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 are highly variable and depend 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 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 patterns may contribute to differences in the actual metals and metal 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 shortly 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 shortly 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.
• 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 an 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 chronic obstructive pulmonary disease (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.

• 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 e-cigarette use compared with use of 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.

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