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

Journal Article 1)

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.

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Selected excerpts

For this systematic review (Figure 2), we searched the PubMed electronic database by using keywords related to ECs and/or their combination (e-cigarette, electronic cigarette, electronic nicotine delivery systems). We obtained a total of 354 results, and selected 41 studies we judged relevant to research on EC safety/risk profile. Reference lists from these studies were also examined to identify relevant articles. We searched additional information in abstracts presented at scientific congresses (respiratory, cardiovascular, tobacco control, toxicology), and in reports of chemical analyses on EC samples that were available online.

We also looked for selected studies on chemicals related to EC ingredients (e.g. nicotine, propylene glycol, glycerol, cinnamaldehyde, microparticles emission, etc.), but not specifically evaluated in EC research. In total, 97 publications were found, from which 15 chemical analyses of single or a limited number of EC samples were excluded because they were discussed in a review paper [Cahn and Siegel, 2011]. In total, 114 studies are cited in this paper.

Table 1. Types of studies performed to determine safety and to estimate risk from EC use.

Type of studies Research subject Advantages Disadvantages
Chemical studies Evaluate the chemical composition of liquids and/or aerosol. Examine environmental exposure (passive ‘vaping’). Easier and faster to perform. Less expensive. Could realistically be implemented for regulatory purposes. Usually targeted on specific chemicals. Unknown effects of flavorings when inhaled. No validated protocols for vapor production. Provide no objective evidence about the end results (effects) of use (besides by applying theoretical models).
Toxicological studies Evaluate the effects on cell cultures or experimental animals. Provide some information about the effects from use. Difficult to interpret the results in terms of human in vivo effects. More expensive than chemical studies. Need to test aerosol and not liquid. Standards for exposure protocols have not been clearly defined.
Clinical studies Studies on human in vivo effects. Provide definite and objective evidence about the effects of use. Difficult and expensive to perform. Long-term follow up is needed due to the expected lag from initiation of use to possible development of any clinically evident disease. For now, limited to acute effects from use.

Table 2. Summary of chemical toxicity findings.

Study What was investigated? What were the key findings?
Liquid Vapor
Laugesen [2009] Evaluation of 62 toxicants in the EC vapour from Ruyan 16 mg and mainstream tobacco smoke using a standard smoking machine protocol. N/A No acrolein, but small quantities of acetaldehyde and formaldehyde found. Traces of TSNAs (NNN, NNK, and NAT) detected. CO, metals, carcinogenic PAHs and phenols not found in EC vapour. Acetaldehyde and formaldehyde from tobacco smoke were 55 and 5 times higher, respectively.
Westenberger [2009] Evaluation of toxicants in EC cartridges from two popular US brands. TSNAs and certain tobacco specific impurities were detected in both products at very low levels. Diethylene glycol was identified in one cartridge. N/A
Hadwiger et al. [2010] Evaluation of four refill solutions and six replacement cartridges advertised as containing Cialis or rimonambant. Small amounts of amino- tandalafil and rimonambant present in all products tested. N/A
Cahn and Siegel [2011] Overview of 16 chemical toxicity studies of EC liquids/ vapours. TSNAs levels in ECs 500- to 1400-fold lower than those in conventional cigarettes and similar to those in NRTs. Other chemicals found very low levels, which are not expected to result in significant harm.
Pellegrino et al. [2012] Evaluation of PM fractions and PAHs in the vapour generated from cartomizers of an Italian EC brand. Total TSNAs averaged 12.99 ng/ml EC liquid; daily total TSNA exposure from conventional cigarettes estimated to be up to 1800 times higher. PM fractions were found, but levels were 6– 18 times lower compared with conventional cigarettes. Traces of PAHs detected.
Kim and Shin [2013] TSNAs (NNN, NNK, NAT, and NAB) content in 105 refill liquids from 11 EC brands purchased in Korean shops. The levels of nicotine degradation products represented 0–4.4% of those for nicotine, but for most samples the level was 1–2%. Neither ethylene glycol nor diethylene glycol were detected. N/A
Etter et al. [2013] Nicotine degradation products, ethylene glycol and diethylene glycol evaluation of 20 EC refill liquids from 10 popular brands The levels of nicotine degradation products represented 0–4.4% of those for nicotine, but for most samples the level was 1–2%. Neither ethylene glycol nor diethylene glycol were detected. N/A
Goniewicz et al. [2013] Vapours generated from 12 brands of ECs and a medicinal nicotine inhaler using a modified smoking machine protocol N/A Carbonyl compounds (formaldehyde, acetaldehyde and acrolein), VOCs (toluene and trace levels of xylene), trace levels of TSNAs (NNN and NNK) and very low levels of metals (cadmium, nickel and lead) were found in almost all examined EC vapours. Trace amounts of formaldehyde, acetaldehyde, cadmium, nickel and lead were also detected from the Nicorette inhalator. Compared with conventional cigarette, formaldehyde, acetaldehyde and acrolein were 9–450 times lower; toluene levels 120 times lower; and NNN and NNK levels 380 and 40 times lower respectively.
Williams et al. [2013] Vapour generated from cartomizers of a popular EC brand using a standard smoking machine protocol N/A Trace levels of several metals (including tin, copper, silver, iron, nickel, aluminium, chromium, lead) were found, some of them at higher level compared with conventional cigarettes. Silica particles were also detected. Number of microparticles from 10 EC puffs were 880 times lower compared with one tobacco cigarette.
Burstyn [2014] Systematic review of 35 chemical toxicity studies/ technical reports of EC liquids/vapours. No evidence of levels of contaminants that may be associated with risk to health. These include acrolein, formaldehyde, TSNAs, and metals. Concern about contamination of the liquid by a nontrivial quantity of ethylene glycol or diethylene glycol remains confined to a single sample of an early technology product and has not been replicated.
Abbreviations. CO, carbon monoxide; EC, electronic cigarette; NAT, N-Nitrosoanatabine; NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; NNN, N-Nitrosonornicotine; PAHs, polycyclic aromatic hydrocarbons; PM, particulate matter; TSNAs, tobacco-specific nitrosamines; VOCs, volatile organic carbons.

Conclusions . . . .
Consumers deserve, and should make, informed decisions and research will definitely promote this. In particular, current data on safety evaluation and risk assessment of ECs is sufficient enough to avert restrictive regulatory measures as a consequence of an irrational application of the precautionary principle [Saitta et al. 2014].

ECs are a revolutionary product in tobacco harm reduction. Although they emit vapor, which resembles smoke, there is literally no fire (combustion) and no ‘fire’ (suspicion or evidence that they may be the cause for disease in a similar way to tobacco cigarettes). Due to their unique characteristics, ECs represent a historical opportunity to save millions of lives and significantly reduce the burden of smoking-related diseases worldwide.

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Farsalinos & Polosa (2014), Safety evaluation and risk assessment of electronic cigarettes as tobacco cigarette substitutes: a systematic review, accessed: 2014-02-26
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