The adverse health effects of waterpipe smoking in adolescents and young adults: A narrative review

Waterpipe (WP) smoking has rapidly grown in popularity in the United States and other Western countries with the fastest uptake among younger individuals. This growth has been encouraged by the misperception that WP smoke is harmless or less harmful than cigarette smoke. To better understand how WP affects the health of young people, we conducted a narrative review of the literature focusing on the adverse health effects of WP smoking in adolescents and younger adults. We searched scientific literature databases including PubMed, MEDLINE, EMBASE, and ISI Web and selected papers that met the inclusion criteria. Sixty-three papers met the inclusion criteria and were selected for review. Data were abstracted from the selected papers into a standardized table. The evidence demonstrates that WP smoking can cause acute lung infection and injury, and carbon monoxide (CO) poisoning, in adolescents and young adults. It is also associated with adverse subclinical effects in this sub-population, including oral and systemic genotoxicity, lung function decline, and the alteration of vascular and hemodynamic functions. Limited evidence that is available indicates associations with psychological and neurological effects and asthma. No identified publications examined the association between WP use and type 2 diabetes, a condition that is associated with cigarette smoking among young people. WP smoking by younger individuals can result in their hospitalization due to systemic CO poisoning and acute lung disease, and induce subclinical adverse effects in the oral cavity, pulmonary system, and in circulation, that are involved in the pathogenesis of local and systemic chronic diseases.

INTRODUCTION smoking 1,4 . As can be seen in Figure 1, WPs involve smoking tobacco that is heated by charcoal in the WP head. When a user sucks on the mouthpiece of the hose that is attached to the WP, the resulting smoke bubbles through water before inhalation. Many WP tobacco smokers believe that the water in the bowl filters out the toxic agents in tobacco smoke 1,4 . The combination of tobacco flavoring and water in the WP bowl results in a humid, milder smoke that is less irritating compared to cigarette smoke 1,4 .
The lower irritation potential of WP tobacco smoke and the significantly lower draw resistance of the WP, compared to other combustible tobacco products, encourage deeper inhalation and longer smoking sessions 1 . The volume of smoke inhaled during a 1-hour session of WP smoking is about 200 times the volume that is drawn from smoking one cigarette 7,8 . Also, one WP smoking session can yield two, five and ten times the amount of nicotine, tar, and carbon monoxide (CO), respectively [7][8][9] , and produces larger amounts of heavy metals, polycyclic aromatic hydrocarbons, and semi-volatile furans compared to yields from smoking one cigarette [9][10][11] . Therefore, the associations between WP smoking and chronic respiratory diseases, cardiometabolic diseases, lung cancer, oral and gastrointestinal cancers, and other cancers are not unexpected and are similar to the adverse health effects of cigarette smoking 12,13 .
Although, most of the global growth in the popularity of WP smoking has been among youth and young adults, few studies of its adverse health effects have been conducted among these age groups. We reviewed the available evidence of the health impacts of WP use among youth/young adults (aged 14-34 years, following the US Census categorization of young adults) 14 . While related reviews including recent publications have been conducted 12,13,[15][16][17] , none has focused on adverse effects observed among younger individuals.

Literature search
Since there are a limited number of studies of the adverse health effects of WP smoking among adolescents and young adults, all epidemiological studies, including case studies, were included in this narrative review. Reviewed studies met the following criteria: 1) must include a WP smoking group and some quantification (at least binary yes/no) of WP smoking; 2) must have collected information about adverse physiological, subclinical or clinical outcomes from study participants; 3) must have determined the association between WP smoking and the adverse health outcome; 4) must have reported the association between WP smoking and the health outcome(s) specific to a study group that is all or mostly adolescents/youths/young adults; and 5) must have been published in English.
Four scientific research databases including PubMed, MEDLINE, EMBASE, and ISI Web Science were electronically searched between April and June 2020 for potentially eligible peer-reviewed articles. The keywords used consisted of synonyms of WP, smoking-related health effects, and terms identifying the age group of interest as outlined below: • Keyword Group 1 (WP synonyms): waterpipe, hookah, narghile, shisha;

DEVELOPMENTS Effects in the oral cavity
The following effects of WP smoking have been studied in the oral cavity in young adults: physiological and biochemical changes in saliva 18,19 ; inflammation and cytological effects including chromosomal aberrations in the oral mucosa [20][21][22][23][24][25][26] ; oral infection and alteration of the oral microbiome 24,27 ; and impairment of periodontal health [28][29][30] (Table 1). The evidence indicates that WP smoking impairs oral health among young adults, and the demonstration of its genotoxicity in oral mucosal cells is consistent across studies. WP smoking may also alter saliva biochemistry and the oral microbiome, and results suggest that it is associated with tooth and periodontal diseases.

Genotoxicity
Indicators of cell death (apoptosis and necrosis) including pyknosis, karyorrhexis, and karyolysis are consistently higher in buccal cells of WP smoking young adults compared to non-smoking controls [24][25][26] . Similar results have been observed for markers of DNA damage including binucleation, micronuclei, broken eggs, nuclear buds, and chromosome breakage, and chromosome/chromatid fragments and gaps 20,21,23,25,26 .
In one study, a greater degree of DNA damage as indicated by micronucleus frequency in exfoliated buccal epithelial cells was observed among persons who exclusively smoked WP compared to those who exclusively smoked cigarettes 23 . Also, micronucleus frequency was associated with the frequency of WP smoking among young adults in a study that did control for cigarette smoking 22 . However, repair index, which was assessed as the ratio of nuclear changes that are evident of both apoptosis and necrosis (karyorrhexis and karyolysis) to nuclear changes that are evident of damage (broken eggs and micronuclei), was 0.6-fold lower in the buccal cells of WP smokers compared to non-smokers 26 . Furthermore, cytometric alterations indicating premalignant and malignant lesions including changes in nuclear size and shape, and increase in the nuclear to cytoplasm ratio were observed in buccal, tongue and mouth floor mucosa cells of WP smokers compared to non-smoking controls. These observations in WP smokers were accompanied by increased inflammation in cytological samples of the mucosa cells of the three oral areas 24 .

Effects on saliva biochemistry and oral microbiome
Changes in saliva that can impair oral health have been observed in WP smokers 18,19 . Although, stimulated saliva pH was similar, its buffering capacity was lower among young adult WP smokers compared to age-matched non-smoking controls 19 . This suggests a WP smoke-mediated impairment in the capacity of saliva to protect against enamel demineralization and dental caries 19 . Also, results indicate reduced saliva antioxidant capacity in WP smokers 18 . Peroxidase and 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) activities were less increased and more reduced, Self-reported WPS, convenience sample but from same dentist practice; excluded patients taking/ needing antibiotic prior to procedure; did not control for other potential risk factors for dry socket.
*WPS: waterpipe smokers. CS: cigarette smokers. C: control. respectively, in WP smoking young adults following exhaustive acute exercise, which is an oxidative stress inducing activity 18 . WP smoking may also alter the oral microbiome 27 . The frequency of detection of Candida albicans, the fungus that causes oral thrush, was higher in the subgingival plaque of young adult WP smokers compared to age-matched non-smoking controls. Acinetobacter and Moraxella spp. in the subgingival plaque were only detected in the WP smokers, while the colony forming unit (CFU) of black-pigmented bacteria Porphyromonas gingivalis and Prevotella intermedia was higher in their oral cavity samples (cheek, teeth, and tongue). Some Acinetobacter and Moraxella species cause respiratory airway infections, while both black-pigmented bacteria species are periodontal pathogens 27 . Meanwhile, the detection frequency of Fusobacterium nucleatum, a ubiquitous and mostly commensal microbe in the oral cavity, was lower in the subgingival plaque of the WP smokers 27,31 . The frequency of candida detection in cytological smears of the cheeks, tongue and floor of the mouth of WP smokers was similar to the frequency among cigarette smokers, but lower than the observations made among age-and sex-matched non-smoking young adult controls in another study 24 .

Tooth and periodontal effects
Khemiss et al. 29 reported similar (decayed/missing/ filled teeth, plaque index, and tooth mobility) or better (gingival index, probing pocket depth, and periodontal disease) degrees for indicators of teeth and gum health in young adult WP smokers compared to cigarette smokers. However, the same authors had observed higher plaque index in WP smokers in a prior study 30 . Neither study included non-smoking controls for comparison. In another study, young adult WP smokers had a similar likelihood of developing an occurrence of oral dry socket (a very painful condition caused by the dislodgement of the clot and the disruption of the healing at a tooth extraction site) after the extraction of the third mandibular molar tooth compared to cigarette smokers, and a three times higher likelihood compared to non-smokers 28 . The incidence of oral dry socket also increased with smoking frequency, and the outcome was five times more likely to be observed in young adults who smoked WP twelve times per day compared to those who smoked three times per day 28 .

Comments about studies of effects in the oral cavity
All the studies of the adverse oral effects of WP smoking in young adults included age-and sexmatched positive and/or negative controls, i.e. cigarette smoking and/or non-smoking groups, which sometimes excluded males or females. However, differences in outcomes based on sex were not investigated in any of the studies. Most of the studies excluded persons with chronic systemic disease or previous oral infection or disease, use of medication and/or radiation exposure. However, there was potential for residual confounding of the results by factors such as consumption of alcohol and confections, environmental chemical exposures, and oral hygiene. All but one of the studies were conducted in Middle Eastern countries 25 . Smoking was self-reported and not objectively measured in all the studies. Lastly, dose-response relationship was assessed in only two studies with an observation that micronucleus frequency in the oral cavity increased in association with a higher frequency of WP usage 20,22 .

Pulmonary effects
Study results (Table 2) indicate that WP smoking is associated with changes in the molecular milieu (genetic material) and cellular composition in the lungs, decrements in lung function, and respiratory symptoms among adolescents and/or young adults.

Molecular and cellular effects
Associations between WP smoking and epigenetic modifications, which in some cases overlapped with differential gene expression (mRNA transcripts), have been observed 32 . Walters et al. 32 reported that there was at least a 1.5-fold difference in the degree of methylation of the DNA in 623 unique genes in the cells of the small airway epithelium (SAE) of 'light' (≤5 sessions per week) young adult users of WP, relative to non-smoking controls. Xenobiotic metabolism and cellular signaling (e.g. aryl hydrocarbon and G-coupled receptors), which are associated with cigarette smoking and smokingassociated pulmonary disease, were among the biological pathways that were mostly impacted by the observed differential methylation. Furthermore, there were differences in the expression of 11.3%   WPS > C for secretory cells; WPS < C for basal and ciliated cells.
159 differentially expressed genes in SAE, 181 differentially expressed in AM in WPS vs C; WPS > C for transcriptome response score for both SAE and AM.
Self-reported exposure verified with cotinine and nicotine measurements; convenience sample used; no confounder control but study participants in C group and WPS group were comparable in terms of sex, ethnicity, body mass index, and alpha-1 antitrypsin levels.  While there was some overlap between WP and cigarette smokers in the cellular pathways that were affected by differential methylation (xenobiotic metabolism, and aryl hydrocarbon and G-coupled receptor signaling), other impacted pathways were unique to WP smokers 32 . Additionally, there was a predominance of hypermethylation in affected genes in SAE among WP smokers compared to nonsmokers, whereas hypomethylation was predominant in cigarette smokers 32,33 . There was also little overlap in the differentially expressed genes in SAE between WP and cigarette smokers relative to non-smokers. These observations suggest differences in pulmonary pathology that is potentially driven by the differences in the emission contents of tobacco combustion between WP and cigarette smoking.
Similar to cigarette smokers, the composition of recovered SAE cells was altered in young adult WP smokers when compared with non-smokers 33 . However, the pattern of the alteration was different between the two smoking groups. While there was an increased proportion of secretory cells and a decreased proportion of ciliated cells in recovered SAE cells in both groups compared to non-smokers, WP smokers, unlike cigarette smokers, had an increased proportion of basal cells that are the progenitor cells in the airway epithelium 33 .

Effects on pulmonary physiology
Meo et al. 34 observed a significant decrease in fractional exhaled nitric oxide (FENO) among young adult WP smokers compared to non-smokers. This result indicates the potential oxidative effect of WP smoking in the respiratory airways, possibly partly due to the conversion of nitric oxide to peroxynitrite by reactive oxygen and nitrogen species released in WP smoke 34 . It also suggests that WP smoking can impair nitric oxide physiological function in regulating both pulmonary function and its bronchodilatory effect which plays an important role in homeostasis and disease 35 . A few studies have reported an effect of WP smoking on pulmonary or lung function among adolescents and young adults 33,34,[36][37][38] . Meo et al. 34 reported lower values for various spirometry measures including forced expiratory volume in one second (FEV 1 ), its ratio (FEV 1 /FVC) to forced vital capacity (FVC), and forced expiratory flows (FEFs) at different percentages (25,50,75, and 75-85%) of FVC among WP smokers compared to non-smoking young adults. Additionally, peak expiratory flow (PEF) was lower among young tobacco smoking adults 37 . Although, the types of tobacco smoking were not differentiated in the comparison with non-smokers in the study, PEF was lower (insignificantly) among persons who exclusively smoked WP compared to those who exclusively smoked cigarettes 37 . Lower percentages of predicted spirometry values, especially for FVC, FEV 1 , and PEF, were similarly observed among young adult WP smokers vs non-smokers 33,36,39 . These findings suggest that WP smoking could contribute to obstructive and restrictive lung pathologies and the development of chronic pulmonary disease 40,41 . Furthermore, acute decline in lung function following WP smoking has been demonstrated 36,38 , and this was accompanied by increased breathing rate in one of the studies 38 .
Respiratory symptoms, lung injury, lung infection, and lung disease WP smoke exposure was consistently associated with increased risk of respiratory symptoms across studies 39,42,43 . In a cross-sectional study, Hawari et al. 39 reported that a significantly higher proportion of young adult WP smokers, compared with non-smoking controls, self-reported any respiratory symptom (72.5% vs 21.7%), chest illness that prevented them from working within the previous three years (25.0% vs 10.1%), and coughing up phlegm lasting more than three weeks (11.6% vs 0.0%). In another study that was conducted across multiple Middle Eastern countries, the same research group observed that college student WP smokers were 60% more likely to report respiratory symptoms, e.g. cough and phlegm, compared to non-smokers 42 . There was no difference in the risk for these outcomes compared to cigarette smokers in both studies. Relative to secondhand smoke exposure, elementary school children who lived at home with at least one person who smoked WP and/or cigarettes, compared with children who did not, had increased incidence of wheezing and/or nasal  43 . Consistent with the evidence indicating increased risk of respiratory symptoms, cases of acute lung injury (granulomatous lesions and pneumomediastinum) 44,45 , pulmonary eosinophilic inflammation 46,47 , and pulmonary infection (mycobacterium tuberculosis and burkholderia pseudomallei) 48,49 following WP smoking activities have been reported in young adult individuals. However, there was no apparent increase in the risk of respiratory symptoms among WP smoking young adults compared to non-smokers in another study 37 . Finally, higher prevalence or odds of WP smoking was observed among persons with asthma in crosssectional surveys of 9th to12th graders in Florida 50,51 .
Comments about studies of pulmonary effects All but one (a cross-over study) of the studies of pulmonary effects of WP smoking in adolescents and/or young adults were case studies, pre-post, or cross-sectional studies. Most (66%) of the 15 studies were conducted in the Middle East. Also, most relied on self-reported smoking information, and did not control for potential confounders. Whereas some of the studies included both male and female participants, none of the studies tested gender effects and none provided dose-response information.

Cardiovascular effects
WP smoke is associated with adverse cardiovascular outcomes 16 . Several studies have reported that WP smoking induces hemodynamic and vascular responses, and impairs cardiac autonomic control in adolescents and young adults (Table 3).

Hemodynamic effects
The acute vascular response to WP smoking among young adults reflects the differential effects of tobacco smoke components in different tissue beds. In one study, calf muscle blood flow and vascular resistance measured by venous occlusion straingauge plethysmography increased and decreased, respectively, in young adults following WP smoking 52 . Similarly, Nelson et al. 53 observed an increase in myocardial blood flow and conductance in young adults following WP smoking. In contrast, blood flow decreased and vascular resistance increased in the forearm and foot skin following WP smoking 52,54,55 . These differential effects are the consequence of the dilatory effect of nicotine in skeletal muscles and coronary vessels versus its constrictive effect in cutaneous vessels 52,53 . Carbon monoxide, another major component of WP tobacco smoke, also has a dilatory effect in the skeletal muscle beds and coronary vessels, but not in the skin 52,53 .
Also, evidence in the literature suggests opposite directionality for the effects of acute and chronic WP smoking on blood pressure. Although, diastolic blood pressure (DBP), systolic blood pressure (SBP) and heart rate (HR) did not change across work shifts among WP bar workers exposed to secondhand smoke 56 , observations about increases in these measures and mean arterial pressure (MAP) among young adults following WP smoking are consistent across studies 52-54,57-60 . Al-Safi et al. 61 also reported higher SBP, DBP, MAP and HR in young adult WP smokers compared to non-smokers in a large population-based study (n=7845), while WP smoking was not associated with the prevalence of high BP among young adults in another study 37 . However, results in other studies suggest an opposite chronic effect among adolescents with WP smoking-associated decreases in BP being observed only among boys in one of the studies 62,63 . The apparent opposed directions in the BP effect of acute (increased BP) and chronic (decreased BP) WP smoke exposure is similar to what has been reported for cigarette smoke [64][65][66][67][68][69][70][71] . Alomari et al. 64 observed reduced BP among WP smoking adolescents compared to non-smoking controls.
Although the basis for the seeming dichotomy in BP effects has not been clarified, the intermittent stimulation of the sympathetic nervous system, that is causal for vasoconstriction and increased hemodynamic activity, by repeated exposure to nicotine from tobacco smoking, and subsequent 'overcompensation' of the body and excessive vasodilation in the absence of nicotine during non-smoking periods have been hypothesized as a potential mechanism [62][63][64] . It is important to note that reduced BP is not necessarily beneficial or harmless as it could be a risk factor for cardiovascular (especially coronary) events 62,[72][73][74][75] .

Impairment of vascular function and other cardiovascular effects
WP smoking impairs vascular function in young adults 58,59,76 . A 30-minute smoking session of a     18 standard charcoal-heated WP increased central arterial stiffness as indicated by increased pulse wave velocity and augmentation index 58 . However, charcoal-heated WP smoking in another study induced a contrary effect on endothelial function with flow-mediated dilation (FMD) increasing after smoking 59 . This was attributed to the high content of vasodilatory CO in smoke from the combustion of the charcoal. In the study, inhalation of a CO gas mixture that achieved a similar CO boost as the smoking of the charcoal-heated WP caused a larger increase in FMD. In contrast, FMD decreased after the smoking of an electronically heated WP. Therefore, it was concluded that CO masks the induction of endothelial dysfunction by other components of WP smoke including nicotine and particulates. The authors of the study hypothesized that this attenuating effect is temporary and that FMD will eventually decrease following CO clearance from circulation 59 . Indeed, Selim et al. 76 reported that FMD was reduced 0.66x and 0.37x in WP smoking young adults compared to cigarette smoking and non-smoking controls, with an inverse relationships between FMD and the number of WP smoking session per day. Furthermore, the impairment of cardiac autonomic control, which is associated with adverse cardiovascular events, is observed following WP smoking in young adults 60,77 . Also, Hawari et al. 39 observed that exercise performance, as indicated by components of the cardiopulmonary exercise test (CPET), was impaired among young adult WP smokers compared to nonsmokers. Heart rate, perceived exertion (Borg scale), and self-reported leg fatigue were increased, and peak oxygen consumption and exercise time were reduced among the smokers.

Comments about studies of cardiovascular effects
All 19 studies of the cardiovascular effect of WP smoking among adolescents and young adults that were identified were either cross-sectional or prepost in design. Thirteen studies reported on acute effects; twelve studies were conducted in the Middle East, six in the United States, and one in the United Kingdom. Most of the studies controlled for potential confounders by using them as selection criteria of the study. Although only six of the studies were exclusively composed of male participants, or did not report gender distribution, just one study reported on testing for gender differences. Finally, dose-response association was reported by only one of the studies.

Neurological and psychological effects
In general, tobacco use is linked with the impairment of mental health. However, the etiology and the directionality of the association is not clear [78][79][80] . Depression, for example, could predispose a person towards tobacco smoking [78][79][80] . On the other hand, smoking might be a cause of depression [78][79][80] . A third alternative is that there is not a causal link between the two, and that they both occur due to common risk factors 79 . Nonetheless, there are few studies (Table  4) about the association between WP smoking and mental health disorders among adolescents and young adults, but the results of the studies are inconsistent.

Psychological effects
No association was observed for depressive symptoms, anxiety, or stress, in three studies of college students 78,81,82 . In contrast, the odds of past 30-day WP smoking increased by 30-140% with self-reported mental health diagnosis (including depression, anxiety, sleeping disorder, attentiondeficit disorder, and addictive disorder) in a national survey of college students 80 . The odds of current use of WP was also associated with a psychological stress scale (on Cohen's Perceived Stress Scale) and a depression scale (the Center for Epidemiologic Studies Depression Iowa Short Form) but not with self-reported mental health diagnosis in another study of college students 83 . Marsden et al. 79 observed that the score on the Center for Epidemiologic Studies Depression 10 Scale increased by 3% with every 5-day increase in usage in the past 30 days in their study. Also, the score increased by 4% and 9% for at least 5 days and 15 days of usage in the past 30 days, respectively, among college students 79 . Unlike the other studies, the results from the Marsden et al. [84][85][86] study were based on longitudinally collected and repeated measures data with some information about directionality. They were also able to adjust for the use of other tobacco products in their analyses.

Neurocognitive effects
A few studies have examined the association between WP smoking and cognitive function in young adults. There was no difference in the assessed cognitive   21 function between WP smoking and non-smoking male young adults before and immediately after supramaximal exercise in one of the studies 84 . The complexity of the cognitive test (number-recall) that was administered in the study may have been insufficient to detect a difference, and the sample size (10 per group) was small. However, the two-hands coordination, attention and concentration, reactive stress tolerance and reaction speed parameters on the Vienna Test System's traffic test battery improved after WP smoking among male college student participants in a pre-post study 85 . This effect was theorized as being due to the acute enhancement of fine motor performance, alerting attention accuracy, and response time, by nicotine. The potential chronic effect of WP smoking on these driving test parameters was not tested since the study did not include non-smoking controls. On the other hand, Meo et al. 86 reported significant decline in attention switching, complex reaction time, and pattern recognition memory variables on the Cambridge Neuropsychological Automated Battery (CANTAB) test among WP smoking young adults compared to non-smoking controls. Notwithstanding the inconsistencies in the results of the aforementioned studies, decreased circulating brain-derived neurotrophic factor (BDNF) among middle school adolescent smokers (vs nonsmokers) indicate the potential for adverse effect of WP smoking on mental health at a young age 87 . BDNF is a neurotrophin that is important for neural development and synaptogenesis, and plays a key role in learning and memory 87,88 . Consequently, a decline in its circulating concentration, which is correlated with BDNF levels in the brain, might be expected to result in cognitive and behavioral deficits 87 .

Comments about studies of neurological and psychological effects
It is unique that all the studies of the association between WP smoking and mental disorders were conducted in the US. All the studies of mental health were large population-based studies that relied on self-reported smoking status information. The four studies on cognitive and potential neurological effects were conducted in the Middle East, and three of these included only male participants. However, none but one evaluated the effect of gender or race on the associations between WP smoking effect and the outcomes. Primack et al. 7 reported higher odds of WP smoking in college women versus men with addictive disorders.

General health and systemic effects
WP smoke contains considerably larger amounts of CO than cigarette smoke 9 . As would be expected, multiple cases of CO poisoning due to WP smoking among adolescents and young adults have been reported in the literature (Table 5) [89][90][91][92] . Also, WP smoking induces systemic oxidative stress and inflammatory responses ( Table 5) 36,56,[93][94][95] . In one study, total oxidative status and antioxidant status, and their ratio (oxidative stress index), were increased by 205%, 15%, and 180%, respectively, in young adults following WP smoking compared to levels in non-smokers, whereas saltstimulated activity of antioxidant enzyme paraoxonase was correspondingly reduced 36 . However, the baseline pre-smoking levels of these biomarkers were not measured in the WP smokers. The expression of the xenobiotic-detoxifying enzymes NAD(P)H:quinone oxidoreductase 1 and glutathione S-transferase A1 in peripheral blood were also reduced in WP smokers compared to non-smoking controls in another small study (15 per group) comprised mostly of young adults 93 .
Increased oxidative DNA damage in peripheral blood and lymphocytes has been reported in WP smoking young adults [96][97][98] . While no difference was observed in one study 21 , increased chromosomal aberrations including chromosome and chromatid gaps and breaks, sister chromatid exchange and/ or chromosome fragments in blood cells were reported among young adult WP smokers in all other studies [96][97][98] . Chromosomal aberrations were about 2x and about 4x more likely among those that used WP at least once a day compared to those who smoked 4-5 and <3 times per week, respectively 96 . Additionally, increased biomarker of DNA damage, 8-hydroxy-2'deoxyguanosine (8-OHdG), but reduced expression of DNA repair genes including oxoguanine glycosylase 1 and X-ray repair cross complementing 1 protein, were observed in the blood of WP smokers compared to non-smoking controls 93 . The chromosomal aberrations were even more increased in WP smokers compared to cigarette smokers, which aligns with the higher yields of mutagenic and carcinogenic compounds in    WP smoke 96 . In contrast, the blood concentration of 8-OHdG was higher in cigarette smokers, but this may be due to the reduced expression of DNA repair genes among WP smokers compared to cigarette smokers 93 . Furthermore, a dose-response relationship was observed between sister chromatid exchange and the frequency of WP smoking 97 . Based on its oxidative effects, it is expected that WP smoking would induce systemic inflammation in adolescents and young adults. Nonetheless, no cross-shift change was observed in circulating proinflammatory cytokines interleukin-1β (IL-1β), IL-6 and IL-8 among WP bar workers 56 , and the blood concentration of acute phase C-reactive protein was similar in female WP smoking and non-smoking university students 99 . However, interferon-γ and tumor necrosis factor-α increased across the work shift among the bar workers 56 . Furthermore, there is an apparent effect of WP smoking on biological processes that are regulated by proinflammatory cytokines, including coagulation and angiogenesis 100,101 . Coagulation factors, fibrinogen, and factors VII and VIII, were increased in WP smokers compared to cigarette smokers and non-smokers with the levels of fibrinogen and factor VIII being associated with the duration of WP usage 94 . In contrast, vascular endothelial growth factor (VEGF), an angiogenic factor, was reduced in adolescents who smoked both cigarettes and WP, and those who smoked WP exclusively, compared to non-smoking controls 95 . Table 6. Implications of related subclinical physiological changes that are observed in relation to WP smoking in adolescents and young adults for chronic disease pathology Outcome measures Implication/meaning Alteration of saliva biochemistry Changes in the acidity (pH) and ability to buffer against it in the saliva can cause loss of enamel, increase potential for infection and disease (e.g. oral thrush). Alteration of background microorganism composition (microbiome) in the oral cavity as observed for WP may increase the risk of infection 18,19 .

Spirometry or lung function
Decline in lung function was often associated with WP smoking in the studies. Rapid (non-age related) decline in lung function (volume capacity and air flow from the lungs) is involved in the pathogenesis of respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD), and lung cancer 39 .

Cellular composition in small airway epithelium
The decrease in ciliated cells and increase in mucous secreting cells in small airway epithelium degrades the lung clearance mechanism. Such alterations can be caused by exogenous insults, were observed in relation to WP smoking, and do occur during the development of chronic respiratory diseases 33 .
Hematological parameters WP increased hematological parameters including hematocrit (proportion of red blood cells in the blood) and white blood cell counts. Chronic changes in these parameters alter cardiovascular function and may contribute to or indicate disease 84 .

Hemodynamic measurements
Measures of blood flow dynamics including BP are altered by WP smoking. An overly elevated BP (hypertension) or reduced BP (hypotension) may precipitate or indicate chronic diseases including in the cardiovascular system 63 .

Vascular function measures
Measures of vascular function including FMD, arterial stiffness, and pulse wave velocity indicate the stiffness and reactivity of blood vessels. Changes in vascular function is an early indicator of atherosclerotic cardiovascular disease and is induced by WP smoking 59,76 .

Cardiac autonomic control
Change in the autonomic control of cardiovascular function is a predictor of coronary heart disease and mortality and is induced by WP smoking 60,77 .
Brain-derived neurotrophic factor (BDNF) BDNF is involved in brain function and homeostasis. Reduced circulating BDNF concentration in the blood was observed in association with WP smoking and may result in cognitive and behavioral deficit in the long-term 87 .

Genotoxicity
This includes damage to the structure of the DNA and chromosomes. Genotoxicity initiates the cancer mechanism and its continuous induction by exogenous insults, similar to the observations for WP, can overwhelm cellular defence mechanisms and increase cancer risk 21,25 .

Epigenetic modification
These are modifications on the DNA or histone that do not change the DNA sequence. They may affect gene transcription and associated expression (production) of protein. Deleterious epigenetic changes, such as was observed in relation to WP smoking, adversely alter cellular metabolism and are often involved in the pathogenesis of chronic diseases including cancer and COPD 32,33 .

Oxidative stress and inflammatory measures
Oxidative stress (imbalance between production of oxidant species and antioxidant defences in the body) and inflammation (triggering of the immune response) are involved in the pathogenesis of chronic inflammatory diseases (e.g. cardiovascular disease, COPD, and cancer) and are both induced by WP smoking.
The effect that was associated with exclusive WP smoking was due to differences in boys and not girls. Although, the relationship between tobacco smoking and VEGF is inconsistent in the literature, Alomari et al. 95 hypothesized that the increased amounts of CO and polycyclic aromatic hydrocarbons in WP smoke may inhibit the production and/or enhance the depletion of VEGF mRNA and protein in blood vessels. Finally, folate was reduced among female WP smoking university students compared to nonsmoking controls 99

CONCLUSION
As expected in studies of adolescents and young adults, subclinical effects were the most investigated outcomes. Notwithstanding the weaknesses in the studies, results were consistent for the genotoxic effects of WP smoking which were observed to be more potent than cigarette smoking in a few studies. Similarly, results were consistent for effects on lung function and in the oral cavity. As reported in case studies, WP smoking can also result in acute clinical cases of lung injury and infection, and systemic CO poisoning. The plausibility of these effects, which are also reported for cigarette smoking, is obvious as WP smoke contains many of the same toxic components of cigarette smoke, and many of these in much larger amounts (e.g. particulate matter, CO, polycyclic aromatic hydrocarbons, and semi-volatile furans). Furthermore, these effects are involved in the pathogenesis of local and systemic chronic diseases ( Table 6). Alteration of saliva biochemistry including its pH, buffering capacity, and the oral microbiome, increases the risk of tooth decay and oral infection 18,19 , while decline in lung function (spirometry measures) above age-related decrease and adverse changes in cellular composition in the small airways of the lungs, which are indicative of impairment in clearance mechanisms, contribute to the development of chronic lung diseases 33,39 . Also, chronic hematological changes, elevated BP, impaired vascular function, and altered cardiac autonomic function can be induced by continuous exposure to exogenous insults and are risk factors for cardiovascular disease 59,63,76,77,84 . Finally, chronic induction of genotoxicity, including damage to the DNA and chromosomes and deleterious epigenetic modification, is integral to the development of cancer 21,25,32,33 . Although asthma and type 2 diabetes are associated with cigarette smoking in young adults [102][103][104][105] , studies of the relationships between WP smoking and both diseases are lacking. Nonetheless, findings from two cross-sectional surveys of high school students in Florida suggest that there might be an association with asthma 50,51 . While 65 studies met the criteria for selection in this narrative review, the literature on this topic is still quite nascent. Most of the studies are case studies, cross-sectional, or pre-post in design; one is a crossover study while only two are longitudinal in design. Most relied on convenience samples, included only male or only female participants, and/or relied solely on selfreported smoking as the exposure metric. Therefore, information about exposure-response relationships and differences by demographic factors are mostly lacking. Also, there is a dearth of information about the effect of WP smoking among young adults in Western countries such as the US, the demographic group experiencing the greatest growth in prevalence of WP use. However, confounding of the associations of outcomes with WP usage, due to the smoking of alternative tobacco products, was mitigated in most of the studies. Twenty-two of the selected studies were case or pre-post studies that investigated outcomes following WP use, while smoking more than one tobacco product was an exclusion criterion, or controlled for, in 31 of the remaining 43 studies.
To comprehensively understand the effect of WP smoking, the generalizability of findings must be improved by conducting more studies outside the Middle East, in countries where there has been a recent rapid uptake of WP smoking among adolescents and young adults. In addition, future research should include sufficient sample sizes of participants distributed equally among the sexes so that gender differences can be explored, should be longitudinal in design, and should sufficiently control for confounders including the objective measurement of tobacco smoking, such as urinary or salivary cotinine. The results from such studies will underpin the development of effective regulations and effective educational campaigns designed to curb WP smoking among young adults.