TY - JOUR
AU1 - Farsalinos, Konstantinos, E
AU2 - Yannovits,, Nikoletta
AU3 - Sarri,, Theoni
AU4 - Voudris,, Vassilis
AU5 - Poulas,, Konstantinos
AB - Abstract Introduction The purpose was to measure nicotine levels to the tobacco and levels emitted to the aerosol of a heat-not-burn product (HnB, IQOS) compared to e-cigarettes (ECs) and a tobacco cigarette. Methods The HnB device and regular and menthol sticks were purchased from Italy. Three types of ECs (ciga-like, eGo-style, and variable wattage) and a commercially-available tobacco cigarette were also tested. A custom-made liquid containing 2% nicotine was used with ECs. Products were tested using Health Canada Intense puffing regime while HnB and ECs were additionally tested using a 4-second puff duration regime while maintaining the same puff volume. Results Nicotine content in HnB regular and menthol tobacco sticks was 15.2 ± 1.1 mg/g and 15.6 ± 1.7 mg/g tobacco respectively. The levels of nicotine to the aerosol were similar for regular and menthol HnB products (1.40 ± 0.16 and 1.38 ± 0.11 mg/12 puffs respectively) and did not change significantly with prolonged puff duration. The tobacco cigarette delivered the highest level of nicotine (1.99 ± 0.20 mg/cigarette), with levels being higher than HnB and ECs under Health Canada Intense regime but similar to eGo-style and variable wattage ECs at prolonged puff duration regime. Conclusions The HnB product delivers nicotine to the aerosol at levels higher than ECs but lower than a tobacco cigarette when tested using Health Canada Intense puffing regime. No change in HnB nicotine delivery was observed at prolonged puff duration with the same puff volume, unlike ECs which deliver more nicotine with longer puff duration. Implications Nicotine delivery to the smoker is expected to play an important role in the ability of any harm-reduction product to successfully substitute smoking. This study evaluated the content and nicotine delivery to the aerosol of a heat-not-burn tobacco product (IQOS) in comparison with e-cigarettes and a tobacco cigarette. The main findings were that the heat-not-burn tobacco sticks contained similar nicotine concentration to tobacco cigarettes, and that the levels of nicotine delivered to the aerosol of the heat-not-burn products were lower than tobacco cigarette, higher than e-cigarettes at low puff duration but lower than high-power e-cigarettes at longer puff duration. Introduction Tobacco cigarette use is a highly addictive habit, making cessation a difficult and challenging task. One of the reasons for this is related to the speed and level of nicotine delivery to smokers. Nicotine replacement therapies typically deliver low doses of nicotine with a slower rate of delivery,1 making them largely ineffective as smoking substitutes. Other smoking cessation medications are not popular among smokers, but also fail in the majority of those who choose to use them.2,3 Quitting without the use of any aid is the most common cessation method used by smokers but it is also the least effective, with a success rate of less than 5% in 1 year.4 Due to these limitations, tobacco harm reduction has been advocated as an additional option for smokers unable or unwilling to quit by themselves or with medications. This approach is based on the principle of providing nicotine through less harmful, noncombustible products. Electronic cigarettes (ECs) are currently the most popular harm-reduction products, but still not all smokers find them effective or satisfactory enough in fully substituting smoking. This could be related, at least in part and for less advanced products, to insufficient nicotine delivery compared to tobacco cigarettes. Surveys of EC users have shown that high nicotine levels are used initially, with some of them having to increase the nicotine concentration in order to successfully quit smoking.5 Studies of nicotine delivery from first-generation ECs showed minimal and slow absorption of nicotine.6,7 This is related to the low nicotine delivery to the aerosol of such products.8,9 Laboratory studies of newer generation devices have shown more effective nicotine delivery to the aerosol,8 while some studies have shown that nicotine absorption from EC use can be as effective and fast as smoking,10,11 but not for all products.12 In any case, evidence suggests that nicotine delivery plays a major role in an attempt to quit smoking with the use of harm-reduction products. On the other side, nicotine delivery might affect the abuse liability and addictiveness of ECs, especially among youth. Another concept relevant to tobacco harm reduction is to develop heated rather than combustible tobacco cigarettes. In the past, attempts were made to introduce such products to the market in the late 80s.13 One such product (Premier, R.J Reynolds) could deliver nicotine to the smoker when used intensively on a laboratory setting and had low environmental emissions,14 but had limited acceptability because of unpleasant flavor and difficulty to use on a daily basis.13,15 As a result, it was rapidly removed from the market but was reintroduced later as a redesigned product with another name (Eclipse).16–18 This product, which was using a carbon tip with a glass fiber insulator and contained tobacco in an aluminum chamber stick, delivered more nicotine compared to the previous version15,19 had reduced in vitro toxicity20–22 but delivered higher levels of carbon monoxide.18 A new product, IQOS (Philip Morris International, Neuchâtel, Switzerland), was recently introduced to the market. It has been characterized as a heat-not-burn product (HnB), and is in reality an electrically-heated tobacco product. Unlike Premier and Eclipse, it consists of a battery part, which contains a metal plate acting as a heater, a short tobacco stick which is introduced into the battery system, and a battery-pack acting as a charger for the battery device (Figure 1). According to information from the manufacturer, it operates at a maximum temperature of 350°C,23,24 much lower compared to the 900°C measured at the burning zone of a tobacco cigarette,25 and there is no combustion. Studies performed by the manufacturer of the product have shown reduced emissions of toxic chemicals, lower in vitro and in vivo (animal) adverse effects and lower human exposure to harmful and potentially harmful chemicals,26–28 findings that are probably related to the low working temperature of the product. Figure 1. Open in new tabDownload slide The heat-not-burn product tested in this study, composed of a battery charger (A), the battery device (B), and the tobacco sticks box (regular, C). Figure 1. Open in new tabDownload slide The heat-not-burn product tested in this study, composed of a battery charger (A), the battery device (B), and the tobacco sticks box (regular, C). The potential of this product to substitute smoking is expected to be dependent on the level of nicotine that can be delivered to the aerosol and subsequently inhaled by the user. The purpose of this study was to evaluate the levels of nicotine emitted to the aerosol of the HnB product, and compare them with a commercially-available tobacco cigarette and different types of ECs. Methods Materials The HnB device and tobacco sticks were obtained from a tobacco shop in Milan, Italy since they were not available in the Greek market at the time of the study (2015). The sticks were available in two flavors, regular and menthol; both types were purchased. A commercially available tobacco cigarette (Marlboro Regular, Papastratos-Philip Morris International, Athens, Greece) was obtained from a tobacco shop in Athens, Greece. Three types of ECs were obtained from online and physical EC shops. One was a “ciga-like,” first-generation, device consisting of a rechargeable battery and a cartomizer (Vapour 2 cigs, Prague, Czech Republic). The choice was based on the availability of empty cartomizers that can be filled with liquid by the consumer. An “eGo style,” second-generation EC device (Epsilon, Nobacco, Athens, Greece) was also used, consisting of an eGo battery with a capacity of 1100 mAh and a tank-type bottom coil atomizer. Finally, a variable wattage device, consisting of a battery device (EVIC VTC Mini, Joyetech, Shenzhen, China) and a tank-type atomizer (Nautilus Mini, Aspire, Shenzhen, China) was purchased from an EC shop in Greece. This was the only device with the ability to adjust power settings. The liquid used for the ECs was custom made at the laboratory, composed of 45% propylene glycol, 45% glycerol, 8% water and 2% nicotine. This is the maximum concentration of nicotine legally available to the European Union market according to the 2014 Tobacco Products Directive, while the proportion of humectants represents a common formulation for commercial EC liquids.8 Protocol Design A custom-made, programmable for puff number, duration and volume, smoking machine was used to produce and collect the aerosol and smoke from each product. An automatic push mechanism was connected to the controller, which pushed the activation button of the second and third-generation EC devices at the time of puff initiation and during the whole puff duration time. The first-generation EC product was automatically activated during puff initiation through an internal pressure switch. The variable wattage device was tested at a power setting of 8 W. No information on the power delivery of the other EC devices was available but, in general, eGo style batteries provide more power delivery than ciga-likes. Smoke and aerosol from all products was produced using Health Canada Intense puffing regime (55 mL puff volume, 27.5 mL/s puff flow rate, 2 s puff duration, 30 s interpuff interval). For ECs and IQOS, an additional puffing regime (55 mL puff volume, 13.75 mL/s puff flow rate, 4 s puff, and 30 s interpuff interval) was used to collect aerosol. It has been shown that nicotine delivery from ECs depends on puff duration,29 so the purpose of the second puffing regime was to assess the effect of prolonged puffs on nicotine delivery to the aerosol of the HnB product. The battery device of the HnB is discharged after approximately 6 minutes, while the device needs to be preheated for approximately 20 seconds before being used. Therefore, we considered a usable puffing time of 5 minutes and 30 seconds, and 12 puffs were obtained before the battery was discharged. Two HnB tobacco sticks were used for each aerosol collection (24 puffs in total). For all EC products, each aerosol collection also consisted of 24 puffs. Six repetitions (aerosol and smoke collections) were performed for each product and each puffing pattern, with the exception of the tobacco cigarette for which three smoke collections were performed with the Health Canada Intense regime only. The batteries of all products were fully charged before each aerosol collection. Additionally, the amount of nicotine in unused tobacco sticks (both regular and menthol flavor) of HnB was measured. Nicotine Measurements The method for quantification of nicotine was based on the WHO official method SOP 04.30 Unused tobacco sticks from HnB were examined for the levels of nicotine per weight of tobacco. After careful removal of paper and filter from the tobacco stick, the tobacco was weighted. Subsequently, 200 mg of tobacco was mixed with 1 mL of 2% quinoline solution in n-hexane (used as internal standard), 4 mL distilled water, and 2 mL NaOH. The solution was allowed to rest for 15 minutes. Then, it was introduced to a round bottom flask and 200 mL n-hexane was added. The solution was stirred strongly using a magnetic stirrer for 1 hour and then it was transferred in a separator funnel for the separation of two layers. From the supernatant layer, 200 μL was further diluted with n-hexane to a final volume of 10 mL (extract I). The lower, aqueous layer was re-extracted with 200 mL n-hexane. From the supernatant layer of this second extraction, 200 μL were further diluted with n-hexane to a final volume of 10 mL (extract II). Finally, both extracts were analyzed with GC-NPD for the nicotine content, and the nicotine concentration was calculated as mg/g tobacco. All batteries were fully charged before use. Aerosol and smoke were collected with the use of Cambridge glass fiber filters of 44 mm diameter positioned into a filter holder. The filters were stored at −20°C until analyzed. Nicotine was extracted from the filter using a solution consisting of 2% quinoline as internal standard (0.5 mL), and 19.5 mL isopropanol. The filter with the solution was inserted in a 50 mL tube and was centrifuged for 5 minutes at 3500 rpm. The organic solvent was subsequently decanted and 0.5 mL of it was further diluted with 9.5 mL of isopropanol. Four microliters of the diluted solution were injected in a Gas Chromatography equipped with Nitrogen—Phosphorous Detector (GC-NPD). The analytical methods for the measurement of nicotine in tobacco and aerosol were validated according the Guideline ICH Q2 (R1) of the International Conference on Harmonisation.31 For the calculation of nicotine in tobacco a calibration curve of 5 points was prepared by spiking tobacco with additional nicotine at concentrations 0%, 1%, 2%, 3%, and 4%. Mean recovery of the analytical method was 89.55%, repeatability was 95.45%, and reproducibility was 89.6%. SD ranged from 6.6% to 11.0% and relative SD ranged from 6.5% to 13.2%. For the calculation of nicotine in aerosol collected in Cambridge filters, a calibration curve of 5 points was prepared by spiking Cambridge filters with 0, 0.5, 1.0, 1.5, and 2.0 mg nicotine. Mean recovery of the analytical method was 86.85%, repeatability was 86.85%, and reproducibility was 86.6%. SD ranged from 5.4% to 7.7% and relative SD ranged from 5.5% to 9.7%. Statistical Analysis Values of nicotine in the aerosol of electronic cigarettes and heated tobacco product were expressed as mg/12 puffs. For HnB, this represents nicotine per tobacco stick. For tobacco cigarette smoke, nicotine was expressed as mg/cigarette. The mean value and SD were reported. The levels of nicotine per gram of tobacco in the two HnB tobacco sticks (regular and menthol) were compared with independent samples t-test. Comparisons between different products were performed by one-way analysis of variance (ANOVA) with post-hoc Bonferroni correction. A p value of less than .05 was considered statistically significant and all analyses were performed using commercially-available software (SPSS v22, Chicago, IL). Results Figure 2 displays the level of nicotine per gram of tobacco in the two HnB products. HnB regular was found to contain 15.2 ± 1.1 mg/g while HnB menthol contained 15.6 ± 1.7 mg/g. No statistically significant difference was observed between the two products. Figure 2. Open in new tabDownload slide Nicotine levels (mg/g tobacco) in the regular and menthol heat-not-burn (HnB) sticks. Figure 2. Open in new tabDownload slide Nicotine levels (mg/g tobacco) in the regular and menthol heat-not-burn (HnB) sticks. Figure 3 displays the levels of nicotine delivered to the aerosol of different products (mg/12 puffs) and smoke of tobacco cigarette (mg/cigarette). Statistically significant differences were observed between products and puffing regimes (F = 131.9, p < .001). No difference was observed between HnB regular and menthol at both 2 seconds (1.40 ± 0.16 mg vs. 1.38 ± 0.11 mg) and 4 seconds (1.41 ± 0.08 mg vs. 1.43 ± 0.13 mg) puffing regime. Additionally, no statistically significant difference was observed between 2 seconds and 4 seconds puff with each HnB product. Both HnB products delivered more nicotine than the ciga-like EC at both puffing duration regimes (0.46 ± 0.06 mg at 2 seconds and 0.86 ± 0.08 mg at 4 seconds, p < .001). The eGo style EC delivered less nicotine at 2 seconds (0.51 ± 0.05 mg, p < .001) but more at 4 seconds (1.73 ± 0.09 mg, p < .001) while the variable wattage EC also delivered less nicotine at 2 seconds (0.82 ± 0.06 mg) but more nicotine at 4 seconds (1.84 ± 0.11 mg, p < .001) compared to the HnB products. The tobacco cigarette delivered the highest level of nicotine (1.99 ± 0.20 mg/cigarette); the levels were not statistically different from the eGo style and variable wattage ECs at 4 seconds puffing regime but were higher than both HnB products, ciga-like EC at both puffing regimes and eGo style and variable wattage ECs at 2 seconds puffing regime (p < .001 for all differences). Figure 3. Open in new tabDownload slide Mean levels of nicotine delivered to the aerosol of heat-not-burn (HnB) and e-cigarettes (EC), in mg/12 puffs, at different puffing regimes and of tobacco cigarette (mg/cigarette) at Health Canada Intense puffing regime. Error bars represent SD. Figure 3. Open in new tabDownload slide Mean levels of nicotine delivered to the aerosol of heat-not-burn (HnB) and e-cigarettes (EC), in mg/12 puffs, at different puffing regimes and of tobacco cigarette (mg/cigarette) at Health Canada Intense puffing regime. Error bars represent SD. Discussion To the best of our knowledge, this is the first independent (not performed or funded by the manufacturer) study evaluating nicotine delivery to the aerosol of a novel heat-not burn tobacco product which is already commercially available in several countries. The study showed that the tobacco sticks of this product contain nicotine at concentration (per gram of tobacco) similar to tobacco cigarettes.32 With the puffing regimes tested herein, the delivery of nicotine to the aerosol was lower than a tobacco cigarette, higher than ECs at low puff duration and lower than eGo style and variable wattage ECs at longer puff duration. HnB differed from ECs in terms of the effect of puff duration on aerosol nicotine delivery. Previous studies have shown that puff duration was one of the main determinants of nicotine delivery to the aerosol of ECs.29 This is expected since heat production depends on the total energy (J = W * s) delivered to the atomizer.33 The change in puff duration did not affect the nicotine delivery potential of HnB, mainly because the puff volume was kept constant in the two puffing regimes. However, HnB was able to deliver more nicotine than even third generation ECs with short puff durations. HnB is preheated for approximately 20 seconds and then continuously heats the tobacco stick. Thus, the temperature remains elevated and at levels high enough to produce aerosol during the whole period of use and until the battery is discharged. Contrary to that, ECs deliver energy and generate heat only when activated. After puff intake, there is a progressive drop in coil temperature which may reach to levels very close to environmental temperature until the next puff is taken. Much of the energy delivered at the beginning of the next puff is used to increase the temperature of the coil until the point that evaporation of liquid can begin.34 Thus, it is not unexpected that ECs emitted low levels of nicotine during the short puff duration regime. This finding is in agreement with previous research showing that vapers typically take longer puffs from ECs compared to smokers34,35 and that puff duration is positively associated with plasma nicotine levels.10,36 One limitation of the study is that only puff duration was evaluated as a parameter affecting the levels of nicotine emissions, while the puff volume was the same in both regimes tested. Increasing power delivery has been shown to increase aerosol yield and nicotine emissions in ECs29; thus, variable wattage devices at higher power settings could increase aerosol nicotine delivery even at short puff durations. For HnB, while our findings were similar to nicotine yields reported in a study by the manufacturer (1.32 mg/stick), levels can exceed 2 mg/stick under more intense puffing regimes (110 mL puff volume, 14 puffs/stick).26 It should be noted that the HnB device is automatically deactivated after taking 14 puffs. Other puffing regimes without blocking all the ventilation holes of the tobacco cigarettes (eg, Massachusetts puffing regime) could reduce nicotine delivery from tobacco cigarettes. The observed differences between the products tested in nicotine delivery to the aerosol do not necessarily translate into similar differences in nicotine absorption and plasma nicotine levels. The difference in vehicle transport of nicotine to the lungs might have an impact on the efficiency of nicotine absorption. A study evaluating nicotine intake from HnB showed rapid nicotine delivery, similar concentration–time curves, but lower peak plasma levels of nicotine compared to tobacco cigarettes.37 We are not aware of any study comparing HnB with ECs in nicotine pharmacokinetics. Finally, it should be mentioned that the HnB battery device currently available in the market is different in design from the one available at the time of purchase, while the name of the tobacco sticks has also changed (now called “HEETS”). We cannot confirm if the newer battery device and tobacco sticks have any differences in functional characteristics (eg, heating temperature) or composition. In conclusion, HnB products deliver less nicotine to the aerosol compared to the smoke of a tobacco cigarette under the puffing regimes tested herein. Compared to EC products, higher levels of nicotine emissions were observed at low puff duration, but newer-generation ECs was able to deliver more nicotine at prolonged puffs. Clinical studies should compare the different products in their ability to successfully deliver nicotine and substitute tobacco cigarette use among smokers, while additional studies should assess the difference in toxin emissions and safety-risk profile so that smokers are properly informed about the risk continuum of different smoking substitutes. Of course, the abuse liability and potential addictiveness for nonsmokers should also be examined. Funding No funding was provided for this study. Declaration of Interests Two studies by KEF were funded by the nonprofit association AEMSA in 2013 and one study was funded by the nonprofit association Tennessee Smoke-Free Association in 2015. 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TI - Nicotine Delivery to the Aerosol of a Heat-Not-Burn Tobacco Product: Comparison With a Tobacco Cigarette and E-Cigarettes
JF - Nicotine and Tobacco Research
DO - 10.1093/ntr/ntx138
DA - 2018-07-09
UR - https://www.deepdyve.com/lp/oxford-university-press/nicotine-delivery-to-the-aerosol-of-a-heat-not-burn-tobacco-product-0CSou9DVWC
SP - 1004
VL - 20
IS - 8
DP - DeepDyve
ER -