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Research paper
Levels of selected carcinogens and toxicants in vapour from electronic cigarettes
  1. Maciej Lukasz Goniewicz1,2,3,
  2. Jakub Knysak3,
  3. Michal Gawron3,
  4. Leon Kosmider3,4,
  5. Andrzej Sobczak3,4,
  6. Jolanta Kurek4,
  7. Adam Prokopowicz4,
  8. Magdalena Jablonska-Czapla5,
  9. Czeslawa Rosik-Dulewska5,
  10. Christopher Havel6,
  11. Peyton Jacob III6,
  12. Neal Benowitz6
  1. 1Department of Health Behavior, Division of Cancer Prevention and Population Sciences, Roswell Park Cancer Institute, Buffalo, New York, USA
  2. 2Tobacco Dependence Research Unit, Queen Mary University of London, London, UK
  3. 3Department of General and Analytical Chemistry, Medical University of Silesia, Sosnowiec, Poland
  4. 4Department of Chemical Hazards, Institute of Occupational and Environmental Health, Sosnowiec, Poland
  5. 5Polish Academy of Science, Institute of Environmental Engineering, Zabrze, Poland
  6. 6Division of Clinical Pharmacology and Experimental Therapeutics, Departments of Medicine and Bioengineering & Therapeutic Sciences, University of California, San Francisco, California, USA
  1. Correspondence to Dr Maciej L Goniewicz,  Department of Health Behavior, Division of Cancer Prevention and Population Sciences, Roswell Park Cancer Institute, Elm & Carlton Streets / Carlton House A320, Buffalo, NY 14263, USA; maciej.goniewicz{at}roswellpark.org

Abstract

Significance Electronic cigarettes, also known as e-cigarettes, are devices designed to imitate regular cigarettes and deliver nicotine via inhalation without combusting tobacco. They are purported to deliver nicotine without other toxicants and to be a safer alternative to regular cigarettes. However, little toxicity testing has been performed to evaluate the chemical nature of vapour generated from e–cigarettes. The aim of this study was to screen e-cigarette vapours for content of four groups of potentially toxic and carcinogenic compounds: carbonyls, volatile organic compounds, nitrosamines and heavy metals.

Materials and methods Vapours were generated from 12 brands of e-cigarettes and the reference product, the medicinal nicotine inhaler, in controlled conditions using a modified smoking machine. The selected toxic compounds were extracted from vapours into a solid or liquid phase and analysed with chromatographic and spectroscopy methods.

Results We found that the e-cigarette vapours contained some toxic substances. The levels of the toxicants were 9–450 times lower than in cigarette smoke and were, in many cases, comparable with trace amounts found in the reference product.

Conclusions Our findings are consistent with the idea that substituting tobacco cigarettes with e-cigarettes may substantially reduce exposure to selected tobacco-specific toxicants. E-cigarettes as a harm reduction strategy among smokers unwilling to quit, warrants further study. (To view this abstract in Polish and German, please see the supplementary files online.)

  • Electronic nicotine delivery devices
  • Toxicology
  • Carcinogens
  • Harm Reduction

https://doi.org/10.1136/tobaccocontrol-2012-050859

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    Introduction

    An electronic cigarette, also known as e-cigarette, is a type of nicotine inhaler, imitating ordinary cigarettes. Although the majority of e-cigarettes look similar to other tobacco products, such as cigarettes or cigars, certain types resemble pens, screwdrivers or even harmonicas. E-cigarettes contain nicotine solution in a disposable cartridge. The cartridge is replaced when the solution is finished or might be refilled by the e-cigarette user. In contrast with ordinary cigarettes, which involve tobacco combustion, e-cigarettes use heat to transform nicotine solution into vapour. Processed and purified nicotine from tobacco leaves, suspended in a mixture of glycerin or propylene glycol with water, is vapourised. Nicotine present in such vapour enters the respiratory tract, from where it is absorbed to the bloodstream.1–4

    Distributors of e-cigarettes promote the product as completely free of harmful substances. The basis for the claim of harmlessness of the e-cigarettes is that they do not deliver toxic doses of nicotine and the nicotine solution lacks harmful constituents. E-cigarettes are new products and, as such, require further testing to assess their toxic properties. Currently, the scientific evidence on the lack or presence of toxic chemicals in the vapour generated from e-cigarettes, and inhaled by their users is very limited. In August 2008, Ale Alwen, the Assistant Director-General for Non-communicable Diseases and Mental Health, stated that ‘the electronic cigarette is not a proven nicotine replacement therapy. WHO has no scientific evidence to confirm the product's safety and efficacy. However, WHO does not discount the possibility that the electronic cigarette could be useful as a smoking cessation aid. The only way to know is to test.5 Douglas Bettcher, Director of the WHO's Tobacco Free Initiative stated that only clinical tests and toxicity analysis could permit considering e-cigarettes a viable method of nicotine replacement therapy.6

    The majority of tests carried out on e-cigarettes until now consist of analysing the chemicals in the cartridges or nicotine refill solutions.7–18 The current tests show that the cartridges contain no or trace amounts of potentially harmful substances, including nitrosamines, acetaldehyde, acetone and formaldehyde. However, using e-cigarettes requires heating the cartridges and under such conditions chemical reactions may result in formation of new compounds. Such a situation takes place in the case of ordinary cigarettes, where a number of toxic compounds are formed during combustion. The US Department of Health and Human Services of the Food and Drug Administration agency carried out tests which showed the presence of trace amounts of nitrosamines and diethylene glycol in e-cigarette vapour. These tests were conducted in a manner which simulated the actual use of the products.19

    We developed analytical methods and measured concentrations of selected compounds in the vapour generated by different brands and types of e-cigarettes. We focused our study on the four most important groups of toxic compounds present in the tobacco smoke: carbonyl compounds, volatile organic compounds (VOCs), tobacco-specific nitrosamines and metals (table 1).

    View this table:
    Table 1

    Selected toxic compounds identified in tobacco smoke 20–23

    Materials and methods

    Electronic cigarettes and reference product (Nicorette inhalator)

    Since the internet is currently the main distribution channel for the products, we searched price comparison websites, online marketplace (Allegro.pl auction service) and internet discussion forums for e–cigarette users to identify the most popular brands of e–cigarettes distributed from within Poland. The searching was limited to web pages from Poland, and only Polish language was allowed for in retrieval options. Some 30 brands were identified. The brands were entered into Google.pl, and ranked according to the number of hits they generated. The number of hits in the search engine for the selected 30 models allowed selection of the 11 most popular e-cigarettes brands. Additionally, one e-cigarette model purchased in Great Britain was used in the study. All e–cigarette models selected for the study were purchased online. Characteristics of the product tested in the study are shown in table 2.

    View this table:
    Table 2

    Characteristics of products tested in the study

    The suitable cartridges of the same brand name were used for the study. They were purchased from the same sources as that of the e-cigarette and were matched to selected models. All cartridges were characterised by high nicotine content (16–18 mg). As a reference product the medicinal nicotine inhalator was used (Nicorette 10 mg, Johnson&Johnson, Poland). The inhalator for the study was purchased in one of the local pharmaceutical warehouses.

    Generation of vapour from e-cigarettes and reference product

    Vapour from e-cigarettes was generated using the smoking machine Palaczbot (Technical University of Lodz, Poland) as described previously.3 This is a one-port linear piston-like smoking machine with adjustable puffing regimes in a very wide range, controlled by computer interface.

    Pilot samples demonstrated that it was impossible to generate vapour from e–cigarettes in standard laboratory conditions assumed for conventional cigarettes testing (International Organization for Standardization (ISO) 3808).24 Inhalation of a volume of 35 ml anticipated in conventional cigarette standard is insufficient for activation of most of the e-cigarettes. Thus, we decided to generate vapour in conditions reflecting the actual manner of e-cigarettes using, determined based on the results of inhalation topography measurement among 10 ‘e–smokers’, who declared that they regularly use e-cigarettes for a period longer that 1 month.3 All testing procedures in this work were carried out using the same averaged puffing conditions: puff duration of 1.8 s, intervals between puffs of 10 s, puff volume 70 ml and number of puffs taken in one puffing session was 15. A total of 150 puffs were taken from each e-cigarette in 10 series of 15 puffs with intervals between series of 5 min each. Each e-cigarette was tested three times on three following days after batteries were recharged during nights. A fresh cartridge was placed on the e-cigarettes each day they were tested. Vapour was visibly being produced during the full 150 puffs taken from each product tested.

    Analytical chemistry

    Note: The details of the sample preparation and analysis are given in the online supplementary materials.

    It was planned to absorb the analysed vapour components in bulbs containing an organic solvent (extraction to liquid) or on suitable sorbents (extraction to solid phase). This required the modification of the system described above, in such a manner to enable quick connection of desirable sorption system. Carbonyl compounds and organic compounds due to their volatility were trapped in tubes packed with solid adsorbent. Metals and nitrosamines in turn, which are characterised by lower volatility, were to be absorbed in two gas washing bottles with methanol (50 ml in each bottle). Both washing bottles were immersed in acetone-dry ice bath in order to avoid any losses of volatile solvent. A picture of the set for vapour generation from e–cigarette and metals or nitrosamines absorption is presented in online supplementary figure S2.

    The samples, after the preparation and condensation procedure, were analysed using analytical methods with high specificity and sensitivity allowing detection of even trace amounts of analysed compounds. Figure 1 shows the sample preparation procedure; and all analytical methods are described in details in the online supplementary materials. The following carbonyl compounds were analysed in this work using high-performance liquid chromatography with diode array detector (HPLC-DAD): formaldehyde, acetaldehyde, acrolein, acetone, propionic aldehyde, crotonaldehyde, butanol, benzaldehyde, isovaleric aldehyde, valeric aldehyde, m-methylbenzaldehyde, o-methylbenzaldehyde, p-methylbenzaldehyde, hexanal, 2,5-dimethylbenzaldehyde. VOCs included benzene, toluene, chlorobenzene, ethylbenzene, m,p-xylene, o-xylene, styrene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, 1,2-dichlorobenzene, naphthalene and were analysed with gas chromatography-mass spectrometry. Among tobacco-specific nitrosamines two compounds were measured: N′–nitrosonornicotine (NNN) and 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK) with ultra-performance liquid chromatography-mass spectrometry. An inductively coupled plasma mass spectrometry technique was used to quantify following metals: cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), cadmium (Cd), lead (Pb), arsenic (As), chromium (Cr), selenium (Se), manganese (Mn), barium (Ba), rubidium (Rb), strontium (Sr), silver (Ag), thallium (Tl) and vanadium (V). All analytical methods used in this work were validated as per the International Conference on Harmonisation guideline Q2(R1).25

    Figure 1
    Figure 1

    Analytical procedures applied in the study to test carcinogens and selected toxicants in vapour from e-cigarettes. GC-MS, gas chromatography-mass spectrometry; HPLC-DAD, high-performance liquid chromatography with diode array detector; ICP-MS, inductively coupled plasma-mass spectrometry; TSNA, tobacco-specific nitrosamine; UPLC-MS, ultra-performance liquid chromatography-mass spectrometry; VOC, volatile organic compound.

    Statistical analysis

    Results were presented as mean±SEM levels of selected compounds in vapour generated from e–cigarettes (per 150 puffs). The study aimed to compare the results obtained for aerosol from Nicorette inhalator with the results obtained for all examined e–cigarette models. Due to the small size of the groups, the difference between the mean from two groups was assessed based on Student's t test. All statistical analyses were conducted using the software for statistical data analysis Statistica V.9.0 (StaftSoft, Tulsa, USA). The significance level was established as p<0.05.

    Results

    Carbonyl compounds

    Among 15 carbonyls analysed, only 4 were found in vapour generated from e–cigarettes (table 3); and these compounds were identified in almost all examined e–cigarettes. The exception was one e-cigarette marked with code EC09, where acrolein was not detected. Three of the carbonyls have known toxic and irritating properties: formaldehyde, acetaldehyde and acrolein. The content of formaldehyde ranged from 2.0 µg to 56.1 µg, acetaldehyde from 1.1 µg to 13.6 µg, and acrolein from 0.7 µg to 41.9 µg per one e-cigarette (150 puffs). Trace amounts of formaldehyde, acetaldehyde and o-methylbenzaldehyde were also detected from the Nicorette inhalator. None of these compounds were detected in blank samples.

    View this table:
    Table 3

    Levels of selected compounds in vapour generated from e–cigarettes (per 150 puffs)

    Volatile organic compounds

    Among 11 VOCs analysed, only two were found in samples of vapour generated from e-cigarettes (table 3), and these compounds were identified in almost all examined e–cigarettes. The only one exception was e-cigarette marked with code EC02, where toluene and m,p-xylene were not detected. The content of toluene ranged from 0.2 µg to 6.3 µg per one e–cigarette (150 puffs). Although the m,p-xylene levels found in analysed samples of e–cigarette vapours ranged from 0.1 µg to 0.2 µg, it was also found on the same level in blank samples. In Nicorette inhalator in turn, none of the compounds analysed in that group were noted.

    Tobacco-specific nitrosamines

    Both nitrosamines analysed in the study were identified in all but three vapours generated from e-cigarettes (table 3). NNN was not found in e–cigarettes marked with codes EC01, EC04 and EC05 and NNK was not identified in products EC04, EC05 and EC12. The content of NNN ranged from 0.8 ng to 4.3 ng, and NNK from 1.1 ng to 28.3 ng per one e–cigarette (150 puffs). In Nicorette inhalator or in blank samples in turn, none of these compounds was noted.

    Metals

    Among 12 metals analysed in the study, cadmium, nickel and lead were identified, and were present in all vapours generated from e-cigarettes (except cadmium, which was not detected in a product of code EC12; table 3). The content of cadmium ranged from 0.01 µg to 0.22 µg, nickel from 0.11 µg to 0.29 µg and lead from 0.03 µg to 0.57 µg per one e-cigarette (150 puffs). The same metals in trace amounts were detected in Nicorette inhalator and in blank samples.

    Discussion

    We examined vapours generated from 12 models of e-cigarettes for the presence of four groups of toxic compounds found in tobacco smoke. The Nicorette inhalator was used as a reference product. Such a choice was dictated by the premise that a therapeutic product like Nicorette inhalator should fulfil specified safety standards and should not contain significant levels of any of the analysed toxic compounds.

    Our results confirm findings from the previous studies, in which small amounts of formaldehyde and acetaldehyde were detected in cartridges. 9 ,18 However, the presence of acrolein in a cartridge or nicotine solution has not been reported so far. Formaldehyde and acetaldehyde were also found in vapour exhaled to test chamber by volunteers who used e–cigarette filled with three various nicotine solutions.26 Recently, Uchiyama et al27 demonstrated that vapour generated from a single brand of e–cigarette contained low levels of formaldehyde, acetaldehyde and acrolein. There is a possibility that acrolein is present in vapour only, since this compound may be formed as a result of heating glycerin which is a component of the solution. Pyrolysis of glycerin has been studied in steam with acrolein, formaldehyde and acetaldehyde observed as the major products.28 ,29 These products appear to result from dehydration and fragmentation of glycerin. Although energy calculations of the dehydration of glycerin by the neutral mechanisms indicate that these processes can only occur at relatively high temperatures such as in pyrolysis or combustion, the addition of acids allows substantially lower dehydration temperatures.30

    All three carbonyl compounds found in the study and discussed above have been shown to be toxic in numerous studies: formaldehyde is classified as carcinogenic to humans (group 1 by International Agency for Research on Cancer, IARC)31; acetaldehyde as possibly carcinogenic to humans (group 2B),31 and acrolein causes irritation to the nasal cavity, and damage to the lining of the lungs and is thought to contribute to cardiovascular disease in cigarette smokers.32 Exposure to carbonyl compounds found in vapour might cause mouth and throat irritation which is the most frequently reported adverse event among e–cigarette users.1 ,33 A study by Cassee et al34 showed that sensory irritation in rats exposed to mixtures of formaldehyde, acetaldehyde and acrolein is more pronounced than that caused by each of the compounds separately. Future studies should evaluate possible adverse health outcomes of short term and long term exposure to these compounds among users of e–cigarettes and people involuntarily exposed to exhaled vapours.

    We found that the vapour of some e-cigarettes contains traces of the carcinogenic nitrosamines NNN and NNK, whereas neither was detected in aerosol from the Nicorette inhalator. The studies conducted previously reported the presence of NNN and NNK in e–cigarette cartridges in amounts of 3.9–8.2 ng per cartridge,18 ,19 which corresponds with the results on vapour obtained in the present paper. However some other studies have reported that some cartridges are free of nitrosamines.12 This inconsistency of findings of various studies might be due to different analytical methodologies of variable sensitivity applied in the studies discussed above.

    Two of the analysed VOCs were detected: toluene and m,p-xylene. None of the studies conducted until now reported the presence of these compounds in a cartridge, nicotine solution or e–cigarette vapour. None of these compounds were found in a study by Schripp et al26 on passive exposure to e–cigarette vapours. Three toxic metals, cadmium, nickel and lead, were detected in the vapour of analysed e–cigarettes. Since the same elements were also detected in trace amounts in Nicorette inhalator and in blank samples it is possible that there were other sources of these metals. This limitation of the study does not allow us to conclude whether e–cigarette alone may be a significant source of exposure to these chemicals.

    Recently, we published a study on tests for nicotine delivery of Polish and UK e–cigarette brands.3 Many of the same brands in that paper have also been included in this study and tested for toxicants delivery. It should be mentioned that the leading brands with the highest nicotine delivery did not have the highest yields for toxicant delivery. This is important as while selecting the brands for nicotine the worst brands for toxicants generally can be avoided.

    The results allowed us to compare the content of harmful substances between various e–cigarette models and conventional cigarettes (based on literature data).35 To compare levels of selected toxins in e-cigarette vapour and mainstream smoke of a conventional cigarette we assumed that users of e-cigarettes take on overage 15 puffs during one session of product use, and it would correspond to smoking one conventional cigarette. In our study the vapours from e-cigarettes were generated from 150 puffs (10 series of 15 puffs each). For comparison purposes, we assumed that 150 puffs of an e-cigarette correspond to smoking 10 cigarettes. The comparison of toxic substance levels between conventional cigarettes and e-cigarettes is presented in table 4.

    View this table:
    Table 4

    Comparison of toxins levels between conventional and electronic cigarettes

    As shown in table 4 levels of selected toxic compounds found in the smoke from a conventional cigarette were 9–450-fold higher than levels in the vapour of an e–cigarette. Smoking an e-cigarette (also referred to as ‘vaping’) can result in exposure to carcinogenic formaldehyde comparable with that received from cigarette smoking. Formaldehyde was also found in the vapour of medicinal inhalators, at levels that overlapped with those found in e-cigarette vapour. Exposure to acrolein, an oxidant and respiratory irritant thought to be a major contributor to cardiovascular disease from smoking, is 15 times lower on average in e-cigarette vapour compared with cigarette smoke. The amounts of toxic metals and aldehydes in e-cigarettes are trace amounts and are comparable with amounts contained in an examined therapeutic product.

    The results of the study support the proposition that the vapour from e–cigarettes is less injurious than the smoke from cigarettes. Thus one would expect that if a person switched from conventional cigarettes to e-cigarettes the exposure to toxic chemicals and related adverse health effects would be reduced. The confirmation of that hypothesis however, requires further studies involving people using e-cigarette devices.

    The primary limitation of our research is that the puffing profile we used may not reflect actual user puff topography. Hua et al36 reported that e–cigarette users take longer puffs, and that puff duration varied significantly among e–cigarette brands and users. This suggests that actual doses of toxicants inhaled by e–cigarette users might be higher than measured in our study. Similarly to results of tobacco cigarette testing with smoking machines (International Organization for Standardization (ISO), Federal Trade Commission (FTC)) the values obtained in our study should be interpreted with caution. The other limitation of our research is that we have tested only 12 brands of e-cigarettes. There are numerous different brands in the market, and there is little information on their quality control.

    Conclusions

    The vapour generated from e-cigarettes contains potentially toxic compounds. However, the levels of potentially toxic compounds in e-cigarette vapour are 9–450-fold lower than those in the smoke from conventional cigarettes, and in many cases comparable with the trace amounts present in pharmaceutical preparation. Our findings support the idea that substituting tobacco cigarettes with electronic cigarettes may substantially reduce exposure to tobacco-specific toxicants. The use of e-cigarettes as a harm reduction strategy among cigarette smokers who are unable to quit, warrants further study.

    What this paper adds

    • Distributors of e–cigarettes promote the product as completely free of harmful substances. Currently, there is no comprehensive research on the presence of toxic chemicals in the vapour generated from e-cigarettes and inhaled by their users.

    • This study of chemical composition of vapour generated from 12 brands of e-cigarettes revealed that the vapour contained some toxic substances.

    • The levels of potentially toxic compounds in e-cigarette vapour were found to be from ninefold to almost 450-fold lower compared with smoke from conventional cigarettes, and in many cases comparable with trace amounts present in pharmaceutical preparations.

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    Supplementary materials

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    Footnotes

    • Contributors MLG and NB designed the study and wrote the paper. JK, MG and LK tested the products using smoking machine. AS and JK developed the analytical method and measured carbonyl compounds and VOCs. AP, MJC, and CRD developed the analytical method and measured metals. CH and PJ developed the analytical method and measured TSNAs. MLG and JK analysed the data. All contributors approved the final version of the manuscript.

    • Funding This study was conducted while the first author was at Medical University of Silesia, Poland and was supported by the Ministry of Science and Higher Education of Poland under grant number N N404 025638. The study sponsor had no involvement in the study design, collection, analysis and interpretation of data, the writing of the manuscript or the decision to submit the manuscript for publication. Analysis of nitrosamines at the University of California, San Francisco was supported by grants P30 DA012393 and S10 RR026437 from the National Institutes of Health.

    • Competing interests MLG received research funding from Pfizer, manufacturer of stop smoking medication and is currently funded by the UK Centre for Tobacco Control Studies (UKCTCS), UK Public Health Centre of Excellence. UKCTCS receives it funding from the Economic and Social Research Council (ESRC), British Heart Foundation (BHF), Cancer Research UK, National Institute for Health Research (NIHR), and Medical Research Council (MRC). Dr Benowitz is a consultant for several companies that market smoking cessation medications and has been a paid expert in litigation against tobacco companies. The other authors declare they have no actual or potential competing financial interests.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement Data could be made available to qualified researchers by request to the corresponding author.