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6 Research Needs: E-Cigarette Devices, Constituents, and Exposures The committee was tasked to provide a list of research needs to inform the Food and Drug Administration (FDA) and e-cigarette regula- tion that will be prioritized with respect to â¢ Research to gather information of most importance for the regula- tion of e-cigarettes to protect the population health â¢ Research that should be a priority for federal funding Given the relatively short time that e-cigarettes have been in use, it is understandable that the evidence base regarding their effects is limited. There is a great need for more evidence, as other research groups have documented (Walton et al., 2015). 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 con- tracts 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 a new important 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. 217
218 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES The committee identified many gaps in the literature during its review and identified dozens of specific research needs that are important for understanding the effects of e-cigarettes and for FDA regulatory action. 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 Recommendation 6-1: The committee recommends that the Food and Drug Administration and other federal research spon- sors 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. Specific items for consideration follow. â¢ Study the effects of carrier solvents and additives, including fla- vor ingredients and device characteristics (including the type of coil and power), on aerosol generation, aerosol physical proper- ties, and the chemical profile of e-cigarette emissions. â¢ Study the stability of e-liquid ingredients when heated, identify potential by-products of thermal degradation and of compounds that were not initially present in the e-liquid, and ascertain deter- minants of change in aerosol composition. â¢ Study the impact of e-cigarette use on indoor air quality and biomarkers of secondhand e-cigarette exposure in scenarios and exposure surveys that are relevant for the populations exposed, including workers in vape shops and vaping convention attend- ees, children, pregnant women, and patients with cardiorespira- tory disease who live with adults who use e-cigarettes. â¢ Conduct research that would inform product standards regarding ingredient purity, batteries and chargers, and priority and novel emissions. â¢ Establish procedures to rapidly evaluate changes to products currently on the U.S. market, focusing on device designs, design evolution (initiated by both manufacturers and users) and the corresponding alteration of chemical substance release patterns.
RESEARCH NEEDS 219 IMPROVING RESEARCH METHODS AND QUALITY Recommendation 6-2: 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 to better under- stand 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. Specific examples are given below. â¢ Develop one or more standardized puffing protocols that are dif- ferent from the standard puffing protocol for combustible tobacco cigarettes and reflect a range of how e-cigarettes are used in real- life settings, including extreme use. â¢ Develop and validate methods to produce aerosols and to ana- lyze 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. â¢ Develop and validate a standardized method to measure par- ticle size distribution and respiratory deposition of e-cigarette aerosols. â¢ Develop analytical methods to test chemicals in e-cigarette liquids and aerosols with a focus on screening and identifying potentially toxic compounds, including study of the effects of power and temperature and other device characteristics that generate such compounds. â¢ Use exposure conditions and animal models that are relevant to real-life inhalation exposure in humans. â¢ Evaluate potentially biologically relevant interactions between nicotine and other constituents, such as flavorings, in in vitro and in vivo bioassays. 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):259â269.
Section II Effects of E-Cigarettes on Health Although laboratory tests of e-cigarette ingredients, in vitro toxico- logical tests, and short-term human studies suggest that e-cigarettes are likely less harmful than combustible tobacco cigarettes, due to lack of long-term epidemiological studies and large clinical trials, the implica- tions for long-term effects on morbidity and mortality are not yet clear and the absolute safety of the products cannot be unambiguously assessed at this time. Use of e-cigarettes instead of combustible tobacco cigarettes by those with existing respiratory disease might be less harmful. 7 MODES OF ACTION 223 8 DEPENDENCE AND ABUSE LIABILITY 255 9 CARDIOVASCULAR DISEASE 339 10 CANCERS 381 11 RESPIRATORY DISEASES 405 12 ORAL DISEASES 455 13 DEVELOPMENTAL AND REPRODUCTIVE EFFECTS 461 14 INJURIES AND POISONINGS 473 15 RESEARCH NEEDS: EFFECTS OF E-CIGARETTES ON HEALTH 481 221