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15 Research Needs: Effects of E-Cigarettes on Health 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: â¢ Research to gather information of most importance for the regulation of e-cigarettes to protect the population health â¢ 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. ADDRESSING GAPS IN SUBSTANTIVE KNOWLEDGE: HEALTH EFFECTS Recommendation 15-1: The committee recommends that 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. Specific items for consideration follow. Animal Models and In Vitro Mechanistic Studies: â¢ 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 doseâresponse and time course effects throughout the period of gestation. â¢ Conduct long-term (2-year) animal studies, 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 15-1 PREPUBLICATION COPY: UNCORRECTED PROOFS
15-2 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES 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 diseases, and respiratory diseases and other relevant clinical outcomes. â¢ 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 â¢ 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. â¢ Periodontal disease should be evaluated in e-cigarette users who have not been users of combustible tobacco cigarettes and smokers, including the effects of e- cigarettes on the subgingival microbiome. â¢ Short-term biomarker studies in humans are needed that focus on pathways with relevance to cancer, cardiovascular disease, respiratory disease, and other disease endpoints, including biomarkers of inflammation and immune status, oxidative stress, and gene expression. â¢ 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 disease (lung function, lung imaging) under real-life conditions. â¢ Short-term physiologic effects of e-cigarettes on the mother and fetus should evaluate the potential for more clinically consequential changes. Longer Term Clinical and Epidemiological Studies â¢ 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. â¢ Because prospective studies for clinical disease take very long, cross-sectional studies of e-cigarette use with subclinical measures of cardiovascular disease and respiratory disease 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. â¢ Studies are needed on the association of second and thirdhand exposures with health outcomes in vulnerable populations, such as pregnant women, infants, young children, the elderly, and patients with cardiovascular and respiratory PREPUBLICATION COPY: UNCORRECTED PROOFS
RESEARCH NEEDS: EFFECTS OF E-CIGARETTES ON HEALTH 15-3 disease compared with secondhand tobacco smoke and the absence of secondhand exposure to both combustible tobacco smoke or to e-cigarettes. â¢ More research is needed on clinical and epidemiologic 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 vapers. â¢ Systematic collection of data is needed on injuries, poisonings, and other harms caused by e-cigarette devices in prospective observational studies of e-cigarettes. â¢ Identify and evaluate strategies, including product standards, to minimize the number of accidental burns and injuries caused by e-cigarette malfunctions and explosions. â¢ Conduct epidemiological studies of the âdependence constructâ and whether the symptomatic manifestation of e-cigarette dependence is different from those of other tobacco or nicotine-containing products. â¢ The relationship between smoking history and nicotine pharmacokinetics (PK) should be assessed. Specific areas for examination include how smokersâ history and dependence influence nicotine PK and effects when switching to e-cigarettes and how nicotine PK would be predicted to change over time. â¢ 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. â¢ Develop effective communication strategies about the relative risk of e-cigarettes compared with combustible tobacco products. IMPROVE RESEARCH METHODS AND QUALITY 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. Specific examples are given below. Animal and Mechanistic Studies â¢ Develop inhalation exposure models for animal studies that are representative of human inhalation exposure to e-cigarette aerosols. â¢ Include measures of exposure to e-cigarette constituents to assess relevance to human exposure. Human Clinical and Epidemiological Studies â¢ Conduct psychometric studies and measurement development research for developing standardized interview and questionnaire-based assessments of dependence, patterns of use, and device characteristics. PREPUBLICATION COPY: UNCORRECTED PROOFS
15-4 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES â¢ 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. â¢ 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. â¢ In clinical and epidemiologic 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. â¢ Leverage existing population-based epidemiologic 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 cancer 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. â¢ 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. â¢ Develop guidelines for reporting studies on e-cigarette use to standardize the published information and ensure 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. REFERENCE 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. PREPUBLICATION COPY: UNCORRECTED PROOFS