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HomeMy WebLinkAboutCOM 1091.144 2012-2014Murashige, Laura _ From: PK<counciltestimony@hawaiicounty.gov> Sent: Monday, December 15, 2014 4:15 PM ?Hifi 0Er :6 !;= 11 3 To: Council Testimony Subject: Bill 302 OPPOSE Attachments: safety_evaluation.pdf Councilmembers, thank you for the opportunity to testify in STRONG OPPOSITION to Bill 302 banning ecigarettes/vapor, aka vaping, indoors throughout Hawaii county. This bill is both unjustified and unnecessary. Despite widespread scaremongering, the science on the issue shows that vapor poses little risk to the user and no risk to bystanders. Weighed against the massive benefit of replacing smoking, these negligible risks absolutely must not be used to attack vaping. Instead it should be encouraged as a potentially huge public health boon. The point of indoor bans was to protect bystanders and business employees from risk -- there is no real risk here. Banning vaping indoors by statute is unnecessary because it is already within the power of all public and private entities to disallow vaping on premises if desired. The only thing this bill will do is make it impossible for entities that wish to ALLOW vaping to do so. This includes vapor shops and lounges, making this bill tantamount to an attack on those businesses. I have attached a recent study that outlines the current state of scientific knowledge about vaping and includes policymaking guidance based on that science. As the study states: "(A)ny regulatory decisions should not compromise the variability of choices for consumers and should make sure that ECs are more easily accessible compared with their main competitor, the tobacco cigarette ... 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]." Please do the wise thing and do not pass this bill. Thank you for your time. P Kuromoto Honolulu, HI 7q Ref. Date QEC 1 2(114 Therapeutic Advances in Drug Safe 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), Review Ther Adv Drug Saf 2014, Vol. 512) 67-86 D01: 10.1177/ 2042098614524430 © The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions. nav Correspondence to: Konstantinos E. Farsalinos, MD Onassis Cardiac Surgery Center, Sygrou 356, Kaltithea 17674, Greece kfarsatinosragmait.com Riccardo Polosa, PhD Centro per la Prevenzione e Cura del Tabagismo ICPCT) and Institute of Internal Medicine, University di Catania. Catania, Italy 67 http://taw.sagepub.com Therapeutic Advances in Drug Safety 5(2) Ist generation 2nd generation 3rd generation device device device j 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. 20131. 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 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. 20111 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, 20111. 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 x 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. 68 http://taw.sagepub.com P7RIS,�1A [`L(J��` DIAGFU3jN _� Search in online databases Keywords: electronic cigarette. e -cigarette, electronic nicotine delivery systems Studies found tiom all keywords, n = 154 1 Studies included, n 41 [ Studies included, n = 97 �] Removal ot'double entries and studies irrelevant to safetyrtsk profile Additional documents: congress presentations, doctnnents discussing, about health-related issues, studies on chemicals present in e -cigarettes {nicotine, propylene glycol, glycerol, cinnamaldehyde, tnicroparticles) 15 studies not cited because they were included in a review paper Total number of references in this manuscript: 114 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, 20041 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. 19981, 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. 20051. Up to 5 years of nicotine gum use in the Lung Health Study was unrelated KE Farsalinos and R Polosa 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 69 htt p://taw.,agepu b.c.om The utic Advances in Drug Safety 5(2) 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. 19891 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 Sullen, 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, 20131 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, 20091. The temperature of the resistance of the tested EC was 54°C 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 70 http://taw.sagepub.com KE Farsalinos and R Polosa Table 1. Types of studies performed to determine safety and to estimate risk from EC use. Type of studies Research subject Advantages Disadvantages Chemical Evaluate the chemical Easier and faster to Usually targeted on specific chemicals. studies composition of liquids perform. Less expensive. Unknown effects of flavorings when inhaled. and/or aerosol. Examine Could realistically No validated protocols for vapor production. environmental exposure be implemented for Provide no objective evidence about the end (passive 'vaping'). regulatory purposes. results (effects) of use (besides by applying theoretical models). Toxicological Evaluate the effects on cell Provide some information Difficult to interpret the results in terms of studies cultures or experimental about the effects from use. human in vivo effects. More expensive than animals. 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 Provide definite and Difficult and expensive to perform. Long-term effects. objective evidence about follow up is needed due to the expected lag the effects of use. 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 thatTSNA 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 r)g 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 http://taw.sagepub.com 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 ofTSNAs, 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. 20131. 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 71 Therapeutic Advances in Druq Safety 5(2) Table 2. Summary of chemical toxicity findings. Study What was investigated? What were the key findings? Laugesen [20091 Westenberger [20091 Hadwiger et at. [20101 Cahn and Siegel [20111 Pellegrino et al. [20121 Kim and Shin [20131 Etter et at. [20131 Goniewicz et al. [20131 Evaluation of 62 toxicants in the EC vapour from Ruyan 16 mg and mainstream tobacco smoke using a standard smoking machine protocol. Evaluation of toxicants in EC cartridges from two popular US brands. Evaluation of four refill solutions and six replacement cartridges advertised as containing Ciatis 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 Vapours generated from 12 brands of ECs and a medicinal nicotine inhaler using a modified smoking machine protocol Liquid N/A TSNAs and certain tobacco specific impurities were detected in both products at very low levels. Oiethylene glycol was identified in one cartridge. Small amounts of amino- tandalafil and rimonambant present in all products tested. 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 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 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 PM fractions were found, but levels were 6- 18 times tower compared with conventional cigarettes. Traces of PAHs detected. 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 tow 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) http://taw.sagepub.com 77 KE Farsalinos and R Polosa Table 2. (Continued) Study What was investigated? What were the key findings? Liquid Vapor Williams et at. Vapour generated from N/A Trace levels of several metals (including [20131 cartomizers of a popular tin, copper, silver, iron, nickel, aluminium, EC brand using a standard chromium, lead] were found, some of them smoking machine protocol 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 Systematic review of 35 No evidence of levels of contaminants that may be associated with risk to [20141 chemical toxicity studies/ health. These include acrolein, formaldehyde, TSNAs, and metals. Concern technical reports of EC about contamination of the liquid by a nontrivial quantity of ethylene glycol or Liquids/vapours. 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; NNN, N-Nitrosonornicotine; PAHs, polycyclic aromatic NAT, N-Nitro.soanatabine; NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; hydrocarbons; PM, particulate matter; TSNAs, tobacco -specific nitrosamines; VOCs, vota- tile organic carbons. 150 , 134125 109 100 100 s0 0 0 ---E E— _ . _ W Ho" Nlar0oro Rad NZ Holiday Canadian Ruyan V8 Extra-mtd Regular regular regular "igarette brands 2601 Figure 3. Toxic emissions score, adjusted for nicotine, for electronic cigarette and popular cigarette brands. (Reproduced with permission from Laugesen [20091). 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 Etg 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 nickel, cadmium and lead emitted [Goniewicz et al. 20131; 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, 20131. 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 73 http://taw.sagepub.com Therapeutic Advances in Drug Safety 5121 Table 3. Levels of nitrosamines found in electronic and tobacco cigarettes. Prepared based on information from Laugesen [20091, Cahn and Siegel [2011] and Kim and Shin [2013]. Product Total nitrosamines levels (ng) Daily exposure (ng) Ratio4 Electronic cigarette (per ml) 13 52' 1 Nicotine gum (per piece) 2 482 0.92 Winston (per cigarette) 3365 50475 3 971 Newport (per cigarette) 3885 50 7753 976 Marlboro (per cigarette) 6260 93 9003 1806 Camel (per cigarette) 5191 778653 1497 'Based on average daily use of 4ml liquid 2Based on maximum recommended consumption of 24 pieces per day 'Based on consumption of 15 cigarettes per day 4 Difference (number-fotdl between electronic cigarette and all other products in daily exposure to nitrosamines 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. 20121 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. 20131. Regrettably, a set of experiments with cigarette smoke extracts as 74 http://taw.sagepub.com 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 the cell, medium final concentration was 1%. However, cells were cultured for 48 hours with continuous exposure to the liquid, while in real use the lungs come in contact with aerosol instead of liquid, the contact lasts for 1-2 seconds per puff and most of the aerosol is visibly exhaled. Finally, Cinnamon Ceylon, the liquid found to be mostly cytotoxic in this study, was not a refill liquid but a concen- trated flavor which is not used in ECs unless it is diluted to 3-5%. Romagna and colleagues [Romagna et al. 2013] performed the first cytotoxicity study of EC vapor on fibroblast cells. They used a standardized ISO 10993-5 protocol, which is used for regulatory purposes of medical devices and products. They tested the vapor of 21 liquid samples containing the same amount of nicotine (9 mg/ml), gener- ated by a commercially available EC device. Cells were incubated for 24 hours with each of these vapors and with smoke from a conventional ciga- rette. Only one sample was found to be margin- ally cytotoxic, whereas cigarette smoke was highly cytotoxic (approximately 795% more cytotoxic), even when the extract was diluted up to 25%, of the original concentration. The same group also investigated the cytotoxic potential of 20 EC liquid samples in cardiomyo- blasts [Farsalinos et al. 2013a] . Vapor was produced by using a commercially available EC device. Samples contained a wide range of nicotine con- centrations. A base liquid mixture of propylene gly- col and glycerol (no nicotine and no flavorings) was also included as an additional experimental control. Four of the samples examined were made by using cured tobacco leaves in a steeping process, allowing them to impregnate a mixture of propylene glycol and glycerol for several days before being filtered and bottled for use. Of note, this was the first study which evaluated a limited number of samples with an EC device delivering higher voltage and energy to the atomizer (third -generation device). In total, four samples were found to be cytotoxic; three of them were liquids made by using cured tobacco leaves, with cytotoxicity observed at both 100% and 50% extract concentration, while one sample (cinnamon flavor) was marginally cytotoxic at 100%, extract concentration only. In comparison, smoke from three tobacco cigarettes was highly cytotoxic, with toxicity observed even when the KE Farsalinos and R Polosa extract was diluted to 12.5%. The samples made with tobacco leaves were three times less cytotoxic compared with cigarette smoke; this was probably due to the absence of combustion and the signifi- cantly lower temperature of evaporation in EC use. Concerning high-voltage EC use, the authors found slightly reduced cell viability without any of the samples being cytotoxic according to the ISO 10993-5 definition. Finally, no association between cell survival and the amount of nicotine present in the liquids was noted. A recent study evaluated in more detail the cyto- toxic potential of eight cinnamon -flavored EC liq- uids in human embryonic stem cells and human pulmonary fibroblasts [Behar et al. 2014]. The authors found that the flavoring substance pre- dominantly present was cinnamaldehyde, which is approved for food use. They observed significant cytotoxic effects, mostly on stem cells but also on fibroblasts, with cytotoxicity associated with the amount of cinnamaldehyde present in the liquid. However, major methodological issues arose from this study. Once again, cytotoxicity was just restricted to EC liquids and not to their vapors. Moreover, the authors mentioned that the amount of cinnamaldehyde differed between liquids by up to 100 times, and this raises the suspicion of test- ing concentrated flavor rather than refills. By searching the internet and contacting manufactur- ers, based on the names of samples and suppliers mentioned in the manuscript, it was found that at least four of their samples were not refills but con- centrated flavors. Surprisingly, the levels of cinna- maldehyde found to be cytotoxic were about 400 times lower than those currently approved for use [Environmental Protection Agency, 2000] . Few animal studies have been performed to eval- uate the potential harm of humectants in EC liq- uids (i.e. propylene glycol and glycerol) when given by inhalation. Robertson and colleagues tested the effects on primates of inhaling propyl- ene glycol vapor for several months and found no evidence of toxicity on any organ (including the lungs) after post-mortem examination of the ani- mals [Robertson et al. 1947] . Similar observa- tions were made in a recent study in rats and dogs [Werley et al. 2011]. Concerns have been raised in human use, based on studies of people exposed to theatrical fog [Varughese et al. 2005; American Chemistry Council, 2003] or propylene glycol used in the aviation industry [Wieslander et al. 2001]. Irritation of the respiratory tract was found, but no permanent lung injury or other 75 http://tawsagepuh.com Therapeutic Advances in Drug Safety 5(2) long-term health implications were detected. It should be reminded that, in these circumstances, nonpharmaceutical purity propylene glycol is used and in some cases oils are added, making it difficult to interpret the results in the context of EC use. Evidence for the potential harm of inhaled glycerol is sparse. A study using Sprague— Dawley rats found minimal to mild squamous metaplasia of the epiglottis epithelium in the high -dose group only, without any changes observed in lungs or other organs [Renne et al. 1992]. No comparative set of experiments with cigarette smoke was included, but it is well known that exposure to tobacco smoke in similar animal models leads to dramatic changes in the lungs, liver and kidneys [Czekaj et al. 2002]. In conclusion, toxicological studies have shown significantly lower adverse effects of EC vapor compared with cigarette smoke. Characteristically, the studies performed by using the liquids in their original liquid form have found less favorable results; however, no comparison with tobacco smoke was performed in any of these studies, and they cannot be considered relevant to EC use since the samples were not tested in the form con- sumed by vapers. More research is needed, including studies on different cell lines such as lung epithelial cells. In addition, it is probably necessary to evaluate a huge number of liquids with different flavors since a minority of them, in an unpredictable manner, appear to raise some concerns when tested in the aerosol form pro- duced by using an EC device. Clinical studies and research surveys Clinical trials can be very informative, but they require monitoring of hundreds of users for many years to adequately explore the safety/risk profile of the products under investigation. Research sur- veys of EC users, on the other hand, can quickly provide information about the potential harm of these products and are much cheaper to run. However, self-reported data, highly self-selected study populations, and the cross-sectional design are some of the most common limitations of research surveys. Taken together, findings from surveys and follow-up studies of vapers have shown that EC use is relatively safe. Polosa and colleagues followed up smokers for 24 months, after a 6 -month period of intervention during which ECs were given [Polosa et al. 2013a] . Only mild symptoms such as mouth and throat irritation and dry cough were observed. Farsalinos and colleagues retrospectively evaluated a group of 111 EC users who had completely quit smoking and were daily EC users for a median period of 8 months [Farsalinos et al. 2013b]. Throat irritation and cough were the most commonly reported side effects. Similar findings have been observed in surveys [Dawkins et al. 2013; Etter et al. 2011]. However, it is expected that dedicated users who have more positive experiences and fewer side effects compared with the general population par- ticipate in such studies, therefore interpretation should be done with caution. The only two exist- ing randomized controlled trials have also included detailed EC safety analysis. The ECLAT study [Caponnetto et al. 2013b], a three -arm, con- trolled, randomized, clinical trial designed to com- pare efficacy and safety of a first -generation device with 7.2, 5.4, or 0 mg nicotine cartridges, reported clinically significant progressive health improve- ments already by week two of continuous use of the device, and no serious adverse events (i.e. major depression, abnormal behavior or any event requiring an unscheduled visit to the family prac- titioner or hospitalization) occurred during the study. The ASCEND study [Bullen et al. 2013], a three -arm, controlled, randomized, clinical trial designed to compare the efficacy and safety of a first -generation device (with or without nicotine) with nicotine patches, reported no serious adverse events in any of the three study groups. Few clinical studies have been performed to evalu- ate the short-term in vivo effects of EC use in cur- rent or former smokers. Vardavas and colleagues evaluated the acute effects of using an EC for 5 minutes on respiratory function [Vardavas et al. 2012]. Although they did not report the results of commonly -used spirometry parameters, they found that a sensitive measure of airways resistance and nitric oxide levels in exhaled breath were adversely affected. Similar elevations in respiratory resistance were reported by other research groups [Palamidas et al. 2013; Gennimata et al. 20121, who also documented some bizarre elevation in exhaled carbon monoxide levels after EC use; this finding has been challenged by several other stud- ies [Farsalinos et al. 2013f; Nides et al. 2014; Van Staden et al. 20131. Schober and colleagues found that EC use led to elevated exhaled nitric oxide [Schober et al. 20131, contradicting the findings from Vardavas and colleagues [Vardavas et al. 2012] . Characteristically, none of the above studies performed any comparative tests after smoking tobacco cigarettes. Flouris and colleagues found 76 http://taw.sa9epub.com that only smoking had an acute adverse effect on respiratory function [Flouris et al. 2013]; no differ- ence was observed after the group of smokers was exposed to active or passive EC use. Two studies have evaluated the short-term effects of ECs on the cardiovascular system. Farsalinos and colleagues evaluated the acute effects of using ECs with an 11 mg/ml nicotine -containing liquid on hemodynamics and left ventricular function, in comparison with the effects of cigarette smok- ing [Farsalinos et al. 2012]. They found that EC use resulted in a slight elevation in diastolic blood pressure while, after smoking, both systolic and diastolic blood pressure and heart rate were sig- nificantly elevated. Obviously, this was due to the relatively low nicotine content of the EC (which is considered medium strength). Diastolic dysfunc- tion was observed in smokers after smoking, which was in line with findings from previous studies. However, no adverse effects were observed in EC users after using the device ad lib for 7 minutes. Another study by the same group [Farsalinos et al. 2013f], evaluated the acute effects of EC use on coronary flow. In particular, they measured the flow velocity reserve of the left anterior descending coronary artery by echocar- diography after intravenous infusion of adeno- sine, representing the maximal ability of the artery to deliver blood to the myocardium. Smoking was associated with a decline in flow velocity reserve by 16% and an elevation in resistance to flow by 19%. On the contrary, no difference was observed in any of these parameters after using the EC. Blood carboxyhemoglobin levels were also meas- ured in participants; baseline values were signifi- cantly higher in smokers compared with vapers and were further elevated after smoking but were not altered after EC use. Similar observations for carboxyhemoglobin levels were observed by Van Staden and colleagues [Van Staden et al. 20131. A clinical case report of a smoker suffering from chronic idiopathic neutrophilia was published. According to that report [Farsalinos and Romagna, 2013], switching from smoking to EC use led to a reversal of the condition after 6 months. In addition, C-reactive protein levels, which were consistently elevated for more than 6 years, decreased to normal levels. Another case report of a patient with lipoid pneumonia was published, with the condition attributed to glyc- erin -based EC liquids used by the patient [McCauley et al. 20121. However, glycerin is an alcohol (polyol) and thus it is impossible to cause http://taw.sagep a 6.com KE Farsalinos and R Polosa lipoid pneumonia. Only oil-based liquids could be the cause for this condition; such liquids should not be used with ECs. One study evaluated the acute effects of tobacco and EC use on white blood cell count [Flouris et al. 2012]. Smoking one tobacco cigarette caused an immediate elevation in white blood cells, neutrophils and lymphocytes, indicating acute inflammatory distress. On the contrary, no differences were observed after using ECs. In conclusion, clinical studies evaluating the effects of short-term EC use on selected cardio- vascular and respiratory functional outcomes have shown that even if some harmful effects of vaping are reported, these are considerably milder compared with smoking conventional cigarettes. However, it is difficult to assess the prognostic implications of these studies; longer-term data are needed before any definite conclusions are made. Passive vaping Passive smoking is an established risk factor for a variety of diseases [Barnoya and Navas-Acien, 2013] . Therefore, it is important from a public health perspective to examine the impact of EC use on bystanders. Indirect data can be derived from chemical studies in vapor mentioned above, which show that the potential of any significant adverse effects on bystanders is minimal. In fact, since side - stream exposure is nonexistent in EC (aerosol is produced only during activation of the device, while tobacco cigarettes emit smoke even when no puffs are taken), such studies are undoubtedly overesti- mating the risk of environmental exposure. Few studies have focused on second-hand vaping. McAuley and colleagues [McAuley et al. 20121, although mentioning indoor air quality in the title of their study and finding minimal health-related impact, did not in fact evaluate second-hand vap- ing because aerosol was produced from an EC device and was evaluated without previously being inhaled by any user. Moreover, there were some problems with cross -contamination with tobacco cigarette smoke, which made the results somewhat questionable, at least for some of the parameters tested. Schripp and colleagues [Schripp et al. 2013] evaluated the emissions from an EC by ask- ing a volunteer to use three different EC devices in a closed 8 m; chamber. From a selection of 20 chemicals analyzed, only formaldehyde, acrolein, isoprene, acetaldehyde and acetic acid were 77 The tic Advances in Drug Safety 5(2) detected. The levels were 5-40 times lower com- pared with emissions from a conventional ciga- rette. For formaldehyde, the authors specifically mentioned that the levels were continuously rising from the time the volunteer entered the room, even before he started using the EC. Moreover, no acute elevation was observed when the smoker used the three EC devices, contrary to the acute elevation and spiking of levels when a tobacco cig- arette was lit. The authors concluded that formal- dehyde was not emitted from the ECs but was due to human contamination, since low amounts of formaldehyde of endogenous origin can be found in exhaled breath [Riess et al. 2010]. Romagna and colleagues [Romagna et al. 2012] evaluated chemicals released in a realistic setting of a 60 m3 room, by asking five smokers to smoke ad lib for 5 hours and five vapers to use ECs ad lib for a similar period of time on two separate days. Nicotine, acr- olein, toluene, xylene and polycyclic aromatic hydrocarbons were detected in room air after the smoking session, with the amount of total organic carbon (TOC) reaching to 6.66 mg/ml. In con- trast, after the EC session, only glycerol was detected in minimal levels (72 µg/m3), while TOC reached a maximum level of 0.73 mg/m3. Characteristically, the amount of TOC accumu- lated after 5 hours of EC use was similar to the amount found after just 11 minutes of smoking. The study on heavy metals mentioned previously [Williams et al. 2013] could also be used to exam- ine any potential risk of bystanders' exposure to toxic metals. The levels of heavy metals found in vapor were minimal, and considering the disper- sion of these molecules in the whole room air, it is unlikely that any of these metals could be present in measurable quantities in the environment. Therefore, the risk for bystanders would be liter- ally nonexistent. Contrary to that, Schober and colleagues [Schober et al. 2013] found that levels of aluminum were raised by 2.4 times in a 45 m3 room where volunteers were asked to use ECs for 2 hours. This is a highly unexpected finding which cannot be supported by the findings of the study by Williams and colleagues [Williams et al. 2013]; because the levels found in the latter could not result in such elevation of the environmental levels of aluminum, unless nothing is retained in or absorbed from the lungs. Moreover, Schober and colleagues [Schober et al. 2013] found that levels of polycyclic aromatic hydrocarbons (PAHs) were raised by 20% after EC use. However, a major methodological problem of this study is that con- trol environmental measurements were performed on a separate day and not on the same day of EC use. This is a major limitation, because the levels of environmental PAHs have significant diurnal and day-to-day variations [Ravindra et al. 2008]; therefore, it is highly likely that the differences in levels of PAHs (which are mainly products of combustion and are not expected to be emitted from EC use) represented changes due to environ- mental conditions and not due to EC use. Bertholon and colleagues [Bertholon et al. 2013] examined the EC aerosol exhaled from a user, in comparison with exhaled smoke from a smoker. The authors found that particle size diameters were 0.29-0.0331im. They observed that the half life of EC aerosol was 11 seconds compared with 20 minutes for cigarette smoke, indicating that risk of passive vaping exposure is significantly lower compared with passive smoking. The recent findings by Czogala and colleagues [Czogala et al. 2013] led to similar conclusions. The authors compared the emissions of electronic and conventional cigarettes generated by experi- enced dual users in a ventilated full-sized room and found that ECs may emit detectable amounts of nicotine (depending on the specific EC brand tested), but no carbon monoxide and volatile organic carbons. However, the average ambient levels of nicotine of ECs were 10 times lower than those of conventional cigarettes (3.32 ± 2.49 ver- sus 31.60 ± 6.91 µg/m3). In his review and comparison with TLVs, Burstyn found that emissions from ECs to the environ- ment are not expected to pose any measurable risk for bystanders [Burstyn, 20141. An issue that needs further clarification relates to the findings of microparticles emitted from ECs. In most studies, these findings are presented in a way implying that the risk is similar to environmental or smoking microparticles. In reality, it is not just the size but the composition of the microparticles that matters. Environmental microparticles are mainly carbon, metal, acid and organic microparticles, many of which result from combustion and are commonly called particulate matter. Particulate matter exposure is definitely associated with lung and cardiovascular disease [Peters, 2005; Seaton et al. 1995]. In the case of ECs, microparticles are expected to consist mostly of propylene glycol, glycerol, water and nicotine droplets. Metal and silica nanoparticles may also be present [Williams et al. 2013], but, in general, emissions from ECs are incomparable to environmental particulate matter or cigarette smoke microparticles. 78 http://taw.5agepub.com Flouris and colleagues [Flouris et al. 2013] per- formed the only clinical study evaluating the res- piratory effects of passive vaping compared with passive smoking. Researchers found significant adverse effects in spirometry parameters after being exposed to passive smoking for I hour, while no adverse effects were observed after expo- sure to passive vaping. Although evaluating the effects of passive vap- ing requires further work, based on the existing evidence from environmental exposure and chemical analyses of vapor, it is safe to conclude that the effects of EC use on bystanders are minimal compared with conventional cigarettes. Miscellaneous safety issues Specific subpopulations: psychiatric and chronic obstructive pulmonary disorder patients A challenging population subgroup with unique smoking patterns is that of psychiatric patients and in particular schizophrenic patients. This subpopulation is characterized by a very high smoking prevalence [De Leon and Diaz, 2005] with an excess of smoking-related mortality [Brown et al. 2000], Currently, only NRTs are recommended to treat nicotine dependence in this specific subpopulation, but in general they are not particularly effective [Rubin et al. 2012]. ECs could be used as an alternative to smoking products in this group. Caponnetto and col- leagues performed a prospective 12 -month pilot study to evaluate the efficacy of EC use in smok- ing reduction and cessation in a group of 14 patients with schizophrenia [Caponnetto et al. 2013a]. In 50%, of participants, smoking con- sumption went from 30 to 15 cigarettes per day at 52 weeks of follow up, while 14.3% managed to quit smoking. Importantly, no deterioration in their psychiatric condition was observed, and side effects were mild and temporary. The results were promising although an outdated. EC device was used in this study. There is also anecdotal evidence that successful smoking cessation could be attained by using an EC in smokers with other psychiatric conditions such as depression [Caponnetto et al. 2011a]. Both patients described in this case series stated that EC use was well tolerated and no adverse events were reported. KE Farsalinos and R Polosa Considering that first-line oral medications for nicotine addiction are contraindicated in such patients (prescribing information for bupropion and varenicline carry a `black -box' warning for certain psychiatric conditions), ECs may be a promising tool in these challenging patient groups. Another subpopulation that may benefit from regular EC use is that of respiratory patients with chronic obstructive pulmonary disease (COPD), a progressive disease characterized by a persistent inflammatory response to tobacco smoke that generally leads to decline in lung function, res- piratory failure, cor pulmonale and death. Consequently, smoking cessation plays a crucial part in the management of COPD patients. However, the available evidence in the medical literature indicates that COPD patients who smoke respond poorly to smoking cessation efforts [Schiller and Ni, 2006].To date, no formal efficacy and safety assessment of EC use in COPD patients has been conducted. 'There is only evi- dence from a case report of inveterate smokers with COPD and a documented history of recur- ring relapses, who eventually quit tobacco smok- ing on their own by using an EC [Caponnetto et al. 201 lb]. Significant improvement in quality of life and reduction in the number of disease exacerbations were noted. EC use was well toler- ated with no reported adverse events. Accidental nicotine exposure Accidental ingestion of nicotine, especially by children, or skin contact with large amounts of liquid or highly concentrated nicotine solution can be an issue. However, the historically refer- enced lethal dose of 60 mg has recently been chal- lenged in a review by Mayer [Mayer, 2013]; he found that the lethal levels currently reproduced in every document originated from dubious experiments performed in the 19th century. Based on post-mortem studies, he suggested that the acute dose associated with a lethal outcome would be 500-1000 mg. Taking into account that voluminous vomiting is the first and characteristic symptom of nicotine ingestion, it seems that far higher levels of nicotine need to be ingested in order to have lethal consequences. A surveillance system of adverse events has been developed by the FDA, which identifies safety concerns in relation to tobacco products. Since 2008, 47 adverse events were reported for ECs 79 http://taw.sagepub.com Therapeutic Advances in Drug Safety 5(2) [Chen, 2013]. Eight of them were serious events such as hospitalizations for pneumonia, heart fail- ure, seizures and hypotension and burns. A case of second-degree burns was caused by a battery explosion, which is generally a problem observed in lithium batteries and has occurred in other products (such as mobile phones). The author emphasized that the reported events were not necessarily associated with EC use but may have been related to pre-existing conditions or other causes. No condition was characteristically asso- ciated with EC use. A recent review of the California Poison Control System database from 2010 to 2012 identified 35 cases (14 children) associated with EC exposure (accidental exposure in 25 cases) [Cantrell, 2013]. A total of five patients were evaluated in an emergency department and all were discharged within 4 hours. Nausea, vomiting, dizziness and oral irritation were most commonly reported. Taken together, data from surveillance systems of adverse events suggest that short-term adverse effects and accidental exposures to EC cartridges are unlikely to result in serious toxicity. Notwithstanding, avoiding preventable contact with highly concentrated nicotine solution remains important; this can be achieved by spe- cific labeling of the products, child -proof caps and proper education of consumers. There is no evidence that nicotine -containing EC liquids should be treated in any different way compared with other consumer products used every day in households (such as bleach, washing machine powder, etc.). Electrical accidents and fires The electronic equipment of ECs may be the cause for accidents. ECs are mainly composed of lithium batteries. There have been reports of explosions of batteries, caused either by pro- longed charging and use of improper chargers or by design defects. Similar accidents have occurred with batteries of other popular devices, such as mobile phones. Therefore, this does not occur specifically with ECs, however, quality standards of production should be used in order to avoid such accidents. Smoking is a major cause of residential fires. Between 2008 and 2010, an estimated annual average of 7600 smoking-related fires occurred in residential buildings in the US [US Fire Administration, 20121 . They account for only 2% of all residential building fires but for 14%, of fire deaths. Since ECs are activated only when used by the person and there is no combustion involved, there is the potential to avoid the risk of smoking- related fires. Use by youngsters and nonsmokers Although beyond the scope of this review, it is important to briefly discuss the potential for addic- tion from EC use. It should be acknowledged that nicotine is addictive, although recent studies have shown that several other chemicals present in tobacco are associated with a significant enhance- ment of the addictiveness of nicotine [Lotfipour et al. 2011; Rose, 2006; Guillem et al. 2005]. Still, nicotine intake should not be recommended to nonsmokers. Smokers are already addicted to nic- otine, thus ECs will be a cleaner form of nicotine intake, while at the same time they will maintain their sensory stimulation and motor simulation of smoking; these are important aspects of the addic- tion to smoking. Regulatory authorities have expressed concern about EC use by youngsters or by never -smokers, with ECs becoming a gateway to smoking or becoming a new form of addiction. However, such concerns are unsubstantiated; research has shown that EC use by youngsters is virtually nonexistent unless they are smokers. Camenga and colleagues [Camenga et al. 2013] examined the use of ECs and tobacco in a group of adolescents, in a survey conducted in three waves. In the first wave of the survey (February 2010), 1719 adolescents were surveyed from which only one nonsmoker was found to be using ECs. In the second and third wave of the surveys, only five nonsmoking adolescents were using ECs. In fact, these are adolescents who reported first ever use of ECs in the past 30 days; therefore they were not necessarily regular or daily EC consumers. The increased prevalence of EC use from 0.9% in 2010 to 2.3%, in 2011 concerned smoking adolescents, therefore it should be considered a positive finding that smokers are experimenting with the signifi- cantly less harmful ECs. Similarly, the Medicines and Healthcare Products Regulatory Agency (MHRA) found that less than I% of EC users are never -smokers [MHRA, 2013]. Data from the Centers for Disease Control [2013] NationalYouth Tobacco Survey reported doubling in EC experi- mentation by 13-18 year old students from 1.1% in 2011 to 2.1 % in 2012; however, 90.6% of them were smokers. From the whole population, only 0.5% were nonsmokers experimenting with ECs. 80 http://taw.sagepub.c0m Once again, participants were asked about ever experimenting with an EC in the past 30 days, not regular or daily EC use. Recently, a survey of more than 75,000 students in South Korea was pub- lished [Lee et al. 2013]. Although they found that 12.6% of them were daily smokers (8.6% were using only tobacco cigarettes and 3.6% were using both tobacco and ECs), only 0.6% of nonsmokers had used ECs in the past 30 days. Although the above mentioned data have been used as argu- ments to support the fact that a new epidemic of nicotine addiction through the use of ECs is appearing, in reality they are showing that any experimentation with ECs is done by smokers. This is in fact a positive finding, and could lead to reduced smoking prevalence through adoption of EC use. Therefore, ECs could serve as gateway from smoking; on the contrary, there is no evidence indicating that they could be a gateway to smoking. It is promising to see that penetration of EC use in youngsters is virtually nonexistent, especially when you take into consideration that there is currently no official regulation in most countries to prohibit the access to ECs by youngsters. Conclusion Existing evidence indicates that EC use is by far a less harmful alternative to smoking. There is no tobacco and no combustion involved in EC use; therefore, regular vapers may avoid several harm- ful toxic chemicals that are typically present in the smoke of tobacco cigarettes. Indeed, some toxic chemicals are released in the EC vapor as well, but their levels are substantially lower compared with tobacco smoke, and in some cases (such as nitrosamines) are comparable with the amounts found in pharmaceutical nicotine products. Surveys, clinical, chemistry and toxicology data have often been mispresented or misinterpreted by health authorities and tobacco regulators, in such a way that the potential for harmful conse- quences of EC use has been largely exaggerated [Polosa and Caponnetto, 2013]. It is obvious that some residual risk associated with EC use may be present, but this is probably trivial compared with the devastating consequences of smoking. Moreover, ECs are recommended to smokers or former smokers only, as a substitute for conven- tional cigarettes or to prevent smoking relapse; thus, any risk should be estimated relative to the risk of continuing or relapsing back to smoking and the low efficacy of currently approved medi- cations for smoking cessation should be taken into consideration [Moore et al. 2009; Rigotti http://taw,sagepub.com KE Farsalinos and R Polosa et al. 2010;Yudkin et al. 2003]. Nonetheless, more research is needed in several areas, such as atom- izer design and materials to further reduce toxic emissions and improve nicotine delivery, and liq- uid ingredients to determine the relative risk of the variety of compounds (mostly flavorings) inhaled. Regulations need to be implemented in order to maintain the current situation of minimal penetration of EC use in nonsmokers and young- sters, while manufacturers should be forced to provide proof for the quality of the ingredients used and to perform tests on the efficiency and safety of their products. However, any regulatory decisions should not compromise the variability of choices for consumers and should make sure that ECs are more easily accessible compared with their main competitor, the tobacco cigarette. Consumers deserve, and should make, informed decisions and research will definitely promote this. In particular, current data on safety evalua- tion 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 (com- bustion) 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 char- acteristics, ECs represent a historical opportu- nity to save millions of lives and significantly reduce the burden of smoking-related diseases worldwide. Funding This research received no specific grant from any funding agency in the public, commercial, or not- for-profit sectors. Conflict of interest statement Riccardo Polosa is a Professor of Medicine and is supported by the University of Catania, Italy. He has received lecture fees and research funding from G1axoSmithKline and Pfizer, manufacturers of stop smoking medications. He has also served as a consultant for Pfizer and Arbi Group Srl (Milano, Italy), the distributor of Categoria"m e -Cigarettes. His research on electronic cigarettes is currently supported by LIAF (Lega Italiana AntiFumo). Konstantinos Farsalinos is a researcher at Onassis Cardiac Surgery Center. He has never been funded by the pharmaceutical or the tobacco at The utic Advances in Drug Safety 5(2) industry. For some of his studies, the institution has received financial compensation from elec- tronic cigarette companies for the studies' cost. His salary is currently being paid by a scholarship grant from the Hellenic Society of Cardiology. References Adkison, S., O'Connor, R., Bansal-Travers, M., Hyland, A., Borland, R., Yong, H.H. et al. (2013) Electronic nicotine delivery systems: international tobacco control four -country survey. Am _7 Prev Med 44:207-215. Ambrose, J. and Barua, R. (2004) The pathophysiology of cigarette smoking and cardiovascular disease: an update. _7Am Coll Cardiol 43: 1731--1737. American Chemistry Council (2003) Ethylene Glycols: Considerations Against Use in Theatrical Fogs/Mist and Artificial Smoke. Available at: http:// www.americanchemistry.com/ProductsTechnology/ Ethylene-Glycols-2/PDF-Ethyl enc-Glycols-Fog- Information-Sheet.pdf (Accessed: 20 November 2013). Antal, M., Mok, W., Roy, J. and T-Raissi, A. (198 5) Pyrolytic sources of hydrocarbons from biomass. ,7 Anal Appl Pyrol 8: 291-303. Aubin, H., Rollema, H., Svensson, T. and Winterer, G. (2012) Smoking, quitting, and psychiatric disease: A review. Neurosci Biobehav Rev 36: 271-284. Bahl, V., Lin, S., Xu, N., Davis, B., Wang, Y. and Talbot, P. (2012) Comparison of electronic cigarette refill fluid cytotoxicity using embryonic and adult models. Reprod Toxicol 34: 529--537. Barnoya, J. and Navas-Acien, A. (2013) Protecting the world from secondhand tobacco smoke exposure: where do we stand and where do we go from here? Nicotine Tob Res 15: 789--804. Behar, R., Davis, B., Wang,Y., Bahl, V, Lin, S. and Talbot, P. (2014) Identification of toxicants in cinnamon -flavored electronic cigarette refill fluids. Toxicolln Vitro 28: 198-208. Benowitz, N. and Gourlay, S. (1997) Cardiovascular toxicity of nicotine: implications for nicotine replacement therapy. YAm Coll Cardiol 29: 1422- 1431. Benowitz, N., Zevin, S. and Jacob, P. III (1998) Suppression of nicotine intake during ad libitum cigarette smoking by high -dose transdermal nicotine _` Pharmacol Exp Ther 287: 958-962, Bertholon, J., Becquemin, M., Roy, M., Roy, F., Ledur, D., Annesi Maesano, I. et al. (2013) Comparison of the aerosol produced by electronic cigarettes with conventional cigarettes and the shisha. Rev Mal Respir 30: 752-757. Brown, S., Inskip, H. and Barraclough, B. (2000) Causes of the excess mortality of schizophrenia. 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(2012) Characterization of chemicals released to the environment by electronic cigarettes use (C1earStream-Air project): is passive vaping a reality? 85 http://taw,sageptib.com Murashige, Laura From: Edith Bikle <tarogifts@aol.com> Sent: Monday, December 15, 2014 8:16 PM To: Council Testimony Subject: appeal testimony Dear Respected Council Members, We have all been down this road so many times and here we are again facing down the monster of Big Ag and Biotech companies who are determined to poison this beautiful and pristine island that we love. Russia has just banned ALL GMO crops. Many other countries have as well. You have been elected to protect us and future generations. The Big Island is in a perfect geographical location to maintain purity -as most prevailing winds come from the wide Pacific with little chance of carrying polluted pollen. It is my prayer that everyone here can see the beauty of claiming pure organic food and seeds grown for export all over the world. We could make so much more money and feed so many more people. Please think about future generations. These big corporations are nasty and evil. Do not allow them here. would love to be in the chambers giving testimony in person. If anything changes with my schedule, I will try to come. I support the motion to appeal 13-121 and support resolution 22-14. Thank -you for all that you do -be strong, be brave and be wise. Mostly enjoy the holidays with your families -and know in your hearts that you are making the best decision - for all of us, for your children and for future generations. We don't need corrupt judges and all of the other greed motivated players on our field. Thank -you in advance and Warm Aloha, Edie Bikle P.O. Box 1888 Honoka'a, Hi. 96727 808-775-9009 tarogifts _aol.com Therapeutic Advances in Drug Safety 5(2) Visit SAGE journals online http://taW.SagePLib.com ($)SAGEjournals SRNT Europe Annual Congress, Helsinki, Finland. Poster RRP18. 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