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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Summary E-cigarette aerosol contains fewer numbers and lower levels of most toxicants than smoke from combustible tobacco cigarettes does. Exposure to nicotine and to toxicants from the aerosolization of e-cigarette ingredients is dependent on user and device characteristics. Laboratory tests of e-cigarette ingredients, in vitro toxicological tests, and short-term human studies suggest that e-cigarettes are likely to be far less harmful than combustible tobacco cigarettes. However, the absolute risks of the products cannot be unambiguously determined at this time. Long-term health effects, of particular concern for youth who become dependent on them, are not yet clear. Although e-cigarette use might cause youth to transition to combustible tobacco products, they might also increase adult cessation of combustible tobacco cigarettes. The net public health effect, harm or benefit, of e-cigarettes depends on three factors: their effect on youth initiation of combustible products, their effect on adult cessation of combustible products, and their intrinsic toxicity. If e-cigarette use by adult smokers leads to long-term abstinence from combustible tobacco cigarettes, the benefit to public health could be considerable. Without that health benefit for adult smokers, e-cigarette use could cause considerable harm to public health in the short- and long-term due both to the inherent harms of exposure to e-cigarette toxicants and to the harms related to subsequent combustible tobacco use by those who begin using e-cigarettes in their youth. Population modeling is a useful strategy to help estimate the balance of potential benefits and harms from e-cigarettes in the short-term before more definite scientific data are available. Factors that would promote the potential health benefits associated with these products include determining with more precision under which conditions e- cigarettes could serve as an effective smoking cessation aid, discouraging their use among youth through tobacco control strategies such as education and restrictions on products particularly appealing to youth, and increasing their safety through data-driven product engineering and design. Millions of Americans use electronic cigarettes (e-cigarettes), even as rates of smoking1 combustible tobacco cigarettes continue to decline among youth and adults. In 2016 youth e- cigarette use was substantially higher than cigarette smoking or use of any other tobacco product. A common picture emerges from national surveys. Prevalence of use increases with age in children and youth. E-cigarette use also varies by gender, with typically greater use among boys than girls. E-cigarette use also varies by race and ethnicity, with higher rates of use among youth who identify as Hispanic and non-Hispanic white compared with black, Asian, and other races. Early results suggest that use stabilized or decreased in youth between 2015 and 2016, despite 1 The committee uses the verb “smoke” to refer to use of combustible tobacco cigarettes and “vape” to refer to use of e-cigarettes. Similarly “smoker” refers to someone who uses combustible tobacco cigarettes. S-1 PREPUBLICATION COPY: UNCORRECTED PROOFS

S-2 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES increases between 2011 and 2015 across a range of measures and surveys. Substantial proportions of youth report using non-nicotine electronic cigarettes. Rates of e-cigarette use among adults are relatively low when compared with youth e-cigarette use and to adult combustible tobacco cigarette smoking. Most adult e-cigarette users report currently using other tobacco products. Among adults, as among youth, patterns of use vary by demographic subgroups—age, gender, and race and ethnicity. E-cigarette use is generally greatest among young adults and decreases with age in adults. Few adults begin using e-cigarettes who are not already using combustible tobacco cigarettes. Despite their popularity, little is known about their health effects, and perceptions of potential risks and benefits of e-cigarette use vary widely among the public, users of e-cigarettes, health care providers and the public health community. For example, whether e-cigarette use confers lower risk of addiction compared with combustible tobacco cigarettes is one point of controversy. Electronic cigarettes contain constituents that are not inert and are likely to have some negative health effects on their own. However, because the known risks of combustible tobacco are so great, understanding the net public health effect of e-cigarettes requires understanding not only the inherent risks of e-cigarettes, but also the relationship between e- cigarette use and combustible tobacco cigarette use. Further, concerns have been raised that e-cigarettes will induce youth to begin using combustible tobacco cigarettes. E-cigarette use among youth and young adults is especially worrying if e-cigarettes cause dependence or the normalization of smoking behavior, and subsequently lead youth and young adults to start smoking combustible tobacco cigarettes. This is of particular concern for youth who otherwise would never have smoked. Among adult populations, to the extent that e-cigarette use promotes either reduction or complete abstinence from combustible tobacco smoking, e-cigarettes may help to reduce health risks. E-cigarettes are regulated as tobacco products2 by the Center for Tobacco Products of the Food and Drug Administration (FDA), which requested that the National Academies of Sciences, Engineering, and Medicine convene a committee of experts to conduct a review of the emerging evidence about e-cigarettes and health, make recommendations for the improvement of this research, and highlight gaps that are a priority for future research. The Statement of Task can be found in Box S-1. The committee undertook a comprehensive review of the scientific literature regarding key constituents in e-cigarettes, human health effects, initiation and cessation of combustible tobacco cigarette use, and harm reduction. The committee considered the quality of individual studies, as well as the totality of the evidence to provide structured and consistent conclusions on the strength of the evidence. See Box S-2 for a summary of the framework the committee used for those conclusions. The committee notes that the framework is a guide, but that a great deal of expert judgment—in the evaluation of individual studies and in bodies of evidence—is always involved. The Annex to this Summary includes a compilation of the conclusions grouped by level of evidence, whereas they are listed by type of outcome in the sections that follow. 2 If an e-cigarette manufacturer made a claim in packaging or advertising that the products were useful for smoking cessation, the product would be regulated as a drug-delivery device under different statutory authorities and not by the Center for Tobacco Products. E-cigarettes are regulated as tobacco products because the nicotine in the e-liquids derives from tobacco plants. The Food and Drug Administration recently exerted authority over e-cigarettes; those that do not contain nicotine may be reviewed on a case-by-case basis. PREPUBLICATION COPY: UNCORRECTED PROOFS

SUMMARY S-3 CONSTITUENTS E-cigarettes contain liquids (referred to as e-liquids) that are aerosolized upon operation of the device. E-liquids typically contain nicotine (although some users prefer zero-nicotine solutions), flavorings, and humectants. Nicotine is a well-understood compound with known central and peripheral nervous system effects. It causes dependence and addiction, and exposure to nicotine from e-cigarettes likely elevates the cardiovascular disease risk in people with pre- existing cardiovascular disease(s), but the cardiovascular risk in people without cardiovascular disease(s) is uncertain. Based on studies of long-term users of NRT or smokeless tobacco, nicotine exposure from e-cigarette use will likely pose minimal cancer risk to users. Most flavorings in e-liquids are designated as generally-recognized-as-safe (also known as GRAS) by FDA, but those designations are for oral consumption in food and do not apply to flavorings used in e-cigarettes; most of these were never studied for toxicity via the inhalation route. The primary humectants are propylene glycol and vegetable glycerin, compounds also in widespread use for other purposes and about which significant scientific literature exists. In reviewing the literature about the constituents in and exposures from e-cigarettes, the committee made nine conclusions: Conclusion 3-1. There is conclusive evidence that e-cigarette use increases airborne concentrations of particulate matter and nicotine in indoor environments compared with background levels. Conclusion 3-2. There is limited evidence that e-cigarette use increases levels of nicotine and other e-cigarette constituents on a variety of indoor surfaces compared with background levels. Conclusion 4-1. There is conclusive evidence that exposure to nicotine from e- cigarettes is highly variable and depends on product characteristics (including device and e-liquid characteristics) and how the device is operated. Conclusion 4-2. There is substantial evidence that nicotine intake from e- cigarette devices among experienced adult e-cigarette users can be comparable to that from combustible tobacco cigarettes. Conclusion 5-1. There is conclusive evidence that in addition to nicotine, most e- cigarette products contain and emit numerous potentially toxic substances. Conclusion 5-2. There is conclusive evidence that, other than nicotine, the number, quantity, and characteristics of potentially toxic substances emitted from e-cigarettes is highly variable and depends on product characteristics (including device and e-liquid characteristics) and how the device is operated. Conclusion 5-3. There is substantial evidence that except for nicotine, under typical conditions of use, exposure to potentially toxic substances from e- cigarettes is significantly lower compared with combustible tobacco cigarettes. Conclusion 5-4. There is substantial evidence that e-cigarette aerosol contains metals. The origin of the metals could be the metallic coil used to heat the e- liquid, other parts of the e-cigarette device, or e-liquids. Product characteristics and use-patterns may contribute to differences in the actual metals and metal concentrations measured in e-cigarette aerosol. PREPUBLICATION COPY: UNCORRECTED PROOFS

S-4 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES Conclusion 5-5. There is limited evidence that the number of metals in e-cigarette aerosol could be greater than the number of metals in combustible tobacco cigarettes, except for cadmium, which is markedly lower in e-cigarettes compared with combustible tobacco cigarettes. Taken together, the evidence in support of these conclusions suggests that e-cigarette aerosol contains fewer numbers and lower levels of toxicants than smoke from combustible tobacco cigarettes. Nicotine exposure can mimic that found with use of combustible tobacco cigarettes, but is highly variable. The exposure to nicotine and toxicants from the aerosolization of flavorings and humectants is dependent on user and device characteristics, however. HUMAN HEALTH EFFECTS Combustible tobacco cigarettes pose serious risks to human health; these risks are well documented and well understood. Many of those health effects emerge only after decades of cigarette smoking. E-cigarettes have only been on the market in the United States since 2006, making scientific comparisons between e-cigarettes and combustible tobacco cigarettes about most health effects difficult. However, research on short-term exposures to e-cigarettes and effects on disease symptoms and intermediate outcomes exist. An important distinction when considering these data is whether the effects are seen in an e-cigarette user who had never used combustible tobacco cigarettes (usually children or youth) or in a combustible tobacco cigarette user, with and without preexisting tobacco-related disease, usually adults. The committee reviewed evidence on the effects of e-cigarettes in several health domains: dependence, cardiovascular, cancer, respiratory diseases, oral diseases, maternal and fetal outcomes, and injuries and poisonings. Although the amount of literature is relatively scant and complicated by the multiple types of e-cigarettes in use even within a given study, the committee made 26 conclusions about the effects of e-cigarettes on health. Conclusion 7-1. There is substantial evidence that e-cigarette aerosols can induce acute endothelial cell dysfunction, although the long-term consequences and outcomes on these parameters with long-term exposure to e-cigarette aerosol are uncertain. Conclusion 7-2. There is substantial evidence that components of e-cigarette aerosols can promote formation of reactive oxygen species/oxidative stress. Although this supports the biological plausibility of tissue injury and disease from long-term exposure to e-cigarette aerosols, generation of reactive oxygen species and oxidative stress induction is generally lower from e-cigarettes than from combustible tobacco cigarette smoke. Conclusion 8-1. There is substantial evidence that e-cigarette use results in symptoms of dependence on e-cigarettes. Conclusion 8-2. There is moderate evidence that risk and severity of dependence are lower for e-cigarettes than combustible tobacco cigarettes. PREPUBLICATION COPY: UNCORRECTED PROOFS

SUMMARY S-5 Conclusion 8-3. There is moderate evidence that variability in e-cigarette product characteristics (nicotine concentration, flavoring, device type, and brand) is an important determinant of risk and severity of e-cigarette dependence. Conclusion 9-1. There is no available evidence whether or not e-cigarette use is associated with clinical cardiovascular outcomes (coronary heart disease, stroke, and peripheral artery disease) and subclinical atherosclerosis (carotid intima media-thickness and coronary artery calcification). Conclusion 9-2. There is substantial evidence that heart rate, increases after nicotine intake from e-cigarettes. Conclusion 9-3. There is moderate evidence that diastolic blood pressure increases after nicotine intake from e-cigarettes. Conclusion 9-4. There is limited evidence that e-cigarette use is associated with a short-term increase in systolic blood pressure, changes in biomarkers of oxidative stress, increased endothelial dysfunction and arterial stiffness, and autonomic control. Conclusion 9-5. There is insufficient evidence that e-cigarette use is associated with long-term changes in heart rate, blood pressure, and cardiac geometry and function. Conclusion 10-1. There is no available evidence whether or not e-cigarette use is associated with intermediate cancer endpoints in humans. This holds true for comparisons of e-cigarette use compared with combustible tobacco cigarettes and e-cigarette use compared with no use of tobacco products. Conclusion 10-2. There is limited evidence from in vivo animal studies using intermediate biomarkers of cancer to support the hypothesis that long-term e- cigarette use could increase the risk of cancer; there is no available evidence from adequate long-term animal bioassays of e-cigarette aerosol exposures to inform cancer risk. Conclusion 10-3. There is limited evidence that e-cigarette aerosol can be mutagenic or cause DNA damage in humans, animal models, and human cells in culture. Conclusion 10-4. There is substantial evidence that some chemicals present in e- cigarette aerosols (e.g., formaldehyde, acrolein) are capable of causing DNA damage and mutagenesis. This supports the biological plausibility that long-term exposure to e-cigarette aerosols could increase risk of cancer and adverse reproductive outcomes. Whether or not the levels of exposure are high enough to contribute to human carcinogenesis remains to be determined. Conclusion 11-1. There is no available evidence whether or not e-cigarettes cause respiratory diseases in humans. Conclusion 11-2. There is limited evidence for improvement in lung function and respiratory symptoms among adult smokers with asthma who switch to e- cigarettes completely or in part (dual use). PREPUBLICATION COPY: UNCORRECTED PROOFS

S-6 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES Conclusion 11-3. There is limited evidence for reduction of chronic obstructive pulmonary disease (COPD) exacerbations among adult smokers with COPD who switch to e-cigarettes completely or in part (dual use). Conclusion 11-4. There is moderate evidence for increased cough and wheeze in adolescents who use e-cigarettes and an association with e-cigarette use and an increase in asthma exacerbations. Conclusion 11-5. There is limited evidence of adverse effects of e-cigarette exposure on the respiratory system from animal and in vitro studies. Conclusion 12-1. There is limited evidence suggesting that switching to e- cigarettes will improve periodontal disease in smokers. Conclusion 12-2. There is limited evidence suggesting that nicotine and non- nicotine containing e-cigarette aerosol can adversely affect cell viability and cause cell damage of oral tissue in non-smokers. Conclusion 13-1. There is no available evidence whether or not e-cigarettes affect pregnancy outcomes. Conclusion 13-2. There is insufficient evidence whether or not maternal e- cigarette use affects fetal development. Conclusion 14-1. There is conclusive evidence that e-cigarette devices can explode and cause burns and projectile injuries. Such risk is significantly increased when batteries are of poor quality, stored improperly or are being modified by users. Conclusion 14-2. There is conclusive evidence that intentional or accidental exposure to e-liquids (from drinking, eye contact, or dermal contact) can result in adverse health effects including but not limited to seizures, anoxic brain injury, vomiting, and lactic acidosis. Conclusion 14-3. There is conclusive evidence that intentionally or unintentionally drinking or injecting e-liquids can be fatal. Taken together, the evidence reviewed by the committee suggests that e-cigarettes are not without physiological activity in humans, but the implications for long-term effects on morbidity and mortality are not yet clear. Use of e-cigarettes instead of combustible tobacco cigarettes by those with existing respiratory disease might be less harmful. INITIATION AND CESSATION The Family Smoking Prevention and Tobacco Control Act of 2009, which is the basis for FDA’s regulatory authority of tobacco products, including e-cigarettes, defined a unique regulatory standard, the public health standard. This requires that tobacco products introduced on the market after February 15, 2007 be shown to have a net population health benefit to users and non-users of the product. Operationally, if a product caused more people to begin harmful tobacco use and fewer people to quit tobacco use, even if the product itself poses less risk to the user than other products, it could be determined that the product poses a public health burden and PREPUBLICATION COPY: UNCORRECTED PROOFS

SUMMARY S-7 would be kept off the market. Thus, the tobacco control field must pay close attention to the effects of e-cigarette use on initiation and cessation of combustible tobacco use, regardless of the effects of e-cigarettes on health outcomes. Although the studies reviewed had limitations, the committee was able to make seven conclusions: Conclusion 16-1. There is substantial evidence that e-cigarette use increases risk of ever using combustible tobacco cigarettes among youth and young adults. Conclusion 16-2. Among youth and young adult e-cigarette users who ever use combustible tobacco cigarettes, there is moderate evidence that e-cigarette use increases the frequency and intensity of subsequent combustible tobacco cigarette smoking. Conclusion 16-3. Among youth and young adult e-cigarette users who ever use combustible tobacco cigarettes, there is limited evidence that e-cigarette use increases, in the near term, the duration of subsequent combustible tobacco cigarette smoking. Conclusion 17-1. Overall, there is limited evidence that e-cigarettes may be effective aids to promote smoking cessation. Conclusion 17-2. There is moderate evidence from randomized controlled trials that e-cigarettes with nicotine are more effective than e-cigarettes without nicotine for smoking cessation. Conclusion 17-3. There is insufficient evidence from randomized controlled trials about the effectiveness of e-cigarettes as cessation aids compared with no treatment or to Food and Drug Administration–approved smoking cessation treatments. Conclusion 17-4. While the overall evidence from observational trials is mixed, there is moderate evidence from observational studies that more frequent use of e-cigarettes is associated with increased likelihood of cessation. Taken together the evidence suggests that while e-cigarettes might cause youth who use them to transition to use of combustible tobacco products, they might increase adult cessation of combustible tobacco cigarettes. HARM REDUCTION The committee reviewed evidence from the sections discussed above to specifically look at what is known about e-cigarette exposures and health effects when compared with combustible tobacco cigarettes. The committee reached five conclusions. Conclusion 18-1. There is conclusive evidence that completely substituting e- cigarettes for combustible tobacco cigarettes reduces users’ exposure to numerous toxicants and carcinogens present in combustible tobacco cigarettes. PREPUBLICATION COPY: UNCORRECTED PROOFS

S-8 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES Conclusion 18-2. There is substantial evidence that completely switching from regular use of combustible tobacco cigarettes to e-cigarettes results in reduced short-term adverse health outcomes in several organ systems. Conclusion 18-3. There is no available evidence whether or not long-term e- cigarette use among smokers (dual use) changes morbidity or mortality compared with those who only smoke combustible tobacco cigarettes. Conclusion 18-4. There is insufficient evidence that e-cigarette use changes short-term adverse health outcomes in several organ systems in smokers who continue to smoke combustible tobacco cigarettes (dual users). Conclusion 18-5. There is moderate evidence that second-hand exposure to nicotine and particulates is lower from e-cigarettes compared with combustible tobacco cigarettes. The evidence about harm reduction suggests that across a range of studies and outcomes, e- cigarettes pose less risk to an individual than combustible tobacco cigarettes. MODELING The committee used population dynamic modeling to examine the possible effects of e- cigarette use at the population level. The specific time frame and magnitude of population health effects of e-cigarettes will depend on their impact on the rates of initiation and cessation of combustible tobacco cigarettes and on their intrinsic harm. Any population health effect includes the possibility of some groups incurring harm (e.g., youth who initiate smoking combustible tobacco cigarettes), while others benefit (e.g., adult combustible users who completely quit or reduce smoking). As with other models of population health effects of tobacco use, the effects of changing cessation rates are seen earlier than effects of changing initiation rates, due to the lag in time for serious chronic health effects of combustible tobacco cigarettes to manifest. Under the assumption that the use of e-cigarettes increases the net cessation rate of combustible tobacco cigarettes among adults (i.e., the increase in permanent quitting offsets the potential relapse of former smokers because of e-cigarettes), the modeling projects that use of these products will generate a net public health benefit, at least in the short run. The harms from increased initiation by youth will take time to manifest, occurring decades after the benefits of increased cessation are seen. However, for long-range projections (e.g., 50 years out), the net public health benefit is substantially less and is negative under some scenarios. With the range of assumptions used, the model projects that there would be net public health harm in the short and long terms if the products do not increase combustible tobacco cessation in adults. Factors that would maximize potential health benefits associated with these products include determining with more precision whether and under which conditions e-cigarettes could serve as an effective smoking cessation aid, discouraging their use among youth through standard tobacco control strategies such as education and access restrictions, and increasing their safety through data-driven product engineering and design. PREPUBLICATION COPY: UNCORRECTED PROOFS

SUMMARY S-9 RESEARCH RECOMMENDATIONS Given the relatively short time that e-cigarettes have been used, it is understandable that the evidence base regarding their effects is limited. There is a great need for more evidence. Manufacturers will need to produce this research in a short amount of time if current statutory deadlines remain in place. Researchers from academia will also be involved directly (in contracts with manufacturers and in grants from government and others) in the generation of these data. Some types of research involve a long-term horizon; other important and informative research requires much less time to conduct. One type of research does not substitute for the other; a complete portfolio of research is needed. The committee understands that, in any new field, researchers struggle to conduct optimal research due to limitations of knowledge. Also, researchers feel the urgency to study an important new question and adapt what they know, without complete adjustments in research design or methods sufficient to address the nuances of the problem. Finally, the rapidly changing nature of the devices has made comparisons among studies difficult. The committee identified gaps in the literature in every aspect in its work and provides overarching categories of research needs and specific research suggestions within the final chapters of each of the three major sections of the report. These overarching categories include (1) addressing gaps in substantive knowledge and (2) improving research methods and quality through protocol and methods validation and development, including the use of appropriate study design. The six specific research recommendations and select suggestions can be found in Boxes S-3, S-4, and S-5. The specific suggestions illustrate the range of priority research areas provided in the body of the report. FINAL OBSERVATIONS Much of the research on e-cigarettes suffers from methodological flaws and many important areas have not yet been researched. Nonetheless, the committee found sufficient literature to suggest that, while there are risks associated with e-cigarettes, compared with combustible tobacco cigarettes, e-cigarettes contain fewer toxicants; can deliver nicotine in a manner similar to combustible tobacco cigarettes; show significantly less biological activity in a number of in vitro, animal, and human systems; and might be useful as a cessation aid in smokers who use e-cigarettes exclusively. However, youth who begin with e-cigarettes are more likely to transition to combustible tobacco cigarette use and become smokers who may be at risk to suffer the known health burdens of combustible tobacco cigarettes. Moreover, although infrequent, e-cigarettes can explode, leading to burns and other injuries and consumption of or dermal exposure to e-liquids is dangerous, even fatal. More and better research on short- and long-term health effects of e-cigarettes, as well as their effects on initiation and cessation of combustible tobacco products, will bring clarity to the question of whether e-cigarettes will prove to reduce harm or induce harm at the individual and the population levels. Given how rapidly the e-cigarette product marketplace and user population are changing, there will undoubtedly be many new issues, which are currently unknown and will require careful surveillance and scientific scrutiny. The approach taken by the committee to evaluate the health effects of e-cigarettes in this report is anticipated to provide a generalizable template for future evaluations of the evidence. PREPUBLICATION COPY: UNCORRECTED PROOFS

S-10 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES BOX S-1 Statement of Task The Health and Medicine Division of the National Academies of Sciences, Engineering, and Medicine shall convene a committee to evaluate the available evidence of the health effects related to the use of electronic nicotine delivery systems (ENDS) and identify future federally funded research needs. As part of its work, the committee will conduct a comprehensive and systematic assessment and review of the literature. The literature review shall include analysis of data on both short- and long-term health effects in: • Users of ENDS, including health effects associated with the use of the full range of these devices (e.g., “cig-a-likes,” tank systems, mods). • Vulnerable populations of users (e.g., youth, pregnant women, individuals with underlying medical conditions [e.g., heart disease, pulmonary disease]). • Non-users of ENDS exposed to second-hand and third-hand aerosol generated by use of these devices. A committee report will document the findings and provide a list of recommendations for future research. The list of research needs to inform the Food and Drug Administration and ENDS regulation will be prioritized with respect to: • Research to gather information of most importance for the regulation of ENDS to protect the population health. • Research that should be a priority for federal funding. PREPUBLICATION COPY: UNCORRECTED PROOFS

SUMMARY S-11 BOX S-2 Levels of Evidence Framework for Conclusions Conclusive evidence: There are many supportive findings from good-quality controlled studies (including randomized and non-randomized controlled trials) with no credible opposing findings. A firm conclusion can be made, and the limitations to the evidence, including chance, bias, and confounding factors, can be ruled out with reasonable confidence. Substantial evidence: There are several supportive findings from good-quality observational studies or controlled trials with few or no credible opposing findings. A firm conclusion can be made, but minor limitations, including chance, bias, and confounding factors, cannot be ruled out with reasonable confidence. Moderate evidence: There are several supportive findings from fair-quality studies with few or no credible opposing findings. A general conclusion can be made, but limitations, including chance, bias, and confounding factors, cannot be ruled out with reasonable confidence. Limited evidence: There are supportive findings from fair-quality studies or mixed findings with most favoring one conclusion. A conclusion can be made, but there is significant uncertainty due to chance, bias, and confounding factors. Insufficient evidence: There are mixed findings or a single poor study. No conclusion can be made because of substantial uncertainty due to chance, bias, and confounding factors. No available evidence: There are no available studies; health endpoint has not been studied at all. No conclusion can be made. PREPUBLICATION COPY: UNCORRECTED PROOFS

S-12 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES BOX S-3 Research Needs: E-Cigarette Devices, Constituents, and Exposures The following specific suggestions illustrate the range of priority research areas provided in the body of the report: Recommendation 6-1: The committee recommends that the Food and Drug Administration (FDA) and other federal research sponsors and/or device manufacturers prioritize e- cigarette research that addresses key gaps regarding knowledge about e-cigarette devices, constituents, and exposures. This might include rapid response funding opportunities. • Study the stability of e-liquid ingredients when heated, identify potential byproducts of thermal degradation and of compounds that were not initially present in the e-liquid, and ascertain determinants of change in aerosol composition. • Study the impact of e-cigarette use in indoor air quality and biomarkers of second- hand e-cigarette exposure in scenarios and exposure surveys that are relevant for the populations exposed, including workers in vape shops and vaping convention attendees, and children, pregnant women, and patients with cardiorespiratory disease who live with adults who use e-cigarettes. Recommendation 6-2: The committee recommends that FDA and other federal research sponsors and/or device manufacturers prioritize research that improves the quality of e- cigarette research to better understand the devices, constituents, and exposures. This includes protocol and methods validation and development and use of appropriate study design, including the use of the appropriate control groups. • Develop and validate methods to produce aerosols and to analyze target constituents in e-cigarettes; the standardized method should reflect not only the average puffing conditions observed among the users in real-life settings, but also intensive puffing behaviors. • Use exposure conditions and animal models that are relevant to real-life inhalation exposure in humans. PREPUBLICATION COPY: UNCORRECTED PROOFS

SUMMARY S-13 BOX S-4 Research Needs: Effects of E-Cigarettes on Human Health The following specific suggestions illustrate the range of priority research areas provided in the body of the report: Recommendation 15-1: The committee recommends that the Food and Drug Administration (FDA) and other federal research sponsors and/or device manufacturers prioritize e-cigarette research that addresses key gaps regarding health effects in individuals. This might include rapid response funding opportunities. • Particle deposition in the human airways should be evaluated to assess where e- cigarette-derived particles impact in the upper versus lower airways and alveoli in the human airway and how area of impaction in the lung may influence health effects caused by e-cigarettes. Such studies should also include evaluation of airway epithelium repair. • Studies are needed on the association of second- and third-hand exposures with health outcomes in vulnerable populations, such as pregnant women, infants, young children, the elderly, and patients with cardiovascular and respiratory disease compared with second-hand tobacco smoke and the absence of second-hand exposure to both tobacco smoke or to e-cigarettes. • Longitudinal cohort studies of youth and young adults need to be conducted to understand the trajectory of dependence over time in users with little or no combustible tobacco product exposure. Recommendation 15-2: The committee recommends that FDA and other federal research sponsors and/or device manufacturers prioritize research that improves the quality of e- cigarette research on health outcomes. This includes protocol and methods validation and development and use of appropriate study design, including the use of the appropriate control groups and relevant biomarkers. • In clinical and epidemiologic studies, use as comparison groups those individuals who continue to smoke, those who try to quit with other evidence-based tobacco cessation treatments, and those who are not users of tobacco products, including e- cigarettes. • Methods development research is needed to create or adapt existing abuse liability testing for e-cigarettes to better understand the development of dependence on e- cigarettes. PREPUBLICATION COPY: UNCORRECTED PROOFS

S-14 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES BOX S-5 Research Recommendations: Public Health Implications of E-Cigarettes The following specific suggestions illustrate the range of priority research areas provided in the body of the report: Recommendation 20-1: The committee recommends that the Food and Drug Administration (FDA) and other federal research sponsors and/or device manufacturers prioritize e-cigarette research that addresses key gaps regarding harm reduction and the public health implications of e-cigarettes. This might include rapid response funding opportunities. • Research on the mechanisms through which e-cigarette use affects combustible tobacco cigarette smoking (both initiation among youth and quitting among current combustible tobacco cigarette smokers). • Research on potential harm reduction to bystanders exposed involuntarily to tobacco smoke after second-hand or third-hand exposure to combustible tobacco smoke is replaced by second-hand or third-hand exposure to emissions of e- cigarettes. Recommendation 20-2: The committee recommends that FDA and other federal research sponsors and/or device manufacturers prioritize research on the public health implications of e-cigarettes that improves the quality of e-cigarette research. This includes protocol and methods validation and development and use of appropriate study design, including the use of appropriate control groups. • Studies that build on existing, nationally representative population surveys of adults to monitor patterns of e-cigarette use in detail on an ongoing basis to include characterization of patterns of e-cigarette use such as the frequency and duration of use, type of device used, and reason for use. PREPUBLICATION COPY: UNCORRECTED PROOFS

Summary Annex Report Conclusions by Level of Evidence CONCLUSIVE EVIDENCE • Conclusion 3-1. There is conclusive evidence that e-cigarette use increases airborne concentrations of particulate matter and nicotine in indoor environments compared with background levels. • Conclusion 4-1. There is conclusive evidence that exposure to nicotine from e- cigarettes is highly variable and depends on product characteristics (including device and e-liquid characteristics) and how the device is operated. • Conclusion 5-1. There is conclusive evidence that in addition to nicotine, most e- cigarette products contain and emit numerous potentially toxic substances. • Conclusion 5-2. There is conclusive evidence that, other than nicotine, the number, quantity, and characteristics of potentially toxic substances emitted from e-cigarettes is highly variable and depends on product characteristics (including device and e- liquid characteristics) and how the device is operated. • Conclusion 14-1. There is conclusive evidence that e-cigarette devices can explode and cause burns and projectile injuries. Such risk is significantly increased when batteries are of poor quality, stored improperly or are being modified by users. • Conclusion 14-2. There is conclusive evidence that intentional or accidental exposure to e-liquids (from drinking, eye contact, or dermal contact) can result in adverse health effects, including but not limited to seizures, anoxic brain injury, vomiting, and lactic acidosis. • Conclusion 14-3. There is conclusive evidence that intentionally or unintentionally drinking or injecting e-liquids can be fatal. • Conclusion 18-1. There is conclusive evidence that completely substituting e- cigarettes for combustible tobacco cigarettes reduces users’ exposure to numerous toxicants and carcinogens present in combustible tobacco cigarettes. SUBSTANTIAL EVIDENCE • Conclusion 4-2. There is substantial evidence that nicotine intake from e-cigarette devices among experienced adult e-cigarette users can be comparable to that from combustible tobacco cigarettes. • Conclusion 5-3. There is substantial evidence that except for nicotine, under typical conditions of use, exposure to potentially toxic substances from e-cigarettes is significantly lower compared with combustible tobacco cigarettes. • Conclusion 5-4. There is substantial evidence that e-cigarette aerosol contains metals. The origin of the metals could be the metallic coil used to heat the e-liquid, other parts of the e-cigarette device, or e-liquids. Product characteristics and use- PREPUBLICATION COPY: UNCORRECTED PROOFS

SA-2 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES patterns may contribute to differences in the actual metals and meal concentrations measured in e-cigarette aerosol. • Conclusion 7-1. There is substantial evidence that e-cigarette aerosols can induce acute endothelial cell dysfunction, although the long-term consequences and outcomes on these parameters with long-term exposure to e-cigarette aerosol are uncertain. • Conclusion 7-2. There is substantial evidence that components of e-cigarette aerosols can promote formation of reactive oxygen species/oxidative stress. Although this supports the biological plausibility of tissue injury and disease from long-term exposure to e-cigarette aerosols, generation of reactive oxygen species and oxidative stress induction is generally lower from e-cigarettes than from combustible tobacco cigarette smoke. • Conclusion 8-1. There is substantial evidence that e-cigarette use results in symptoms of dependence on e-cigarettes. • Conclusion 9-2. There is substantial evidence that heart rate increases after nicotine intake from e-cigarettes. • Conclusion 10-4. There is substantial evidence that some chemicals present in e-cigarette aerosols (e.g., formaldehyde, acrolein) are capable of causing DNA damage and mutagenesis. This supports the biological plausibility that long-term exposure to e-cigarette aerosols could increase risk of cancer and adverse reproductive outcomes. Whether or not the levels of exposure are high enough to contribute to human carcinogenesis remains to be determined. • Conclusion 16-1. There is substantial evidence that e-cigarette use increases risk of ever using combustible tobacco cigarettes among youth and young adults. • Conclusion 18-2. There is substantial evidence that completely switching from regular use of combustible tobacco cigarettes to e-cigarettes results in reduced short- term adverse health outcomes in several organ systems. MODERATE EVIDENCE • Conclusion 8-2. There is moderate evidence that risk and severity of dependence are lower for e-cigarettes than combustible tobacco cigarettes. • Conclusion 8-3. There is moderate evidence that variability in e-cigarette product characteristics (nicotine concentration, flavoring, device type, and brand) is an important determinant of risk and severity of e-cigarette dependence. • Conclusion 9-3. There is moderate evidence that diastolic blood pressure increases after nicotine intake from e-cigarettes. • Conclusion 11-4. There is moderate evidence for increased cough and wheeze in adolescents who use e-cigarettes and an association with e-cigarette use and an increase in asthma exacerbations. • Conclusion 16-2. Among youth and young adult e-cigarette users who ever use combustible tobacco cigarettes, there is moderate evidence that e-cigarette use increases the frequency and intensity of subsequent combustible tobacco cigarette smoking. PREPUBLICATION COPY: UNCORRECTED PROOFS

SUMMARY ANNEX SA-3 • Conclusion 17-2. There is moderate evidence from randomized controlled trials that e-cigarettes with nicotine are more effective than e-cigarettes without nicotine for smoking cessation. • Conclusion 17-4. While the overall evidence from observational trials is mixed, there is moderate evidence from observational studies that more frequent use of e- cigarettes is associated with increased likelihood of cessation. • Conclusion 18-5. There is moderate evidence that secondhand exposure to nicotine and particulates is lower from e-cigarettes compared with combustible tobacco cigarettes. LIMITED EVIDENCE • Conclusion 3-2. There is limited evidence that e-cigarette use increases levels of nicotine and other e-cigarette constituents on a variety of indoor surfaces compared with background levels. • Conclusion 5-5. There is limited evidence that the number of metals in e-cigarette aerosol could be greater than the number of metals in combustible tobacco cigarettes, except for cadmium, which is markedly lower in e-cigarettes compared with combustible tobacco cigarettes. • Conclusion 9-4. There is limited evidence that e-cigarette use is associated with a short-term increase in systolic blood pressure, changes in biomarkers of oxidative stress, increased endothelial dysfunction and arterial stiffness, and autonomic control. • Conclusion 10-2. There is limited evidence from in vivo animal studies using intermediate biomarkers of cancer to support the hypothesis that long-term e-cigarette use could increase the risk of cancer; there is no available evidence from adequate long-term animal bioassays of e-cigarette aerosol exposures to inform cancer risk. • Conclusion 10-3. There is limited evidence that e-cigarette aerosol can be mutagenic or cause DNA damage in humans, animal models, and human cells in culture. • Conclusion 11-2. There is limited evidence for improvement in lung function and respiratory symptoms among adult smokers with asthma who switch to e-cigarettes completely or in part (dual use). • Conclusion 11-3. There is limited evidence for reduction of COPD exacerbations among adult smokers with COPD who switch to e-cigarettes completely or in part (dual use). • Conclusion 11-5. There is limited evidence of adverse effects of e-cigarette exposure on the respiratory system from animal and in vitro studies. • Conclusion 12-1. There is limited evidence suggesting that switching to e-cigarettes will improve periodontal disease in smokers. • Conclusion 12-2. There is limited evidence suggesting that nicotine and non-nicotine containing e-cigarette aerosol can adversely affect cell viability and cause cell damage of oral tissue in non-smokers. • Conclusion 16-3. Among youth and young adult e-cigarette users who ever use combustible tobacco cigarettes, there is limited evidence that e-cigarette use increases, in the near term, the duration of subsequent combustible tobacco cigarette smoking. PREPUBLICATION COPY: UNCORRECTED PROOFS

SA-4 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES • Conclusion 17-1. Overall, there is limited evidence that e-cigarettes may be effective aids to promote smoking cessation. INSUFFICIENT EVIDENCE • Conclusion 9-5. There is insufficient evidence that e-cigarette use is associated with long-term changes in heart rate, blood pressure, and cardiac geometry and function. • Conclusion 13-2. There is insufficient evidence whether or not maternal e-cigarette use affects fetal development. • Conclusion 17-3. There is insufficient evidence from randomized controlled trials about the effectiveness of e-cigarettes as cessation aids compared with no treatment or to Food and Drug Administration-approved smoking cessation treatments. • Conclusion 18-4. There is insufficient evidence that e-cigarette use changes short- term adverse health outcomes in several organ systems in smokers who continue to smoke combustible tobacco cigarettes (dual users). NO AVAILABLE EVIDENCE • Conclusion 9-1. There is no available evidence whether or not e-cigarette use is associated with clinical cardiovascular outcomes (coronary heart disease, stroke and peripheral artery disease) and subclinical atherosclerosis (carotid intima media- thickness and coronary artery calcification). • Conclusion 10-1. There is no available evidence whether or not e-cigarette use is associated with intermediate cancer endpoints in humans. This holds true for comparisons of e-cigarette use compared with combustible tobacco cigarettes and e- cigarette use compared with no use of tobacco products. • Conclusion 11-1. There is no available evidence whether or not e-cigarettes cause respiratory diseases in humans. • Conclusion 13-1. There is no available evidence whether or not e-cigarettes affect pregnancy outcomes. • Conclusion 18-3. There is no available evidence whether or not long-term e-cigarette use among smokers (dual use) changes morbidity or mortality compared with those who only smoke combustible tobacco cigarettes. PREPUBLICATION COPY: UNCORRECTED PROOFS

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Millions of Americans use e-cigarettes. Despite their popularity, little is known about their health effects. Some suggest that e-cigarettes likely confer lower risk compared to combustible tobacco cigarettes, because they do not expose users to toxicants produced through combustion. Proponents of e-cigarette use also tout the potential benefits of e-cigarettes as devices that could help combustible tobacco cigarette smokers to quit and thereby reduce tobacco-related health risks. Others are concerned about the exposure to potentially toxic substances contained in e-cigarette emissions, especially in individuals who have never used tobacco products such as youth and young adults. Given their relatively recent introduction, there has been little time for a scientific body of evidence to develop on the health effects of e-cigarettes.

Public Health Consequences of E-Cigarettes reviews and critically assesses the state of the emerging evidence about e-cigarettes and health. This report makes recommendations for the improvement of this research and highlights gaps that are a priority for future research.

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