A systematic review of health effects of electronic …

1 A systematic review of health effects of electronic cigarettesA systematic review of health effects of electronic cigarettesCharlotta Pisinger, MD, PhD, MPHR esearch Centre for Prevention and health , Glostrup Hospital, Building 84/85 Nordre Ringvej 57 DK-2600 Glostrup, Denmark Email: Phone: (+45) 38633260 Fax: (+45) 38633977 Document prepared for the World health Organization December 2015A systematic review of health effects of electronic cigarettesThis report was prepared at the request of WHO Prevention of Noncommunicable Diseases. The findings, interpretations, and conclusions expressed in this work do not necessarily reflect the views of The authors have no conflict of interest. This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. CP is partly funded by a Danish fund, health Foundation (Helsefonden), which had no influence on choice of research topic, study conduct, analyses or interpretation of results.

2 The author CP has received compensation for lost work time, two months, from WHO to update a review from 2014. WHO had no influence on study conduct, analyses or interpretation of the approvalNot report was prepared at the request of WHO Prevention of Noncommunicable Diseases. The findings, interpretations, and conclusions expressed in this work do not necessarily reflect the views of 71. Methods 8 Search 8 Exclusion criteria 8 Eligibility criteria 8 Study selection 82. Overview of the studies 10 Topics 10 Conflicts of interest 103. Presentation of results 12 Content of fluid and vapour 12 Experiments with cells exposed to fluid, vapour or vapour extract: in vitro studies 20 Human experimental studies 23 Animal experimental studies 25 Adverse events 26 Passive exposure to vapour 29 The major ingredients: glycols, nicotine and flavours 304.

3 General considerations 34 General considerations of quality of studies and other research challenges 34 General health risk considerations 35 Impact of the diversity of products 35 Dual use 36 Other general risk considerations 385. Conclusions 396 A systematic review of health effects of electronic cigarettesThis report was prepared at the request of WHO Prevention of Noncommunicable Diseases. The findings, interpretations, and conclusions expressed in this work do not necessarily reflect the views of 41 Overview of studies investigating the effect of electronic cigarettes and health 64 Annexes with search strategies and detailed description of studies 105 Boxes Box 1. Identified content of fluids and vapour: glycols, nicotine, particles, metals, TSNAs 14 Box 2. Identified content of fluids and vapour: carbonyls, VOCs, hydrocarbons and PAHs, other measures 18 Box 3.

4 effects observed in experiments with cells (in vitro studies) 22 Box 4. effects observed in human experimental studies 24 Box 5. effects observed in animal experimental studies 26 Box 6. Reported adverse events 28 Box 7. Findings from studies on passive vaping 30 Box 8. Higher risk as identified in studies 36 Box 9. Some of the findings causing concern 407 A systematic review of health effects of electronic cigarettesThis report was prepared at the request of WHO Prevention of Noncommunicable Diseases. The findings, interpretations, and conclusions expressed in this work do not necessarily reflect the views of fractional exhaled nitric oxideNNK nicotine-derived nitrosamine ketoneNNN N-nitrosonornicotinePAHs polyaromatic hydrocarbons/polycyclic aromatic hydrocarbonsPM particulate particulate matter less than micrometres in diameter TSNAs tobacco-specific nitrosaminesVOC volatile organic compoundWHO World health Organization8 A systematic review of health effects of electronic cigarettesThis report was prepared at the request of WHO Prevention of Noncommunicable Diseases.

5 The findings, interpretations, and conclusions expressed in this work do not necessarily reflect the views of SearchA search was carried out in PubMed, EMBASE and CINAHL (Annex 1). Keywords were electronic cigarette or e-cigarette or electrically heated cigarette or ENDS and cigarette or electronic nicotine delivery system or electronic nicotine delivery device or e-liquid . The search was performed several times to update the evidence (Annex 1). Exclusion criteriaRecommendations, expert statements, reviews, technical reports and other non-original papers were excluded, as were papers on smoking cessation, abuse liability, nicotine levels, withdrawal symptoms, poisonings (intentional and unintentional), prevalence, attitudes and beliefs. Eligibility criteriaOriginal articles or abstracts on electronic cigarettes (or e- cigarettes ) of any topic relevant to health , published before 26 November 2015, were considered eligible.

6 Additionally, a few studies published after that date, found accidentally, have been included. We included studies in any language except a paper in Japanese by Ohta et al. (1) that we assumed to be the same paper as that by Uchiyama et al. (2). Almost all studies were peer-reviewed. A few risk modelling studies have been included as they are based on original findings and typically are presented for decision-makers or the Study selectionThe first part of the search was performed by two authors Charlotta Pisinger (CP) and Dr Med. Martin D ssing who both read and discussed the articles (3). The second updated search was performed by CP we screened the titles. After reading the abstract, papers that did not report a health -related topic were rejected. Agreement of the authors was necessary to exclude a paper (first review ). Papers on adverse events were included even if the main focus of 9 A systematic review of health effects of electronic cigarettesThis report was prepared at the request of WHO Prevention of Noncommunicable Diseases.

7 The findings, interpretations, and conclusions expressed in this work do not necessarily reflect the views of article was, for example, smoking cessation. Then, we excluded duplicates and papers describing the same study population or did not report original data. Full documents were obtained for the final inclusion. Additionally, we looked through the reference lists of the articles for missed papers and we investigated reports for overlooked papers. Finally, we included grey literature that we found accidentally or that others sent to us. We investigated all papers for conflict of interest, funding and workplace of authors. If in doubt, we contacted the authors and asked about funding and conflict of interest or searched the Internet. 10 A systematic review of health effects of electronic cigarettesThis report was prepared at the request of WHO Prevention of Noncommunicable Diseases.

8 The findings, interpretations, and conclusions expressed in this work do not necessarily reflect the views of Overview of the TopicsWe identified 175 studies 99 more than in Pisinger and D ssing (3) the majority (n=105) of these investigating the content of e-cigarette fluid and vapour and/or performing experiments with cells, exposing them to e-cigarette fluid, vapour or extract of vapour. Thirty-one studies reported on adverse events, 32 were human experimental studies and 11 were animal experimental studies. Four papers investigated effects on both cells and animals (4 7). These papers are described in both sections but they only count as one paper. Figure 1. Categorization of 175 studies Conflicts of interestIn 34% of the studies the authors had stated a conflict of interest or described funding, or reviewers found a non-declared conflict of interest (for details, see footnotes in Tables 1 to 4 and Annexes 2 to 5).

9 Most of the studies with conflict of interest were funded or otherwise supported by manufacturers of e- cigarettes , but many authors had also been consultants for manufacturers of medicinal smoking cessation therapy or received research grants from them. In several cases for example, when an author had previously received lecture fees, research grants or travel expenses from a manufacturer ( 8 10) no major influence on the actual study is expected. However, it is important 11 A systematic review of health effects of electronic cigarettesThis report was prepared at the request of WHO Prevention of Noncommunicable Diseases. The findings, interpretations, and conclusions expressed in this work do not necessarily reflect the views of note that in recent years the tobacco industry, a manufacturer of e- cigarettes , has published 17 out of the 60 studies with conflict of interest (28%), primarily studies investigating content of fluid.

10 History has shown that we should be very careful in trusting results of studies influenced by the tobacco industry (11 13). Therefore, in-text citations for these studies are marked with an asterisk (*) to alert the reader. Studies funded by ecigarette manufacturers or performed in collaboration with the ecigarette industry are labelled with a chevron (^).12 A systematic review of health effects of electronic cigarettesThis report was prepared at the request of WHO Prevention of Noncommunicable Diseases. The findings, interpretations, and conclusions expressed in this work do not necessarily reflect the views of Presentation of Content of fluid and vapour(See Table 1 for overview of studies; for details see Annex 2.)General findings. Most studies have used conventional cigarettes as reference and investigated presence or concentrations of substances that are known to be harmful in conventional cigarettes .