524430 TAW0010.1177/2042098614524430Therapeutic Advances in Drug SafetyKE Farsalinos and R Polosa
`
`research-article2014
`
`Review
`
`Ther Adv Drug Saf
`
`2014, Vol. 5(2) 67 –86
`
`DOI: 10.1177/
`2042098614524430
`
`© The Author(s), 2014.
`Reprints and permissions:
`http://www.sagepub.co.uk/
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`Correspondence to:
`Konstantinos E.
`Farsalinos, MD
`Onassis Cardiac Surgery
`Center, Sygrou 356,
`Kallithea 17674, Greece
`kfarsalinos@gmail.com
`Riccardo Polosa, PhD
`Centro per la Prevenzione
`e Cura del Tabagismo
`(CPCT) and Institute
`of Internal Medicine,
`Università di Catania,
`Catania, Italy
`
`Safety evaluation and risk assessment of
`electronic cigarettes as tobacco cigarette
`substitutes: a systematic review
`
`Konstantinos E. Farsalinos and Riccardo Polosa
`
`Abstract: 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.
`
`Keywords: electronic cigarettes, e-liquid, e-vapor, harm reduction, nicotine, safety, tobacco
`
`Introduction
`Complete tobacco cessation is the best outcome
`for smokers. However, the powerful addictive
`properties of nicotine and the ritualistic behavior
`of smoking create a huge hurdle, even for those
`with a strong desire to quit. Until recently, smok-
`ers were left with just two alternatives: either quit
`or suffer the harmful consequences of continued
`smoking. This gloomy scenario has allowed the
`smoking pandemic to escalate, with nearly 6 mil-
`lion deaths annually and a predicted death toll of
`1 billion within the 21st century [World Health
`Organization, 2013]. But a third choice, involving
`the use of alternative and much safer sources of
`nicotine with the goal to reduce smoking-related
`diseases is now available: tobacco harm reduction
`(THR) [Rodu and Godshall, 2006].
`
`Electronic cigarettes (ECs) are the newest and
`most promising products for THR [Polosa et al.
`2013b]. They are electrically-driven devices con-
`sisting of the battery part (usually a lithium bat-
`tery), and an atomizer where liquid is stored and
`is aerosolized by applying energy and generating
`heat to a resistance encircling a wick. The liquid
`used mainly consists of propylene glycol, glycerol,
`
`distilled water, flavorings (that may or may not be
`approved for food use) and nicotine. Consumers
`(commonly called ‘vapers’) may choose from sev-
`eral nicotine strengths, including non-nicotine
`liquids, and a countless list of flavors; this assort-
`ment is a characteristic feature that distinguishes
`ECs from any other THR products. Since their
`invention in 2003, there has been constant inno-
`vation and development of more efficient and
`appealing products. Currently, there are mainly
`three types of devices available [Dawkins, 2013],
`depicted in Figure 1. (1) First-generation devices,
`generally mimicking the size and look of regular
`cigarettes and consisting of small lithium batteries
`and cartomizers (i.e. cartridges, which are usually
`prefilled with a liquid that bathes the atomizer).
`Batteries may be disposable (to be used once
`only) or rechargeable. (2) Second-generation
`devices, consisting mainly of higher-capacity lith-
`ium batteries and atomizers with the ability to
`refill them with liquid (sold in separate bottles).
`In the most recent atomizers you can simply
`change the atomizer head (resistance and wick)
`while keeping the body of the atomizer, thus
`reducing the operating costs. (3) Third-generation
`devices (also called ‘Mods’, from modifications),
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`medications for nicotine dependence, whereas
`ECs are unique in that they provide rituals asso-
`ciated with smoking behavior (e.g. hand-to-
`mouth movement, visible ‘smoke’ exhaled) and
`sensory stimulation associated with it [Farsalinos
`et  al. 2013b]. This explains why these products
`can be effective in reducing consumption of
`tobacco smoking [Bullen et al. 2013; Caponnetto
`et al. 2013b; Polosa et al. 2011] and are efficient
`as long-term substitutes of conventional ciga-
`rettes [Farsalinos et al. 2013b].
`
`Methods
`For this systematic review (Figure 2), we searched
`the PubMed electronic database by using key-
`words related to ECs and/or their combination
`(e-cigarette, electronic cigarette, electronic nico-
`tine 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, propyl-
`ene glycol, glycerol, cinnamaldehyde, microparti-
`cles 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.
`
`Risk differences compared with
`conventional cigarettes and the issue of
`nicotine
`Conventional cigarettes are the most common
`form of nicotine intake. Smoking-related diseases
`are pathophysiologically attributed to oxidative
`stress, activation of inflammatory pathways and
`the toxic effect of more than 4000 chemicals and
`carcinogens
`present
`in
`tobacco
`smoke
`[Environmental Protection Agency, 1992]. In
`addition, each puff contains >1 × 1015 free radi-
`cals [Pryor and Stone, 1993]. All of these chemi-
`cals are emitted mostly during the combustion
`process, which is absent in ECs. Although the
`addictive potential of nicotine and related com-
`pounds is largely documented [Guillem et  al.
`
`Figure 1. Examples of electronic cigarette devices
`currently available on the market.
`
`consisting of very large-capacity lithium batteries
`with integrated circuits that allow vapers to
`change the voltage or power (wattage) delivered
`to the atomizer. These devices can be combined
`with either second-generation atomizers or with
`rebuildable atomizers, where the consumers have
`the ability to prepare their own setup of resistance
`and wick.
`
`Awareness and use (vaping) of ECs has increased
`exponentially in recent years. Data obtained from
`the HealthStyles survey showed that, in the US,
`awareness of ECs rose from 40.9–57.9% from
`2010 to 2011, with EC use rising from 3.3–6.2%
`over the same time period [King et al. 2013]. In
`the United Kingdom, EC use in regular smokers
`increased from 2.7% in 2010 to 6.7% in 2012
`[Dockrell et  al. 2013]. Similar findings were
`obtained from the International Tobacco Control
`Four-Country Survey [Adkison et  al. 2013]. A
`recent prospective study in Swiss army recruits
`showed that 12% of smokers who tried ECs pro-
`gressed to daily use [Douptcheva et al. 2013]. It
`must be noted that this increase in EC use has
`occurred despite the concerns raised by public
`health authorities about the safety and appropri-
`ateness of using these products as alternatives to
`smoking [National Association of Attorneys
`General, 2013; Food and Drug Administration,
`2009; Mayers, 2009].
`
`The popularity of ECs may be due to their ability
`to deal both with the physical (i.e. nicotine) and
`the behavioral component of smoking addiction.
`In particular, sensory stimulation [Rose and
`Levin, 1991] and simulation of smoking behavior
`and cigarette manipulation [Hajek et  al. 1989]
`are important determinants of a product’s effec-
`tiveness in reducing or completely substituting
`smoking. These features are generally absent in
`nicotine replacement therapies (NRTs) and oral
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`KE Farsalinos and R Polosa
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`Figure 2. Methodology for literature research and selection of studies.
`
`2005], much less dissemination has been given to
`the notion that nicotine does not contribute to
`smoking-related diseases. It is not classified as a
`carcinogen by the International Agency for
`Research on Cancer [WHO-IARC, 2004] and
`does not promote obstructive lung disease. A
`major misconception, commonly supported even
`by physicians, is that nicotine promotes cardio-
`vascular disease. However, it has been established
`that nicotine itself has minimal effect in initiating
`and promoting atherosclerotic heart disease
`[Ambrose and Barua, 2004]. It does not promote
`platelet aggregation [Zevin et al. 1998], does not
`affect coronary circulation [Nitenberg and
`Antony, 1999] and does not adversely alter the
`lipid profile [Ludviksdottir et al. 1999]. An obser-
`vational study of more than 33,000 smokers
`found no evidence of increased risk for myocar-
`dial infarction or acute stroke after NRT sub-
`scription, although follow up was only 56 days
`[Hubbard et al. 2005]. Up to 5 years of nicotine
`gum use in the Lung Health Study was unrelated
`
`to cardiovascular diseases or other serious side
`effects [Murray et al. 1996]. A meta-analysis of 35
`clinical trials found no evidence of cardiovascular
`or other life-threatening adverse effects caused by
`nicotine intake [Greenland et al. 1998]. Even in
`patients with established cardiovascular disease,
`nicotine use in the form of NRTs does not
`increase cardiovascular risk [Woolf et  al. 2012;
`Benowitz and Gourlay, 1997]. It is anticipated
`that any product delivering nicotine without
`involving combustion, such as the EC, would
`confer a significantly lower risk compared with
`conventional cigarettes and to other nicotine con-
`taining combustible products.
`
`The importance of using nicotine in the long-
`term was recognized several years ago by Russell,
`indicating that the potential of nicotine delivery
`systems as long-term alternatives to tobacco
`should be explored in order to make the elimina-
`tion of tobacco a realistic future target [Russell,
`1991]. However, current regulations restrict the
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`long-term use of pharmaceutical or recreational
`nicotine products (such as snus) [Le Houezec
`et al. 2011]. In other words, nicotine intake has
`been demonized, although evidence suggests that,
`besides being useful in smoking cessation, it may
`even have beneficial effects in a variety of disor-
`ders such as Parkinson’s disease [Nielsen et  al.
`2013], depression [McClernon et  al. 2006],
`dementia [Sahakian et  al. 1989] and ulcerative
`colitis [Guslandi, 1999]. Obviously, the addictive
`potential is an important factor in any decision to
`endorse nicotine administration; however,
`it
`should be considered as slight ‘collateral damage’
`with minimal impact to vapers’ health compared
`with the tremendous benefit of eliminating all
`disease-related substances coming from tobacco
`smoking. In fact, smokers are already addicted to
`nicotine; therefore the use of a ‘cleaner’ form of
`nicotine delivery would not represent any addi-
`tional risk of addiction. Surveys have shown that
`ECs are used as long-term substitutes to smoking
`[Dawkins et  al. 2013; Etter and Bullen, 2012].
`Although consumers try to reduce nicotine use
`with ECs, many are unable to completely stop its
`intake, indicating an important role for nicotine
`in the ECs’ effectiveness as a smoking substitute
`[Farsalinos et al. 2013b].
`
`Nicotine overdose or intoxication is unlikely to
`occur with vaping, since the amount consumed
`[Farsalinos et  al. 2013c] and absorbed [Nides
`et al. 2014; Dawkins and Corcoran, 2013] is quite
`low. Moreover, although not yet proven, it is
`expected that vapers will self-titrate their nicotine
`intake in a similar way to tobacco cigarettes
`[Benowitz et al. 1998]. Last, but not least, there is
`evidence suggesting that nicotine cannot be deliv-
`ered as fast and effectively from ECs compared to
`tobacco cigarettes [Farsalinos et  al. 2014].
`Therefore, it seems that ECs have a huge theoreti-
`cal advantage in terms of health risks compared
`with conventional cigarettes due to the absence of
`toxic chemicals that are generated in vast quanti-
`ties by combustion. Furthermore, nicotine deliv-
`ery by ECs is unlikely to represent a significant
`safety issue, particularly when considering they
`are intended to replace tobacco cigarettes, the
`most efficient nicotine delivery product.
`
`Studies on the safety/risk profile of ECs
`Findings on the safety/risk profile of ECs have
`just started to accumulate. However, this research
`must be considered work in progress given that
`the safety/risk of any product reflects an evolving
`
`body of knowledge and also because the product
`itself is undergoing constant development.
`
`Existing studies about the safety/risk profile of
`ECs can be divided into chemical, toxicological
`and clinical studies (Table 1). Obviously, clinical
`studies are the most informative, but also the
`most demanding because of several methodologi-
`cal, logistical, ethical and financial challenges. In
`particular, exploring safety/risk profile in cohorts
`of well-characterized users in the long-term is
`required to address the potential of future disease
`development, but it would take hundreds of users
`to be followed for a substantial number of years
`before any conclusions are made. Therefore, most
`research is currently focused on in vitro effects,
`with clinical studies confined into evaluation of
`short-term use or pathophysiological mechanisms
`of smoking-related diseases.
`
`Chemical studies
`Chemical studies are relatively simple and cheap
`to perform and provide quick results. However,
`there are several disadvantages with this approach.
`Research is usually focused on the known specific
`chemicals (generally those known to be toxic from
`studies of cigarette smoke) and fails to address
`unknown, potentially toxic contaminants that
`could be detected in the liquid or the emitted aer-
`osol. Problems may also arise from the detection
`of the chemicals in flavors. Such substances,
`although approved for use in the food industry,
`have largely unknown effects when heated and
`inhaled; thus, information on the presence of such
`substances is difficult to interpret in terms of
`in vivo effects. In fact, chemical studies do not pro-
`vide any objective information about the effects of
`use; they can only be used to calculate the risk
`based on theoretical models and on already
`established safety levels determined by health
`authorities. An overview of the chemical studies
`performed on ECs is displayed in Table 2.
`
`Laugesen performed the first studies evaluating
`the chemical composition of EC aerosols
`[Laugesen, 2008, 2009]. The temperature of the
`resistance of the tested EC was 54oC during acti-
`vation, which is approximately 5–10% of the tem-
`perature of a burning tobacco cigarette. Toxic
`chemicals such as heavy metals, carcinogenic
`polycyclic aromatic hydrocarbons and phenols
`were not detected, with the exception of trivial
`amounts of mercury (0.17 ng per EC) and traces
`of formaldehyde and acetaldehyde. Laugesen
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`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.
`
`Toxicological
`studies
`
`Evaluate the effects on cell
`cultures or experimental
`animals.
`
`Provide some information
`about the effects from use.
`
`Clinical studies
`
`Studies on human in vivo
`effects.
`
`Provide definite and
`objective evidence about
`the effects of use.
`
`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).
`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.
`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.
`
`evaluated emissions based on a toxicant emissions
`score and reported a score of 0 in ECs compared
`with a score of 100–134 for tobacco cigarettes
`(Figure 3). The US Food and Drug Administration
`(FDA) also performed chemical analyses on 18
`commercially available products
`in 2009
`[Westenberger, 2009]. They detected the pres-
`ence of tobacco-specific nitrosamines (TSNAs)
`but did not declare the levels found. Small
`amounts of diethylene glycol were also found in
`one sample, which was unlikely to cause any harm
`from normal use. Another study identified small
`amounts of amino-tandalafil and rimonambant in
`EC liquids [Hadwiger et al. 2010]. Subsequently,
`several
`laboratories performed similar tests,
`mostly on liquids, with Cahn and Siegel publish-
`ing a review on the chemical analyses of ECs and
`comparing the findings with tobacco cigarettes
`and other tobacco products [Cahn and Siegel,
`2011]. They reported that TSNA levels were simi-
`lar to those measured in pharmaceutical NRTs.
`The authors concluded that, based on chemical
`analysis, ECs are far less harmful compared with
`tobacco cigarettes. The most comprehensive
`study on TSNAs has been performed recently by
`a South Korean group, evaluating 105 liquids
`obtained from local retailers [Kim and Shin,
`2013]. On average, they found 12.99 ηg TSNAs
`per ml of liquid, with the amount of daily expo-
`sure to the users estimated to be similar to users
`of NRTs [Farsalinos et al. 2013d]. The estimated
`daily exposure to nitrosamines from tobacco ciga-
`rettes (average consumption of 15 cigarettes per
`day) is estimated to be up to 1800 times higher
`
`compared with EC use (Table 3). Etter and col-
`leagues evaluated the accuracy of nicotine labe-
`ling and the presence of nicotine impurities and
`degradation products in 20 EC liquid samples
`[Etter et al. 2013]. They found that nicotine levels
`were 85–121% of what was labeled, while nico-
`tine degradation products were present at levels
`of 0–4.4%. Although in some samples the levels
`were higher than those specified in European
`Pharmacopoeia, they are not expected to cause
`any measurable harm to users.
`
`Besides the evaluation for the presence of TSNAs,
`analyses have been performed for the detection of
`carbonyl compounds. It is known that the thermal
`degradation of propylene glycol and glycerol can
`lead to the emission of toxic compounds such as
`aldehydes [Antal et  al. 1985; Stein et  al. 1983].
`Goniewicz and colleagues evaluated the emission
`of 15 carbonyls from 12 brands of ECs (mostly
`first-generation) [Goniewicz et al. 2013]. In order
`to produce vapor, researchers used a smoking
`machine and followed a regime of 1.8-second
`puffs with a very short 10-second interpuff inter-
`val, which does not represent realistic use
`[Farsalinos et al. 2013c]; although the puff dura-
`tion was low, interpuff interval was remarkably
`short, which could potentially lead to overheating.
`In addition, the same puff number was used in all
`devices tested, although there was a significant
`difference in the design and liquid content
`between devices. Despite these limitations, out of
`15 carbonyls, only 3 were detected (formalde-
`hyde, acetaldehyde and acrolein); levels were
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`Table 2. Summary of chemical toxicity findings.
`
`Study
`
`
`
`Laugesen
`[2009]
`
`What was investigated?
`
`What were the key findings?
`
`Liquid
`
`N/A
`
`Evaluation of 62 toxicants in
`the EC vapour from Ruyan 16
`mg and mainstream tobacco
`smoke using a standard
`smoking machine protocol.
`
`Vapor
`
`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.
`N/A
`
`N/A
`
`TSNAs and certain tobacco
`specific impurities were
`detected in both products at
`very low levels. Diethylene
`glycol was identified in one
`cartridge.
`Small amounts of amino-
`tandalafil and rimonambant
`present in all products tested.
`
`Westenberger
`[2009]
`
`Evaluation of toxicants in EC
`cartridges from two popular
`US brands.
`
`Hadwiger
`et al. [2010]
`
`Cahn and
`Siegel [2011]
`
`Pellegrino
`et al. [2012]
`
`Kim and Shin
`[2013]
`
`Etter et al.
`[2013]
`
`Evaluation of four refill
`solutions and six replacement
`cartridges advertised
`as containing Cialis or
`rimonambant.
`Overview of 16 chemical
`toxicity studies of EC liquids/
`vapours.
`Evaluation of PM fractions and
`PAHs in the vapour generated
`from cartomizers of an Italian
`EC brand.
`TSNAs (NNN, NNK, NAT, and
`NAB) content in 105 refill
`liquids from 11 EC brands
`purchased in Korean shops.
`
`Nicotine degradation
`products, ethylene glycol and
`diethylene glycol evaluation
`of 20 EC refill liquids from 10
`popular brands
`
`Goniewicz
`et al. [2013]
`
`Vapours generated from 12
`brands of ECs and a medicinal
`nicotine inhaler using a
`modified smoking machine
`protocol
`
`72
`
`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.
`N/A
`PM fractions were found, but levels were 6–
`18 times lower compared with conventional
`cigarettes. Traces of PAHs detected.
`
`Total TSNAs averaged
`12.99 ng/ml EC liquid; daily
`total TSNA exposure from
`conventional cigarettes
`estimated to be up to 1800
`times higher.
`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
`
`N/A
`
`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.
`
`(Continued)
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`Table 2. (Continued)
`
`KE Farsalinos and R Polosa
`
`What was investigated?
`
`What were the key findings?
`
`Liquid
`
`Vapor
`
`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.
`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.
`
`Study
`
`
`
`Williams et al.
`[2013]
`
`Vapour generated from
`cartomizers of a popular
`EC brand using a standard
`smoking machine protocol
`
`Burstyn
`[2014]
`
`Systematic review of 35
`chemical toxicity studies/
`technical reports of EC
`liquids/vapours.
`
`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, vola-
`tile organic carbons.
`
`nickel, cadmium and lead emitted [Goniewicz
`et  al. 2013]; the levels of nickel were similar to
`those present in a pharmaceutical nicotine inhala-
`tor, while lead and cadmium were present at 2–3
`times higher levels compared with the inhalator.
`Still, the absolute levels were very low (few nano-
`grams per 150 puffs). Williams et  al. [2013]
`focused their research on the presence of heavy
`metals and silicate particles emitted from ECs.
`They tested poor quality first-generation cart-
`omisers and found several metals emitted in the
`aerosol of the EC, specifying that in some cases
`the levels were higher compared with conven-
`tional cigarettes. As mentioned earlier, it is not
`unusual to find trace levels of metals in the vapor
`generated by these products under experimental
`conditions that bear little relevance to their nor-
`mal use; however, it is unlikely that such small
`amounts pose a serious threat to users’ health.
`Even if all the aerosol was absorbed by the con-
`sumer (which is not the case since most of the
`aerosol is visibly exhaled), an average user would
`be exposed to 4–40 times lower amounts for most
`metals than the maximum daily dose allowance
`from impurities in medicinal products [US
`Pharmacopeia, 2013]. Silicate particles were also
`found in the EC aerosol. Such particles come
`from the wick material, however the authors did
`not clarify whether crystalline silica oxide parti-
`cles were found, which are responsible for respira-
`tory disease. In total, the number of microparticles
`(< 1000 nm) estimated to be inhaled by EC users
`from 10 puffs were 880 times lower compared
`
`Figure 3. Toxic emissions score, adjusted for
`nicotine, for electronic cigarette and popular cigarette
`brands. (Reproduced with permission from Laugesen
`[2009]).
`
`9–450 times lower compared with emissions from
`tobacco cigarettes (derived from existing litera-
`ture but not tested in the same experiment).
`Formaldehyde and acetaldehyde were also emit-
`ted from the nicotine inhalator, although at lower
`levels. In addition, they examined for the presence
`of 11 volatile organic carbons and found only
`trace levels of toluene (at levels from 0.2–6.3 µg
`per 150 puffs) and xylene (from 0.1–0.2 µg per
`150 puffs) in 10 of the samples; toluene levels
`were 120 times lower compared with tobacco cig-
`arettes (again derived from existing literature but
`not tested in the same experiment).
`
`Given that ECs have several metal parts in direct
`contact with the e-liquid, it is quite obvious to
`expect some contamination with metals in the
`vapor. Goniewicz and colleagues examined sam-
`ples for the presence of 12 metals and found
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`Therapeutic Advances in Drug Safety 5(2)
`
`Table 3. Levels of nitrosamines found in electronic and tobacco cigarettes. Prepared based on information from Laugesen [2009],
`Cahn and Siegel [2011] and Kim and Shin [2013].
`
`Product
`
`Total nitrosamines levels (ng)
`
`Daily exposure (ng)
`
`Electronic cigarette (per ml)
`Nicotine gum (per piece)
`Winston (per cigarette)
`Newport (per cigarette)
`Marlboro (per cigarette)
`Camel (per cigarette)
`
` 13
` 2
`3365
`3885
`6260
`5191
`
`521
`482
`50 4753
`50 7753
`93 9003
`77 8653
`
`1Based on average daily use of 4ml liquid
`2Based on maximum recommended consumption of 24 pieces per day
`3Based on consumption of 15 cigarettes per day
`4 Difference (number-fold) between electronic cigarette and all other products in daily exposure to nitrosamines
`
`Ratio4
`
`1
`0.92
`971
`976
`1806
`1497
`
`with one tobacco cigarette. Similar findings con-
`cerning microparticles were reported by Pellegrino
`and colleagues who found that, for each particu-
`late matter
`fraction, conventional cigarettes
`released 6–18 times higher amounts compared
`with the EC tested [Pellegrino et al. 2012].
`
`Burstyn has recently reviewed current data on the
`chemistry of aerosols and the liquids of ECs
`(including reports which were not peer-reviewed)
`and estimated the risk to consumers based on
`workplace exposure standards (i.e. Threshold
`Limit Values [TLVs]) [Burstyn, 2014]. After
`reviewing all available evidence, the author con-
`cluded that there was no evidence that vaping
`produced inhalable exposure to contaminants of
`aerosol that would warrant health concerns. He
`added that surveillance of use is recommended
`due to the high levels of propylene glycol and
`glycerol inhaled (which are not considered con-
`taminants but ingredients of the EC liquid).
`There are limited data on the chronic inhalation
`of these chemicals by humans, although there is
`some evidence from toxicological studies (which
`are discussed later in this paper).
`
`In conclusion, chemical studies have found that
`exposure to toxic chemicals from ECs is far lower
`compared with tobacco cigarettes. Besides com-
`paring the levels of specific chemicals released
`from tobacco and ECs, it should be taken into
`consideration that the vast majority of the >4000
`chemicals present in tobacco smoke are com-
`pletely absent from ECs. Obviously, surveillance
`of use is warranted in order to objectively evaluate
`the in vivo effects and because the effects of inhal-
`ing flavoring substances approved for food use are
`largely unknown.
`
`Toxicological studies
`To date, only a handful of toxicological studies
`have been performed on ECs, mostly cytotoxicity
`studies on established cell lines. The cytotoxicity
`approach also has its flaws. Findings cannot be
`directly applied to the in vivo situation and there
`is always the risk of over- (as well as under-)esti-
`mating the interpretation of the toxic effects in
`these investigational models. An ample degree of
`results variability is to be expected from different
`cell lines and, sometimes, also within the same
`cell line. Comparing the potential cytotoxicity
`effects of EC vapor with those resulting from the
`exposure of cigarette smoke should be manda-
`tory, but standards for vapor production and
`exposure protocols have not been clearly defined.
`
`Bahl and colleagues [Bahl et al. 2012] performed
`cytotoxicity tests on 36 EC liquids, in human
`embryonic stem cells, mouse neural stem cells
`and human pulmonary fibroblasts and found that
`stem cells were more sensitive to the effects of the
`liquids, with 15 samples being moderately cyto-
`toxic and 12 samples being highly cytotoxic.
`Propylene glycol and glycerol were not cytotoxic,
`but a correlation between cytotoxicity and the
`number and height of the flavoring peaks in high-
`performance liquid chromatography was noted.
`Investigations were just restricted to the effect of
`EC liquids and not to their vapors, thus limiting
`the importance of the study findings; this is not a
`trivial issue considering that the intended use of
`these products is by inhalation only and that it is
`unlikely that flavoring substances in the EC liq-
`uids will still be present in the aerosol in the same
`amount due to differences in evaporation tem-
`perature [Romagna et al. 2013]. Regrettably, a set
`of experiments with cigarette smoke extracts as
`
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`KE Farsalinos and R Polosa
`
`comparator was not included. Of note, the authors
`emphasized that the study could have underesti-
`mated the cytotoxicity by 100 times because when
`they added the EC liquids to