As described in Chapter 6, the committee was tasked to provide a list of research needs to inform the Food and Drug Administration (FDA) and e-cigarette regulation that will be prioritized with respect to
- Research to gather information of most importance for the regulation of e-cigarettes to protect the population health
- Research that should be a priority for federal funding
The committee identified many gaps in the literature during its review and identified dozens of specific research needs important for understanding the health effects of e-cigarettes and for FDA regulatory action, as other research groups have documented (Walton et al., 2015). The committee identified two overarching research needs: addressing gaps in substantive knowledge and improving research methods and quality. Specific items for consideration identified by the committee are noted for each of these and are not listed in any priority order.
Recommendation 15-1: The committee recommends that the Food and Drug Administration 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. Specific items for consideration follow.
Animal Models and In Vitro Mechanistic Studies:
- Mechanistic and in vivo animal studies should be done to determine the potential effects of e-cigarette aerosol on organ development and tissue growth during embryonic and fetal development. Such studies should assess effects of nicotine and flavorings separately, and include both dose–response and time-course effects throughout the period of gestation.
- Long-term (2-year) animal studies should be conducted, using inhalation exposure to e-cigarette aerosol, to better understand disease risks from inhaling reactive carbonyl compounds and other potentially toxic constituents of e-cigarette aerosol, including flavoring chemicals and additives. These studies should include two controls: combustible tobacco smoke–exposed animals and those exposed to ambient air. Endpoints evaluated should include clinical outcomes and biomarkers relevant for, at a minimum, cancers, cardiovascular disease, and respiratory diseases and other relevant clinical outcomes.
- The effect of e-cigarette aerosol on pulmonary inflammation and clearance of viral and bacterial pathogens in the lungs should be studied in appropriate animal models following inhalation exposures.
Short-Term Human Studies with Clinically Relevant Biomarkers
- Particle deposition in the human airways should be evaluated to assess where e-cigarette–derived particles impact the upper versus lower airways and alveoli, 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.
- Periodontal disease should be evaluated in e-cigarette users who have not been users of combustible tobacco cigarettes, including the effects of e-cigarettes on the subgingival microbiome.
- Short-term biomarker studies in humans are needed that focus on pathways with relevance to cancers, cardiovascular disease, respiratory diseases, and other disease endpoints, including biomarkers of inflammation and immune status, oxidative stress, and gene expression.
- Panel studies should assess the association of changes in e-cigarette use, including device characteristics and patterns of use, with relevant markers of subclinical cardiovascular disease (blood pressure, endothelial dysfunction, arterial stiffness, cardiac geometry and function, and autonomic function) and respiratory diseases (lung function, lung imaging) under real-life conditions.
- Short-term physiological effects of e-cigarettes on the mother and fetus should evaluate the potential for more clinically consequential changes.
Longer-Term Clinical and Epidemiological Studies
- Longitudinal cohort studies should be done to assess the association of long-term use of e-cigarettes with clinical and subclinical cardiovascular, respiratory, and other health outcomes as compared with smoking combustible tobacco cigarettes, dual use of e-cigarettes and combustible tobacco cigarettes, and never smoking or vaping.
- Because prospective studies for clinical disease take very long, cross-sectional studies of e-cigarette use with subclinical measures of cardiovascular disease and respiratory diseases can be very useful. For instance, carotid atherosclerosis and coronary artery calcification can be measured subclinically and inform on clinical cardiovascular risk. Similarly, lung imaging data can provide relevant information on the effects of chronic e-cigarette use before clinical respiratory disease has manifested.
- Studies are needed on the association of secondhand and thirdhand exposures with health outcomes in vulnerable populations, such as pregnant women, infants, young children, the elderly, and patients with cardiovascular and respiratory diseases, compared with secondhand tobacco smoke and the absence of secondhand exposure to either combustible tobacco smoke or to e-cigarettes.
- More research is needed on clinical and epidemiological studies of e-cigarette use during pregnancy, evaluating the association of patterns of use (including sole and dual e-cigarette use) with maternal and infant outcomes, building on known effects of tobacco on pregnancy complications and neonatal health indexes, compared with mothers who continue to smoke during pregnancy and never smokers or never vapers.
- Systematic collection of data is needed on injuries, poisonings, and other harms caused by e-cigarette devices in prospective observational studies of e-cigarettes.
- Identification and evaluation of strategies, including product standards, are needed to minimize the number of accidental burns and injuries caused by e-cigarette malfunctions and explosions.
- Epidemiological studies should be conducted on the “dependence construct” and whether the symptomatic manifestations of e-cigarette dependence are different from those of other tobacco or nicotine-containing products.
- The relationship between smoking history and nicotine pharmacokinetics (PK) should be assessed. Specific areas for examination include how smokers’ history and dependence influence nicotine PK and effects when switching to e-cigarettes and how nicotine PK would be predicted to change over time.
- Longitudinal cohort studies are needed of youth and young adults to understand the trajectory of dependence over time in users with little or no combustible tobacco product exposure.
- Effective communication strategies about the relative risk of e-cigarettes compared with combustible tobacco products are needed.
Recommendation 15-2: The committee recommends that the Food and Drug Administration 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. Specific examples are given below.
Animal and Mechanistic Studies
- Develop inhalation exposure models for animal studies that are representative of human inhalation exposure to e-cigarette aerosols.
- Include measures of exposure to e-cigarette constituents to assess relevance to human exposure.
Human Clinical and Epidemiological Studies
- Conduct psychometric studies and measurement development research for developing standardized interview and questionnaire-based assessments of dependence, patterns of use, and device characteristics.
- Develop biomarkers of exposure and biomarkers of potential harm in e-cigarette users and compare these to the same biomarkers in the use of various tobacco products.
- Use methods development research to create or adapt existing abuse liability testing for e-cigarettes to better understand the development of dependence on e-cigarettes.
- In clinical and epidemiological studies, use as comparison groups 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.
- Leverage existing population-based epidemiological cohort studies to enhance the quality and quantity of information collected on the use of e-cigarettes and other tobacco-related products and smoking-cessation pharmacotherapies. Some of the existing cohorts for cancers and cardiorespiratory disease would need to recruit additional e-cigarette users, as very few might have been included in the original study population. Specially designed cohorts such as the Population Assessment of Tobacco and Health study will provide the highest-quality data, but additional evidence from existing cohorts could be essential for accelerating the generation of more evidence on cancer and cardiorespiratory diseases and their related endpoints, including intermediate endpoints for these diseases.
- For cohort studies, the age of the study population is important, as the age should be adequate in order to study cancer or cardiorespiratory outcomes, but not so old that it can cause difficulty in distinguishing the health effects of cigarette smoking versus e-cigarettes.
- Develop guidelines for reporting studies on e-cigarette use to standardize the published information and ensure that the studies are useful to understand the health effects of e-cigarette products and to inform product evaluation and regulation. In particular, it is important that studies of the health effects of e-cigarette use in humans provide information on the product characteristics, including the type of device, coil, and e-liquid used, and the patterns of use.
Walton, K. M., D. B. Abrams, W. C. Bailey, D. Clark, G. N. Connolly, M. V. Djordjevic, T. E. Eissenberg, M. C. Fiore, M. L. Goniewicz, L. Haverkos, S. S. Hecht, J. E. Henningfield, J. R. Hughes, C. A. Oncken, L. Postow, J. E. Rose, K. L. Wanke, L. Yang, and D. K. Hatsukami. 2015. NIH electronic cigarette workshop: Developing a research agenda. Nicotine & Tobacco Research 17(2):259–269.
This page intentionally left blank.
While e-cigarettes might cause youth who use them to transition to use of combustible tobacco products, they could increase adult cessation of combustible tobacco cigarettes if they are used frequently. Across a range of studies and outcomes, e-cigarettes pose less risk to an individual than combustible tobacco cigarettes. With the range of assumptions used, population modeling projects that there would be net public health harm in the short and long term 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 engineering and design.
Understanding the public health implications of e-cigarette use at the population level requires consideration of not only the risks of e-cigarettes on individual health outcomes, as described in the preceding chapters, but also the relation between e-cigarette use and use of other tobacco products—namely, combustible tobacco cigarettes. Given the well-documented and strong influence of combustible tobacco cigarette smoking on health (HHS, 2014) and the emerging evidence that, although not harm free, e-cigarettes likely expose users to lower health risks compared with combustible tobacco cigarettes, any link between e-cigarette use and patterns of combustible tobacco cigarette smoking would have a considerable impact on both individual and population health. Thus, a question
relevant to the committee’s task is whether and to what extent e-cigarette use affects patterns of combustible tobacco cigarette smoking. The challenge of evaluating the effect of e-cigarette use on combustible tobacco cigarette use is that e-cigarettes could influence combustible tobacco cigarette smoking through a number of pathways, which together could lead to net public health benefit or harm. To understand the potential effects of e-cigarette use on combustible tobacco cigarette smoking, the committee developed a conceptual framework illustrating these plausible pathways, or the possible transitions among e-cigarette use, cigarette smoking, and non-use (see Figure III-1). There are many plausible pathways, and smoking and tobacco use trajectories are often complex. To assess the potential effects of e-cigarette use on combustible tobacco cigarette smoking and corresponding health effects, this section of the report focuses on the influence of e-cigarette use on combustible tobacco cigarette use initiation and cessation, as well as the harm from e-cigarettes relative to that from combustible tobacco cigarettes.
Combustible tobacco cigarette initiation reflects transitions from no smoking to established or regular smoking, and therefore involves multiple steps within the tobacco progression trajectory. Consequently, to study markers along the continuum of smoking initiation, the committee first examined transitions from never smoking combustible tobacco cigarettes to any report of ever using combustible tobacco cigarettes, alone or concurrent with e-cigarettes (dual use). Ever use could reflect either a period
of temporary experimentation that does not progress to regular smoking or the beginning of a trajectory toward becoming a regular smoker. Thus, the committee then examined the progression to becoming a regular smoker as indicated by increases in the frequency (i.e., number of days used in past 30), intensity (i.e., cigarettes smoked per day on smoking day), and duration (i.e., length of time in which smoking behavior continues versus ceases following initiation) of smoking after becoming an ever smoker. In the framework, cigarette initiation is depicted by the red arrows that denote any transition from non-smoking to smoking. Estimates of e-cigarettes as a risk factor for cigarette initiation most commonly involve a ratio of these red lines, such as the level of combustible tobacco cigarette initiation among e-cigarette users as compared with those who do not use e-cigarettes.
Because nearly all adult combustible tobacco cigarette smokers report first use of cigarettes before age 26 (IOM, 2015), smoking initiation pertains primarily to youth and young adults. E-cigarette use among youth and young adults could influence subsequent combustible tobacco cigarette initiation in several ways. One scenario is that youth and young adults begin using e-cigarettes and subsequently initiate use of combustible tobacco cigarettes, either through switching or in addition to e-cigarettes. In this scenario, e-cigarette use is associated with combustible tobacco cigarette smoking initiation and thus tobacco-related health risks. Another scenario suggests that some portion of youth and young adults who otherwise would have begun smoking combustible tobacco cigarettes would not do so, and would instead begin using e-cigarettes. Here, e-cigarette use would reduce or delay initiation of combustible tobacco cigarette use and could reduce tobacco-related health risks. These potential pathways and corresponding evidence are described further in Chapter 16.
E-cigarette use could affect combustible tobacco use among adult smokers through several pathways, with different implications for public health. For example, it is plausible that e-cigarettes promote cessation of combustible tobacco cigarette smoking. The committee defined cigarette cessation as transitions from any combustible tobacco cigarette smoking to non-smoking. By this definition, cessation may involve the outcome of e-cigarette use alone or non-use of both e-cigarettes and combustible tobacco cigarettes. In other words, smokers could either transition completely from combustible tobacco cigarettes to e-cigarette use only or they could start using e-cigarettes in addition to combustible tobacco cigarettes (dual use) for a limited time, and then completely switch to e-cigarette use alone. Smokers could also subsequently quit both combustible tobacco cigarette and e-cigarette use. As the committee previously concluded, e-cigarettes are likely to expose users to fewer and lower levels
of potentially toxic substances compared with exposure from combustible tobacco cigarettes and thus to confer lower health risks. Therefore, complete switching from combustible tobacco cigarettes to e-cigarettes would be expected to reduce tobacco-related health risks. E-cigarette users who subsequently stopped using both e-cigarettes and combustible tobacco cigarettes would incur additional benefits. In the framework, combustible tobacco cigarette cessation is depicted by the green arrows that denote any transition from smoking to non-smoking. Estimates for e-cigarettes as a cessation tool most commonly involve a ratio using at least one of these green lines, such as the level of cigarette cessation among active smokers (E1) compared with smokers who recently quit and use e-cigarettes as a replacement (recent members of B1). In these scenarios, e-cigarettes would benefit public health.
If, on the other hand, e-cigarettes are not effective cessation aids, e-cigarettes could cause relapse, whereby current e-cigarette use by former or non-active combustible tobacco cigarette users leads these users to transition back to combustible tobacco smoking either alone or concurrently with e-cigarettes. This could occur, for example, if a former smoker uses e-cigarettes under the belief that they are safe and will provide many of the same pleasures as combustible tobacco cigarettes, and follow a path that eventually leads back to active cigarette smoking. In the framework, cigarette relapse is depicted by the purple arrows that denote any transition from non-active to active smoking. As with initiation and cessation, estimates of relapse are based primarily on the ratio of the relevant transition probabilities. In this case, cigarette relapse levels among e-cigarette users are compared with relapse levels among former smokers who do not use e-cigarettes. Among e-cigarette users who relapse, the potential reduction in tobacco-related health risks from a period of temporary switching would likely be minimal. The influence of e-cigarettes on relapse would be especially worrying if e-cigarettes cause relapse among those who otherwise would have remained abstinent from combustible tobacco cigarette smoking, as this would increase both individual and overall public health risk. Discussion of the potential influence of e-cigarettes on combustible tobacco cigarette smoking among current and former adult smokers and corresponding evidence can be found in Chapter 17.
Finally, current smokers could start using e-cigarettes in addition to combustible tobacco cigarettes (dual use) and persist in using both products concurrently. If use of both products led to smoking reduction, this could confer health benefits. However, it is also feasible that dual users do not reduce combustible tobacco cigarette use, which could expose them to adverse health effects from the e-cigarettes in addition to those from combustible tobacco use. Discussion and evidence on the influence of
concurrent e-cigarette and combustible tobacco cigarette use (dual use) on smoking cessation as well as health outcomes are presented in Chapter 18.
In addition to the tobacco use trajectories, the committee considered whether certain factors (or moderators) might strengthen or weaken the association between e-cigarette use and combustible tobacco cigarette use. Much remains unknown about potential moderators, but potentially important moderators that warrant serious consideration include age, motivation of e-cigarette users to smoke or stop smoking, substance vaped in e-cigarettes (e.g., nicotine concentration or flavorings), and whether e-cigarette use is part of a structured cessation program. Information on these moderators is currently scarce, but noted below when available.
To understand the overall effect of these different hypothesized pathways among e-cigarette use, combustible tobacco cigarette smoking, and non-use on the U.S. population as a whole, the committee used population-dynamic modeling and presents results of a range of scenarios in Chapter 19.
HHS (U.S. Department of Health and Human Services). 2014. The health consequences of smoking—50 years of progress: A report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Disease Prevention and Health Promotion, Office on Smoking and Health.
IOM (Institute of Medicine). 2015. Public health implications of raising the minimum age of legal access to tobacco products. Washington, DC: The National Academies Press.
This page intentionally left blank.