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12 Oral Diseases Smoking is a significant risk factor for the development of periodontal disease. This is a plaque-induced inflammatory disease of the mouth characterized by the presence of gum recession, loss of periodontal ligaments, bone resorption, and loss of teeth (Gross et al., 2017). The global prevalence of severe periodontitis in 2010 was between 10.1 and 11.6 percent of the worldâs population, affecting approximately 743 million people world-wide (Kassebaum et al., 2014). Pathogenic bacteria in the mouth contribute to the development and severity of periodontitis (Chahboun et al., 2015). Tobacco smoke can alter the oral microbiota, leading to more severe periodontal disease in the smoker (Coretti et al., 2017). Souto and colleagues reported suppression of immune responses in smokers, leading to more severe periodontal disease (Souto et al., 2014a). In another study by Souto and colleagues, higher levels of CCL3 and CXCL8 were found in people with more severe periodontitis (Souto et al., 2014b). Host characteristics have also been shown to contribute to the aggressiveness of periodontal disease, resulting in subsets of people who are at highest risk for developing a rapid form of progressive periodontal disease (Nibali, 2015). Few studies have examined the impact of e-cigarette use on periodontal disease. Emerging research suggests that switching to e-cigarettes may improve periodontal disease in smokers (Tatullo et al., 2016). Other studies indicate that e-cigarette use may have a detrimental effect on gingival health in smokers who switched to e-cigarettes (Wadia et al., 2016). CHARACTERIZATION OF DISEASE ENDPOINTS AND INTERMEDIATE OUTCOMES In studying the effects of e-cigarette use on oral health, development and severity of periodontal disease should be a primary disease endpoint. The presence and status of periodontal disease in people who smoke tobacco should be compared with people who use e-cigarettes to quit or reduce smoking. In addition, the presence and status of periodontal disease in adolescents and adults who use e-cigarettes, but who were never smokers should be compared with age- matched people who never used e-cigarettes or smoked. Intermediate outcomes to assess presence and severity of periodontitis should include indexes that are used to diagnose periodontitis and to determine severity of periodontitis. These include bleeding after probing, plaque index, quantification of gingival crevicular fluid, gum recession, bone resorption, and 12-1 PREPUBLICATION COPY: UNCORRECTED PROOFS
12-2 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES tooth loss. Measurements of gingival cytokines and subgingival microbiota should be used to determine the impact of e-cigarette aerosols on immune responses that impact oral health. OPTIMAL STUDY DESIGN The optimal study design to address potential benefits and harms of e-cigarettes on oral health would be a randomized controlled study. Such studies assess whether e-cigarette substitution can attenuate severity of periodontal disease in smokers unable to quit using standard nicotine replacement therapy. Observational studies also are needed to address the long- term effects on the oral health of adolescents and young adults who initiate e-cigarette use and to determine if e-cigarette aerosol can increase prevalence of periodontal disease in non-smokers. Studies are also needed that investigate the effects of e-cigarette aerosols on the microbiota of the oral cavity, the immune responses of the gingiva, and other markers of inflammation. QUESTIONS ADDRESSED BY THE LITERATURE Because e-cigarettes are so new, there is a lack of rigorously designed studies examining the effects of e-cigarettes on oral health. STUDIES IN HUMANS (CLINICAL AND EPIDEMIOLOGICAL) A study from Javed and colleagues (2017) examined the dental health of three groups of adult men from Saudi Arabia. These groups consisted of men who smoked combustible tobacco cigarettes (group 1), men who smoked e-cigarettes exclusively (group 2), and men who were non-smokers (group 3). The men who smoked cigarettes had a significantly higher plaque index and probing depth than group 2 or group 3. The men in group one also reported more gum pain compared with individuals in groups 2 (p < 0.01) and 3 (p < 0.01). This finding suggested poorer dental health in the men who smoked combustible tobacco cigarettes. However, limitations to the study may confound these comparisons because the men in group 1 smoked for a mean of 5.4 years whereas men in group 2 used e-cigarettes for an average of 2.2 years, and the men in group 1 were exposed to higher daily nicotine levels. Tatullo and colleagues (2016) conducted a clinical observational pilot study involving 110 smokers who switched to e-cigarettes by self-report. A small subset of subjects had carbon monoxide (CO) levels measured to assess whether they were smoking during the study. Of the 22/110 subjects tested, most were found to have CO levels consistent with very light combustible tobacco smoking. Smokers were divided into two groups, according to the number of years each group smoked: group 1 (less than 10 years of combustible tobacco cigarette smoking) and group 2 (more than 10 years of combustible tobacco cigarette smoking). Patients were subjected to oral examinations to investigate the following parameters: plaque index, bleeding index, and papillary bleeding index. A questionnaire to self-assess the variations of some parameters of general health and to self-assess the need to smoke combustible tobacco cigarettes was distributed to such subjects involved in the study. At the end of this pilot study, it was noted that the subjects had progressive improvement in the periodontal indexes, as well as in the general health perception. This study suggests a beneficial effect on the oral health of smokers who switch to e-cigarette use. PREPUBLICATION COPY: UNCORRECTED PROOFS
ORAL DISEASES 12-3 Reuther and colleagues (2016) performed a pilot study investigating the effect of nicotine and non-nicotine electronic cigarette aerosols on blood flow in the buccal mucosa in 10 volunteers after 5 minutes of e-cigarette use. They used a laser Doppler probe at 5-minute intervals after 5 minutes of e-cigarette use and found a small but significant rise (p = 0.008) in blood flow in the buccal mucosa. In the volunteers that used the nicotine containing e-cigarettes, flow fell to the same levels as before within 30 minutes. Finally, a pilot study by Wadia and colleagues (2016) examined the gingival health in 20 established smokers before and after substituting e-cigarettes for combustible tobacco cigarettes for 2 weeks. The primary outcome measurement of gingival inflammation was bleeding on probing. Levels of selected pro-inflammatory cytokines in gingival crevicular fluid, saliva, and serum samples were also determined. There was a statistically significant increase in gingival inflammation when tobacco smokers switched from smoking to vaping for 2 weeks. This study although a pilot study, suggested that e-cigarette use in smokers who switched caused more gingival inflammation when compared with the gingival inflammation at baseline in smokers. IN VITRO STUDIES Ji and colleagues (2016) reported increased cytotoxicity in normal human oral keratinocytes exposed to different nicotine concentrations. They concluded that toxicity in their study was due in part to oxidative stress induced by toxic substances from the nanoparticles and chemical present in the e-cigarette aerosols. They reported increased oxidative stress in the cells exposed to the e-cigarette aerosols as characterized by a significant decrease in intracellular glutathione levels and ATP. A decline in intracellular ATP levels has been associated with a decrease in cell proliferation and cell death (Henrich and Buckler, 2008). Rouabhia and colleagues (2016) used primary human gingival epithelial cells retrieved from healthy non- smoking donors. Cells were grown and exposed to nicotine containing e-cigarette aerosols. The investigators found increased apoptotic/necrotic epithelial cell percentages compared with that observed in the control. Sancilio and colleagues (2016) used gingival fibroblasts exposed to nicotine and non-nicotine e-cigarette aerosols. They found peaked reactive oxygen species (ROS) production after 24 hours, by measurements of CM-H2DCFDA oxidation, higher Bax expression at 24 hours and increased apoptosis after 48 hours post-exposure in both nicotine and non-nicotine containing e-cigarette aerosols. Sundar and colleagues (2016) exposed human periodontal ligament fibroblast to nicotine-containing e-cigarette aerosols and non-nicotine, menthol-flavored e-cigarettes and found, using a Human 3-D model of EpiGingival tissues, that both nicotine and non-nicotine menthol-flavored e-cigarette aerosols caused increased inflammation and DNA damage. Willershausen and colleagues (2014) examined the effects of nicotine and various flavorings on cell viability and proliferation of human periodontal ligament fibroblasts. They found decreased cell proliferation rates and a decrease in adenosine triphosphate detection in cells incubated with nicotine and with various e-cigarette flavorings when compared with control cells. Menthol e-cigarette solutions also caused a decrease in fibroblast proliferation. Taken together these in vitro studies suggest a detrimental effect of nicotine, and flavorings contained in e-cigarette vapors, on cell viability of epithelial and fibroblast cells in culture. These studies indicate that e-cigarette aerosols may cause harm to cells in the oral cavity, which in turn may contribute to poor oral health. In addition, several of these studies suggest that PREPUBLICATION COPY: UNCORRECTED PROOFS
12-4 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES menthol flavorings can cause additional harm to cells by impairing cell migration and inducing cell inflammation and DNA damage. SYNTHESIS Taken together human studies and in vitro studies suggest the e-cigarette aerosols can cause harm to oral health by inducing gingival inflammation in the oral cavity. In vitro studies indicate that e-cigarette aerosols can cause direct cell death and DNA damage to epithelial cells. Other studies comparing and contrasting the dental health of smokers to e-cigarette users suggest that e-cigarette use may be less harmful to oral health than continued smoking. Finding: There are no epidemiological studies examining the associations between e-cigarette use and incidence or progression of periodontal disease. 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. REFERENCES Chahboun, H., M. M. Arnau, D. Herrera, M. Sanz, and O. K. Ennibi. 2015. Bacterial profile of aggressive periodontitis in Morocco: A cross-sectional study. BMC Oral Health 15:25. Coretti, L., M. Cuomo, E. Florio, D. Palumbo, S. Keller, R. Pero, L. Chiariotti, F. Lembo, and C. Cafiero. 2017. Subgingival dysbiosis in smoker and nonsmoker patients with chronic periodontitis. Molecular Medicine Reports 15(4):2007-2014. Gross, A. J., K. T. Paskett, V. J. Cheever, and M. S. Lipsky. 2017. Periodontitis: A global disease and the primary care providerâs role. Postgraduate Medical Journal 93(1103):560-565. Henrich, M., and K. J. Buckler. 2008. Effects of anoxia, aglycemia, and acidosis on cytosolic Mg2+, ATP, and pH in rat sensory neurons. American Journal of PhysiologyâCell Physiology 294(1):C280. Javed, F., T. Abduljabbar, F. Vohra, H. Malmstrom, I. Rahman, and G. E. Romanos. 2017. Comparison of periodontal parameters and self-perceived oral symptoms among cigarette smokers, individuals vaping electronic cigarettes, and never-smokers. Journal of Periodontology 88(10):1059-1065. Ji, E. H., B. B. Sun, T. K. Zhao, S. Shu, C. H. Chang, D. Messadi, T. Xia, Y. F. Zhu, and S. Hu. 2016. Characterization of electronic cigarette aerosol and its induction of oxidative stress response in oral keratinocytes. PLoS ONE 11(5):1-13. Kassebaum, N. J., E. Bernabe, M. Dahiya, B. Bhandari, C. J. Murray, and W. Marcenes. 2014. Global burden of severe periodontitis in 1990â2010: A systematic review and meta- regression. Journal of Dental Research 93(11):1045-1053. Nibali, L. 2015. Aggressive periodontitis: Microbes and host response, who to blame? Virulence 6(3):223-228. PREPUBLICATION COPY: UNCORRECTED PROOFS
ORAL DISEASES 12-5 Reuther, W. J., B. Hale, J. Matharu, J. N. Blythe, and P. A. Brennan. 2016. Do you mind if I vape? Immediate effects of electronic cigarettes on perfusion in buccal mucosal tissueâa pilot study. British Journal of Oral and Maxillofacial Surgery 54(3):338-341. Rouabhia, M., H. J. Park, A. Semlali, A. Zakrzewski, W. Chmielewski, and J. Chakir. 2016. E- cigarette vapor induces an apoptotic response in human gingival epithelial cells through the caspase-3 pathway. Journal of Cellular Physiology 232:1539-1547. Sancilio, S., M. Gallorini, A. Cataldi, and V. di Giacomo. 2016. Cytotoxicity and apoptosis induction by e-cigarette fluids in human gingival fibroblasts. Clinical Oral Investigations 20(3):477-483. Souto, G. R., C. M. Queiroz-Junior, F. O. Costa, and R. A. Mesquita. 2014a. Smoking effect on chemokines of the human chronic periodontitis. Immunobiology 219(8):633-636. Souto, G. R., C. M. Queiroz, Jr., F. O. Costa, and R. A. Mesquita. 2014b. Relationship between chemokines and dendritic cells in human chronic periodontitis. Journal of Periodontology 85(10):1416-1423. Sundar, I. K., F. Javed, G. E. Romanos, and I. Rahman. 2016. E-cigarettes and flavorings induce inflammatory and pro-senescence responses in oral epithelial cells and periodontal fibroblasts. Oncotarget 7(47):77196-77204. Tatullo, M., S. Gentile, F. Paduano, L. Santacroce, and M. Marrelli. 2016. Crosstalk between oral and general health status in e-smokers. Medicine (Baltimore) 95(49):e5589. Wadia, R., V. Booth, H. F. Yap, and D. L. Moyes. 2016. A pilot study of the gingival response when smokers switch from smoking to vaping. British Dental Journal 221(11):722-726. Willershausen, I., T. Wolf, V. Weyer, R. Sader, S. Ghanaati, and B. Willershausen. 2014. Influence of e-smoking liquids on human periodontal ligament fibroblasts. Head & Face Medicine 10:39. PREPUBLICATION COPY: UNCORRECTED PROOFS