Oral health risks in users of new generation nicotine/tobacco products (NGPs): Systematic review and qualitative meta-analyses

Oral health risks in users of new generation nicotine/tobacco products (NGPs): Systematic review and qualitative meta-analyses | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Oral health risks in users of new generation nicotine/tobacco products (NGPs): Systematic review and qualitative meta-analyses Gerhard Scherer, Nikola Pluym, Max Scherer This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4206242/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Use of traditional tobacco products, including combustible cigarettes (CCs) and smokeless oral products, is an established risk factor for various oral diseases. A potential oral health risk of using new generation tobacco/nicotine products (NGPs) such as electronic cigarettes (ECs), heated tobacco products (HTPs) and oral nicotine pouches (ONPs) is not yet well established. Methods In this systematic review, we evaluated published human studies on detrimental oral health effects in NGP users compared to CC smokers and non-users (NU). We identified 52 studies, of which almost all investigations were on EC users. The studies were extremely heterogeneous in terms of design, subjects, endpoints and quality. Reported outcomes, based on both single and grouped endpoints were qualitatively evaluated by comparing NGP users with NU and CC users. Significant increases (indicating a worsening in oral health), significant decreases (indicating an improvement) and no significant difference between groups were assigned scores of + 1, -1 and 0, respectively. Results With this approach, comparisons of EC versus NU yielded mean scores of 0.29 (pre-cancerous lesions, N = 14 observations), 0.27 (inflammatory processes, N = 83), 0.43 (oral clinical parameters, N = 93) and 0.70 (shifts in the oral microbiome, N = 10). The corresponding values for the EC versus CC comparisons amounted to: -0.33 (N = 15), -0.14 (N = 76), -0.27 (N = 78) and 0.57 (N = 7). Most of the evaluated studies have severe limitations in terms of group sizes, duration of NGP use and validity of self-reported exclusive NGP use. In particular, any dual use (EC + CC) was mostly not adequately taken into account. Conclusions The evaluated studies suggest that use of ECs is associated with some improvement of oral health effects compared to cigarette smoking (CC), but oral health is still found to be worse compared to NU. These results have to be interpreted with caution due to a number of limitations and uncertainties in the underlying studies. Toxicology Combustible cigarettes Electronic cigarettes Heated tobacco products Oral nicotine pouches Oral health Figures Figure 1 Figure 2 Figure 3 1. Introduction New generation nicotine/tobacco products (NGPs), such as e-cigarettes (ECs), heated tobacco products (HTPs), oral nicotine pouches (ONPs) and Swedish snus, have gained popularity as alternatives to combustible cigarettes (CCs) due to the perception of being potentially less harmful ( 1 ). In contrast to ECs, HTPs and NPs, snus has a long history of use particularly in Sweden. Its chemical and biological properties, as compared to other oral tobacco types, allow snus justifiably to be regarded as tobacco harm reduction product ( 2 ). However, this systematic review is limited to only “new” generation products. The oral cavity is the first organ affected by all tobacco and nicotine habits, especially oral products like snus and nicotine pouches, which are in contact with the oral mucosa for up to several hours per day. However, also the use of inhalable products such as CCs, ECs and HTPs implies a direct contact of the released aerosols with the oral epithelial cells for a considerable time span. The use of conventional tobacco products including CCs and various forms of oral tobacco is an established risk factor for oral cancer ( 3 – 5 ) as well as a number of non-malignant disorders such as leukoplakia ( 6 – 8 ), gingivitis ( 9 , 10 ), periodontitis ( 11 , 12 ), salivary gland function ( 13 ) and teeth damage ( 14 , 15 ), delayed wound healing ( 16 ), bad breath (halitosis) ( 17 ), and dental staining ( 18 ). NGPs deliver similar or somewhat reduced amounts of nicotine ( 19 ), but significantly lower amounts of toxicants ( 1 , 20 ). Use of NGPs was shown to be implicated with substantial reductions in the exposure to all classes of toxicants including aldehydes, epoxides, tobacco-specific nitrosamines (TSNAs), polycyclic aromatic hydrocarbons (PAHs), aromatic amines compared to smokers of CCs by measuring suitable biomarkers of exposure ( 21 – 24 ) (for review, see: ( 20 , 25 – 28 )). Apart from the considerable reduction (80–95%) in the exposure to tobacco combustion chemicals, use of NGPs involves the daily exposure to nicotine, matrix components and flavor compounds in larger amounts and some toxicants more likely in trance amounts (microgram to nanogram range ( 20 )). A systematic biomarker of exposure (BOE) study under controlled conditions with users of CCs, ECs, HTPs, oral tobacco (OT) and nicotine gum in comparison to non-users (NU) revealed that OT users (various products, not only snus) showed elevations in the exposure to TSNAs lower or close to that in CC smokers ( 21 – 24 ). There was some weak evidence that HTP users’ exposure to acrolein, acrylamide, acrylonitrile, o-toluidine and TSNA was slightly (but not significantly) higher than that of NU and the other non-CC groups, but much lower than that of smokers (CC). Analytical data of product releases suggest that vapers (EC) and HTP users might experience slightly elevated exposures to formaldehyde and acetaldehyde. However, there is no BOE-based support for this, due to lack of suitable BOEs. Vapers are exposed to 1,2-propylene and glycerol in the upper mg range per day ( 29 , 30 ). These considerations on the exposure of NGP user to toxic chemicals suggest that the exposure is low to negligible with the exception of nicotine, 1,2-propylene glycol and glycerol as well as some flavors. However, the frequent and long-lasting contact of the oral mucosa with low amounts of toxicants and presumably toxicological inert chemicals might have detrimental effects, including physical irritation, allergic reaction, drying or dehydration, disruption of the oral microbiome, local pH changes, and others ( 31 – 33 ). As a consequence, despite of distinct reduction of exposure to a bulk of toxicants in users of NGPs compared to conventional tobacco products, it is important to investigate possible detrimental effects in the oral cavity in long-term users of the new, allegedly risk reduced tobacco/nicotine products. In a recent review of our group ( 34 ), the present knowledge of the overall health risks (including cancer, cardiovascular and respiratory diseases, oral cavity disorders, general oxidative stress and inflammation, reproduction, metabolic syndrome, and several others) and the particular role of nicotine in these disorders was summarized. The purpose of this review is to elucidate in more detail the reported effects of NGP use (ECs, HTPs and ONPs) on the oral mucosa in comparison to non-users (NU) and cigarette smokers (CC). The biological endpoints of interest can be assigned to the following categories: Oral cancer and precancerous lesions, including DNA adducts in oral mucosa cells Periodontitis and gingivitis as well as inflammation markers and other biomarkers of effect in oral mucosa cells Changes in clinical markers of oral cavity, gum and tooth distortions Shifts in the oral microbiome These endpoints would be primarily of interest in mid- to long-term users of NGPs in comparison to non-users (NU) and/or users of conventional tobacco products (for the main part combustible cigarettes, CCs). However, due to the relatively short market presence of the NGPs of interest (< 20 years), there are as yet no long-term studies available which would allow to investigate outcomes such as cancer. Furthermore, the expectable heterogeneity of the available studies in terms of type, subjects, products and endpoints investigated would render the conduct of a classical (quantitative) meta-analysis impossible. We, therefore, decided to aggregate various biological or clinical endpoints to the four categories of detrimental effects mentioned above followed by qualitative (or at best semi-quantitative) meta-analysis. We are aware of the fact that this approach is disputable, however, we believe that it is defensible for a number or reasons discussed in detail. 2. Methods This systematic review was conducted according to the guidelines of PRISMA (Preferred reporting items for systemic reviews and meta-analyses) ( 35 ). 2.1 Libraries, search strategy, inclusion and exclusion criteria The online literature databases PubMed, LIVIVO and Cochrane Library were searched for the major topics NGPs of interest (ECs, HTPs, ONPs) and oral health disorders with simultaneous application of filters for human studies and the languages English or German. The number of hits were in total 259, with 121, 118 and 20 obtained from PubMed, LIVIVO and Cochrane Library, respectively. After removing 78 duplicates, 181 articles remained, of which the titles and abstracts were screened for meeting the inclusion and exclusion criteria. Inclusion criteria comprised human studies with users of the NGPs ECs, HTPs and ONPs. Observed effects or outcomes need to be compared to NU (negative controls) and/or smokers (CC, positive controls). Study endpoints must be any oral health effects, including cancer, pre-cancerious lesions (including cytogenetic effects and DNA adducts), inflammatory processes (including changes in pro- or anti-inflammation BMs in oral tissues, GCF, saliva or other oral fluids), dental issues, any changes in clininal oral health parameters such as BOP, CAL, PD, PI, PS, MBL, PIBL. Exclusion criteria comprised animal, in vitro and clinical case studies, reviews, commentaries and letters as well as studies in the planning phase. Application of these inclusion and exclusion criteria resulted in 49 articles for evalution in this review. Cross referencing from recent reviews and meta-analyses on NGPs and oral health revealed additonal 4 studies suitable for this systemic review so that a total of 52 studies were included in the final evaluation, 14 of the LS and 38 of the CSS type (Fig. 1 ). 2.2 Information extracted from the included studies The information of the included studies was extracted according to a standardized procedure and presented in Table S1 (Supplemental files). The NGP(s) investigated (ECs, HTPs, ONPs) together with negative (-) controls (NU or non-smokers) and positive (+) controls (usually cigarette smokers, CC) are shown in column 2 of Table S1. Study type, study groups with group sizes as well as mean age and gender of the subjects is provided in column 3. The history of tobacco/nicotine (T/N) product use of the investigated study groups is summarized in column 4. The extracted information T/N history comprises how the product use was assessed (self-reports, questionnaires) and whether or not the exclusive NGP use was verified (e.g. with suitable BOEs). Endpoints and outcomes (if possible in quantitative terms) together with statistical significances for the differerences between groups are shown in column 5. The studies were assigned to four major outcome groups: (i) pre-cancerous lesions in oral cells, fluids and tissues, including cytogenetic changes (e.g. micronuclei), DNA adducts and oxidative stress markers; (ii) inflammatory processes and changes in related BOBEs; (iii) changes in clinical parameters of the oral cavity including including teeth; (iv) shifts in the oral microbiome in various oral fluids. In the last column of Table S1, comments are provided, mainly on the strengths and weaknesses of the study. 2.3 Synthesis of the reported results from various studies (qualitative meta-analysis) For synthesis of the extracted results from the included studies (Table S1), the reported findings were transformed to ‘qualitative’ measures, in order to perform a ‘qualitative meta-analysis’. The rationale for this approach is the fact that a large number of endpoints (N = 68) have to be evaluated, with 15, 24, 26 and 3 different endpoints for the categories pre-cancerous lesions (i), inflammatory processes (ii), clinical parameters for oral disturbances (iii) and shifts in the microbiome (iv), respectively. Furthermore, the data extracted from the included studies entail a high degree of heterogeneity in terms of study types and group sizes, subjects (gender, age), product properties, clinical and analytical methodologies applied and clinical/biological endpoints measured, which precludes the application of classical, quantitative meta-analyses ( 36 , 37 ). Of major interest in this systematic review were significant differences in endpoints or categories of endpoints between groups, namely NGP users versus NU and NGP users versus cigarette smokers (CC). Outcomes of cross-sectional studies (CSS) as well as baseline (BL) results of longitudinal studies (LS) were represented as statistical significant (p < 0.05 or better) increase (risk score: +1), significant decrease (-1) or no (significant) difference (0). The risk scores + 1 or -1 for the various endpoints were assigned to the effect that they represent a worsening (+ 1) or an improvement (-1) of oral health in the NGP group. Outcomes for single endpoints as well as the groupwise (i – iv) synthesis (‘qualitative’ meta-analyse) are shown in Table S2. Risk scores for endpoint groups (i – iv) are were calculated as means with 95% confidence intervals (CI). If 10 or more observations for single endpoints were available, means and 95% CIs were also calculated for these. This was the case for the endpoints TNF-∝, IL-1ß, IL-6, PI, BOP, PD and MBL (Table S2). BL results of LS were treated as CSS. Differences over time (BL versus follow-up (FU)) were originally planed to be evaluated as changes within ( intra ) or between groups ( inter ). However, reported results of LS were too heterogeneous so that evaluation across studies was not meaningful. 3. Results 3.1 General study characteristics For this systematic review on detrimental oral health effects in NGP users compared to NU and cigarette smokers (CC), 52 human studies, 38 cross-sectional (CSS) and 14 longitudinal studies (LS) fulfilled the inclusion criteria as described in Chap. 2.1. The information extracted from these studies is shown in Table S1. Study sizes were highly variable and comprised between 30 and 1 million subjects with most studies encompassing 60–120 subjects. Subjects in general were healthy adults, but some studies included patients with oral health problems such as periodontitis, caries or other issues. Subjects’ ages covered a range of 20–80 years with a focus on young to middle ages (25–50 years). Most studies comprise both sexes, while a few included only males. It was planned to include ECs, HTPs and ONPs as NGPs. However, in the selected 52 studies almost only the effects of EC use was investigated. In 2 studies ( 38 , 39 ) ONPs and in one study ( 23 ) HTPs together with other NGPs were investigated. In the qualitative meta-analyses only EC studies were included. A differentiation between EC types, generations, nicotine content, and added flavors was not considered in the analysis, primarily to avoid too small group sizes. History of tobacco/nicotine products habits is of particular impotance for the oral health risks associated with NGP use. Most studies rely on self-reports assessed with questionnaires (Table S1). In 11 studies ( 40 – 49 ), cotinine or other nicotine metabolites have been determined in body fluids (blood, saliva, urine), which allows the distinction between users of any tobacco/nicotine product (including NGPs) and NU as well as the extend of product use. However, it does not distinguish between NGP and CC use. This is possible, at least in terms of short-term use with the biomarkers COHb and COex, which had been applied in 10 studies ( 41 , 44 , 46 – 48 , 50 – 53 ). A longer period of CC use versus NGP use is assessable by NNAL in urine and was reported in one study ( 50 ). Urinary CEMA, a BOE to the combustion product acrylonitile and, therefore, a very suitable biomarker for assessing CC use alongside with NGP use, was determined in three studies ( 23 , 41 , 50 ). Duration of NGP use was reported in only part of the selected studies. In 4 investigations ( 54 – 57 ), NGP (mostly EC) use of at least 1 year was required for study participation. In another 5 studies ( 42 , 45 , 58 – 60 ), mean NGP use durations between 2 and 3 year were reported. The longest average NGP use duration in the selected studies amounted to 6.4 ( 61 ), 9.2 ( 62 ), 12.2 ( 63 ) and 12.5 years ( 64 ). One study ( 51 ) provided a mean use time for ECs of 21.6 years, which probably is an error, given the fact that ECs are on the market since about 2006 and the mean age of EC users in that study is reported to be 41.5 years. Dual use (mostly EC together with CC) is heterogeneously wielded in the selected studies. In 8 studies ( 45 , 49 , 65 – 70 ), self-reported dual users were assigned to a separate group or conciously included in a special NGP group. In 12 studies ( 40 , 57 – 59 , 64 , 71 – 76 ), it is stated that dual users were excluded. The remaining studies did not mention or consider the issue of dual or multi-product use although it is likely that it occurs in the respective investigations. Our evaluation is based on exclusive NGP users, as far as this is possible with the study information provided. Dual use can play an important role as bias and confounding factor in the estimated oral health risks of NGP use (discussed later). The evaluation of oral health risks in NGP users comprised 65 different endpoints (Table S2), which were assigned to 4 groups: Pre-cancereous lesions in oral mucosa including markers known to be involved in genotoxic events Inflammatory processes including BOBEs for inflammation in various oral fluids Clinical parameters for detrimental effects in the oral cavity and related to teeth Shifts in the oral microbiome. In total, 199 single observations were extracted and evaluated from the 52 selected studies as outlined in the Methods section (Table S2). 3.2 Pre-cancerous endpoints In total, 12 different endpoints could be extracted from 12 studies ( 23 , 41 , 45 , 47 – 49 , 51 , 54 , 57 , 63 , 75 , 77 )with 16 single observations (Table S2). Only the endpoints ‘micronulei’ ( 51 , 75 , 77 ) and ‘NNN in saliva’ ( 23 , 63 ) were investigated in more than one study. All other endpoints were determined in only one investigation. There were 14 EC versus NU and 15 EC versus CC comparisons included in the qualitative meta-analysis, which yielded mean scores for vapers of 0.29 (95% CI: -0.09–0.67) and − 0.33 (-0.58 - -0.09), respectively. The results of the meta-analysis are graphically depicted in Fig. 2 . In one investigation ( 23 ), the endpoint ‘NNN in saliva’ HTP users was compared to NU and to smokers (CC), resulting in scores of 1 and 0, respectively. 3.3 Inflammatory processes This group comprised 21 different endpoints derived from 19 studies ( 38 , 42 – 44 , 46 , 49 , 55 – 58 , 64 , 67 , 68 , 70 – 72 , 78 – 80 ) with 83 single observations (Table S2). The most frequently determined endpoints were IL-1ß (12 observations), IL-6 (10 observations) and TNF-∝ (10 observations). A qualitative meta-analysis for markers with at least 10 observations including then inflammation biomarkers TNF-∝, IL-6 and IL-1ß, is provided in Chap. 3.7. There were 76 EC user versus NU comparisons resulting in a synthesized mean score for inflammatory processes of 0.28 (95% CI: 0.15–0.41) and 69 EC versus CC user comparisons with a mean score of -0.16 (95%-CI: -0.28 - -0.04) (Fig. 2 ). Note that due to their anti-inflammatory properties, the marker IL-8, IL-9, IL-10, IL-13 and IL-RA were inversed (i.e., the algebraic score signs +/- were inverted). 3.4 Clinical parameters for oral disorders This group comprised 25 different endpoints derived from 20 studies ( 40 , 42 , 44 , 54 , 55 , 57 – 62 , 64 – 66 , 69 , 71 – 74 , 76 , 78 , 79 , 81 – 86 ) with 97 single observations (Table S2). The most frequently determined endpoints were PD (15 observations), PI or PS (14 observations), BOP (13 observations) and MBL (11 observations). A qualitative meta-analysis for markers with at least 10 observations, including the clinical biomarkers MBL, BOP, PI of PS, and PD, is provided in Chap. 3.7. There were 93 EC user versus NU comparisons resulting in a synthesized mean score for clinical parameters of oral distortions of 0.43 (95% CI: 0.32–0.54) and 78 EC versus CC user comparisons with a mean score of -0.27 (95% CI: -0.38 - -0.16) (Fig. 2 ). Note that score inversions were performed for IgA, lysozyme, lactoferrin and BOP. 3.5 Shifts in the oral microbiome This group comprised 4 different endpoints derived from 7 studies with 10 single observations (Table S2). Endpoints were hardly comparable between different studies. In the qualitative meta-analysis for shifts in the oral microbiome, no differentiation between improvement (-1) or worsening (+ 1) were made. Rather, all significant shifts between groups were assigned with a score of + 1. There were 10 EC user versus NU comparisons resulting in a synthesized mean score for shifts in the oral microbiome of 0.70 (95% CI: 0.40–1.00) and 7 EC versus CC user comparisons with a mean score of 0.57 (95% CI: 0.53–0.97) (Fig. 2 ). 3.6 All oral endpoints In total, 65 different oral endpoints from 52 studies with 199 single observations (Table S2). There were 200 EC user versus NU comparisons resulting in a synthesized mean score for oral distortions of 0.37 (95% CI: 0.29–0.44) and 176 EC versus CC user comparisons with a mean score of -0.19 (95% CI: -0.26 – -0.11) (Fig. 2 ). 3.7 Qualitative meta-analysis for the most frequently applied single endpoints For single endpoints applied in 10 or more different studies qualitative meta-analyses were conducted. This was the case for 7 out of 65 endpoints, namely IL-1ß, IL-6, TNF-∝, PI or PS, BOP, PD and MBL Results of this analysis are shown in Fig. 3 . It is obvious that CI ranges in general were larger than in Fig. 2 , which primarily is caused by the lower number of observations for the single EPs. It is interesting to note that BOP (for which the score was inverted) showed the highest mean score of all EC vs NU comparisons (0.77) and the lowest of all EC vs CC comparisons (-0.09), indicating that BOP in EC users is most likely different from NU and not different from CC. The reason for this finding is discussed later. 3.8 Outcomes of longitudinal studies (LS) The selected studies on oral health effects in NGP users comprise 14 LS ( 23 , 39 , 41 , 46 , 50 , 53 , 54 , 56 , 58 , 80 , 81 , 83 , 87 , 88 ) (Table S1). Baseline (BL) data from these LS are treated as CSS and included in the results presented in Sections 3.2 to 3.7 . Longitudinal data, which would allow the analysis of changes over time (in LS usually at BL and one or more follow-up (FU) time points are analysed). LS results are regarded as superior to those obtained from CSS (for a number of reasons, discussed below), provided that the covered time periods (BL to FU) are sufficiently long ( 89 , 90 ). For obvious reasons this is not the case in the LS selectable for this review. The time periods in this selection cover a range of from 3 days to about 2 years, with the highest frequency for FUs of 6 months. In general, LS were smaller in group size and more heterogeneous than CSS, thus preventing a synthesized analysis (meta-analysis) across studies. Therefore, in the following, changes over time of oral effects reported in single LS were briefly presented. In an LS with FUs at 2, 4 and 6 weeks, a normalization of reversible histological changes were observed in 60 snus users after replacing snus with ONPs already at the first FU visit ( 39 ). Unfortunately, no negative control group (using no nicotine/tobacco product during the FU period) or positive control group (continue using snus) was included. In an LS with 30 EC and 30 CC users, no differences in the oral clinical parameters CAL, PD, MBL and PS were found at BL, while after 6 months FU, PD, CAL and MBL became worse in the CC compared to the EC group ( 54 ). Both user groups showed significant correlations between the long-term dose and the endpoints MMP-8, CTX, PD, and CAL. This LS did not contain a negative control (NU). In subjects with moderate chronic periodontitis under SRP treatment (36 vapers and 35 NS), PI, PD, MBL, CAL, IL-4, IL-9, IL-10, and IL-13 (the latter 4 in GCF) were reported not to be significantly different at BL ( 56 ). In the EC group at 3 months FU, the endpoints PI, GI, PD, CAL, and MBL were found not to be different from BL, while PI, GI and PD were significantly reduced in the NS group. For the anti-inflammation markers IL-4, IL-9, IL-10, and IL-13 a significantly higher increase was observed in the NS compared to the EC group. Vaping apparently mitigated the SRP treatment effect. Regrettably, no positive controls (smokers of CC) were included in this LS. In another LS with 89 male FMUS patients (30 CC, 28 EC, 31 NS) after 3 as well as 6 months FU, improvements in PI, CAL and PD were observed in all three group. However they were best in NS followed by EC and worst in CC ( 58 ). In an intervention study with 80 smokers suffering from periodontitis, 40 switched to EC and 40 stopped smoking ( 88 ). At 6 months FU, PD improved to a similar extent in both groups. Oral dryness, however, did not change in vapers, while it decreased in NU. Tatullo et al. ( 53 ) investigated the clinical parameter PI and PBI in 60 vapers with ≤ 10 years of previous smoking (CC) compared to 50 vapers with > 10 years previous smoking. Measurements at BL, 60 and 120 days FUs revealed improvements over time in both groups. However, in the group with the longer period of former CC use, the oral clinical parameters were less advantageous than in the comparator group. A cohort study over 6 months with 27 cigarette smokers (CC), 28 vapers (EC) and 29 NU revealed that the ∝-diversity (a measure of microbiome diversity applicable to a single sample) increased across the cohorts longitudinally, yet each cohort maintained a unique microbiome ( 46 ). The authors concluded that EC use promotes a unique periodontal microbiome (as a stable state between CC users and NU), presenting an oral health challenge. In a similar study design, Xu et al. ( 80 ) investigated the salivary microbial composition in 101patients with periodontitis (31 CC, 32 EC, 38 NU). From their results the authors concluded that vaping, similar to smoking, alters the bacterial composition with an increase of disease-associated pathogens. Similar observations were reported by Chopyk et al.( 87 ). Furthermore, it was reported that reducing the EC use over 2 weeks led to a decrease of pathological changes in the salivary but not the buccal microbiome. 4. Discussion 4.1 General considerations For this systematic review on oral health effects of NGP (scheduled to comprise ECs, HTPs and ONPs), 52 human studies (38 or cross-sectional and 14 of longitudinal type) were selected and subjected to a series of qualitative meta-analyses. It turned out that in only 3 studies, NGPs other than ECs were investigated so that the meta-analyses only dealt with the use of ECs (vaping) and refer to comparisons of EC users vs NU and EC users vs CC users. Classical (quantitative) meta-analysis for disease endpoints, for example oral cancer, are presently not possible for a number of reasons. A foremost reason is the fact that duration of NGP use is not sufficiently long to induce chronic diseases (cancer would require more than 2 decades). ECs, also known as ENDS (electronic nicotine delivery systems), in its modern form have been invented in 2003 by the Chinese pharmacist Hon Lik and were first introduced to the market in about 2007 ( 91 ). HTPs (with electric heating systems) have been marketed in the end of the 1990ies. ONPs are the most recent products of the NGPs dealt with in this review. The big tobacco companies started marketing the products as tobacco-free ONPs in 2019 ( 92 ). ECs, which are in the focus of this review, were subject to rapid product changes so that since its general marketing at least four generations were passed through ( 93 , 94 ). This factor significantly contributes to the heterogeneity of the study data to be evaluated. Other factors include study type, group sizes, gender, age as well as endpoints investigated and methods for their determination. Under these premises, we decided to perform qualitative meta-analyses for single endpoints with at least 10 observations in different studies or groups of endpoints belonging to four different types of oral disorders, namely (i) pre-cancerous lesions including oxidative stress markers, (ii) inflammatory processes, (iii) general clinical parameters used for oral (including dental) disorders, and (iv) shifts in the oral microbiome. Assignment to these endpoint categories might appear somewhat arbitrary, however, there is multiple evidence that many, if not all, oral endpoints considered in the this review are mechanistically connected in the development of various oral disease ( 89 , 90 , 95 – 98 ). We, therefore, believe that our approach of combining different endpoints to groups of disorders or even a total score for detrimental effects in the oral cavity is physiologically justified for the purpose of qualitative meta-analyses. The procedure for this analysis is described in detail in Section 2.3 . In essence, the study findings with respect to the EC versus NU and the EC versus CC comparisons for each endpoint were categorized to three ‘scores’, namely ‘+1’ (= significant increase (in the sense of a worsening of an oral health condition), ‘-1’ (= significant decrease (in the sense of an improvement of an oral health condition) and ‘0’ (= no significant difference between groups). It has to be noted that for some endpoints an increase can imply improvement of the health condition. This was considered accordingly in the meta-analysis (Table S2). Furthermore, it has to be emphasized that the calculated means and 95% confidence intervals (CI) represent probabilities for finding a worsening (positive score values) or an improvement (negative score values) for vapers (EC) compared to either NU or smokers (CC). From Figs. 2 and 3 , it is immediately evident that using ECs is associated with more unfavorable oral health endpoints compared to NU. Whereas vapers were generally reported to do better in terms of oral health compared to smokers (CC). This is in general agreement with all reviews on this topic published in the last 5 years ( 89 , 90 , 94 – 116 ). However, score means in Figs. 2 and 3 are most frequently between 0 and + 0.5 (EC vs NU comparisons) or between − 0.5 and 0 (EC vs CC comparisons), indicating that the outcomes of the evaluated studies are not very consistent. The higher mean scores ( > + 0.5) calculated for the oral microbiome (Fig. 1 ) and BOP (Fig. 3 ) are discussed below. In general, smaller numbers of observations were available for the evaluation of the 7 single endpoints (Fig. 3 ), leading to larger CI ranges. Of the 14 comparisons, 5 CIs overlap with the zero axis, suggesting considerable inconsistencies in the outcomes for these endpoints. 4.2 Oral cancer As yet, no epidemiological studies on the oral cancer risk of chronic NGP use are available. As a surrogate, the association between NGP use (usually of moderate duration only) and various pre-cancerous lesions mechanistically related to oral cancer is evaluated in our review (Chap. 3.1) as well as in a number of previously published reviews ( 90 , 95 , 96 , 107 , 114 , 115 ). All evaluations (including our own) came to the conclusion that the available evidence suggests that EC use may have the potential to increase the oral cancer risk by working through one or several possible mechanisms which might include formation DNA adducts by exposure to potentially genotoxic chemicals in EC aerosol (e.g. acrolein, NNN, others), DNA damage (e.g. indicated by the increased formation of MN), oxidative stress, suppression of the immune system, and shifts in the oral microbiome. There is also general agreement in the literature that conclusive answers with regard to the role of chronic vaping in oral cancer induction would require about another decade. The evaluation of an involvement of the habitual use of the other two NGPs of interest (HTPs, ONPs) in oral cancer generation is not possible, due to the lack of suitable data. 4.3 Oral inflammations A large number (N = 24) of different endpoints on inflammatory processes were available from 20 human studies, allowing 83 EC versus NU and 76 EC versus CC comparisons (Chap. 3.2, Fig. 2 ). In addition, qualitative meta-analyses were also conducted for the single inflammation biomarkers IL-ß, IL-6 and TNF-∝ (Fig. 3 ). Although the results are partly inconsistent, the majority of studies reported elevated inflammation in EC users compared to NU and decreased occurrence of inflammation in EC compared to CC users. This is in general agreement with other surveys of the literature ( 89 , 103 , 104 , 109 – 111 ). There is no established knowledge about the mechanism how and the possibly involved chemicals by which vaping can induce inflammatory processes in the oral cavity. Assumption include the involvement of nicotine ( 103 ), metals ( 89 ) or shifts in the oral microbiome caused by dry mouth and reduced salivary flow ( 104 ) or increased growth of Candida albicans ( 97 ). No studies on inflammation effects of HTP or ONP use were identified for this review. 4.4 General clinical endpoints for oral disorders The general clinical parameters for oral disorders comprised 25 different endpoints extracted from 20 human studies, allowing 93 EC versus NU and 78 EC versus CC comparisons (Chap. 3.2, Fig. 2 ). In addition to the group evaluation, qualitative meta-analyses for the single endpoints PD, PI or PS, BOP and MBL were also conducted (Fig. 3 ). The majority of studies showed significantly increase in clinical disorders in EC compared to NU and a decrease in clinical disorders in EC compared to CC users. This ranking of clinical disorders (NU < EC < CC) was also reported in other recent reviews on detrimental oral effects of vaping ( 97 , 109 , 111 , 115 ). With one exception (BOP), the responsible chemicals in EC aerosol and the mechanisms for the reported clinical effects are not established. As possible candidates were discussed nicotine ( 109 , 111 ), metals ( 109 , 111 ), flavor components ( 97 , 109 , 111 ), sucrose and sugar substitutes ( 97 ), acids ( 97 ). BOP is found to be reduced in vapors compared to NU and very similar to that observed in smokers (CC) (Fig. 3 ). This consistent finding can be explained by a nicotine-caused vasoconstriction in gum tissue (for review see ( 34 ). A similar effect on BOP has to be expected in users of HTP and ONP. However, no investigations on BOP and any other clinical parameter on detrimental oral effects was available for this review. 4.5 Oral microbiome For the purpose of this review, 4 endpoints on the oral microbiome were selected from 7 studies. This data set allowed 10 EC versus NU and 7 EC v ersus CC comparisons. In contrast to the evaluation of the other endpoints or groups of endpoints, meta-analysis was modified in that differences (shifts) between groups in the oral microbiome were not divided into significant worsening (+ 1) or improvement (-1), rather, any significant shift was assigned the score value of + 1. The reason for this approach was that the impact of a shift in terms of increasing or decreasing an oral health risk cannot yet predicted with sufficient certainty. It is, therefore, assumed that significant changes in the oral microbiome represents an oral health risk. Figure 2 shows that in most studies vaping was found to lead to a shift in the composition of the oral microbiome, both compared to NU and smokers (CC). This is in agreement with most of the results of other recent reviews ( 94 , 101 , 103 – 105 , 108 , 110 , 115 ). The mechanism by which vaping can change the oral microbiome is not yet well established. An interesting hypothesis assumes that use of ECs can lead to dry mouth (xerostomia) by action or PG and VG (which are hygroscopic) together with an increase in biofilm volume and a reduced salivary flow ( 104 , 105 ). A role of nicotine in oral microbiome change has not yet been reported ( 34 ), which accords with another recent review, stating that nicotine may not be involved oral microbiome shifts ( 103 ). The oral health consequences of shifts in the oral microbiome are as yet not quite clear ( 103 ). Other authors speculated that a chronic change in the oral microbiome can lead to severe health disorders such as periodontitis and periodontal disease and other oral health issues ( 104 , 105 , 108 , 110 ), retarded wound healing ( 104 ) and even increased oral cancer risk ( 104 ). 4.6 Role of major constituents in the EC aerosol (vapor) All e-liquids and hence the EC aerosol inhaled by the vaper contain glycerol (usually vegetable-derived glycol, VG), 1,2-propylene glycol (PG), nicotine and flavor compounds, although in varying ratios and amounts. In particular the added flavors may differ largely in composition as well as quality and quantity of components from brand to brand. The e-liquid matrix usually consists of VG and PG in varying ratios. The mouth-level exposure with these compounds is in the g per day range ( 20 ). It is, therefore, not unreasonable to assume that the vaping habit may lead to changes in the oral biofilm and shifts in the composition of the microbiome, connected with xerostomia ( 68 , 104 – 106 ). Guo et al. ( 50 ) found in vitro evidence that PG can inhibit bacterial inflammation and the formation of AP sites in DNA, thus explaining their finding that EC users have significantly lower AP levels in oral cells than smokers (CC) and NU. The most common nicotine content in e-liquid ranges from 3–36 mg/mL), with an upper limit set for the European Union of 20 mg/ml (Althakfi et al. 2024). The mean daily intake of nicotine by vaping was estimated to be about 10 mg/d ( 20 ). A recent review on the role of nicotine in various oral disorders and diseases did not identify nicotine to be a major risk factor for oral diseases ( 20 ). A consistent finding was that BOP is decreases in users of any nicotine products compared to NU (Table S1, ( 89 )). Our meta-analysis also confirms this nicotine-related in that EC and CC users are comparable in their BOP level, but rather different from NU (Fig. 3 ). By a similar mechanism, nicotine can be involved in retarded wound healing processes in the mouth by inducing local ischemia ( 104 ). Holliday et al. ( 106 ) concluded that salivary nicotine concentrations in vapers (4 - µM) are unlikely to exert cytotoxic effects in the oral cavity. In another review ( 107 ), it was hypothesized that nicotine in the oral cavity can cause a number of detrimental effects, mostly mediated via the nicotinic-acetylcholin-receptor (n-AChR), supportive in the development of oral diseases including oral cancer. Information on detrimental effects of flavors added to NGPs in the oral cavity are sparse. In a review on detrimental oral health effects in EC users, Irusa et al. ( 117 ) focused on the effects of flavors. The authors stated that with certain flavors, investigators were able to show a four-fold increase in microbial adhesion to enamel, a two-fold increase in biofilm formation, and a 27% decrease in enamel hardness. From an evaluation of the literature, Flach et al. came to the conclusion that clinical evidence urges to assume that flavoured e-liquids appear to be more harmful. Ebersole et al. ( 103 ) pointed out that toxic agents can be released from flavor compounds in e-liquid upon heating. In general, it has to be stated that the flavor compounds added to NGPs have GRAS (“generally recognized as safe”) status, meaning that they are safe to be used in food. An issue, however, could be the release of toxicants (mainly aldehydes) as mentioned above ( 103 ). 4.7 Quality of the evaluated studies: bias and confounding It is assumed that the human studies evaluated for this review are subject to severe bias and a number of confounding factors. Table S1 contains comments and statements with respect to bias and confounding for each of the 52 evaluated studies. For quality assessment of the included studies, the Newcastle-Ottawa-Scale (NOS) for observational studies of the case-control type can, with certain restraints, be applied ( 118 ). The NOS defines three domains for quality assessment of case-control studies: (i) selection of cases and controls (in our review: NGP users, non-users (NU) and cigarette smokers (CC), (ii) comparability of groups, and (iii) ascertainment of exposure. A fourth domain would have to added: (iv) outcomes and endpoints, which are of particular importance in this systematic review, as multiple endpoints (actually N = 65) were included in this analysis. In particular, endpoints applied here are less well estblished pre-staged, rather than manifested diseases. As described in Table S1 and at various passages in the text, selected studies are highly heterogeneous in many study features, including the three domains of the NOS. However, we see especially high potential of bias in the domains (i) selection of EC users and (iii) ascertainment of exposure. With a few exemptions, there are weaknesses in almost all studies in Table S1. Given the fact that most vapers are switchers from CC, possible long-term ‘carry-over’ effects of former smoking have to be considered. For example, in a longitudinal study (LS) over 120 d it was shown that vapers who formerly used CC for > 10 years had a worse periodontal status than those with ≤ 10 years of former smoking ( 53 ). In many of the selected studies, the former smoking status of the EC group was not or only insufficiently assessed. Furthermore, the assessment of EC use is most frequently performed by means of (structrued or unstructured) questionnaires or interviews. In only a few studies, at least the short-term compliance of exclusive EC use was verified by suitable biomarkers such as COex or COHb, CEMA, NNAL ( 46 – 48 , 50 , 53 ) ( 23 ). In none of the studies, a long-term biomarker for CC use applied, such as for example the hemoglobin adduct CEVal (2-cyanoethyl valine) ( 119 ). Among adult (18 + years) EC users ) in the US in 2021 (about 11.6 million persons), almost 30% were dual users ( 120 ). It has to be assumed that it is quite likely that the groups of EC users in the evaluated studies of this review contain considerable numbers of un-assessed dual users, which might constitute a potential risk of bias for elevated deterimental oral health effects in the EC groups. The extent of this bias is difficult to quantify, but in all likehood part of the generally observed increase in detrimental oral health effects might be attributable to some smoking (CC) in the EC groups. A well known confounding factor in oral health effects is a lack in dental hygiene. Smokers, on average, were found to practice lower oral hygiene than non-smokers ( 121 ). It is not yet known whether the same applies for EC users compared to NU. In a very recent review, however, no such difference was reported ( 122 ) 4.8 Limitations Beyond the general risk of bias and confounding described in the previous chapter, there is the unavoidable limitation that duration of use of NGPs is presently too short for the investigation of long-term detrimental effects such as oral cancer. As a substitute, precursor lesions or (early) biomarkers of biological effects (BOBEs) were used as endpoints for the evaluation of detrimental oral health effects in NGP users. The predictive power for a subsequent diseases is as yet not well established. Another limitation is that many of the selectable studies have small group sizes (< 50/group), which may prevent finding small differences between groups to be significant. This could have direct impact on the qualitative meta-analyses conducted in this systematic review. The approach of qualitative meta-analysis as introduced here is not an established methodology. Its limitations have been discussed earlier in the text. The calculated scores and CI-values may, be no means, be interpreted as oral health risks. Rather, the score values (range: -1 to + 1) indicate the probability of finding a harm (+) or benefit (-) between two groups when a sufficient number of comparisons is performed. The combination of various endpoints to a new oral health parameter (as was done for the categories ‘pre-cancerious lesions’, ‘inflammatory processes’, ‘oral clinical parameters’, ‘shifts in the oral microbiome’, ‘total oral disorders’) can be criticized to be somewhat arbitrary and not (always) physiologically based. In general we would agree with this criticism. However, we would argue that almost all of the endpoints are interrelated via one or more physiological pathways, so that even combining all detrimental oral endpoints to a variable ‘total oral disorders’ (Fig. 3 ) may have a certain justification. 5. Conclusions Our qualitative meta-analyses of a multitude of endpoints of early oral discorders revealed that vapers (EC) were better off than smokers (CC) but still worse than NU. Systematic bias by presumably underreported dual use might be responsible for part of the oral disorders in EC users. There is a need for further research into the long-term effects of NGP use on oral health outcomes, as well as the underlying biological mechanisms. Abbreviations 3-OH-Cot trans-3’-hydroxycotinine 3-OH-Cot-gluc trans-3’-hydroxycotinine-N,O-glucuronide 8-OH-dG 8-Hydroxy-2’-deoxyguanosine (a BM of oxidative stress) AP Apurinic/apyrimidinic (sites in DNA) B Blood BL Baseline (at start of a longitudinal or prospective study) BLT Bone loss around teeth BM Biomarker BOP Bleeding on probing CAL Clinical attachment loss CBL Crestal bone loss CC Combustible cigarettes (and user) CEMA 2-Cyanoethyl mercapturic acid (MA of acrolonitrile) CI 95%-Confidence interva CNO Cotinine-N-1-oxide CODS Clinical oral dryness score COex Carbon monoxide in exhaled breath COHb Carboxyhemoglobin Cot Cotinine Cot-gluc cotinine-N-glucuronide CRP C-reactive protein (inflammation marker) CSS Cross-sectional study CTX C-terminal cross-links D Duration (of use of T/N products or NGPs) EC Electronic cigarettes EN-RAGE Extracellular newly identified RAGE binding protein FMUS Full mouth ultasonic scaling FS Former smoker (usually of CC) FU Follow-up (in a prospective study G Group GCF Gingival crevicular fluid GCol Gingival color GI Gingival index GM-CSF Granulocyte-macrophage colony-stimulating factor (pro-inflamm. marker) GSH-Px Glutathione peroxidase HNSCC Head and neck scquamous cell cancer HPRT Hypoxanthine phosphoribosyltransferase HTP Heated tobacco product (and user) Hypybut 4-OH-4-(3-pyridyl)-butanoic acid IL-1ß Interleukine-1ß (pro-inflammatory cytokine) IL-2 Interleukine-2 (pro-inflammatory cytokine) IL-4 Interleukine-4 (anti-inflammatory cytokine) IL-6 Interleukine-6 (pro-inflammatory cytokine) IL-8 Interleukine-8 (anti-inflammatory cytokine) IL-9 Interleukine-9 (anti-inflammatory cytokine) IL-10 Interleukine-10 (anti-inflammatory cytokine) IL-12p70 Interleukine-12p70 (?-inflammatory cytokine) IL-13 Interleukine-13 (anti-inflammatory cytokine) IL-RA Interleukine-RA (anti-inflammatory cytokine) IL-15 Interleukine-15 (?-inflammatory cytokine) IL-18 Interleukine-15 (?-inflammatory cytokine) INF-γ Interferon-gamma (pro-inflammatory cytokine) IQR Inter-quartile range (25th – 75th percentile) LA-QPCR Long-amphicon quantitative polymerase chain reaction LC-MS/MS Liquid chromatography with tandem mass spectrometry LDH Lactate dehydrogenase (elevation can indicate oxidative stress, cell damage and cell death) LRG1 Leucine-rich alpha-2-glycoprotein (BM for tumor vascularization) LS Longiturinal study m month MA Mercapturic acid MBL Marginal bone loss mi-RNA micro-RNA (not coding RNA, but involved in gene regulation) MN Micronulei MPO Myeloperoxidase MT Missing teeth N Nicotine NCot Norcotinine Nequ Nicotine equivalents NGP New generation (tobacco/nicotine) product (EC, HTP, NP) NHANES National Health and Nutrition Examination Survey (USA) N(ic) Nicotine Nic-gluc Nicotine-N’-glucuronide Nic + 10 Nicotine and its 10 major metabolites Cot, 3-OH-Cot, Nic-gluc, Cot-gluc, 3-OH-Cot-gluc, NNic, NCot, NNO, CNO, Hypybut NN Nornicotine NNN N-Nitrosonornicotine NNO Nicotine-N-1’-oxide NRT Nicotine replacement therapy ns not (statistically) significant NS Non-smoker nts nucleotides (in DNA) NU Non-user (of any tobacco/nicotine product) NV Non-vaper OML Oral mucosa lesions ONP Oral nicotine pouch OPG Osteoprotegerin OR Odd ratio OT Oral tobacco (and user) P Plasma PATH Population Assessment of Tobacco and Health (study in USA) PBI Papillary bleeding index (indicator of gingival inflammation) PCot Cotinine in plasma PD Probing depth PG 1,2-Propylene glycoöl PGE2 Prostaglandin E2 (involved in inflammatory processes) PI Plaque index PIBL Peri-implant bone loss PISF Peri-implant sulcular fluid POLB (DNA) Polymerase-beta POR Prevalence odd ratio PS Plaque score PY Packyears Q Questionnaire RAGE Receptor for advanced glycation end products RANKL Receptor activator of NF-kappa B ligand RBL Radiographic bone loss S Saliva SD Standard deviation of the mean SEM Standard error of the mean SGP Subgingival plaque SLT Smokeless tobacco SRP Sealing and root paving TIMP-1 Tissue inhibitor metalloproteinase-1 TNF-α Tumornekrosefaktor-α (pro-inflammatory cytokine) TNH History of using tobacco/nicotine products T/N Tobacco/Nicotine (products, history, etc.) U Urine WP Waterpipe w/o with or without Declarations Conflicts of Interest: The authors declare no conflict of interest. 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Journal of the American Dental Association 2021;152(9):720-9 Verma A, Anand K, Bhargava M, Kolluri A, Kumar M, Palve DH (2021) Comparative Evaluation of Salivary Biomarker Levels in e-Cigarette Smokers and Conventional Smokers. J Pharm bioallied Sci 13(Suppl 2):S1642–s5 ArRejaie AS, Al-Aali KA, Alrabiah M, Vohra F, Mokeem SA, Rcdc GB et al (2019) Proinflammatory cytokine levels and peri-implant parameters among cigarette smokers, individuals vaping electronic cigarettes and non-smokers. J Periodontol 90(4):367–374 BinShabaib M, ALHarthi SS, Akram Z, Khan J, Rahman I, Romanos GE et al (2019) Clinical periodontal status and gingival crevicular fluid cytokine profile among cigarette-smokers, electronic-cigarette users and never-smokers. Arch Oral Biol 102:212–217 Cichonska D, Kusiak A, Kochanska B, Ochocinska J, Swietlik D (2019) Influence of Electronic Cigarettes on Selected Antibacterial Properties of Saliva. Int J Environ Res Public Health. ;16(22) Cichońska D, Kusiak A, Kochańska B, Ochocińska J, Świetlik D (2022) Influence of Electronic Cigarettes on Selected Physicochemical Properties of Saliva. Int J Environ Res Public Health. ;19(6) Pop AM, Coroș R, Stoica AM, Monea M (2021) Early diagnosis of oral mucosal alterations in smokers and e-cigarette users based on micronuclei count: a cross-sectional study among dental students. Int J Environ Res Public Health 18(24):13246 Vohra F, Bukhari IA, Sheikh SA, Albaijan R, Naseem M (2020) Comparison of self-rated oral symptoms and periodontal status among cigarette smokers and individuals using electronic nicotine delivery systems. J Am Coll Health: JACH 68(7):788–793 Franco T, Trapasso S, Puzzo L, Allegra E (2016) Electronic Cigarette: Role in the Primary Prevention of Oral Cavity Cancer. Clin Med insights Ear nose throat 9:7–12 AlJasser R, Zahid M, AlSarhan M, AlOtaibi D, AlOraini S (2021) The effect of conventional versus electronic cigarette use on treatment outcomes of peri-implant disease. BMC Oral Health 21(1):480 AlQahtani MA, Alayad AS, Alshihri A, Correa FOB, Akram Z (2018) Clinical peri-implant parameters and inflammatory cytokine profile among smokers of cigarette, e-cigarette, and waterpipe. Clin Implant Dent Relat Res 13(1):55–58 Xu F, Pushalkar S, Lin Z, Thomas SC, Persaud JK, Sierra MA et al (2022) Electronic cigarette use enriches periodontal pathogens. Mol Oral Microbiol Atuegwu NC, Perez MF, Oncken C, Thacker S, Mead EL, Mortensen EM (2019) Association between Regular Electronic Nicotine Product Use and Self-reported Periodontal Disease Status: Population Assessment of Tobacco and Health Survey. 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Journal of the American Dental Association 2022;153(12):1179-83 Jeong W, Choi DW, Kim YK, Lee HJ, Lee SA, Park EC et al (2020) Associations of electronic and conventional cigarette use with periodontal disease in South Korean adults. J Periodontol 91(1):55–64 Chopyk J, Bojanowski CM, Shin J, Moshensky A, Fuentes AL, Bonde SS et al (2021) Compositional Differences in the Oral Microbiome of E-cigarette Users. Front Microbiol 12:599664 Holliday R, Preshaw PM, Ryan V, Sniehotta FF, McDonald S, Bauld L et al (2019) A feasibility study with embedded pilot randomised controlled trial and process evaluation of electronic cigarettes for smoking cessation in patients with periodontitis. Pilot feasibility Stud 5:74 Figueredo CA, Abdelhay N, Figueredo CM, Catunda R, Gibson MP (2021) The impact of vaping on periodontitis: A systematic review. Clin experimental Dent Res 7(3):376–384 Flach S, Maniam P, Manickavasagam J (2019) E-cigarettes and head and neck cancers: A systematic review of the current literature. Clin Otolaryngol Travis N, Knoll M, Cook S, Oh H, Cadham CJ, Sánchez-Romero LM et al (2023) Chemical Profiles and Toxicity of Electronic Cigarettes: An Umbrella Review and Methodological Considerations. Int J Environ Res Public Health. ;20(3) Robichaud MO, Seidenberg AB, Byron MJ (2019) Tobacco companies introduce 'tobacco-free' nicotine pouches. Tob Control Jerzyński T, Stimson GV (2023) Estimation of the global number of vapers: 82 million worldwide in 2021. Drugs Habits Social Policy 24(2):91–103 Chaffee BW, Couch ET, Vora MV, Holliday RS (2021) Oral and periodontal implications of tobacco and nicotine products. Periodontol 2000 87(1):241–253 Guo J, Hecht SS (2023) DNA damage in human oral cells induced by use of e-cigarettes. Drug Test Anal 15(10):1189–1197 Maan M, Abuzayeda M, Kaklamanos EG, Jamal M, Dutta M, Moharamzadeh K (2023) Molecular insights into the role of electronic cigarettes in oral carcinogenesis. Crit Rev Toxicol 53(1):1–14 Rouabhia M (2020) Impact of electronic cigarettes on oral health: a review. J Can Dent Assoc 86:1488–2159 Zanetti F, Zivkovic Semren T, Battey JND, Guy PA, Ivanov NV, van der Plas A et al (2021) A Literature Review and Framework Proposal for Halitosis Assessment in Cigarette Smokers and Alternative Nicotine-Delivery Products Users. Front Oral Health 2:777442 Bestman EG, Brooks JK, Mostoufi B, Bashirelahi N (2021) What every dentist needs to know about electronic cigarettes. Gen Dent 69(3):31–35 Briggs K, Bell C, Breik O (2021) What should every dental health professional know about electronic cigarettes? Aust Dent J 66(3):224–233 Cameron A, Meng Yip H, Garg M (2023) e-Cigarettes and Oral Cancer: What do we know so far? Br J Oral Maxillofac Surg 61(5):380–382 Chhina MS (2023) Are e-cigarettes a safer alternative to reduce incidences of oral cancer? Evid Based Dent Ebersole J, Samburova V, Son Y, Cappelli D, Demopoulos C, Capurro A et al (2020) Harmful chemicals emitted from electronic cigarettes and potential deleterious effects in the oral cavity. Tob Induc Dis 18:41 Ferrazzo KL, Ortigara GB, Bonzanini LIL (2023) Harmful effects of electronic cigarette on oral soft tissues mediated by dysbiosis: State of the art. Oral Dis Holliday R, Chaffee BW, Jakubovics NS, Kist R, Preshaw PM (2021) Electronic Cigarettes and Oral Health. J Dent Res 100(9):906–913 Holliday RS, Campbell J, Preshaw PM (2019) Effect of nicotine on human gingival, periodontal ligament and oral epithelial cells. A systematic review of the literature. J Dent 86:81–88 Jităreanu A, Agoroaei L, Aungurencei OD, Goriuc A, Diaconu Popa D, Savin C et al (2021) Electronic cigarettes' toxicity: from perio-dontal disease to oral cancer. Appl Sci 11(20):9742 Kumar PS, Clark P, Brinkman MC, Saxena D (2019) Novel Nicotine Delivery Systems. Adv Dent Res 30(1):11–15 Ralho A, Coelho A, Ribeiro M, Paula A, Amaro I, Sousa J et al (2019) Effects of Electronic Cigarettes on Oral Cavity: A Systematic Review. J Evid Based Dent Pract. ;19(4) Sharma H, Ruikar M (2023) Electronic cigarettes: Ally or an enemy in combating tobacco-use-associated diseases - An integrative review. Indian J Dent research: official publication Indian Soc Dent Res 34(2):216–222 Thiem DGE, Donkiewicz P, Rejaey R, Wiesmann-Imilowski N, Deschner J, Al-Nawas B et al (2023) The impact of electronic and conventional cigarettes on periodontal health-a systematic review and meta-analysis. Clin Oral Invest Wasfi RA, Bang F, de Groh M, Champagne A, Han A, Lang JJ et al (2022) Chronic health effects associated with electronic cigarette use: A systematic review. Front public health 10:959622 Welti R, Jones B, Moynihan P, Silva M (2023) Evidence pertaining to modifiable risk factors for oral diseases: an umbrella review to Inform oral health messages for Australia. Aust Dent J Wilson C, Tellez Freitas CM, Awan KH, Ajdaharian J, Geiler J, Thirucenthilvelan P (2022) Adverse effects of E-cigarettes on head, neck, and oral cells: A systematic review. J oral Pathol medicine: official publication Int Association Oral Pathologists Am Acad Oral Pathol 51(2):113–125 Yang I, Sandeep S, Rodriguez J (2020) The oral health impact of electronic cigarette use: a systematic review. Crit Rev Toxicol 50(2):97–127 Zhang Q, Wen C (2023) The risk profile of electronic nicotine delivery systems, compared to traditional cigarettes, on oral disease: a review. Front public health 11:1146949 Irusa KF, Vence B, Donovan T (2020) Potential oral health effects of e-cigarettes and vaping: A review and case reports. Journal of esthetic and restorative dentistry: official publication of the American Academy of Esthetic Dentistry Peterson J, Welch V, Losos M, Tugwell P (2011) The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa: Ottawa Hospital Research Institute. ;2(1):1–12 Camacho OM, McEwan M, Gale N, Pluym N, Scherer M, Hardie G et al (2021) Adduct N–(2–cyanoethyl)valine as a Biomarker Of Compliance in Smokers Switching to Tobacco Heating Products. Preprints. ;2021080085 Kramarow EA, Elgaddal N (2023) Current Electronic Cigarette Use Among Adults Aged 18 and Over: United States, 2021. NCHS Data Brief. (475):1–8 Ford PJ, Rich AM (2021) Tobacco Use and Oral Health. Addiction Iacob AM, Escobedo Martínez MF, Barbeito Castro E, Junquera Olay S, Olay García S (2024) Junquera Gutiérrez LM. Effects of Vape Use on Oral Health: A Review of the Literature. Medicina 60(3):365 Additional Declarations The authors declare no competing interests. Supplementary Files TableS1SupplSchererOralHealth.docx Selected studies (N = 53) for the systematic review on oral effects in users of NGPs TableS2SupplSchererOralHealth.xlsx Comparisons between NGP users and non-users (NU) and cigarette smokers (CC) by endpoints (EPs): Single observations and qualitative meta-analyses Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4206242","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":286596866,"identity":"f277371f-4c0d-46ae-b0eb-616ae6e40194","order_by":0,"name":"Gerhard Scherer","email":"data:image/png;base64,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","orcid":"","institution":"ABF Analytisch-Biologisches Forschungslabor","correspondingAuthor":true,"prefix":"","firstName":"Gerhard","middleName":"","lastName":"Scherer","suffix":""},{"id":286596867,"identity":"30947dc3-397f-40ea-b61f-8293807830a4","order_by":1,"name":"Nikola Pluym","email":"","orcid":"","institution":"ABF Analytisch-Biologisches Forschungslabor","correspondingAuthor":false,"prefix":"","firstName":"Nikola","middleName":"","lastName":"Pluym","suffix":""},{"id":286596868,"identity":"e73005ae-1160-4514-85c7-1ef4b0a96394","order_by":2,"name":"Max Scherer","email":"","orcid":"","institution":"ABF Analytisch-Biologisches Forschungslabor","correspondingAuthor":false,"prefix":"","firstName":"Max","middleName":"","lastName":"Scherer","suffix":""}],"badges":[],"createdAt":"2024-04-02 11:16:26","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-4206242/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4206242/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":53989431,"identity":"38dfe6c7-1f41-4530-97d9-42521a1bfd7f","added_by":"auto","created_at":"2024-04-03 05:19:32","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":376091,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart for identification, excluding and including studies for evaluation in this systematic review according to PRISMA (35).\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4206242/v1/78b30f1f088d4fd806552a8a.jpeg"},{"id":53989434,"identity":"6ead1306-a4cf-495a-a021-60f39f1de178","added_by":"auto","created_at":"2024-04-03 05:19:32","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":234085,"visible":true,"origin":"","legend":"\u003cp\u003eMean scores with 95% confidence interval (CI) for all endpoints and the 4 endpoint categories compiled from the 52 studies selected for this systematic review. Open circles (○) : comparison between EC users und NU, filled circels (●): comparison between EC and CC users.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4206242/v1/fbddb9c07af6965b5379cd1b.jpeg"},{"id":53989432,"identity":"c951d8a6-618d-4b2a-95f6-3b6eebe04491","added_by":"auto","created_at":"2024-04-03 05:19:32","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":57376,"visible":true,"origin":"","legend":"\u003cp\u003eMean scores with 95% confidence interval for single endpoints of detrimental oral effects reported in 10 or more of the selected studies. Open circles (○): comparison between EC users und NU, filled circles (●): comparison between EC and CC users.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-4206242/v1/a9af7aab8bb8af3c9a8f38f5.png"},{"id":53990469,"identity":"1b83182b-b4bd-4ac3-ad21-26da7d556f5a","added_by":"auto","created_at":"2024-04-03 05:35:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":751767,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4206242/v1/fdfc6e1c-3c76-41fc-9bd5-db317485d599.pdf"},{"id":53989900,"identity":"4832ee8a-8766-4c78-9bb9-df8950196495","added_by":"auto","created_at":"2024-04-03 05:27:32","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":129188,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSelected studies (N = 53) for the systematic review on oral effects in users of NGPs\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"TableS1SupplSchererOralHealth.docx","url":"https://assets-eu.researchsquare.com/files/rs-4206242/v1/14d23ce2eeda28766e468e55.docx"},{"id":53989435,"identity":"a364e37f-8c5d-4e7f-84f5-7a72573f5d6c","added_by":"auto","created_at":"2024-04-03 05:19:32","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":45473,"visible":true,"origin":"","legend":"\u003cp\u003eComparisons between NGP users and non-users (NU) and cigarette smokers (CC) by endpoints (EPs): Single observations and qualitative meta-analyses\u003c/p\u003e","description":"","filename":"TableS2SupplSchererOralHealth.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4206242/v1/0c3b939c2e5af780ce3d422c.xlsx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eOral health risks in users of new generation nicotine/tobacco products (NGPs): Systematic review and qualitative meta-analyses\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eNew generation nicotine/tobacco products (NGPs), such as e-cigarettes (ECs), heated tobacco products (HTPs), oral nicotine pouches (ONPs) and Swedish snus, have gained popularity as alternatives to combustible cigarettes (CCs) due to the perception of being potentially less harmful (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). In contrast to ECs, HTPs and NPs, snus has a long history of use particularly in Sweden. Its chemical and biological properties, as compared to other oral tobacco types, allow snus justifiably to be regarded as tobacco harm reduction product (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). However, this systematic review is limited to only \u0026ldquo;new\u0026rdquo; generation products.\u003c/p\u003e\u003cp\u003e The oral cavity is the first organ affected by all tobacco and nicotine habits, especially oral products like snus and nicotine pouches, which are in contact with the oral mucosa for up to several hours per day. However, also the use of inhalable products such as CCs, ECs and HTPs implies a direct contact of the released aerosols with the oral epithelial cells for a considerable time span.\u003c/p\u003e\u003cp\u003eThe use of conventional tobacco products including CCs and various forms of oral tobacco is an established risk factor for oral cancer (\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) as well as a number of non-malignant disorders such as leukoplakia (\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), gingivitis (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), periodontitis (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), salivary gland function (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) and teeth damage (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e), delayed wound healing (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e), bad breath (halitosis) (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e), and dental staining (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). NGPs deliver similar or somewhat reduced amounts of nicotine (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), but significantly lower amounts of toxicants (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Use of NGPs was shown to be implicated with substantial reductions in the exposure to all classes of toxicants including aldehydes, epoxides, tobacco-specific nitrosamines (TSNAs), polycyclic aromatic hydrocarbons (PAHs), aromatic amines compared to smokers of CCs by measuring suitable biomarkers of exposure (\u003cspan additionalcitationids=\"CR22 CR23\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) (for review, see: (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan additionalcitationids=\"CR26 CR27\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e)).\u003c/p\u003e\u003cp\u003eApart from the considerable reduction (80\u0026ndash;95%) in the exposure to tobacco combustion chemicals, use of NGPs involves the daily exposure to nicotine, matrix components and flavor compounds in larger amounts and some toxicants more likely in trance amounts (microgram to nanogram range (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e)). A systematic biomarker of exposure (BOE) study under controlled conditions with users of CCs, ECs, HTPs, oral tobacco (OT) and nicotine gum in comparison to non-users (NU) revealed that OT users (various products, not only snus) showed elevations in the exposure to TSNAs lower or close to that in CC smokers (\u003cspan additionalcitationids=\"CR22 CR23\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). There was some weak evidence that HTP users\u0026rsquo; exposure to acrolein, acrylamide, acrylonitrile, o-toluidine and TSNA was slightly (but not significantly) higher than that of NU and the other non-CC groups, but much lower than that of smokers (CC). Analytical data of product releases suggest that vapers (EC) and HTP users might experience slightly elevated exposures to formaldehyde and acetaldehyde. However, there is no BOE-based support for this, due to lack of suitable BOEs. Vapers are exposed to 1,2-propylene and glycerol in the upper mg range per day (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThese considerations on the exposure of NGP user to toxic chemicals suggest that the exposure is low to negligible with the exception of nicotine, 1,2-propylene glycol and glycerol as well as some flavors. However, the frequent and long-lasting contact of the oral mucosa with low amounts of toxicants and presumably toxicological inert chemicals might have detrimental effects, including physical irritation, allergic reaction, drying or dehydration, disruption of the oral microbiome, local pH changes, and others (\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAs a consequence, despite of distinct reduction of exposure to a bulk of toxicants in users of NGPs compared to conventional tobacco products, it is important to investigate possible detrimental effects in the oral cavity in long-term users of the new, allegedly risk reduced tobacco/nicotine products. In a recent review of our group (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e), the present knowledge of the overall health risks (including cancer, cardiovascular and respiratory diseases, oral cavity disorders, general oxidative stress and inflammation, reproduction, metabolic syndrome, and several others) and the particular role of nicotine in these disorders was summarized. The purpose of this review is to elucidate in more detail the reported effects of NGP use (ECs, HTPs and ONPs) on the oral mucosa in comparison to non-users (NU) and cigarette smokers (CC). The biological endpoints of interest can be assigned to the following categories:\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eOral cancer and precancerous lesions, including DNA adducts in oral mucosa cells\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePeriodontitis and gingivitis as well as inflammation markers and other biomarkers of effect in oral mucosa cells\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eChanges in clinical markers of oral cavity, gum and tooth distortions\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eShifts in the oral microbiome\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThese endpoints would be primarily of interest in mid- to long-term users of NGPs in comparison to non-users (NU) and/or users of conventional tobacco products (for the main part combustible cigarettes, CCs). However, due to the relatively short market presence of the NGPs of interest (\u0026lt;\u0026thinsp;20 years), there are as yet no long-term studies available which would allow to investigate outcomes such as cancer. Furthermore, the expectable heterogeneity of the available studies in terms of type, subjects, products and endpoints investigated would render the conduct of a classical (quantitative) meta-analysis impossible. We, therefore, decided to aggregate various biological or clinical endpoints to the four categories of detrimental effects mentioned above followed by qualitative (or at best semi-quantitative) meta-analysis. We are aware of the fact that this approach is disputable, however, we believe that it is defensible for a number or reasons discussed in detail.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"2. Methods","content":"\u003cp\u003eThis systematic review was conducted according to the guidelines of PRISMA (Preferred reporting items for systemic reviews and meta-analyses) (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Libraries, search strategy, inclusion and exclusion criteria\u003c/h2\u003e \u003cp\u003eThe online literature databases PubMed, LIVIVO and Cochrane Library were searched for the major topics NGPs of interest (ECs, HTPs, ONPs) and oral health disorders with simultaneous application of filters for human studies and the languages English or German. The number of hits were in total 259, with 121, 118 and 20 obtained from PubMed, LIVIVO and Cochrane Library, respectively. After removing 78 duplicates, 181 articles remained, of which the titles and abstracts were screened for meeting the inclusion and exclusion criteria. Inclusion criteria comprised human studies with users of the NGPs ECs, HTPs and ONPs. Observed effects or outcomes need to be compared to NU (negative controls) and/or smokers (CC, positive controls). Study endpoints must be any oral health effects, including cancer, pre-cancerious lesions (including cytogenetic effects and DNA adducts), inflammatory processes (including changes in pro- or anti-inflammation BMs in oral tissues, GCF, saliva or other oral fluids), dental issues, any changes in clininal oral health parameters such as BOP, CAL, PD, PI, PS, MBL, PIBL. Exclusion criteria comprised animal, \u003cem\u003ein vitro\u003c/em\u003e and clinical case studies, reviews, commentaries and letters as well as studies in the planning phase. Application of these inclusion and exclusion criteria resulted in 49 articles for evalution in this review. Cross referencing from recent reviews and meta-analyses on NGPs and oral health revealed additonal 4 studies suitable for this systemic review so that a total of 52 studies were included in the final evaluation, 14 of the LS and 38 of the CSS type (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Information extracted from the included studies\u003c/h2\u003e \u003cp\u003eThe information of the included studies was extracted according to a standardized procedure and presented in Table S1 (Supplemental files). The NGP(s) investigated (ECs, HTPs, ONPs) together with negative (-) controls (NU or non-smokers) and positive (+) controls (usually cigarette smokers, CC) are shown in column 2 of Table S1. Study type, study groups with group sizes as well as mean age and gender of the subjects is provided in column 3. The history of tobacco/nicotine (T/N) product use of the investigated study groups is summarized in column 4. The extracted information T/N history comprises how the product use was assessed (self-reports, questionnaires) and whether or not the exclusive NGP use was verified (e.g. with suitable BOEs). Endpoints and outcomes (if possible in quantitative terms) together with statistical significances for the differerences between groups are shown in column 5. The studies were assigned to four major outcome groups: (i) pre-cancerous lesions in oral cells, fluids and tissues, including cytogenetic changes (e.g. micronuclei), DNA adducts and oxidative stress markers; (ii) inflammatory processes and changes in related BOBEs; (iii) changes in clinical parameters of the oral cavity including including teeth; (iv) shifts in the oral microbiome in various oral fluids. In the last column of Table S1, comments are provided, mainly on the strengths and weaknesses of the study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Synthesis of the reported results from various studies (qualitative meta-analysis)\u003c/h2\u003e \u003cp\u003eFor synthesis of the extracted results from the included studies (Table S1), the reported findings were transformed to \u0026lsquo;qualitative\u0026rsquo; measures, in order to perform a \u0026lsquo;qualitative meta-analysis\u0026rsquo;. The rationale for this approach is the fact that a large number of endpoints (N\u0026thinsp;=\u0026thinsp;68) have to be evaluated, with 15, 24, 26 and 3 different endpoints for the categories pre-cancerous lesions (i), inflammatory processes (ii), clinical parameters for oral disturbances (iii) and shifts in the microbiome (iv), respectively. Furthermore, the data extracted from the included studies entail a high degree of heterogeneity in terms of study types and group sizes, subjects (gender, age), product properties, clinical and analytical methodologies applied and clinical/biological endpoints measured, which precludes the application of classical, quantitative meta-analyses (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). Of major interest in this systematic review were significant differences in endpoints or categories of endpoints between groups, namely NGP users \u003cem\u003eversus\u003c/em\u003e NU and NGP users \u003cem\u003eversus\u003c/em\u003e cigarette smokers (CC). Outcomes of cross-sectional studies (CSS) as well as baseline (BL) results of longitudinal studies (LS) were represented as statistical significant (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 or better) increase (risk score: +1), significant decrease (-1) or no (significant) difference (0). The risk scores\u0026thinsp;+\u0026thinsp;1 or -1 for the various endpoints were assigned to the effect that they represent a worsening (+\u0026thinsp;1) or an improvement (-1) of oral health in the NGP group. Outcomes for single endpoints as well as the groupwise (i \u0026ndash; iv) synthesis (\u0026lsquo;qualitative\u0026rsquo; meta-analyse) are shown in Table S2. Risk scores for endpoint groups (i \u0026ndash; iv) are were calculated as means with 95% confidence intervals (CI). If 10 or more observations for single endpoints were available, means and 95% CIs were also calculated for these. This was the case for the endpoints TNF-\u0026prop;, IL-1\u0026szlig;, IL-6, PI, BOP, PD and MBL (Table S2). BL results of LS were treated as CSS. Differences over time (BL versus follow-up (FU)) were originally planed to be evaluated as changes within (\u003cem\u003eintra\u003c/em\u003e) or between groups (\u003cem\u003einter\u003c/em\u003e). However, reported results of LS were too heterogeneous so that evaluation across studies was not meaningful.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003e3.1 General study characteristics\u003c/h2\u003e\n \u003cp\u003eFor this systematic review on detrimental oral health effects in NGP users compared to NU and cigarette smokers (CC), 52 human studies, 38 cross-sectional (CSS) and 14 longitudinal studies (LS) fulfilled the inclusion criteria as described in Chap.\u0026nbsp;2.1. The information extracted from these studies is shown in Table S1. Study sizes were highly variable and comprised between 30 and 1\u0026nbsp;million subjects with most studies encompassing 60\u0026ndash;120 subjects. Subjects in general were healthy adults, but some studies included patients with oral health problems such as periodontitis, caries or other issues. Subjects\u0026rsquo; ages covered a range of 20\u0026ndash;80 years with a focus on young to middle ages (25\u0026ndash;50 years). Most studies comprise both sexes, while a few included only males.\u003c/p\u003e\n \u003cp\u003eIt was planned to include ECs, HTPs and ONPs as NGPs. However, in the selected 52 studies almost only the effects of EC use was investigated. In 2 studies (\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e) ONPs and in one study (\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e) HTPs together with other NGPs were investigated. In the qualitative meta-analyses only EC studies were included. A differentiation between EC types, generations, nicotine content, and added flavors was not considered in the analysis, primarily to avoid too small group sizes.\u003c/p\u003e\n \u003cp\u003eHistory of tobacco/nicotine products habits is of particular impotance for the oral health risks associated with NGP use. Most studies rely on self-reports assessed with questionnaires (Table S1). In 11 studies (\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e49\u003c/span\u003e), cotinine or other nicotine metabolites have been determined in body fluids (blood, saliva, urine), which allows the distinction between users of any tobacco/nicotine product (including NGPs) and NU as well as the extend of product use. However, it does not distinguish between NGP and CC use. This is possible, at least in terms of short-term use with the biomarkers COHb and COex, which had been applied in 10 studies (\u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e46\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e50\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e53\u003c/span\u003e). A longer period of CC use versus NGP use is assessable by NNAL in urine and was reported in one study (\u003cspan class=\"CitationRef\"\u003e50\u003c/span\u003e). Urinary CEMA, a BOE to the combustion product acrylonitile and, therefore, a very suitable biomarker for assessing CC use alongside with NGP use, was determined in three studies (\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e50\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eDuration of NGP use was reported in only part of the selected studies. In 4 investigations (\u003cspan class=\"CitationRef\"\u003e54\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e57\u003c/span\u003e), NGP (mostly EC) use of at least 1 year was required for study participation. In another 5 studies (\u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e58\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e60\u003c/span\u003e), mean NGP use durations between 2 and 3 year were reported. The longest average NGP use duration in the selected studies amounted to 6.4 (\u003cspan class=\"CitationRef\"\u003e61\u003c/span\u003e), 9.2 (\u003cspan class=\"CitationRef\"\u003e62\u003c/span\u003e), 12.2 (\u003cspan class=\"CitationRef\"\u003e63\u003c/span\u003e) and 12.5 years (\u003cspan class=\"CitationRef\"\u003e64\u003c/span\u003e). One study (\u003cspan class=\"CitationRef\"\u003e51\u003c/span\u003e) provided a mean use time for ECs of 21.6 years, which probably is an error, given the fact that ECs are on the market since about 2006 and the mean age of EC users in that study is reported to be 41.5 years.\u003c/p\u003e\n \u003cp\u003eDual use (mostly EC together with CC) is heterogeneously wielded in the selected studies. In 8 studies (\u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e65\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e70\u003c/span\u003e), self-reported dual users were assigned to a separate group or conciously included in a special NGP group. In 12 studies (\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e57\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e59\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e64\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e71\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e76\u003c/span\u003e), it is stated that dual users were excluded. The remaining studies did not mention or consider the issue of dual or multi-product use although it is likely that it occurs in the respective investigations. Our evaluation is based on exclusive NGP users, as far as this is possible with the study information provided. Dual use can play an important role as bias and confounding factor in the estimated oral health risks of NGP use (discussed later).\u003c/p\u003e\n \u003cp\u003eThe evaluation of oral health risks in NGP users comprised 65 different endpoints (Table S2), which were assigned to 4 groups:\u003c/p\u003e\n \u003col style=\"list-style-type: lower-roman;\"\u003e\n \u003cli\u003e\u003cspan\u003ePre-cancereous lesions in oral mucosa including markers known to be involved in genotoxic events\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eInflammatory processes including BOBEs for inflammation in various oral fluids\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eClinical parameters for detrimental effects in the oral cavity and related to teeth\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eShifts in the oral microbiome.\u003cbr\u003e\u003c/span\u003e\u003c/li\u003e\n \u003c/ol\u003e\n \u003cp\u003eIn total, 199 single observations were extracted and evaluated from the 52 selected studies as outlined in the \u003cspan class=\"InternalRef\"\u003eMethods\u003c/span\u003e section (Table S2).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003e3.2 Pre-cancerous endpoints\u003c/h2\u003e\n \u003cp\u003eIn total, 12 different endpoints could be extracted from 12 studies (\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e47\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e54\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e57\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e63\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e75\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e77\u003c/span\u003e)with 16 single observations (Table S2). Only the endpoints \u0026lsquo;micronulei\u0026rsquo; (\u003cspan class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e75\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e77\u003c/span\u003e) and \u0026lsquo;NNN in saliva\u0026rsquo; (\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e63\u003c/span\u003e) were investigated in more than one study. All other endpoints were determined in only one investigation. There were 14 EC versus NU and 15 EC versus CC comparisons included in the qualitative meta-analysis, which yielded mean scores for vapers of 0.29 (95% CI: -0.09\u0026ndash;0.67) and \u0026minus;\u0026thinsp;0.33 (-0.58 - -0.09), respectively. The results of the meta-analysis are graphically depicted in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. In one investigation (\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e), the endpoint \u0026lsquo;NNN in saliva\u0026rsquo; HTP users was compared to NU and to smokers (CC), resulting in scores of 1 and 0, respectively.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003e3.3 Inflammatory processes\u003c/h2\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eThis group comprised 21 different endpoints derived from 19 studies (\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e55\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e58\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e64\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e67\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e68\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e70\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e72\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e78\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e80\u003c/span\u003e) with 83 single observations (Table S2). The most frequently determined endpoints were IL-1\u0026szlig; (12 observations), IL-6 (10 observations) and TNF-\u0026prop; (10 observations). A qualitative meta-analysis for markers with at least 10 observations including then inflammation biomarkers TNF-\u0026prop;, IL-6 and IL-1\u0026szlig;, is provided in Chap. 3.7. There were 76 EC user \u003cem\u003eversus\u003c/em\u003e NU comparisons resulting in a synthesized mean score for inflammatory processes of 0.28 (95% CI: 0.15\u0026ndash;0.41) and 69 EC \u003cem\u003eversus\u003c/em\u003e CC user comparisons with a mean score of -0.16 (95%-CI: -0.28 - -0.04) (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Note that due to their anti-inflammatory properties, the marker IL-8, IL-9, IL-10, IL-13 and IL-RA were inversed (i.e., the algebraic score signs +/- were inverted).\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003e3.4 Clinical parameters for oral disorders\u003c/h2\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eThis group comprised 25 different endpoints derived from 20 studies (\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e54\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e55\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e57\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e62\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e64\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e66\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e69\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e71\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e74\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e76\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e78\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e79\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e81\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e86\u003c/span\u003e) with 97 single observations (Table S2). The most frequently determined endpoints were PD (15 observations), PI or PS (14 observations), BOP (13 observations) and MBL (11 observations). A qualitative meta-analysis for markers with at least 10 observations, including the clinical biomarkers MBL, BOP, PI of PS, and PD, is provided in Chap. 3.7. There were 93 EC user \u003cem\u003eversus\u003c/em\u003e NU comparisons resulting in a synthesized mean score for clinical parameters of oral distortions of 0.43 (95% CI: 0.32\u0026ndash;0.54) and 78 EC \u003cem\u003eversus\u003c/em\u003e CC user comparisons with a mean score of -0.27 (95% CI: -0.38 - -0.16) (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Note that score inversions were performed for IgA, lysozyme, lactoferrin and BOP.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003e3.5 Shifts in the oral microbiome\u003c/h2\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eThis group comprised 4 different endpoints derived from 7 studies with 10 single observations (Table S2). Endpoints were hardly comparable between different studies. In the qualitative meta-analysis for shifts in the oral microbiome, no differentiation between improvement (-1) or worsening (+\u0026thinsp;1) were made. Rather, all significant shifts between groups were assigned with a score of +\u0026thinsp;1. There were 10 EC user \u003cem\u003eversus\u003c/em\u003e NU comparisons resulting in a synthesized mean score for shifts in the oral microbiome of 0.70 (95% CI: 0.40\u0026ndash;1.00) and 7 EC \u003cem\u003eversus\u003c/em\u003e CC user comparisons with a mean score of 0.57 (95% CI: 0.53\u0026ndash;0.97) (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003e3.6 All oral endpoints\u003c/h2\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eIn total, 65 different oral endpoints from 52 studies with 199 single observations (Table S2). There were 200 EC user \u003cem\u003eversus\u003c/em\u003e NU comparisons resulting in a synthesized mean score for oral distortions of 0.37 (95% CI: 0.29\u0026ndash;0.44) and 176 EC \u003cem\u003eversus\u003c/em\u003e CC user comparisons with a mean score of -0.19 (95% CI: -0.26 \u0026ndash; -0.11) (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003e3.7 Qualitative meta-analysis for the most frequently applied single endpoints\u003c/h2\u003e\n \u003cp\u003eFor single endpoints applied in 10 or more different studies qualitative meta-analyses were conducted. This was the case for 7 out of 65 endpoints, namely IL-1\u0026szlig;, IL-6, TNF-\u0026prop;, PI or PS, BOP, PD and MBL Results of this analysis are shown in Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eIt is obvious that CI ranges in general were larger than in Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, which primarily is caused by the lower number of observations for the single EPs. It is interesting to note that BOP (for which the score was inverted) showed the highest mean score of all EC vs NU comparisons (0.77) and the lowest of all EC vs CC comparisons (-0.09), indicating that BOP in EC users is most likely different from NU and not different from CC. The reason for this finding is discussed later.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003e3.8 Outcomes of longitudinal studies (LS)\u003c/h2\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eThe selected studies on oral health effects in NGP users comprise 14 LS (\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e54\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e56\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e58\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e80\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e81\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e83\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e87\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e88\u003c/span\u003e) (Table S1). Baseline (BL) data from these LS are treated as CSS and included in the results presented in Sections \u003cspan class=\"InternalRef\"\u003e3.2\u003c/span\u003e to \u003cspan class=\"InternalRef\"\u003e3.7\u003c/span\u003e. Longitudinal data, which would allow the analysis of changes over time (in LS usually at BL and one or more follow-up (FU) time points are analysed). LS results are regarded as superior to those obtained from CSS (for a number of reasons, discussed below), provided that the covered time periods (BL to FU) are sufficiently long (\u003cspan class=\"CitationRef\"\u003e89\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e90\u003c/span\u003e). For obvious reasons this is not the case in the LS selectable for this review. The time periods in this selection cover a range of from 3 days to about 2 years, with the highest frequency for FUs of 6 months. In general, LS were smaller in group size and more heterogeneous than CSS, thus preventing a synthesized analysis (meta-analysis) across studies. Therefore, in the following, changes over time of oral effects reported in single LS were briefly presented.\u003c/p\u003e\n \u003cp\u003eIn an LS with FUs at 2, 4 and 6 weeks, a normalization of reversible histological changes were observed in 60 snus users after replacing snus with ONPs already at the first FU visit (\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e). Unfortunately, no negative control group (using no nicotine/tobacco product during the FU period) or positive control group (continue using snus) was included.\u003c/p\u003e\n \u003cp\u003eIn an LS with 30 EC and 30 CC users, no differences in the oral clinical parameters CAL, PD, MBL and PS were found at BL, while after 6 months FU, PD, CAL and MBL became worse in the CC compared to the EC group (\u003cspan class=\"CitationRef\"\u003e54\u003c/span\u003e). Both user groups showed significant correlations between the long-term dose and the endpoints MMP-8, CTX, PD, and CAL. This LS did not contain a negative control (NU).\u003c/p\u003e\n \u003cp\u003eIn subjects with moderate chronic periodontitis under SRP treatment (36 vapers and 35 NS), PI, PD, MBL, CAL, IL-4, IL-9, IL-10, and IL-13 (the latter 4 in GCF) were reported not to be significantly different at BL (\u003cspan class=\"CitationRef\"\u003e56\u003c/span\u003e). In the EC group at 3 months FU, the endpoints PI, GI, PD, CAL, and MBL were found not to be different from BL, while PI, GI and PD were significantly reduced in the NS group. For the anti-inflammation markers IL-4, IL-9, IL-10, and IL-13 a significantly higher increase was observed in the NS compared to the EC group. Vaping apparently mitigated the SRP treatment effect. Regrettably, no positive controls (smokers of CC) were included in this LS.\u003c/p\u003e\n \u003cp\u003eIn another LS with 89 male FMUS patients (30 CC, 28 EC, 31 NS) after 3 as well as 6 months FU, improvements in PI, CAL and PD were observed in all three group. However they were best in NS followed by EC and worst in CC (\u003cspan class=\"CitationRef\"\u003e58\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eIn an intervention study with 80 smokers suffering from periodontitis, 40 switched to EC and 40 stopped smoking (\u003cspan class=\"CitationRef\"\u003e88\u003c/span\u003e). At 6 months FU, PD improved to a similar extent in both groups. Oral dryness, however, did not change in vapers, while it decreased in NU.\u003c/p\u003e\n \u003cp\u003eTatullo et al. (\u003cspan class=\"CitationRef\"\u003e53\u003c/span\u003e) investigated the clinical parameter PI and PBI in 60 vapers with \u0026le;\u0026thinsp;10 years of previous smoking (CC) compared to 50 vapers with \u0026gt;\u0026thinsp;10 years previous smoking. Measurements at BL, 60 and 120 days FUs revealed improvements over time in both groups. However, in the group with the longer period of former CC use, the oral clinical parameters were less advantageous than in the comparator group.\u003c/p\u003e\n \u003cp\u003eA cohort study over 6 months with 27 cigarette smokers (CC), 28 vapers (EC) and 29 NU revealed that the \u0026prop;-diversity (a measure of microbiome diversity applicable to a single sample) increased across the cohorts longitudinally, yet each cohort maintained a unique microbiome (\u003cspan class=\"CitationRef\"\u003e46\u003c/span\u003e). The authors concluded that EC use promotes a unique periodontal microbiome (as a stable state between CC users and NU), presenting an oral health challenge.\u003c/p\u003e\n \u003cp\u003eIn a similar study design, Xu et al. (\u003cspan class=\"CitationRef\"\u003e80\u003c/span\u003e) investigated the salivary microbial composition in 101patients with periodontitis (31 CC, 32 EC, 38 NU). From their results the authors concluded that vaping, similar to smoking, alters the bacterial composition with an increase of disease-associated pathogens.\u003c/p\u003e\n \u003cp\u003eSimilar observations were reported by Chopyk et al.(\u003cspan class=\"CitationRef\"\u003e87\u003c/span\u003e). Furthermore, it was reported that reducing the EC use over 2 weeks led to a decrease of pathological changes in the salivary but not the buccal microbiome.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e4.1 General considerations\u003c/h2\u003e \u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eFor this systematic review on oral health effects of NGP (scheduled to comprise ECs, HTPs and ONPs), 52 human studies (38 or cross-sectional and 14 of longitudinal type) were selected and subjected to a series of qualitative meta-analyses. It turned out that in only 3 studies, NGPs other than ECs were investigated so that the meta-analyses only dealt with the use of ECs (vaping) and refer to comparisons of EC users \u003cem\u003evs\u003c/em\u003e NU and EC users \u003cem\u003evs\u003c/em\u003e CC users. Classical (quantitative) meta-analysis for disease endpoints, for example oral cancer, are presently not possible for a number of reasons. A foremost reason is the fact that duration of NGP use is not sufficiently long to induce chronic diseases (cancer would require more than 2 decades). ECs, also known as ENDS (electronic nicotine delivery systems), in its modern form have been invented in 2003 by the Chinese pharmacist Hon Lik and were first introduced to the market in about 2007 (\u003cspan citationid=\"CR91\" class=\"CitationRef\"\u003e91\u003c/span\u003e). HTPs (with electric heating systems) have been marketed in the end of the 1990ies. ONPs are the most recent products of the NGPs dealt with in this review. The big tobacco companies started marketing the products as tobacco-free ONPs in 2019 (\u003cspan citationid=\"CR92\" class=\"CitationRef\"\u003e92\u003c/span\u003e). ECs, which are in the focus of this review, were subject to rapid product changes so that since its general marketing at least four generations were passed through (\u003cspan citationid=\"CR93\" class=\"CitationRef\"\u003e93\u003c/span\u003e, \u003cspan citationid=\"CR94\" class=\"CitationRef\"\u003e94\u003c/span\u003e). This factor significantly contributes to the heterogeneity of the study data to be evaluated. Other factors include study type, group sizes, gender, age as well as endpoints investigated and methods for their determination. Under these premises, we decided to perform qualitative meta-analyses for single endpoints with at least 10 observations in different studies or groups of endpoints belonging to four different types of oral disorders, namely (i) pre-cancerous lesions including oxidative stress markers, (ii) inflammatory processes, (iii) general clinical parameters used for oral (including dental) disorders, and (iv) shifts in the oral microbiome. Assignment to these endpoint categories might appear somewhat arbitrary, however, there is multiple evidence that many, if not all, oral endpoints considered in the this review are mechanistically connected in the development of various oral disease (\u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e, \u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e, \u003cspan additionalcitationids=\"CR96 CR97\" citationid=\"CR95\" class=\"CitationRef\"\u003e95\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR98\" class=\"CitationRef\"\u003e98\u003c/span\u003e). We, therefore, believe that our approach of combining different endpoints to groups of disorders or even a total score for detrimental effects in the oral cavity is physiologically justified for the purpose of qualitative meta-analyses. The procedure for this analysis is described in detail in Section \u003cspan refid=\"Sec5\" class=\"InternalRef\"\u003e2.3\u003c/span\u003e. In essence, the study findings with respect to the EC \u003cem\u003eversus\u003c/em\u003e NU and the EC \u003cem\u003eversus\u003c/em\u003e CC comparisons for each endpoint were categorized to three \u0026lsquo;scores\u0026rsquo;, namely \u0026lsquo;+1\u0026rsquo; (=\u0026thinsp;significant increase (in the sense of a worsening of an oral health condition), \u0026lsquo;-1\u0026rsquo; (=\u0026thinsp;significant decrease (in the sense of an improvement of an oral health condition) and \u0026lsquo;0\u0026rsquo; (=\u0026thinsp;no significant difference between groups). It has to be noted that for some endpoints an increase can imply improvement of the health condition. This was considered accordingly in the meta-analysis (Table S2). Furthermore, it has to be emphasized that the calculated means and 95% confidence intervals (CI) represent probabilities for finding a worsening (positive score values) or an improvement (negative score values) for vapers (EC) compared to either NU or smokers (CC).\u003c/p\u003e\u003cp\u003eFrom Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, it is immediately evident that using ECs is associated with more unfavorable oral health endpoints compared to NU. Whereas vapers were generally reported to do better in terms of oral health compared to smokers (CC). This is in general agreement with all reviews on this topic published in the last 5 years (\u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e, \u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e, \u003cspan additionalcitationids=\"CR95 CR96 CR97 CR98 CR99 CR100 CR101 CR102 CR103 CR104 CR105 CR106 CR107 CR108 CR109 CR110 CR111 CR112 CR113 CR114 CR115\" citationid=\"CR94\" class=\"CitationRef\"\u003e94\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR116\" class=\"CitationRef\"\u003e116\u003c/span\u003e). However, score means in Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e are most frequently between 0 and +\u0026thinsp;0.5 (EC \u003cem\u003evs\u003c/em\u003e NU comparisons) or between \u0026minus;\u0026thinsp;0.5 and 0 (EC \u003cem\u003evs\u003c/em\u003e CC comparisons), indicating that the outcomes of the evaluated studies are not very consistent. The higher mean scores (\u0026thinsp;\u0026gt;\u0026thinsp;+\u0026thinsp;0.5) calculated for the oral microbiome (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and BOP (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) are discussed below.\u003c/p\u003e\u003cp\u003eIn general, smaller numbers of observations were available for the evaluation of the 7 single endpoints (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), leading to larger CI ranges. Of the 14 comparisons, 5 CIs overlap with the zero axis, suggesting considerable inconsistencies in the outcomes for these endpoints.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e4.2 Oral cancer\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eAs yet, no epidemiological studies on the oral cancer risk of chronic NGP use are available. As a surrogate, the association between NGP use (usually of moderate duration only) and various pre-cancerous lesions mechanistically related to oral cancer is evaluated in our review (Chap.\u0026nbsp;3.1) as well as in a number of previously published reviews (\u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e, \u003cspan citationid=\"CR95\" class=\"CitationRef\"\u003e95\u003c/span\u003e, \u003cspan citationid=\"CR96\" class=\"CitationRef\"\u003e96\u003c/span\u003e, \u003cspan citationid=\"CR107\" class=\"CitationRef\"\u003e107\u003c/span\u003e, \u003cspan citationid=\"CR114\" class=\"CitationRef\"\u003e114\u003c/span\u003e, \u003cspan citationid=\"CR115\" class=\"CitationRef\"\u003e115\u003c/span\u003e). All evaluations (including our own) came to the conclusion that the available evidence suggests that EC use may have the potential to increase the oral cancer risk by working through one or several possible mechanisms which might include formation DNA adducts by exposure to potentially genotoxic chemicals in EC aerosol (e.g. acrolein, NNN, others), DNA damage (e.g. indicated by the increased formation of MN), oxidative stress, suppression of the immune system, and shifts in the oral microbiome. There is also general agreement in the literature that conclusive answers with regard to the role of chronic vaping in oral cancer induction would require about another decade. The evaluation of an involvement of the habitual use of the other two NGPs of interest (HTPs, ONPs) in oral cancer generation is not possible, due to the lack of suitable data.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e4.3 Oral inflammations\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eA large number (N\u0026thinsp;=\u0026thinsp;24) of different endpoints on inflammatory processes were available from 20 human studies, allowing 83 EC \u003cem\u003eversus\u003c/em\u003e NU and 76 EC \u003cem\u003eversus\u003c/em\u003e CC comparisons (Chap.\u0026nbsp;3.2, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In addition, qualitative meta-analyses were also conducted for the single inflammation biomarkers IL-\u0026szlig;, IL-6 and TNF-\u0026prop; (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Although the results are partly inconsistent, the majority of studies reported elevated inflammation in EC users compared to NU and decreased occurrence of inflammation in EC compared to CC users. This is in general agreement with other surveys of the literature (\u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e, \u003cspan citationid=\"CR103\" class=\"CitationRef\"\u003e103\u003c/span\u003e, \u003cspan citationid=\"CR104\" class=\"CitationRef\"\u003e104\u003c/span\u003e, \u003cspan additionalcitationids=\"CR110\" citationid=\"CR109\" class=\"CitationRef\"\u003e109\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR111\" class=\"CitationRef\"\u003e111\u003c/span\u003e). There is no established knowledge about the mechanism how and the possibly involved chemicals by which vaping can induce inflammatory processes in the oral cavity. Assumption include the involvement of nicotine (\u003cspan citationid=\"CR103\" class=\"CitationRef\"\u003e103\u003c/span\u003e), metals (\u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e) or shifts in the oral microbiome caused by dry mouth and reduced salivary flow (\u003cspan citationid=\"CR104\" class=\"CitationRef\"\u003e104\u003c/span\u003e) or increased growth of \u003cem\u003eCandida albicans\u003c/em\u003e (\u003cspan citationid=\"CR97\" class=\"CitationRef\"\u003e97\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eNo studies on inflammation effects of HTP or ONP use were identified for this review.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e4.4 General clinical endpoints for oral disorders\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe general clinical parameters for oral disorders comprised 25 different endpoints extracted from 20 human studies, allowing 93 EC \u003cem\u003eversus\u003c/em\u003e NU and 78 EC \u003cem\u003eversus\u003c/em\u003e CC comparisons (Chap.\u0026nbsp;3.2, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In addition to the group evaluation, qualitative meta-analyses for the single endpoints PD, PI or PS, BOP and MBL were also conducted (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The majority of studies showed significantly increase in clinical disorders in EC compared to NU and a decrease in clinical disorders in EC compared to CC users. This ranking of clinical disorders (NU\u0026thinsp;\u0026lt;\u0026thinsp;EC\u0026thinsp;\u0026lt;\u0026thinsp;CC) was also reported in other recent reviews on detrimental oral effects of vaping (\u003cspan citationid=\"CR97\" class=\"CitationRef\"\u003e97\u003c/span\u003e, \u003cspan citationid=\"CR109\" class=\"CitationRef\"\u003e109\u003c/span\u003e, \u003cspan citationid=\"CR111\" class=\"CitationRef\"\u003e111\u003c/span\u003e, \u003cspan citationid=\"CR115\" class=\"CitationRef\"\u003e115\u003c/span\u003e). With one exception (BOP), the responsible chemicals in EC aerosol and the mechanisms for the reported clinical effects are not established. As possible candidates were discussed nicotine (\u003cspan citationid=\"CR109\" class=\"CitationRef\"\u003e109\u003c/span\u003e, \u003cspan citationid=\"CR111\" class=\"CitationRef\"\u003e111\u003c/span\u003e), metals (\u003cspan citationid=\"CR109\" class=\"CitationRef\"\u003e109\u003c/span\u003e, \u003cspan citationid=\"CR111\" class=\"CitationRef\"\u003e111\u003c/span\u003e), flavor components (\u003cspan citationid=\"CR97\" class=\"CitationRef\"\u003e97\u003c/span\u003e, \u003cspan citationid=\"CR109\" class=\"CitationRef\"\u003e109\u003c/span\u003e, \u003cspan citationid=\"CR111\" class=\"CitationRef\"\u003e111\u003c/span\u003e), sucrose and sugar substitutes (\u003cspan citationid=\"CR97\" class=\"CitationRef\"\u003e97\u003c/span\u003e), acids (\u003cspan citationid=\"CR97\" class=\"CitationRef\"\u003e97\u003c/span\u003e). BOP is found to be reduced in vapors compared to NU and very similar to that observed in smokers (CC) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). This consistent finding can be explained by a nicotine-caused vasoconstriction in gum tissue (for review see (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). A similar effect on BOP has to be expected in users of HTP and ONP. However, no investigations on BOP and any other clinical parameter on detrimental oral effects was available for this review.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003e4.5 Oral microbiome\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eFor the purpose of this review, 4 endpoints on the oral microbiome were selected from 7 studies. This data set allowed 10 EC \u003cem\u003eversus\u003c/em\u003e NU and 7 EC v\u003cem\u003eersus\u003c/em\u003e CC comparisons. In contrast to the evaluation of the other endpoints or groups of endpoints, meta-analysis was modified in that differences (shifts) between groups in the oral microbiome were not divided into significant worsening (+\u0026thinsp;1) or improvement (-1), rather, any significant shift was assigned the score value of +\u0026thinsp;1. The reason for this approach was that the impact of a shift in terms of increasing or decreasing an oral health risk cannot yet predicted with sufficient certainty. It is, therefore, assumed that significant changes in the oral microbiome represents an oral health risk. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows that in most studies vaping was found to lead to a shift in the composition of the oral microbiome, both compared to NU and smokers (CC). This is in agreement with most of the results of other recent reviews (\u003cspan citationid=\"CR94\" class=\"CitationRef\"\u003e94\u003c/span\u003e, \u003cspan citationid=\"CR101\" class=\"CitationRef\"\u003e101\u003c/span\u003e, \u003cspan additionalcitationids=\"CR104\" citationid=\"CR103\" class=\"CitationRef\"\u003e103\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR105\" class=\"CitationRef\"\u003e105\u003c/span\u003e, \u003cspan citationid=\"CR108\" class=\"CitationRef\"\u003e108\u003c/span\u003e, \u003cspan citationid=\"CR110\" class=\"CitationRef\"\u003e110\u003c/span\u003e, \u003cspan citationid=\"CR115\" class=\"CitationRef\"\u003e115\u003c/span\u003e). The mechanism by which vaping can change the oral microbiome is not yet well established. An interesting hypothesis assumes that use of ECs can lead to dry mouth (xerostomia) by action or PG and VG (which are hygroscopic) together with an increase in biofilm volume and a reduced salivary flow (\u003cspan citationid=\"CR104\" class=\"CitationRef\"\u003e104\u003c/span\u003e, \u003cspan citationid=\"CR105\" class=\"CitationRef\"\u003e105\u003c/span\u003e). A role of nicotine in oral microbiome change has not yet been reported (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e), which accords with another recent review, stating that nicotine may not be involved oral microbiome shifts (\u003cspan citationid=\"CR103\" class=\"CitationRef\"\u003e103\u003c/span\u003e). The oral health consequences of shifts in the oral microbiome are as yet not quite clear (\u003cspan citationid=\"CR103\" class=\"CitationRef\"\u003e103\u003c/span\u003e). Other authors speculated that a chronic change in the oral microbiome can lead to severe health disorders such as periodontitis and periodontal disease and other oral health issues (\u003cspan citationid=\"CR104\" class=\"CitationRef\"\u003e104\u003c/span\u003e, \u003cspan citationid=\"CR105\" class=\"CitationRef\"\u003e105\u003c/span\u003e, \u003cspan citationid=\"CR108\" class=\"CitationRef\"\u003e108\u003c/span\u003e, \u003cspan citationid=\"CR110\" class=\"CitationRef\"\u003e110\u003c/span\u003e), retarded wound healing (\u003cspan citationid=\"CR104\" class=\"CitationRef\"\u003e104\u003c/span\u003e) and even increased oral cancer risk (\u003cspan citationid=\"CR104\" class=\"CitationRef\"\u003e104\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003e4.6 Role of major constituents in the EC aerosol (vapor)\u003c/h2\u003e \u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eAll e-liquids and hence the EC aerosol inhaled by the vaper contain glycerol (usually vegetable-derived glycol, VG), 1,2-propylene glycol (PG), nicotine and flavor compounds, although in varying ratios and amounts. In particular the added flavors may differ largely in composition as well as quality and quantity of components from brand to brand.\u003c/p\u003e\u003cp\u003eThe e-liquid matrix usually consists of VG and PG in varying ratios. The mouth-level exposure with these compounds is in the g per day range (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). It is, therefore, not unreasonable to assume that the vaping habit may lead to changes in the oral biofilm and shifts in the composition of the microbiome, connected with xerostomia (\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e, \u003cspan additionalcitationids=\"CR105\" citationid=\"CR104\" class=\"CitationRef\"\u003e104\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR106\" class=\"CitationRef\"\u003e106\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eGuo et al. (\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e) found \u003cem\u003ein vitro\u003c/em\u003e evidence that PG can inhibit bacterial inflammation and the formation of AP sites in DNA, thus explaining their finding that EC users have significantly lower AP levels in oral cells than smokers (CC) and NU.\u003c/p\u003e\u003cp\u003eThe most common nicotine content in e-liquid ranges from 3\u0026ndash;36 mg/mL), with an upper limit set for the European Union of 20 mg/ml (Althakfi et al. 2024). The mean daily intake of nicotine by vaping was estimated to be about 10 mg/d (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). A recent review on the role of nicotine in various oral disorders and diseases did not identify nicotine to be a major risk factor for oral diseases (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). A consistent finding was that BOP is decreases in users of any nicotine products compared to NU (Table S1, (\u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e)). Our meta-analysis also confirms this nicotine-related in that EC and CC users are comparable in their BOP level, but rather different from NU (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). By a similar mechanism, nicotine can be involved in retarded wound healing processes in the mouth by inducing local ischemia (\u003cspan citationid=\"CR104\" class=\"CitationRef\"\u003e104\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eHolliday et al. (\u003cspan citationid=\"CR106\" class=\"CitationRef\"\u003e106\u003c/span\u003e) concluded that salivary nicotine concentrations in vapers (4 - \u0026micro;M) are unlikely to exert cytotoxic effects in the oral cavity. In another review (\u003cspan citationid=\"CR107\" class=\"CitationRef\"\u003e107\u003c/span\u003e), it was hypothesized that nicotine in the oral cavity can cause a number of detrimental effects, mostly mediated via the nicotinic-acetylcholin-receptor (n-AChR), supportive in the development of oral diseases including oral cancer.\u003c/p\u003e\u003cp\u003e Information on detrimental effects of flavors added to NGPs in the oral cavity are sparse. In a review on detrimental oral health effects in EC users, Irusa et al. (\u003cspan citationid=\"CR117\" class=\"CitationRef\"\u003e117\u003c/span\u003e) focused on the effects of flavors. The authors stated that with certain flavors, investigators were able to show a four-fold increase in microbial adhesion to enamel, a two-fold increase in biofilm formation, and a 27% decrease in enamel hardness. From an evaluation of the literature, Flach et al. came to the conclusion that clinical evidence urges to assume that flavoured e-liquids appear to be more harmful. Ebersole et al. (\u003cspan citationid=\"CR103\" class=\"CitationRef\"\u003e103\u003c/span\u003e) pointed out that toxic agents can be released from flavor compounds in e-liquid upon heating.\u003c/p\u003e\u003cp\u003eIn general, it has to be stated that the flavor compounds added to NGPs have GRAS (\u0026ldquo;generally recognized as safe\u0026rdquo;) status, meaning that they are safe to be used in food. An issue, however, could be the release of toxicants (mainly aldehydes) as mentioned above (\u003cspan citationid=\"CR103\" class=\"CitationRef\"\u003e103\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003e4.7 Quality of the evaluated studies: bias and confounding\u003c/h2\u003e \u003cp\u003eIt is assumed that the human studies evaluated for this review are subject to severe bias and a number of confounding factors. Table S1 contains comments and statements with respect to bias and confounding for each of the 52 evaluated studies. For quality assessment of the included studies, the Newcastle-Ottawa-Scale (NOS) for observational studies of the case-control type can, with certain restraints, be applied (\u003cspan citationid=\"CR118\" class=\"CitationRef\"\u003e118\u003c/span\u003e). The NOS defines three domains for quality assessment of case-control studies: (i) selection of cases and controls (in our review: NGP users, non-users (NU) and cigarette smokers (CC), (ii) comparability of groups, and (iii) ascertainment of exposure. A fourth domain would have to added: (iv) outcomes and endpoints, which are of particular importance in this systematic review, as multiple endpoints (actually N\u0026thinsp;=\u0026thinsp;65) were included in this analysis. In particular, endpoints applied here are less well estblished pre-staged, rather than manifested diseases. As described in Table S1 and at various passages in the text, selected studies are highly heterogeneous in many study features, including the three domains of the NOS. However, we see especially high potential of bias in the domains (i) selection of EC users and (iii) ascertainment of exposure. With a few exemptions, there are weaknesses in almost all studies in Table S1. Given the fact that most vapers are switchers from CC, possible long-term \u0026lsquo;carry-over\u0026rsquo; effects of former smoking have to be considered. For example, in a longitudinal study (LS) over 120 d it was shown that vapers who formerly used CC for \u0026gt;\u0026thinsp;10 years had a worse periodontal status than those with \u0026le;\u0026thinsp;10 years of former smoking (\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e). In many of the selected studies, the former smoking status of the EC group was not or only insufficiently assessed. Furthermore, the assessment of EC use is most frequently performed by means of (structrued or unstructured) questionnaires or interviews. In only a few studies, at least the short-term compliance of exclusive EC use was verified by suitable biomarkers such as COex or COHb, CEMA, NNAL (\u003cspan additionalcitationids=\"CR47\" citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e) (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). In none of the studies, a long-term biomarker for CC use applied, such as for example the hemoglobin adduct CEVal (2-cyanoethyl valine) (\u003cspan citationid=\"CR119\" class=\"CitationRef\"\u003e119\u003c/span\u003e). Among adult (18\u0026thinsp;+\u0026thinsp;years) EC users ) in the US in 2021 (about 11.6\u0026nbsp;million persons), almost 30% were dual users (\u003cspan citationid=\"CR120\" class=\"CitationRef\"\u003e120\u003c/span\u003e). It has to be assumed that it is quite likely that the groups of EC users in the evaluated studies of this review contain considerable numbers of un-assessed dual users, which might constitute a potential risk of bias for elevated deterimental oral health effects in the EC groups. The extent of this bias is difficult to quantify, but in all likehood part of the generally observed increase in detrimental oral health effects might be attributable to some smoking (CC) in the EC groups.\u003c/p\u003e \u003cp\u003eA well known confounding factor in oral health effects is a lack in dental hygiene. Smokers, on average, were found to practice lower oral hygiene than non-smokers (\u003cspan citationid=\"CR121\" class=\"CitationRef\"\u003e121\u003c/span\u003e). It is not yet known whether the same applies for EC users compared to NU. In a very recent review, however, no such difference was reported (\u003cspan citationid=\"CR122\" class=\"CitationRef\"\u003e122\u003c/span\u003e)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec23\" class=\"Section2\"\u003e \u003ch2\u003e4.8 Limitations\u003c/h2\u003e \u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eBeyond the general risk of bias and confounding described in the previous chapter, there is the unavoidable limitation that duration of use of NGPs is presently too short for the investigation of long-term detrimental effects such as oral cancer. As a substitute, precursor lesions or (early) biomarkers of biological effects (BOBEs) were used as endpoints for the evaluation of detrimental oral health effects in NGP users. The predictive power for a subsequent diseases is as yet not well established. Another limitation is that many of the selectable studies have small group sizes (\u0026lt;\u0026thinsp;50/group), which may prevent finding small differences between groups to be significant. This could have direct impact on the qualitative meta-analyses conducted in this systematic review.\u003c/p\u003e\u003cp\u003eThe approach of qualitative meta-analysis as introduced here is not an established methodology. Its limitations have been discussed earlier in the text. The calculated scores and CI-values may, be no means, be interpreted as oral health risks. Rather, the score values (range: -1 to +\u0026thinsp;1) indicate the probability of finding a harm (+) or benefit (-) between two groups when a sufficient number of comparisons is performed.\u003c/p\u003e\u003cp\u003eThe combination of various endpoints to a new oral health parameter (as was done for the categories \u0026lsquo;pre-cancerious lesions\u0026rsquo;, \u0026lsquo;inflammatory processes\u0026rsquo;, \u0026lsquo;oral clinical parameters\u0026rsquo;, \u0026lsquo;shifts in the oral microbiome\u0026rsquo;, \u0026lsquo;total oral disorders\u0026rsquo;) can be criticized to be somewhat arbitrary and not (always) physiologically based. In general we would agree with this criticism. However, we would argue that almost all of the endpoints are interrelated via one or more physiological pathways, so that even combining all detrimental oral endpoints to a variable \u0026lsquo;total oral disorders\u0026rsquo; (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) may have a certain justification.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003c/div\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eOur qualitative meta-analyses of a multitude of endpoints of early oral discorders revealed that vapers (EC) were better off than smokers (CC) but still worse than NU. Systematic bias by presumably underreported dual use might be responsible for part of the oral disorders in EC users. There is a need for further research into the long-term effects of NGP use on oral health outcomes, as well as the underlying biological mechanisms.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e3-OH-Cot \u0026nbsp; trans-3\u0026rsquo;-hydroxycotinine\u003c/p\u003e\n\u003cp\u003e3-OH-Cot-gluc \u0026nbsp;trans-3\u0026rsquo;-hydroxycotinine-N,O-glucuronide\u003c/p\u003e\n\u003cp\u003e8-OH-dG \u0026nbsp;8-Hydroxy-2\u0026rsquo;-deoxyguanosine (a BM of oxidative stress)\u003c/p\u003e\n\u003cp\u003eAP Apurinic/apyrimidinic (sites in DNA)\u003c/p\u003e\u003cp\u003eB Blood\u003c/p\u003e\u003cp\u003eBL Baseline (at start of a longitudinal or prospective study)\u003c/p\u003e\u003cp\u003eBLT Bone loss around teeth\u003c/p\u003e\u003cp\u003eBM Biomarker\u003c/p\u003e\u003cp\u003eBOP Bleeding on probing\u003c/p\u003e\u003cp\u003eCAL Clinical attachment loss\u003c/p\u003e\u003cp\u003eCBL Crestal bone loss\u003c/p\u003e\u003cp\u003eCC Combustible cigarettes (and user)\u003c/p\u003e\u003cp\u003eCEMA 2-Cyanoethyl mercapturic acid (MA of acrolonitrile)\u003c/p\u003e\u003cp\u003eCI 95%-Confidence interva\u003c/p\u003e\u003cp\u003eCNO Cotinine-N-1-oxide\u003c/p\u003e\u003cp\u003eCODS Clinical oral dryness score\u003c/p\u003e\u003cp\u003eCOex Carbon monoxide in exhaled breath\u003c/p\u003e\u003cp\u003eCOHb Carboxyhemoglobin\u003c/p\u003e\u003cp\u003eCot Cotinine\u003c/p\u003e\u003cp\u003eCot-gluc cotinine-N-glucuronide\u003c/p\u003e\u003cp\u003eCRP C-reactive protein (inflammation marker)\u003c/p\u003e\u003cp\u003eCSS Cross-sectional study\u003c/p\u003e\u003cp\u003eCTX C-terminal cross-links\u003c/p\u003e\u003cp\u003eD Duration (of use of T/N products or NGPs)\u003c/p\u003e\u003cp\u003eEC Electronic cigarettes\u003c/p\u003e\u003cp\u003eEN-RAGE Extracellular newly identified RAGE binding protein\u003c/p\u003e\u003cp\u003eFMUS Full mouth ultasonic scaling\u003c/p\u003e\u003cp\u003eFS Former smoker (usually of CC)\u003c/p\u003e\u003cp\u003eFU Follow-up (in a prospective study\u003c/p\u003e\u003cp\u003eG Group\u003c/p\u003e\u003cp\u003eGCF Gingival crevicular fluid\u003c/p\u003e\u003cp\u003eGCol Gingival color\u003c/p\u003e\u003cp\u003eGI Gingival index\u003c/p\u003e\u003cp\u003eGM-CSF Granulocyte-macrophage colony-stimulating factor (pro-inflamm. marker)\u003c/p\u003e\u003cp\u003eGSH-Px Glutathione peroxidase\u003c/p\u003e\u003cp\u003eHNSCC Head and neck scquamous cell cancer\u003c/p\u003e\u003cp\u003eHPRT Hypoxanthine phosphoribosyltransferase\u003c/p\u003e\u003cp\u003eHTP Heated tobacco product (and user)\u003c/p\u003e\u003cp\u003eHypybut 4-OH-4-(3-pyridyl)-butanoic acid\u003c/p\u003e\u003cp\u003eIL-1\u0026szlig; Interleukine-1\u0026szlig; (pro-inflammatory cytokine)\u003c/p\u003e\u003cp\u003eIL-2 Interleukine-2 (pro-inflammatory cytokine)\u003c/p\u003e\u003cp\u003eIL-4 Interleukine-4 (anti-inflammatory cytokine)\u003c/p\u003e\u003cp\u003eIL-6 Interleukine-6 (pro-inflammatory cytokine)\u003c/p\u003e\u003cp\u003eIL-8 Interleukine-8 (anti-inflammatory cytokine)\u003c/p\u003e\u003cp\u003eIL-9 Interleukine-9 (anti-inflammatory cytokine)\u003c/p\u003e\u003cp\u003eIL-10 Interleukine-10 (anti-inflammatory cytokine)\u003c/p\u003e\u003cp\u003eIL-12p70 Interleukine-12p70 (?-inflammatory cytokine)\u003c/p\u003e\u003cp\u003eIL-13 Interleukine-13 (anti-inflammatory cytokine)\u003c/p\u003e\u003cp\u003eIL-RA Interleukine-RA (anti-inflammatory cytokine)\u003c/p\u003e\u003cp\u003eIL-15 Interleukine-15 (?-inflammatory cytokine)\u003c/p\u003e\u003cp\u003eIL-18 Interleukine-15 (?-inflammatory cytokine)\u003c/p\u003e\u003cp\u003eINF-γ Interferon-gamma (pro-inflammatory cytokine)\u003c/p\u003e\u003cp\u003eIQR Inter-quartile range (25th \u0026ndash; 75th percentile)\u003c/p\u003e\u003cp\u003eLA-QPCR Long-amphicon quantitative polymerase chain reaction\u003c/p\u003e\u003cp\u003eLC-MS/MS Liquid chromatography with tandem mass spectrometry\u003c/p\u003e\u003cp\u003eLDH Lactate dehydrogenase (elevation can indicate oxidative stress, cell damage and cell death)\u003c/p\u003e\u003cp\u003eLRG1 Leucine-rich alpha-2-glycoprotein (BM for tumor vascularization)\u003c/p\u003e\u003cp\u003eLS Longiturinal study\u003c/p\u003e\u003cp\u003em month\u003c/p\u003e\u003cp\u003eMA Mercapturic acid\u003c/p\u003e\u003cp\u003eMBL Marginal bone loss\u003c/p\u003e\u003cp\u003emi-RNA micro-RNA (not coding RNA, but involved in gene regulation)\u003c/p\u003e\u003cp\u003eMN Micronulei\u003c/p\u003e\u003cp\u003eMPO Myeloperoxidase\u003c/p\u003e\u003cp\u003eMT Missing teeth\u003c/p\u003e\u003cp\u003eN Nicotine\u003c/p\u003e\u003cp\u003eNCot Norcotinine\u003c/p\u003e\u003cp\u003eNequ Nicotine equivalents\u003c/p\u003e\u003cp\u003eNGP New generation (tobacco/nicotine) product (EC, HTP, NP)\u003c/p\u003e\u003cp\u003eNHANES National Health and Nutrition Examination Survey (USA)\u003c/p\u003e\u003cp\u003eN(ic) Nicotine\u003c/p\u003e\u003cp\u003eNic-gluc Nicotine-N\u0026rsquo;-glucuronide\u003c/p\u003e\u003cp\u003eNic\u0026thinsp;+\u0026thinsp;10 Nicotine and its 10 major metabolites Cot, 3-OH-Cot, Nic-gluc, Cot-gluc, 3-OH-Cot-gluc, NNic, NCot, NNO, CNO, Hypybut\u003c/p\u003e\u003cp\u003eNN Nornicotine\u003c/p\u003e\u003cp\u003eNNN N-Nitrosonornicotine\u003c/p\u003e\u003cp\u003eNNO Nicotine-N-1\u0026rsquo;-oxide\u003c/p\u003e\u003cp\u003eNRT Nicotine replacement therapy\u003c/p\u003e\u003cp\u003ens not (statistically) significant\u003c/p\u003e\u003cp\u003eNS Non-smoker\u003c/p\u003e\u003cp\u003ents nucleotides (in DNA)\u003c/p\u003e\u003cp\u003eNU Non-user (of any tobacco/nicotine product)\u003c/p\u003e\u003cp\u003eNV Non-vaper\u003c/p\u003e\u003cp\u003eOML Oral mucosa lesions\u003c/p\u003e\u003cp\u003eONP Oral nicotine pouch\u003c/p\u003e\u003cp\u003eOPG Osteoprotegerin\u003c/p\u003e\u003cp\u003eOR Odd ratio\u003c/p\u003e\u003cp\u003eOT Oral tobacco (and user)\u003c/p\u003e\u003cp\u003eP Plasma\u003c/p\u003e\u003cp\u003ePATH Population Assessment of Tobacco and Health (study in USA)\u003c/p\u003e\u003cp\u003ePBI Papillary bleeding index (indicator of gingival inflammation)\u003c/p\u003e\u003cp\u003ePCot Cotinine in plasma\u003c/p\u003e\u003cp\u003ePD Probing depth\u003c/p\u003e\u003cp\u003ePG 1,2-Propylene glyco\u0026ouml;l\u003c/p\u003e\u003cp\u003ePGE2 Prostaglandin E2 (involved in inflammatory processes)\u003c/p\u003e\u003cp\u003ePI Plaque index\u003c/p\u003e\u003cp\u003ePIBL Peri-implant bone loss\u003c/p\u003e\u003cp\u003ePISF Peri-implant sulcular fluid\u003c/p\u003e\u003cp\u003ePOLB (DNA) Polymerase-beta\u003c/p\u003e\u003cp\u003ePOR Prevalence odd ratio\u003c/p\u003e\u003cp\u003ePS Plaque score\u003c/p\u003e\u003cp\u003ePY Packyears\u003c/p\u003e\u003cp\u003eQ Questionnaire\u003c/p\u003e\u003cp\u003eRAGE Receptor for advanced glycation end products\u003c/p\u003e\u003cp\u003eRANKL Receptor activator of NF-kappa B ligand\u003c/p\u003e\u003cp\u003eRBL Radiographic bone loss\u003c/p\u003e\u003cp\u003eS Saliva\u003c/p\u003e\u003cp\u003eSD Standard deviation of the mean\u003c/p\u003e\u003cp\u003eSEM Standard error of the mean\u003c/p\u003e\u003cp\u003eSGP Subgingival plaque\u003c/p\u003e\u003cp\u003eSLT Smokeless tobacco\u003c/p\u003e\u003cp\u003eSRP Sealing and root paving\u003c/p\u003e\u003cp\u003eTIMP-1 Tissue inhibitor metalloproteinase-1\u003c/p\u003e\u003cp\u003eTNF-α Tumornekrosefaktor-α (pro-inflammatory cytokine)\u003c/p\u003e\u003cp\u003eTNH History of using tobacco/nicotine products\u003c/p\u003e\u003cp\u003eT/N Tobacco/Nicotine (products, history, etc.)\u003c/p\u003e\u003cp\u003eU Urine\u003c/p\u003e\u003cp\u003eWP Waterpipe\u003c/p\u003e\u003cp\u003ew/o with or without\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eConflicts of Interest:\u003c/h2\u003e \u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e \u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThere was no external funding for this project.\u003c/p\u003e\u003ch2\u003eAuthor Contributions:\u003c/h2\u003e \u003cp\u003eConceptualization, M.S., G.S. and N.P.; writing\u0026mdash;original draft preparation, G.S.; writing\u0026mdash;review and editing, N.P. and M.S.; supervision, M.S.; project administration, M.S. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTobacco Advisory Group of the Royal (2016) College of Physicians (RCP), editor Nicotine without smoke\u0026mdash;tobacco harm reduction. Royal College of Physicians\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eClarke E, Thompson K, Weaver S, Thompson J, O\u0026rsquo;Connell G (2019) Snus: a compelling harm reduction alternative to cigarettes. Harm Reduct J 16(1):1\u0026ndash;17\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUS Department of Health and Human Services. The Healh Consequences of Using Smokeless Tobacco. 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Medicina 60(3):365\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Combustible cigarettes, Electronic cigarettes, Heated tobacco products, Oral nicotine pouches, Oral health","lastPublishedDoi":"10.21203/rs.3.rs-4206242/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4206242/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eUse of traditional tobacco products, including combustible cigarettes (CCs) and smokeless oral products, is an established risk factor for various oral diseases. A potential oral health risk of using new generation tobacco/nicotine products (NGPs) such as electronic cigarettes (ECs), heated tobacco products (HTPs) and oral nicotine pouches (ONPs) is not yet well established.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn this systematic review, we evaluated published human studies on detrimental oral health effects in NGP users compared to CC smokers and non-users (NU). We identified 52 studies, of which almost all investigations were on EC users. The studies were extremely heterogeneous in terms of design, subjects, endpoints and quality. Reported outcomes, based on both single and grouped endpoints were qualitatively evaluated by comparing NGP users with NU and CC users. Significant increases (indicating a worsening in oral health), significant decreases (indicating an improvement) and no significant difference between groups were assigned scores of +\u0026thinsp;1, -1 and 0, respectively.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eWith this approach, comparisons of EC \u003cem\u003eversus\u003c/em\u003e NU yielded mean scores of 0.29 (pre-cancerous lesions, N\u0026thinsp;=\u0026thinsp;14 observations), 0.27 (inflammatory processes, N\u0026thinsp;=\u0026thinsp;83), 0.43 (oral clinical parameters, N\u0026thinsp;=\u0026thinsp;93) and 0.70 (shifts in the oral microbiome, N\u0026thinsp;=\u0026thinsp;10). The corresponding values for the EC versus CC comparisons amounted to: -0.33 (N\u0026thinsp;=\u0026thinsp;15), -0.14 (N\u0026thinsp;=\u0026thinsp;76), -0.27 (N\u0026thinsp;=\u0026thinsp;78) and 0.57 (N\u0026thinsp;=\u0026thinsp;7). Most of the evaluated studies have severe limitations in terms of group sizes, duration of NGP use and validity of self-reported exclusive NGP use. In particular, any dual use (EC\u0026thinsp;+\u0026thinsp;CC) was mostly not adequately taken into account.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003e The evaluated studies suggest that use of ECs is associated with some improvement of oral health effects compared to cigarette smoking (CC), but oral health is still found to be worse compared to NU. These results have to be interpreted with caution due to a number of limitations and uncertainties in the underlying studies.\u003c/p\u003e","manuscriptTitle":"Oral health risks in users of new generation nicotine/tobacco products (NGPs): Systematic review and qualitative meta-analyses","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-03 05:19:27","doi":"10.21203/rs.3.rs-4206242/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2b352957-f30b-4aec-920e-853a5f29ef86","owner":[],"postedDate":"April 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":30166431,"name":"Toxicology"}],"tags":[],"updatedAt":"2024-04-03T05:19:27+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-03 05:19:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4206242","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4206242","identity":"rs-4206242","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}