Short-term Pulmonary Effects of Using an Electronic Cigarette. Impact on Respiratory Flow Resistance, Impedance, and Exhaled Nitric Oxide

Transcription

1 CHEST Originl Reserch TOBACCO CESSATION AND PREVENTION Short-term Pulmonry Effects of Using n Electronic Cigrette Impct on Respirtory Flow Resistnce, Impednce, nd Exhled Nitric Oxide Constntine I. Vrdvs, MD, MPH, PhD ; Nektrios Angnostopoulos, MD ; Mrios Kougis, MD ; Vssiliki Evngelopoulou, MD ; Gregory N. Connolly, DMD, MPH ; nd Pngiotis K. Behrkis, MD, PhD, FCCP Bckground: Debte exists over the scientific evidence for clims tht electronic cigrettes (e-cigrettes) hve no helth-relted rmifictions. This study imed to ssess whether using n e-cigrette for 5 min hs n impct on the pulmonry function tests nd frction of exhled nitric oxide (F ENO ) of helthy dult smokers. Methods: Thirty helthy smokers (ged yers, 14 men) prticipted in this lbortory-bsed experimentl vs control group study. Ab lib use of n e-cigrette for 5 min with the crtridge included (experimentl group, n 5 30) or removed from the device (control group, n 5 10) ws ssessed. Results: Using n e-cigrette for 5 min led to n immedite decrese in F ENO within the experimentl group by 2.14 ppb ( P 5.005) but not in the control group ( P 5.859). Totl respirtory impednce t 5 Hz in the experimentl group ws found to lso increse by kp/(l/s) ( P,.001), nd flow respirtory resistnce t 5 Hz, 10 Hz, nd 20 Hz lso sttisticlly incresed. Regression nlyses controlling for bseline mesurements indicted sttisticlly significnt decrese in F ENO nd n increse in impednce by 0.04 kp/(l/s) ( P 5.003), respirtory resistnce t 5 Hz by 0.04 kp/(l/s) ( P 5.003), t 10 Hz by kp/(l/s) ( P 5.008), t 20 Hz by kp/(l/s) ( P 5.007), nd overll peripherl irwy resistnce ( b, kp/[l/s]; P 5.024), fter using n e-cigrette. Conclusions: e-cigrettes ssessed in the context of this study were found to hve immedite dverse physiologic effects fter short-term use tht re similr to some of the effects seen with tobcco smoking; however, the long-term helth effects of e-cigrette use re unknown but potentilly dverse nd worthy of further investigtion. CHEST 2012; 141(6): Abbrevitions: e-cigrette 5 electronic cigrette; FDA 5 US Food nd Drug Administrtion; F eno 5 frction of exhled nitric oxide; IOS 5 impulse oscillometry system; MEF 5 mximl expirtory flow; PEF 5 pek expirtory flow; ppb 5 prts per billion; R5Hz 5 irwy resistnce t 5 Hz; R10Hz 5 irwy resistnce t 10 Hz; R20Hz 5 irwy resistnce t 20 Hz; Z5Hz 5 irwy impednce t 5 Hz Electronic cigrettes (e-cigrettes) re mrketed s potentilly reduced tobcco exposure products. The product resembles, but is not, cigrette in design or function nd is mrketed s sfer thn conventionl cigrette. However, debte exists over the scientific evidence for the clims tht the products hve no helth-relted rmifictions. Becuse e-cigrettes do not contin or burn tobcco, they do not pper to deliver the known toxins found in conventionl cigrette smoke. 1-4 Conversely, US Food nd Drug Administrtion (FDA) nlyses hve 1400 indicted tht e-cigrettes contin number of toxins nd crcinogens, including tobcco-specific nitrosmines, diethylene glycol, nd other components suspected of being hrmful to humns. 5 For editoril comment see pge 1371 Becuse of the increse in interest regrding e-cigrettes nd they clims tht they re potentilly reduced-exposure product, nicotine-delivery device, Originl Reserch

2 or smoking-cesstion tool, it is impertive to ssess the risks relted to lterntive nicotine delivery systems to protect public nd consumer helth Previous reserch hs indicted tht smokers hve significntly higher lung resistnces t 5 Hz nd 20 Hz nd lower concentrtions of frction of exhled nitric oxide (F eno ) noninvsive mrker of bronchil inflmmtion compred with nonsmokers. 11,12 To dte, there is no published evidence of ny direct helthrelted effect of cute physiologic response to using n e-cigrette; thus, the im of the current study ws to investigte whether using n e-cigrette b lib for 5 min could ffect respirtory mechnics nd F eno within the context of n experimentl vs control group study design. Mterils nd Methods Subjects Our study smple ws composed of 30 dults (14 men, 16 women) of men ge of 34.8 yers (rnge yers) recruited from community setting in Athens, Greece. All subjects were smokers with minimum pck-yer index of 5. Exclusion criteri included ny chronic nd/or lung disese (including history of bronchil sthm or bronchil hyperrectivity), cute illness during the previous 2 weeks, current pregnncy or lcttion, or current use of ny mediction. All subjects were instructed not to et or drink ny kind of beverges for t lest 2 h prior to the exmintion nd to void smoking during the prior 4 h. Study Design A lbortory-bsed intervention study design ws pplied, within which two groups were creted: the experimentl group (n 530) nd the control group (n 5 10). The 10 prticipnts of the control group were rndomly selected from the experimentl group nd, in different session, prticipted in the experimentl group. The role of using n e-cigrette ws ssessed through (1) compring the chnges noted mong control group prticipnts with chnges noted mong experimentl group prticipnts fter the interven- Mnuscript received October 3, 2011; revision ccepted November 20, Affilitions: From the Center for Globl Tobcco Control (Drs Vrdvs, Connolly, nd Behrkis), Deprtment of Society, Humn Development, nd Helth, Hrvrd School of Public Helth, Boston, MA; the Smoking nd Lung Cncer Reserch Center (Drs Vrdvs, Angnostopoulos, Kougis, Evngelopoulou, nd Behrkis), Hellenic Cncer Society, Athens, Greece; nd the Lbortory of Respirtory Physiology (Drs Angnostopoulos, Kougis, nd Behrkis), Deprtment of Medicine, University of Athens, Greece. Funding: This project ws prtilly supported by internl funds of the Hellenic Cncer Society, Greece. Correspondence to: Constntine I. Vrdvs, MD, MPH, PhD, Center for Globl Tobcco Control, Deprtment of Society, Humn Development nd Helth, Hrvrd School of Public Helth, 677 Huntington Ave, Lndmrk, 3rd Floor E, Boston, MA 02115; e-mil: vrdvs@hsph.hrvrd.edu 2012 Americn College of Chest Physicins. Reproduction of this rticle is prohibited without written permission from the Americn College of Chest Physicins. See online for more detils. DOI: /chest tion (intrgroup comprison), nd (2) compring pre vs post respirtory function mong experimentl group prticipnts (intergroup comprison). The subjects enrolled in the experimentl group were instructed to use the e-cigrette d lib for 5 min s they would usully smoke. The control group subjects were sked to use the e-cigrette with similr frequency, but without the e-cigrette crtridge included; therefore, e-cigrette vpor ws not creted nor inhled. As vpor ws not formed in the control setting, blinding ws not possible. The ethics committee of the Hellenic Anti-Cncer Society, Athens, Greece, provided ethics pprovl (protocol number: 67-7/10/10). Ech subject red nd signed written nd n informed consent form prior to study enrollment. e-cigrette Usge nd Chemicl Composition The e-cigrettes provided to the subjects were of the sme brnd (NOBACCO e-cigrettes, blck line) nd of the sme nicotine concentrtion. The e-cigrette itself ws composed of steel shell, microprocessor powered by lithium bttery, filter, nd removble (nd renewble) crtridge. Three types of crtridges were vilble in the mrket for this e-cigrette, nd we chose the medium one (NOBACCO MLB-MED filter), for which the mnufcturer reports mesured dose of 11 mg of nicotine. Further informtion on the e-cigrette used in the current study cn be found on the mnufcturer s website. 13 Moreover, the e-cigrette crtridge selected for use in the experimentl group hs been nlyzed for its chemicl composition by the Ntionl Center for Scientific Reserch, Demokritos, in Greece. 14 According to their nlysis, the crtridge contined propylene glycol ( -propylene glycol or 1,2-propnediol) in concentrtion. 60%, linlool (3,7-dimethyloct-1,6-dien-3-ol) in concentrtion, 5%, nicotine (, 10%), tobcco essence (, 5%), nd methyl vnillin (4-hydroxy- 3-methoxybenzldehyde) t, 1%; no polyromtic hydrocrbons were detected. 14 Lung Function Assessment Exhled Nitric Oxide: Mesurements were mde in sitting position with nose clip using n Eco Medics AG CLD 88 Series chemiluminescence nlyzer equipped with Spirowre 3.0 softwre progrm. The ptient ws instructed to inhle s deeply s possible to totl lung cpcity through filter mouthpiece nd consecutively exhle t mouth flow rte of 50 ml/s for 10 s. The exhltion rte ws held stedy by pplying constnt positive pressure (10 cm H 2 O) through resistnce fctor while coching the ptient to exhle stedily using visul stimultion on the system screen. Three con secutive trils were performed with 30-s intervl. Results were mesured in prts per billion (ppb). Dynmic Lung Volumes: Flows nd lung volumes were mesured in the sitting position, using Jeger MsterScreen spirometry system (heted pneumotch, resistnce, 0.05 kp/[l/s] t 10 L/s), with the highest FEV 1 recorded in line with pulmonry guidelines. Spirometry ws mesured ccording to the recommendtions of the Americn Thorcic Society/Europen Respirtory Society tsk force guidelines. 15 FEV 1, FVC, FEV 1 %, pek expirtory flow (PEF), nd mximl expirtory flow (MEF) t 25%, 50%, nd 75% of vitl cpcity were mesured. Ech mneuver ws repeted for t lest three techniclly cceptble forced expirtory flow curves. In order to ttin the best results (the ones tht represent the true sttus of the ptient s respirtory system) from the bsic pulmonry mesurements (spirometry nd dynmic lung volumes), the following criteri were estblished: (1) ech mesurement ws repeted t lest three times to confirm the proper collbortion of the ptient nd give the ptient the chnce to fmilirize themselves with ech process, nd (2) the results of CHEST / 141 / 6 / JUNE,

3 ech mesurement were reproducible (within 10% of the SD fter three mneuvers). Totl Respirtory Resistnces: The ctul vlues of mgnitude of respirtory impednce t 5 Hz (Z5Hz); respirtory resistnce t 5, 10, nd 20 Hz (R5Hz, R10Hz, nd R20Hz, respectively); rectnce t 5, 10, nd 20 Hz; nd resonnt frequency were ssessed with the use of n impulse oscillometry system (IOS). IOS is noninvsive, esy exmintion tht requires minimum, if ny, complince from the subject. During IOS mesurements, smll loudspeker cretes pulse-shped pressure wve in front of the mouth, with lternte pulses (t different cycles per second [ie, 5 Hz, 10 Hz, 25 Hz]). The mesurements were crried out ccording to the operting instructions provided by the mnufcturer (Visys Jeger Msterscreen IOS system). After occluding the nose of the subject, he/she ws instructed to brethe normlly through mouthpiece ttched to the IOS system while seted. Among ll the lung function tests, IOS mesurements hve one of the highest rtes of reproducibility nd sensitivity (s to detect even the erliest of pthophysiologic chnges in the ptient s pulmonry mechnics) nd require the miniml physicin subjectivity to obtin the correct mesurement tht corresponds to the ptient s true pulmonry mechnicl sttus. 16,17 Ptients followed the instructions, nd no discomfort or filure to comply ws noticed. The whole mneuver lsted for 90 s nd ws repeted for verifiction. Results were mesured in kp /(L/s). Sttisticl Anlysis The Kolmogorov-Smirnov tests were pplied to ssess the normlity of the dt; ll mesurements were found to be normlly distributed, with the exception of F eno. Pre vs post mesurements, sex differences, nd experimentl vs control conditions were ssessed through bivrite nlyses. The pired Student t test ws performed mong prmetric dt, wheres nonprmetric dt were compred with the Wilcoxon signed rnk test. Person correltions were pplied to ssess the correltions between the pre nd post respirtory tests. Results re presented s mens nd 95% CIs. To control simultneously for intervention group (experimentl vs control) nd bseline respirtory chrcteristics, dditionl liner regression nlyses were performed; R 2 vlues, b coefficients, nd 95% CI of the b re provided. The sttisticl nlysis ws performed with the sttisticl pckge PASW 18.0 (SPSS, Inc). Results The descriptive chrcteristics nd bseline pulmonry functionl sttus of prticipting subjects re depicted in Tble 1. Differences in bseline respirtory function, IOS, or F eno were not identified when strtified by group (experimentl vs control), wheres when strtified by sex, femle prticipnts were found to hve lower FEV 1, FVC, PEF, MEF t 50% of vitl cpcity, nd MEF t 75% of vitl cpcity; however, bseline F eno concentrtions nd IOS mesurements were not found to differ. Tble 2 depicts the chnges in F eno nd respirtory mechnics before nd fter the use of n e-cigrette (experimentl group) or shm e-cigrette (control group). In ll cses, the internl pre nd post mesurements per prticipnt were highly correlted, wheres no differences between bsic pulmonry me- Tble 1 Bseline Chrcteristics nd Respirtory Function of Study Prticipnts by Sex Chrcteristic Femle MleP Vlue No Age, y, men SD Spirometry FVC, L FEV 1, L PEF, L/s MEF 25, L/s MEF 50, L/s MEF 75, L/s MMEF, L/s F eno, ppb IOS Z5Hz, kp/(l/s) R5Hz, kp/(l/s) R10Hz, kp/(l/s) R20Hz, kp/(l/s) X5Hz, kp/(l/s) X10Hz, kp/(l/s) X20Hz, kp/(l/s) Peripherl R, kp/(l/s) Centrl R, kp/(l/s) Fres, Hz F eno 5 frction of exhled nitric oxide; Fres 5 resonnt frequency; IOS 5 impulse oscillometry system; MEF 5 mximl expirtory flow; MEF 25 5 mximl expirtory flow t 25% of vitl cpcity; MEF 50 5 mximl expirtory flow t 50% of vitl cpcity; MEF 75 5 mximl expirtory flow t 75% of vitl cpcity; MMEF 5 mximl midexpi rtory flow; PEF 5 pek expirtory flow; ppb 5 prts per billion; R 5 resistnce; R5Hz 5 irwy resistnce t 5 Hz; R10Hz 5 irwy resistnce t 10 Hz; R20Hz 5 ir wy resistnce t 20 Hz; X5Hz 5 irwy rec tnce t 5 Hz; X10Hz 5 irwy rectnce t 10 Hz; X20Hz 5 irwy rectnce t 20 Hz; Z5Hz = ir wy impednce t 5 Hz. P vlues bsed on pired Student t tests for ll other thn F eno performed with Wilcoxon signed rnk test. P,.05 clssified s sttisticlly significnt. surements (dt not shown) were identified between the two groups. In regrd to pulmonry oxidtive stress, our findings indicted tht F eno within the experimentl group decresed by 16% (by 2.14 ppb from ppb to ppb, P 5.005) fter the use of n e-cigrette, wheres F eno concentrtions were not found to chnge within the control group (from 8.76 ppb to 8.75 ppb, P 5.859). An dditionl sensitivity nlysis mong the 10 pirs of experimentl group prticipnts who lso prticipted in the control group ws performed nd indicted sttisticlly significnt decrese in F eno, by 1.69 ppb (from 8.76 ppb to 7.07 ppb, P 5.002), fter using n e-cigrette. Using IOS s n indictor of pulmonry function mong the study prticipnts, irwy impednce t Z5Hz incresed in the experimentl group by kp/(l/s) (95% CI, kp/ [L/s], P,.001), wheres no differences were noted mong control group prticipnts (men differ ence of kp/[l/s]; 95% CI, to kp/[l/s]; P 5.591). Correspondingly, lung resistnce in the 1402 Originl Reserch

4 Tble 2 Bseline Chrcteristics by Group nd Subsequent Intersubject nd Intergroup Chnges (Pre vs Post) in F ENO nd Flow Resistnce (IOS) Following Use of n e-cigrette Chrcteristic Group No. Pre-Men Post-Men Men Difference 95% CI of the Men Difference, Lower 2 Upper Pre vs Post P Vlue Experimentl vs Control P Vlueb F eno, ppb Experimentl to c.040 c Control to Flow resistnce IOS Z5Hz, kp/(l/s) Experimentl to 0.050,.001 c.003 c Control to IOS R5Hz, kp/(l/s) Experimentl to c.008 c Control to IOS R10Hz, kp/(l/s) Experimentl to c.020 c Control to IOS R20Hz, kp/(l/s) Experimentl to c.054 Control to IOS X5Hz, kp/(l/s) Experimentl to Control to IOS X10Hz, kp/(l/s) Experimentl to Control to IOS X20Hz, kp/(l/s) Experimentl to Control to IOS peripherl R, Experimentl to c.043 c kp/(l/s) Control to IOS centrl R, kp/(l/s) Experimentl to Control to IOS Fres, Hz Experimentl to Control to e-cigrette 5 electronic cigrette. See Tble 1 legend for expnsion of other bbrevitions. P vlues ssessed within groups (pre vs post usge). b P vlues ssessed between groups (experimentl vs control). csignificnt. experimentl group lso incresed t R5Hz, R10Hz, nd R20Hz by n ver ge of kp/(l/s) (95% CI, kp/[l/s]), kp/(l/s), (95% CI, kp/[l/s]), nd kp/ (L/s), (95% CI, kp/[l/s]), respectively. Moreover, peripherl pulmonry resistnce lso incresed from 0.22 kp/(l/s) to 0.25 kp/(l/s) ( P 5.05). Similr sttisticl results to those previously mentioned were identified through the intergroup comprison (men chnge in control vs men chnge in experimentl group) s seen in Tble 2. Strtifying the experimentl vs control group nlysis by sex did not lter the direction or sttisticl ssocition of the bove findings. Pulmonry function ssessed vi spirometry did not chnge in either group (dt not shown). Subsequently, liner regression nlysis ws performed to ssess the role of using n e-cigrette on the ssessed respirtory outcomes, tking into ccount the bseline mesurement of ech prticipnt nd Tble 3 Regression Anlysis on the Effect of Using n e-cigrette on F ENO nd Airwy Flow Resistnce (IOS), Controlling for the Prticipnts Bseline Mesurements Vrible R 2 b 95% CI P Vlue F eno, ppb to b IOS Z5Hz, kp/(l/s) to b IOS R5Hz, kp/(l/s) to b IOS R10Hz, kp/(l/s) to b IOS R20Hz, kp/(l/s) to b IOS peripherl R, kp/(l/s) to b IOS centrl R, kp/(l/s) to See Tble 1 nd 2 legends for expnsion of bbrevitions. Ech vlue represents seprte liner regression model djusting for the group (control vs experimentl) nd the reltive bseline mesurement (pre vs post). bsignificnt. CHEST / 141 / 6 / JUNE,

5 the group to which they were llocted. The key findings re depicted in Tble 3, strengthening the results iden tified through the bivrite ssocitions, s the chnges noted in respirtory function were even greter once we controlled for the prticipnts bseline responses. It is noteworthy tht peripherl flow resistnce ws found to increse pproximtely 18% fter use of the e-cigrette (by kp/[l/s]), wheres flow resistnce t R5Hz, R10Hz, nd R20Hz incresed by kp/(l/s), kp/(l/s), nd kp/(l/s), respectively. Peripherl resistnce overll incresed by kp/(l/s) ( P 5.024), wheres tendency for overll centrl irwy resistnce ws noted; however, this difference ws borderline nonsttisticlly significnt ( b, kp/[l/s]; 95% CI, to 0.071; P 5.069). Discussion To our knowledge, this is the first study to find physiologic response fter inhling from n e-cigrette. According to our findings, 5 min of use ws sufficient to led to n increse in lung flow resistnce over rnge of frequencies nd ws relted to decrese in F eno concentrtions. Impulse oscillometry s methodologic pproch hs been used previously in clinicl trils, cn be used to dignose obstructive lung disese, nd hs been shown to be superior to spirometry mesurements during pulmonry ssessment This is verified by the fct tht e-cigrette usge ws ssocited with incresed flow resistnce even though spirometryssessed lung function ws deemed norml, finding corroborted by the fct tht IOS cn detect oncoming pthophysiologic chnges of the respirtory system before spirometry. 20 Indeed, it hs been demonstrted tht chnges in flow resistnce precede chnges in PEF nd FEV 1 in experimentlly induced irwy obstruction, nd it is possible tht the chnges we note in this study my indicte similr preliminrily helth effect. 21 We must stte, however, tht while the differences within our study re of sttisticl significnce, the clinicl chnges my be too smll to be of mjor clinicl importnce (ie, to induce dyspne or brething difficulties). However, these mesurements were performed fter only 5 min of d lib e-cigrette use. A norml consumer would use the product likely severl times dy; thus, the clinicl impct might be greter. We hypothesize tht the increse in peripherl flow resistnce is ttributble to the cute nrrowing of the dimeter of the peripherl irwys, which could be due to either loclized mucosl edem, smooth muscle contrction (nd bron chospsm), or secretions. In the regression nl ysis, there ws tendency for centrl irwy resistnce to increse; however, this ws borderline nonsttisticlly significnt. It is pos- sible tht incresing the study s smple size might hve incresed the sttisticl significnce, or we might hypothesize tht using n e-cigrette my hve greter impct on peripherl rther thn centrl irwys. A strong point of our findings ws tht e-cigrette use ws ssocited with n immedite decrese in F eno concentrtions. Nitric oxide is gseous meditor tht hs n importnt role in severl physiologic processes in the respirtory trct, including vsculr regultion, neurotrnsmission, host defense, nd cytotoxicity. 22 Nitric oxide is n dditionl mrker tht hs been implicted in the pthophysiology of irwy diseses ssocited with smoking, is strongly correlted with eosinophilic inflmmtion nd bronchil hyperrectivity, nd hs become n estblished mrker for ssessing oxidtive stress, indicting the immedite effect e-cigrette usge might hve on pulmonry homeostsis As no stndrd definition of electronic nicotine delivery system exists, nd s different mnufcturers use different designs nd incorporte rnge of ingredients, there is limited evidence on the ctul constituents of ech brnd. Although we identified the clinicl chnges in lung function due to electronic nicotine delivery system use, we cn only hypothesize on the ctul substnces (or combintion of sub stnces) tht could hve cused the mesured effect. One of the substnces tht ws reported to be included in the e-cigrette we used ws propylene glycol (other constituents included linlool, nicotine, tobcco essence, nd methyl vnillin), nd this could hve plyed role in the mesured respirtory chnges. Reserch hs indicted tht exposure to propylene glycol cn induce respirtory irrittion nd increse the likelihood of developing sthm. 27,28 However, we cnnot rule out the possibility tht other constituents could be responsible or ct in synergy with propylene glycol to induce the respirtory nd oxidtive responses tht we noted. This study hs significnt implictions for product regultion nd use nd indictes direction for further reserch. Our results were replicble nd differed significntly in the bivrite nlysis following exposure both within the experimentl group (thus controlling for intersubject differences) nd between groups (experimentl vs control) nd lso in the regression nlysis while controlling bseline chrcteristics. Controlling for bseline mesurements llowed us to focus on the chnges due to using the e-cigrette nd not tke into ccount underlying dmge due to previous cigrette smoking or lung condition. The performed liner regression nlysis furthermore llowed us to estimte the quntittive effects of using single e-cigrette on mechnicl nd inflmmtory mesurble prmeters. Moreover, the chemicl com position of the crtridges used in e-cigrette 1404 Originl Reserch

6 be disclosed; knowledge of the contents enbled this study. However, despite these novel findings, our smple size remins reltively smll, nd further reserch is needed to investigte the mechnistic nd toxicologic effects of long-term usge, which re potentilly dverse nd worthy of further investigtion. In conclusion, use of n e-cigrette for 5 min ws found to cuse n increse in impednce, peripherl irwy flow resistnce, nd oxidtive stress mong helthy smokers. We must stte, however, tht lthough the differences within our study re of sttisticl significnce, the clinicl chnges my be too smll to be of mjor clinicl importnce. Notbly, becuse these short-term effects were present even fter only very limited usge, nd norml consumer would use the product most likely mny times dy, it is possible tht if e-cigrette use were short-term bridge to smoking cesstion, the long-term helth benefits ssocited with their use might outweigh the shortterm risks; however, this would need to be clrified. The FDA, s well s other interntionl regultory bodies, should pursue the regultion of the e-cigrette until mnu fcturers provide scientific evidence to support their clims. Additionl reserch is wrrnted to obtin concrete evidence of n dverse helth outcome. Acknowledgments Author contributions: Drs Vrdvs nd Behrkis tke responsibility for the integrity of the dt nd ccurcy of the dt nlysis. Dr Vrdvs: contributed to conception of the ide, dt nlysis, nd mnuscript preprtion. Dr Angnostopoulos: contributed to performing lbortory mesurements nd helping drft the mnuscript. Dr Kougis: contributed to performing lbortory mesurements nd helping drft the mnuscript. Dr Evngelopoulou: contributed to performing lbortory mesurements nd helping drft the mnuscript. Dr Connolly: contributed to study design, dt interprettion, nd mnuscript preprtion. Dr Behrkis: contributed to study supervision, study design, dt interprettion, nd mnuscript preprtion Finncil/nonfinncil disclosures: The uthors hve reported to CHEST tht no potentil conflicts of interest exist with ny compnies/orgniztions whose products or services my be discussed in this rticle. Role of sponsors : The sponsor hd no role in the design of the study, the collection nd nlysis of the dt, or in the preprtion of the mnuscript. References 1. Cobb NK, Abrms DB. E-cigrette or drug-delivery device? Regulting novel nicotine products. N Engl J Med ;365(3): Noel JK, Rees VW, Connolly GN. Electronic cigrettes: new tobcco industry? Tob Control ;20(1): Henningfield JE, Ztri GS. Electronic nicotine delivery systems: emerging science foundtion for policy. Tob Control ;19(2): Flouris AD, Oikonomou DN. Electronic cigrettes: mircle or mence? BMJ ;340:c FDA. Summry of results: lbortory nlysis of electronic cigrettes conducted by FDA. US Deprtment of Helth nd Humn Services website. 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