PITFALLS IN E-CIGARETTE RESEARCH LESSONS FROM THE CURRENT LITERATURE

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1 PITFALLS IN E-CIGARETTE RESEARCH LESSONS FROM THE CURRENT LITERATURE Dr Konstantinos Farsalinos Researcher Onassis Cardiac Surgery Center, Greece University of Patras, Greece

2 COI 2 (unpublished yet) studies using unrestricted funds provided to the institution by e- cigarette companies In 2 studies, institutions unrelated to me were funded by e-cigarette companies 2 studies funded by a non-profit association (1 of them in press) 1 study funded by crowdfunding campaign 25 publications with no funding or other support No funding from tobacco industry No funding from pharmaceutical industry

3 E-CIGARETTE PHENOMENON Consumer initiated and consumer driven Was not developed by medical science/pharma industry The product is more complicated than tobacco Chemistry (liquids heating and aerosol products) Electronics Different mode of function, different characteristics, different patterns of use Many scientists with experience in tobacco research think they are competent to perform research on e-cigarettes Are they?

4 NICOTINE AND CANCER 191 references about the carcinogenic properties of nicotine Not one epidemiological study on humans Interestingly, the 2 nd paragraph of this manuscript discusses about e-cigarettes as a source of nicotine

5 NICOTINE AND CANCER

6 TSNAS IN E-LIQUIDS AND INTERPRETATION Farsalinos et al, J Chromatogr A, 2013 Kim & Shin, J Chromatogr A 2013

7 THERMAL DEGRADATION NEJM STORY

8 THERMAL DEGRADATION NEJM STORY Standard deviation Standard Standard error deviation of mean

9 DRY PUFF PHENOMENON 2013

10 DRY PUFF PHENOMENON Farsalinos et al, Inhal Toxicol 2013

11 DRY PUFF PHENOMENON

12 DRY PUFF PHENOMENON Farsalinos et al, IJERPH 2013

13 DRY PUFF PHENOMENON To evaluate the equipment used in the NEJM study We obtained 10 CE4 atomizers We asked 10 vapers to use them at gradually increasing voltage levels (starting from 3V) All vapers identified dry puffs at volts ( W), compared to 5V (12W) used in the NEJM study.

14 Formaldehyde Acetaldehyde Acetone Acrolein 6.5 watts Atomizer (1.7) ND ND ND Atomizer (1.6) 0.8 (0.4) ND 0.2 (0.1) 7.5 watts Atomizer (1.3) ND ND ND Atomizer 2 ND 0.8 (0.5) ND 1.3 (0.8) 9 watts Atomizer (2.3) 3.5 (0.9) ND 0.8 (0.6) Atomizer 2 DRY PUFFS (15.9) 58.9 (12.8) 4.6 (1.0) 48.4 (10.0) 10 watts Atomizer (2.6) 4.5 (1.2) ND 1.0 (0.6) Atomizer 2 DRY PUFFS (56.0) (33.3) 22.5 (7.1) (48.8) Farsalinos et al, Addiction 2015

15 METALS Expected finding due to the metallic structure of atomizers, coils Heavy metals are common contaminants in water, food and in inhalational pharmaceutical products USP has defined the maximum acceptable daily intake from inhalational medications Once again, it is the amount of a compound that defines its toxicity

16 METALS

17 METALS

18 METALS

19 E-CIGARETTES AND OVERALL TOXICITY ASHRAE = American Association of Heating, Refrigeration and Air Conditioning (and now e- cigarette) engineering

20 E-CIGARETTES AND OVERALL TOXICITY Study conclusion: We conclude that e-cigarettes emit harmful chemicals into the air and need to be regulated in the same manner as tobacco smoking. There is evidence that nitrosamines, a group of carcinogens found specifically in tobacco, are carried over into the e-cigarette fluid from the nicotine extraction process. There is also evidence that the glycol carriers can by oxidized by the heating elements used in e-cigarettes to vaporize the liquids, creating aldehydes such as formaldehyde. Consumers should be warned that, while the health risks associated with the usage of e-cigarettes are less than those associated with tobacco smoking, there remain substantial health risks associated with the use of e-cigarettes. Study assumptions: Direct exposure assessment The respiratory absorption of the inhaled vapor was assumed to be 100% for all compounds Indirect (Passive) Exposure Assessment... For this assessment we assumed that 100% of the inhaled vapor by the user was exhaled into the indoor air and the respiratory absorption by occupants of the exhaled aerosol in the indoor air was 100% for all compounds

21 E-CIGARETTES AND OVERALL TOXICITY Peer reviewed!!!

22 CELL AND ANIMAL STUDIES Cell and animal studies are becoming a trend In many cases, information is irrelevant Nicotine overdose (trying to get cotinine levels similar to humans) No comparison with smoking No evaluation of smoking cessation with e-cigarette use Use of non-smoking animals and comparison with clean air Conclusions are (in many cases) misleading and uninformative due to methodological problems

23 E-CIG AEROSOL AND CYTOTOXICITY 200 e-cigarette puffs, 10sec interpuff interval (!)

24 E-CIG AEROSOL AND CYTOTOXICITY Scheffler et al., Int J Environm Res Public Health 2015

25 E-CIG AEROSOL AND CYTOTOXICITY Why is glycerol aerosol more toxic than e-liquid aerosol? Probably because they used undiluted glycerol high viscosity problematic supply to the wick overheating Main study conclusion: Our results clearly demonstrate that the tested e-cigarette vapor had toxicological effects on primary NHBE cells when exposed directly at the air-liquid interface. What was the criterion to use 200 puffs? Authors response: to generate a response (i.e. to show some cytotoxicity) Is this really a criterion to assess toxicity? You expose the cells to as much aerosol as needed to have toxicity, so, you find toxicity by definition!! With this methodology, any chemical would be toxic Important to use predefined protocols (e.g. ISO ) which determine levels of exposure Scheffler et al., Int J Environm Res Public Health 2015

26 E-CIG AEROSOL AND CYTOTOXICITY

27 E-CIG AEROSOL AND CYTOTOXICITY Nicotine concentrations 16mg/L in the 400mg/L 1600mg/L experiment 80mg/L 800mg/L Nicotine concentration in blood of smokers 0.03mg/L

28 CELL STUDY AND DRIPPERS

29 CELL STUDY AND DRIPPERS Dripping as defined by the authors True dripping atomizer

30 ANIMAL STUDY Study conclusion: In conclusion, E-cig exposure results in immunomodulatory effects that are similar to those observed after exposure to cigarette smoke. Since bacterial and viral exacerbations are major drivers of COPD disease progression, this study raises a concern that COPD patients who switch from cigarettes to E-cigs may not observe substantial improvement in their disease progression. HOWEVER No tobacco cigarette animal group no comparison No spontaneous infections, but instillation of bacteria and viruses No switching from tobacco to e-cigarette in any animal group Study conclusion IRRELEVANT

31 LIPOID PNEUMONIA Secondary school chemistry Glycerin is an ALCOHOL, not a lipid!!!

32 POPULATION STUDIES Study of smoking and e-cigarette use in Korean adolescents

33 POPULATION STUDIES Conclusion: We are witnessing the beginning of a new phase of the nicotine epidemic and a new route to nicotine addiction for kids

34 POPULATION STUDIES Many studies (mine excluded of course!) are of poor quality, due to problems in methodology, interpretation of findings, presentation and subsequent media campaigns E-cigarette is a field generating huge publicity - universities and professors like publicity Cell studies of almost no relevance to human effects get to the headlines, presented as examining human effects (e.g. cell study presented as: e-cigarettes cause emphysema!) Two basic reasons for this phenomenon: Lack of understanding about e-cigarette complexity, mode of function and patterns of use Ideological opposition towards anything beyond complete cessation without alternatives Not sure which of the two is worse

35 Dr Konstantinos Farsalinos Researcher, Onassis Cardiac Surgery Center, Greece Researcher, University of Patras, Greece

WHO study and position on Electronic cigarettes

WHO study and position on Electronic cigarettes 1 Roberto Bertollini MD MPH Presentation Roadmap What are ENDS Scientific Evidence Global Availability WHO s Position Designed to deliver nicotine to the