Konstantinos E. Farsalinos

Nicotine absorption from electronic cigarette use: comparison between experienced consumers (vapers) and naïve users (smokers)

Electronic cigarettes (ECs) are nicotine delivery devices that are proposed as tobacco harm reduction products to smokers. Nicotine delivery from ECs is potentially important in their efficacy as smoking substitutes. Herein, nicotine delivery from using a new-generation EC device (variable-wattage, set at 9 W) was evaluated, comparing experienced (vapers) with naïve users (smokers). Twenty-four vapers and 23 smokers participated to the study. They were asked to obtain 10 puffs in 5 minutes and then use the EC ad lib for 60 more minutes (total duration of use: 65 minutes). An 18 mg/mL nicotine-containing liquid was used. Blood samples were obtained at baseline, 5-minutes and every 15 minutes thereafter, while number of puffs and average puff duration were recorded. Although at baseline both groups had similar plasma nicotine levels, smokers consistently exhibited lower levels at all time-periods; at 5-minutes the levels were lower by 46%, while during the subsequent period they were lower by 43% (at 65-minutes) to 54% (at 20-minutes). Both groups took similar number of puffs, but smokers had average puff duration of 2.3 s compared to 3.5 s in vapers. Even in vapers, plasma nicotine levels at 5 minutes were lower than those observed after smoking 1 tobacco cigarette.

Safety evaluation and risk assessment of electronic cigarettes as tobacco cigarette substitutes: a systematic review:

Electronic cigarettes are a recent development in tobacco harm reduction. They are marketed as less harmful alternatives to smoking. Awareness and use of these devices has grown exponentially in recent years, with millions of people currently using them. This systematic review appraises existing laboratory and clinical research on the potential risks from electronic cigarette use, compared with the well-established devastating effects of smoking tobacco cigarettes. Currently available evidence indicates that electronic cigarettes are by far a less harmful alternative to smoking and significant health benefits are expected in smokers who switch from tobacco to electronic cigarettes. Research will help make electronic cigarettes more effective as smoking substitutes and will better define and further reduce residual risks from use to as low as possible, by establishing appropriate quality control and standards.

Characteristics, Perceived Side Effects and Benefits of Electronic Cigarette Use: A Worldwide Survey of More than 19,000 Consumers

Background: Electronic cigarette (EC) use has grown exponentially over the past few years. The purpose of this survey was to assess the characteristics and experiences of a large sample of EC users and examine the differences between those who partially and completely substituted smoking with EC use. Methods: A questionnaire was prepared, translated into 10 different languages and uploaded in an online survey tool. EC users were asked to participate irrespective of their current smoking status. Participants were divided according to their smoking status at the time of participation in two subgroups: former smokers and current smokers. Results: In total, 19,414 participants were included in the analysis, with 88 of them (0.5%) reported not being smokers at the time of EC use initiation. Complete substitution of smoking was reported by 81.0% of participants (former smokers) while current smokers had reduced smoking consumption from 20 to 4 cigarettes per day. They were using ECs for a median of 10 months. They initiated EC use with a median of 18 mg/mL nicotine-concentration liquids; 21.5% used higher than 20 mg/mL. Only 3.5% of participants were using 0-nicotine liquids at the time of the survey. Former smokers were highly dependent (Fagerström Test for Cigarette Dependence = 7) and were heavier smokers (21 cigarettes per day when smoking) compared to current smokers. The most important reasons for initiating EC use for both subgroups was to reduce the harm associated with smoking and to reduce exposure of family members to second-hand smoking. Most considered ECs as less harmful than tobacco cigarettes, while 11.0% considered them absolutely harmless. Side effects were reported by more than half of the participants (59.8%), with the most common being sore/dry mouth and throat; side effects were mild and in most cases were subsequently resolved (partially or completely). Participants experienced significant benefits in physical status and improvements in pre-existing disease conditions (including respiratory disease such as asthma and chronic obstructive lung disease). Being former smoker was independently associated with positive effects in health and improvements in disease conditions. Conclusions: The results of this worldwide survey of dedicated users indicate that ECs are mostly used to avoid the harm associated with smoking. They can be effective even in highly-dependent smokers and are used as long-term substitutes for smoking. High levels of nicotine are used at initiation; subsequently, users try to reduce nicotine consumption, with only a small minority using non-nicotine liquids. Side effects are minor and health benefits are substantial, especially for those who completely substitute smoking with EC use. Further population and interventional studies are warranted.

Evaluation of Electronic Cigarette Use (Vaping) Topography and Estimation of Liquid Consumption: Implications for Research Protocol Standards Definition and for Public Health Authorities’ Regulation

Background: Although millions of people are using electronic cigarettes (ECs) and research on this topic has intensified in recent years, the pattern of EC use has not been systematically studied. Additionally, no comparative measure of exposure and nicotine delivery between EC and tobacco cigarette or nicotine replacement therapy (NRTs) has been established. This is important, especially in the context of the proposal for a new Tobacco Product Directive issued by the European Commission. Methods: A second generation EC device, consisting of a higher capacity battery and tank atomiser design compared to smaller cigarette-like batteries and cartomizers, and a 9 mg/mL nicotine-concentration liquid were used in this study. Eighty subjects were recruited; 45 experienced EC users and 35 smokers. EC users were video-recorded when using the device (ECIG group), while smokers were recorded when smoking (SM-S group) and when using the EC (SM-E group) in a randomized cross-over design. Puff, inhalation and exhalation duration were measured. Additionally, the amount of EC liquid consumed by experienced EC users was measured at 5 min (similar to the time needed to smoke one tobacco cigarette) and at 20 min (similar to the time needed for a nicotine inhaler to deliver 4 mg nicotine). Results: Puff duration was significantly higher in ECIG (4.2 ± 0.7 s) compared to SM-S (2.1 ± 0.4 s) and SM-E (2.3 ± 0.5 s), while inhalation time was lower (1.3 ± 0.4, 2.1 ± 0.4 and 2.1 ± 0.4 respectively). No difference was observed in exhalation duration. EC users took 13 puffs and consumed 62 ± 16 mg liquid in 5 min; they took 43 puffs and consumed 219 ± 56 mg liquid in 20 min. Nicotine delivery was estimated at 0.46 ± 0.12 mg after 5 min and 1.63 ± 0.41 mg after 20 min of use. Therefore, 20.8 mg/mL and 23.8 mg/mL nicotine-containing liquids would deliver 1 mg of nicotine in 5 min and 4 mg nicotine in 20 min, respectively. Since the ISO method significantly underestimates nicotine delivery by tobacco cigarettes, it seems that liquids with even higher than 24 mg/mL nicotine concentration would be comparable to one tobacco cigarette. Conclusions: EC use topography is significantly different compared to smoking. Four-second puffs with 20–30 s interpuff interval should be used when assessing EC effects in laboratory experiments, provided that the equipment used does not get overheated. Based on the characteristics of the device used in this study, a 20 mg/mL nicotine concentration liquid would be needed in order to deliver nicotine at amounts similar to the maximum allowable content of one tobacco cigarette (as measured by the ISO 3308 method). The results of this study do not support the statement of the European Commission Tobacco Product Directive that liquids with nicotine concentration of 4 mg/mL are comparable to NRTs in the amount of nicotine delivered to the user.

Evaluation of electronic cigarette liquids and aerosol for the presence of selected inhalation toxins.

INTRODUCTION The purpose of this study was to evaluate sweet-flavored electronic cigarette (EC) liquids for the presence of diacetyl (DA) and acetyl propionyl (AP), which are chemicals approved for food use but are associated with respiratory disease when inhaled. METHODS In total, 159 samples were purchased from 36 manufacturers and retailers in 7 countries. Additionally, 3 liquids were prepared by dissolving a concentrated flavor sample of known DA and AP levels at 5%, 10%, and 20% concentration in a mixture of propylene glycol and glycerol. Aerosol produced by an EC was analyzed to determine the concentration of DA and AP. RESULTS DA and AP were found in 74.2% of the samples, with more samples containing DA. Similar concentrations were found in liquid and aerosol for both chemicals. The median daily exposure levels were 56 μg/day (IQR: 26-278 μg/day) for DA and 91 μg/day (IQR: 20-432 μg/day) for AP. They were slightly lower than the strict NIOSH-defined safety limits for occupational exposure and 100 and 10 times lower compared with smoking respectively; however, 47.3% of DA and 41.5% of AP-containing samples exposed consumers to levels higher than the safety limits. CONCLUSIONS DA and AP were found in a large proportion of sweet-flavored EC liquids, with many of them exposing users to higher than safety levels. Their presence in EC liquids represents an avoidable risk. Proper measures should be taken by EC liquid manufacturers and flavoring suppliers to eliminate these hazards from the products without necessarily limiting the availability of sweet flavors.

Impact of Flavour Variability on Electronic Cigarette Use Experience: An Internet Survey

Background: A major characteristic of the electronic cigarette (EC) market is the availability of a large number of different flavours. This has been criticised by the public health authorities, some of whom believe that diverse flavours will attract young users and that ECs are a gateway to smoking. At the same time, several reports in the news media mention that the main purpose of flavour marketing is to attract youngsters. The importance of flavourings and their patterns of use by EC consumers have not been adequately evaluated, therefore, the purpose of this survey was to examine and understand the impact of flavourings in the EC experience of dedicated users. Methods: A questionnaire was prepared and uploaded in an online survey tool. EC users were asked to participate irrespective of their current smoking status. Participants were divided according to their smoking status at the time of participation in two subgroups: former smokers and current smokers. Results: In total, 4,618 participants were included in the analysis, with 4,515 reporting current smoking status. The vast majority (91.1%) were former smokers, while current smokers had reduced smoking consumption from 20 to 4 cigarettes per day. Both subgroups had a median smoking history of 22 years and had been using ECs for 12 months. On average they were using three different types of liquid flavours on a regular basis, with former smokers switching between flavours more frequently compared to current smokers; 69.2% of the former subgroup reported doing so on a daily basis or within the day. Fruit flavours were more popular at the time of participation, while tobacco flavours were more popular at initiation of EC use. On a scale from 1 (not at all important) to 5 (extremely important) participants answered that variability of flavours was “very important” (score = 4) in their effort to reduce or quit smoking. The majority reported that restricting variability will make ECs less enjoyable and more boring, while 48.5% mentioned that it would increase craving for cigarettes and 39.7% said that it would have been less likely for them to reduce or quit smoking. The number of flavours used was independently associated with smoking cessation. Conclusions: The results of this survey of dedicated users indicate that flavours are marketed in order to satisfy vapers’ demand. They appear to contribute to both perceived pleasure and the effort to reduce cigarette consumption or quit smoking. Due to the fact that adoption of ECs by youngsters is currently minimal, it seems that implementing regulatory restrictions to flavours could cause harm to current vapers while no public health benefits would be observed in youngsters. Therefore, flavours variability should be maintained; any potential future risk for youngsters being attracted to ECs can be sufficiently minimized by strictly prohibiting EC sales in this population group.

E‐cigarettes generate high levels of aldehydes only in ‘dry puff’ conditions

BACKGROUND AND AIMS Aldehydes are emitted by electronic cigarettes due to thermal decomposition of liquid components. Although elevated levels have been reported with new-generation high-power devices, it is unclear whether they are relevant to true exposure of users (vapers) because overheating produces an unpleasant taste, called a dry puff, which vapers learn to avoid. The aim was to evaluate aldehyde emissions at different power levels associated with normal and dry puff conditions. DESIGN Two customizable atomizers were prepared so that one (A1) had a double wick, resulting in high liquid supply and lower chance of overheating at high power levels, while the other (A2) was a conventional setup (single wick). Experienced vapers took 4-s puffs at 6.5 watts (W), 7.5 W, 9 W and 10 W power levels with both atomizers and were asked to report whether dry puffs were generated. The atomizers were then attached to a smoking machine and aerosol was trapped. SETTING Clinic office and analytical chemistry laboratory in Greece. PARTICIPANTS Seven experienced vapers. MEASUREMENTS Aldehyde levels were measured in the aerosol. FINDINGS All vapers identified dry puff conditions at 9 W and 10 W with A2. A1 did not lead to dry puffs at any power level. Minimal amounts of aldehydes per 10 puffs were found at all power levels with A1 (up to 11.3 µg for formaldehyde, 4.5 µg for acetaldehyde and 1.0 µg for acrolein) and at 6.5 W and 7.5 W with A2 (up to 3.7 µg for formaldehyde, 0.8 µg for acetaldehyde and 1.3 µg for acrolein). The levels were increased by 30 to 250 times in dry puff conditions (up to 344.6 µg for formaldehyde, 206.3 µg for acetaldehyde and 210.4 µg for acrolein, P < 0.001), while acetone was detected only in dry puff conditions (up to 22.5 µg). CONCLUSIONS Electronic cigarettes produce high levels of aldehyde only in dry puff conditions, in which the liquid overheats, causing a strong unpleasant taste that e-cigarette users detect and avoid. Under normal vaping conditions aldehyde emissions are minimal, even in new-generation high-power e-cigarettes.

Cytotoxicity evaluation of electronic cigarette vapor extract on cultured mammalian fibroblasts (ClearStream-LIFE): comparison with tobacco cigarette smoke extract

Abstract Context: Electronic cigarettes (ECs) are used as alternatives to smoking; however, data on their cytotoxic potential are scarce. Objective: To evaluate the cytotoxic potential of 21 EC liquids compared to the effects of cigarette smoke (CS). Methods: Cytotoxicity was evaluated according to UNI EN ISO 10993-5 standard. By activating an EC device, 200 mg of liquid was evaporated and was extracted in 20 ml of culture medium. CS extract from one cigarette was also produced. The extracts, undiluted (100%) and in five dilutions (50%, 25%, 12.5%, 6.25% and 3.125%), were applied to cultured murine fibroblasts (3T3), and viability was measured after 24-hour incubation by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Viability of less than 70% was considered cytotoxic. Results: CS extract showed cytotoxic effects at extract concentrations above 12.5% (viability: 89.1 ± 3.5% at 3.125%, 77.8 ± 1.8% at 6.25%, 72.8 ± 9.7% at 12.5%, 5.9 ± 0.9% at 25%, 9.4 ± 5.3% at 50% and 5.7 ± 0.7% at 100% extract concentration). Range of fibroblast viability for EC vapor extracts was 88.5–117.8% at 3.125%, 86.4–115.3% at 6.25%, 85.8–111.7% at 12.5%, 78.1–106.2% at 25%, 79.0–103.7% at 50% and 51.0–102.2% at 100% extract concentration. One vapor extract was cytotoxic at 100% extract concentration only (viability: 51.0 ± 2.6%). However, even for that liquid, viability was 795% higher relative to CS extract. Conclusions: This study indicates that EC vapor is significantly less cytotoxic compared tobacco CS. These results should be validated by clinical studies.

Comparison of the Cytotoxic Potential of Cigarette Smoke and Electronic Cigarette Vapour Extract on Cultured Myocardial Cells

Background: Electronic cigarettes (ECs) have been marketed as an alternative-to-smoking habit. Besides chemical studies of the content of EC liquids or vapour, little research has been conducted on their in vitro effects. Smoking is an important risk factor for cardiovascular disease and cigarette smoke (CS) has well-established cytotoxic effects on myocardial cells. The purpose of this study was to evaluate the cytotoxic potential of the vapour of 20 EC liquid samples and a “base” liquid sample (50% glycerol and 50% propylene glycol, with no nicotine or flavourings) on cultured myocardial cells. Included were 4 samples produced by using cured tobacco leaves in order to extract the tobacco flavour. Methods: Cytotoxicity was tested according to the ISO 10993-5 standard. By activating an EC device at 3.7 volts (6.2 watts—all samples, including the “base” liquid) and at 4.5 volts (9.2 watts—four randomly selected samples), 200 mg of liquid evaporated and was extracted in 20 mL of culture medium. Cigarette smoke (CS) extract from three tobacco cigarettes was produced according to ISO 3308 method (2 s puffs of 35 mL volume, one puff every 60 s). The extracts, undiluted (100%) and in four dilutions (50%, 25%, 12.5%, and 6.25%), were applied to myocardial cells (H9c2); percent-viability was measured after 24 h incubation. According to ISO 10993-5, viability of <70% was considered cytotoxic. Results: CS extract was cytotoxic at extract concentrations >6.25% (viability: 76.9 ± 2.0% at 6.25%, 38.2 ± 0.5% at 12.5%, 3.1 ± 0.2% at 25%, 5.2 ± 0.8% at 50%, and 3.9 ± 0.2% at 100% extract concentration). Three EC extracts (produced by tobacco leaves) were cytotoxic at 100% and 50% extract concentrations (viability range: 2.2%–39.1% and 7.4%–66.9% respectively) and one (“Cinnamon-Cookies” flavour) was cytotoxic at 100% concentration only (viability: 64.8 ± 2.5%). Inhibitory concentration 50 was >3 times lower in CS extract compared to the worst-performing EC vapour extract. For EC extracts produced by high-voltage and energy, viability was reduced but no sample was cytotoxic according to ISO 10993-5 definition. Vapour produced by the “base” liquid was not cytotoxic at any extract concentration. Cell survival was not associated with nicotine concentration of EC liquids. Conclusions: This study indicates that some EC samples have cytotoxic properties on cultured cardiomyoblasts, associated with the production process and materials used in flavourings. However, all EC vapour extracts were significantly less cytotoxic compared to CS extract.

Evaluating Nicotine Levels Selection and Patterns of Electronic Cigarette Use in a Group of “Vapers” Who Had Achieved Complete Substitution of Smoking

Background Electronic cigarettes (ECs) are alternative-to-smoking nicotine delivery devices; consumers (commonly called vapers) use them in order to reduce or completely substitute smoking. The European Commission has released a proposal for a new Tobacco Product Directive that might reduce availability of nicotine-containing products, including ECs. In this study, the EC use patterns in subjects who have completely substituted smoking with EC use were examined by personal interviews. The study focused on nicotine levels used in order to achieve smoking cessation, reported benefits, associated side effects, and estimation of EC dependence compared with smoking. Methods Participants were 111 subjects who had completely substituted smoking with EC use for at least 1 month. Smoking abstinence was validated by measuring blood carboxyhemoglobin levels. Nicotine levels at initiation of EC use, at time of smoking cessation, and at time of interview were recorded. Dependence potential was assessed by asking the first question of the Fagerström Test for Cigarette Dependence (time until smoking the first cigarette and until first use of EC in the morning) and questions about perceived past dependence on tobacco cigarettes and present dependence on EC. Results Forty-two percent of participants reported quitting smoking during the first month of EC use. Liquids with nicotine concentration >15 mg/mL were used by 74% of users at initiation of EC use, while 16.2% had to increase the initial nicotine levels in order to achieve complete smoking abstinence. Seventy-two participants (64.9%) reported that from the time of smoking cessation to the time of the interview (8 months median duration of EC use) they reduced the nicotine concentration they were consuming; however, only 12% of the total sample was using ≤5 mg/mL nicotine concentration at the time of the interview. Side effects were mild and temporary. The vast majority of participants reported better exercise capacity and improved olfactory and gustatory senses. Perceived EC dependenct was significantly lower compared to smoking. Conclusions Nicotine levels appear to play an important role in achieving and maintaining smoking cessation in the group of motivated subjects studied. High nicotine-containing liquids were used while few mild and temporary side effects were reported. Proposals about regulation should consider the pragmatic use patterns of ECs, especially in consumers who have completely substituted smoking.