | 1.3 | 19.6 | N/A | No difference in withdrawal symptoms between the e-cigarette and inhalator | Greater decrease in desire to smoke compared to 0 mg placebo (not significant when adjusted for multiple comparisons) | N/A | N/A | N/A | N/A |
| V |
NJOY NPRO (18 mg/mL); Hydro (16 mg/mL) | N/A | N/A | N/A | Some abstinence symptoms suppressed | Decrease in urge to smoke compared to sham condition | No effect on sensory evaluation | No significant change was reported between study products | N/A | N/A |
| N |
NJOY King Bold (26 mg/mL) | 3.5–5.1 | 30 s–30 min | 0.67–0.57 | Reduction in craving with the highest decrease immediately after product use, followed by steady incremental increases in craving | N/A | N/A | Heart rate increased through the 10-min mark after the beginning first puffs, then gradually declined towards baseline. Mean increases in heart rate 5 and 10 min after the first series of puffs were 2.4 and 5.3 bpm | N/A | N/A |
| Y |
Blu (16 mg/mL, two formulations); Blu (24 mg/mL, three formulations) | 10–17 | N/A | N/A | N/A | N/A | N/A | 1.87–4.09 bpm increase in heart rate following product use | 1.13–3.78 |
3.17–6.783 |
| F |
V2 (18 mg/mL) | 2.0 (fixed puff) and ( |
N/A | N/A | Similar levels to craving reduction observed compared to third-generation EC | N/A | Burning throat sensation was significantly lower compared to third-generation EC | N/A | N/A | N/A |
| V |
V2 (11.7 mg/mL) Green smoke (19.4 mg/mL) | 4.07 | 13 | 88.60 | N/A | Low ratings on perceived smoking urge relief | Low satisfaction and sensory ratings | N/A | N/A | N/A |
| 4.16 | 10 | 121.9 | ||||||||
| V |
Mod iTazte (29.9 mg/mL) | 6.6 | 10 | 272.3 | N/A | Provided perceived smoking urge relief | High satisfactionrating, taste, pleasantness, harshness (“throat hit”), and speed of effect | N/A | N/A | N/A |
| H |
KangerTech EVOD (20 mg/mL) | 9.9 | 6.0 | 200.6 | N/A | N/A | N/A | N/A | N/A | N/A |
| F |
EVIC device with EVOD cartomizer (18 mg/mL) | 4.00 (defined) 21.0 ( |
N/A | N/A | Similar levels of craving reduction observed compared to first-generation EC | N/A | Burning throat sensation was significantly higher compared to first-generation EC | N/A | N/A | N/A |
| H |
Innokin (20 mg/mL) | 11.9 | 6 | 232.1 | N/A | N/A | N/A | N/A | N/A | N/A |
| V |
eGO V2 Pro (29.9 mg/mL) | 5.52 | 10 | 121.9 | N/A | Provided fastest perceived urge relief compared to first- and second-generation EC | High satisfaction rating, taste, pleasantness, harshness (“throat hit”), and speed of effect. | N/A | N/A | N/A |
| E |
Vype ePen (18 mg/mL) | 4.79 | 7.0 | 267.0 | N/A | N/A | Poor satisfaction compared to fourth-generation EC | Heart rate increased and decreased in similar trends to PK profiles | N/A | N/A |
| O’C |
5.05 | 8.03 | 99.99 | N/A | Higher Cmax was associated with greater relief on urge to smoke | Similar sensorial perception was reported across all products | N/A | N/A | N/A | |
| 6.51 | 6.97 | 118.5 | ||||||||
| 7.58 | 6.03 | 125.2 | ||||||||
| 10.27 | 7.90 | 190.7 | ||||||||
| blu PRO 48 mg/mL (salt) | 4.85 | 6.91 | 84.84 | |||||||
| E |
Vype ePen3 18 mg/mL (freebase; |
6.38 | 7.0 | 325 | N/A | N/A | Higher Cmax was linked to increased satisfaction, except for the 30-mg/mL product | Heart rate increased and decreased in similar trends to pharmaco-kinetic profiles | N/A | N/A |
| Vype ePen3 18 mg/mL (med salt; |
10.8 | 5.0 | 429 | |||||||
| Vype ePen3 30 mg/mL (high salt; |
14.1 | 5.0 | 533 | |||||||
| Vype ePen3 18 mg/mL (med salt; fixed puff); | 5.64 | 5.0 | 326 | |||||||
| Vype ePen3 12 mg/mL (low salt; |
5.97 | 7.0 | 284 | |||||||
| D |
Nicotine gum (4.2 mg) | 9.10 | 45.0 | 13.1 |
N/A | N/A | All products had little effect on the sensory parameter assessed | N/A | N/A | N/A |
| L |
Nicotine Polarilex gum (4 mg) | 12.8 | N/A | 3190 | Craving decreased similarly to snus | Urges to smoke decreased similarly with snus | Salivation and throat burn were rated higher for the 4 mg gum |
Mean 20 min increase of heart rate 9.3 (± 9.6), 8.9 (± 6.4), and 9.9 (± 5.1) bpm for 9.9 mg snus, 8.7 mg snus, and nicotine gum, respectively | N/A | N/A |
| D |
1 mg Nicotinell lozenges | 2.30 | 66.0 | 8.30 |
N/A | N/A | N/A | N/A | N/A | N/A |
| 2 mg Nicotinell lozenges | 4.80 | 48.0 | 15.8 |
|||||||
| 2 mg Nicorette gum | 2.90 | 48.0 | 10.6 |
|||||||
| C |
4 mg nicotine lozenges | 10.8 | 66.0 | 44.0 |
N/A | N/A | N/A | N/A | N/A | N/A |
| 4 mg nicotine gum | 10.0 | 54.0 | 34.6 |
|||||||
| H |
6 mg nicotine gum | 13.8 | 30.0 | 46.2 |
N/A | N/A | N/A | N/A | N/A | N/A |
| 4 mg nicotine gum | 10.1 | 30.0 | 30.2 |
|||||||
| 2 mg nicotine gum | 5.90 | 30.0 | 17.1 |
|||||||
| 4 mg nicotine lozenge | 9.30 | 45.0 | 35.3 |
|||||||
| K |
1 mg nicotine mouth spray | 3.30 | 10.0 | 6.60 | N/A | N/A | N/A | N/A | N/A | N/A |
| 2 mg nicotine mouth spray | 5.30 | 12.5 | 12.2 | |||||||
| 4 mg nicotine mouth spray | 9.10 | 10.0 | 23.7 | |||||||
| 4 mg nicotine lozenge | 7.00 | 45.0 | 24.3 | |||||||
| 4 mg nicotine gum | 7.80 | 30.0 | 21.1 | |||||||
| S |
4 mg lozenges prototype I | 18.18 | 66.0 | 87.13 |
N/A | N/A | N/A | N/A | N/A | N/A |
| 4 mg lozenges prototype II | 18.11 | 66.0 | 85.69 |
|||||||
| 4 mg lozenges prototype III (I, II, III had different dissolutions) | 17.11 | 66.0 | 84.59 |
|||||||
| 4 mg Nicorette lozenges | 18.67 | 66.0 | 90.03 |
|||||||
| M |
2 mg nicotine sublingual tablet | 13.2 | 20 | 12.4 |
N/A | N/A | N/A | N/A | N/A | N/A |
| 2 mg Nicorette gum | 14.4 | 20 | 13.5 | |||||||
| L |
4 mg Nicorette gum | 12.8 | 46.0 | 52.1 | N/A | N/A | N/A | N/A | N/A | N/A |
| B |
Nicorette inhalator (10 mg) | 2.10 | 32.0 | N/A | No significant decrease in craving compared to placebo or first-generation EC | No significant decrease in craving compared to placebo or first-generation EC | N/A | N/A | N/A | N/A |
| G |
N/A | N/A | 59 mg/mL silica wick provided highest level of satisfaction followed by 18 mg/mL silica wick, 18 mg/mL coil wick and 9 mg/mL coil wick | N/A | N/A | N/A | ||||
| JUUL 59 mg/mL with silica wick | 9.3 | 6.2 | 5.0 |
|||||||
| JUUL 18 mg/mL with silica wick | 3.2 | 6.3 | 1.7 |
|||||||
| JUUL 18 mg/mL with cotton wick | 3.3 | 5.8 | 1.8 |
|||||||
| JUUL 9 mg/mL with cotton wick | 2.1 | 6.6 | 1.2 |
|||||||
| JUUL 59 mg/mL with silica wick | 8.3 | 6.4 | 4.6 |
|||||||
| JUUL 18 mg/mL with silica wick | 3.5 | 6.5 | 1.8 |
|||||||
| JUUL 18 mg/mL with cotton wick | 3.3 | 7.1 | 2.1 |
|||||||
| JUUL 9 mg/mL with cotton wick | 2.3 | 6.7 | 1.2 |
|||||||
Mouthpiece-based ad libitum topography measurement of various electronic cigarette types.
| Reference | Electronic cigarette type | Mode of activation | Topography device | Mean (± SD) puff characteristics | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| No. of pieces | Components | Rechargeable device | Refillable cartridge | Description | No. of puffs per session | Puff volume (mL) | Puff duration (s) | Puff interval (s) | |||
| B |
1 | All-in-one | No | No | Blu | Puff actuated | CReSSmicro | 33 (± 8) | 56 (± 22) | 2.75 (± 0.96) | 16.9 (± 8.2) |
| C |
1 | All-in-one | Yes | No | Cig-a-like | Puff actuated | Modified SA7 | 21.1 (± 14.9) | 52.2 (± 21.6) | 2.0 (± 0.7) | 23.2 (± 10.6) |
| N |
2 | Battery & cartomizer | Yes | No | Cig-a-like | Puff actuated | CReSSmicro | 8.7 (± 1.6) | 118.2 (± 13.3) | 3.0 (± 1.6) | 29.6 (± 11.7) |
| L |
2 | Battery & cartomizer | Yes | No | Cig-a-like | Puff actuated | CReSSmicro | 21.3 (± 2.4) | 63.3 (± 23.4) | 2.9 (± 0.9) | 22.1 (± 22.0) |
| B |
2 | Battery & cartomizer | Yes | No | V2 | Puff actuated | CReSSmicro | 31 (± 8) | 45 (± 22) | 2.54 (± 1.04) | 18.9 (± 7.3) |
| C |
2 | Battery & cartomizer | Yes | No | Vype ePen | Button activated | Modified SA7 | 16.1 (± 8.0) | 83.0 (± 44.3) | 2.2 (± 0.9) | 29.3 (± 19.2) |
| J |
2 | Battery & cartomizer | Yes | No | IS1.0(T) | Button activated | Modified SA7 | 63.6 (± 36.2) | 41.2 (± 17.0) | 1.5 (± 0.6) | 23.3 (± 17.3) |
Connected e-cigarette-based ad libitum topography measurement of various e-cigarette types.
| Reference | Electronic cigarette type | Mode of activation | Topography device | Mean (± SD) puff characteristics | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| No. of pieces | Components | Rechargeable device | Refillable cartridge | Description | No. of puffs per session | Puff volume (mL) | Puff duration (s) | Puff interval (s) | |||
| R |
2 | Battery & cartomizer | Yes | No | Closed | Puff actuated | Wireless personal use monitor | 225 ± 59 | 133 ± 90 | 3.5 ± 1.8 | 42.7 ± 12.1 |
| R |
2 | Battery & cartomizer | Yes | No | Closed | Puff actuated | Wireless personal use monitor | 78 ± 162 | 65.4 ± 24.8 | 2.0 ± 0.6 | NR |
| D |
3 | Battery, cartridge & atomizer | Yes | Yes | Mod | Puff actuated | Connected e-cigarette | 70.7 ± 34.4 |
NR | 5.2 ± 1.4 | NR |
| F |
3 | Battery, cartridge & atomizer | Yes | Yes | Mod | Puff actuated | Connected e-cigarette | 57 ± 14.9 |
NR | 4.6 ± 1.0 | NR |
| L |
2 | Battery & cartomizer | Yes | No | Closed | Puff actuated | Wireless personal use monitor | 13.7 |
110.3 | 13.7 | 38.1 |