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Background/aim Epidemiological studies had confirmed a fundamental association between smoking and tooth loss, but it remains unclear whether metabolites of tobacco products such as total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanonol (TNNAL) play a role in the incidence and progress of tooth loss. This study aims to investigate the relationship between TNNAL and tooth loss as well as how systemic inflammatory indexes mediate this process. Methods The cross-sectional study data were collected from the National Health and Nutrition Examination Survey conducted in the United States. After screening and comparing the baseline data, zero-inflated negative binomial regression models were utilized to evaluate the relationship between urinary TNNAL level and missing teeth among whole population and participants with different smoking status. Furthermore, bootstrapping was applied to test the mediation effect of systemic inflammatory indexes between TNNAL level and missing teeth. Results 7726 participants were included, having 2958 individuals belonging to the TNNAL = 0 group and 4768 in the TNNAL  >  0 group. In the model with covariates fully adjusted (model 3) among whole population, TNNAL level was found to be positively correlated with tooth loss [Incidence Rate Ratio (IRR) = 1.107, 95% confidence interval (95% CI) = 1.074–1.140], especially in the fourth quartile (Q4) of TNNAL level (IRR = 1.715; 95%CI = 1.535–1.916) compared to the Q1. Red blood cell distribution width (RDW) and monocyte/highdensity lipoprotein cholesterol ratio (MHR) played partial mediating role in the association between TNNAL and tooth loss, and the indirect effect of each was 0.0242 (RDW, 95%CI = 0.0076–0.0612) and 0.0151 (MHR, 95%CI = 0.0034–0.0426), respectively. The mediating effect was 0.393 (95%CI = 0.0179–0.958). In the regression model 3 among group of TNNAL  >  0, higher concentration of urinary TNNAL was associated with increasing tooth loss (IRR = 1.079, 95%CI = 1.047–1.112). When group of TNNAL  >  0 was further divided into subgroups according to the smoking status, a positive correlation was found between TNNAL and missing teeth among current active-smokers (Model 3: IRR = 1.508, 95%CI = 1.341–1.696), as well as passive former-smokers (Model 3: IRR = 1.127, 95%CI = 1.021–1.243). Conclusions Our study revealed a positive relationship between urinary TNNAL and tooth loss, and further demonstrated the mediating role of RDW and MHR between the TNNAL and the number of missing teeth in the whole popualtion. These findings will provide new theoretical insights for policy formulation and clinical therapeutic for the target prevention and intervention of related diseases.

During the last decade in Korea, urinary cotinine concentrations in non-current smokers have decreased, making it difficult to distinguish secondhand smoke (SHS) exposure from nonsmokers because of overlapping values between non-current smokers with and without SHS exposure. Additionally, the importance of smoking status verification to avoid misclassification is increasing with the increased use of e-cigarettes. We developed a novel index combining urinary cotinine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and evaluated its diagnostic performance for the classification of smoking status using the KNHANES VII dataset. A total of 10,116 and 5575 Korean participants aged >19 years with measured urinary cotinine concentrations were enrolled in a training set and validation set, respectively. When using 4.0 as the cutoff value for distinguishing current smokers from non-current smokers, urinary cotinine∙NNAL showed a better diagnostic performance than urinary cotinine or urinary NNAL. Among e-cigarette users, urinary cotinine∙NNAL showed more accurate classification rates than urinary NNAL. Furthermore, urinary cotinine∙NNAL had measurable values in non-current smokers, whereas urinary cotinine had unmeasurable values in one-fourth of all participants. This study shows that urinary cotinine∙NNAL might be a useful biomarker for smoking status verification and trend monitoring of tobacco smoking exposure with increased use of e-cigarettes.

The free radicals produced by cigarette smoking are responsible for tissue damage, heart and lung diseases, and carcinogenesis. The effect of tobacco on the central nervous system (CNS) has received increased attention nowadays in research. Therefore, to explore the molecular interaction of cigarette smoke carcinogens (CSC) 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanol (NNAL), 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK), and N′-nitrosonornicotine (NNN) with well-known targets of CNS-related disorders, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) enzymes, a cascade of the computational study was conducted including molecular docking and molecular dynamics simulations (MDS). The investigated results of NNAL+AChE complex , NNK+AChE complex , and NNK+BuChE complex based on intermolecular energies (∆G) were found to −8.57 kcal/mol, −8.21 kcal/mol, and −8.08 kcal/mol, respectively. MDS deviation and fluctuation plots of the NNAL and NNK interaction with AChE and BuChE have shown significant results. Further, Molecular Mechanics Poisson-Boltzmann Surface Area (MM‐PBSA) results shown the best total binding energy ( Binding ∆G) −87.381 (+/−13.119) kJ/mol during NNK interaction with AChE. Our study suggests that CSC is well capable of altering the normal biomolecular mechanism of CNS; thus, obtained data could be useful to design extensive wet laboratory experimentation to know the effects of CSC on human CNS. Graphical abstract

Effects of environmental tobacco smoke (ETS) exposure on children and adolescent health outcomes have been attracted more and more attention. In the present study, we seek to examine the gender-specific difference association of environmental smoke exposure biomarkers and developmental disorders in children and adolescents aged 6–15 years. US nationally representative sample collected from the National Health and Nutrition Examination Survey (NHANES) 2007–2014 was enrolled ( N = 4428). Developmental disorders (DDs) are defined as a positive answer to the question, “Does your child receive special education or early intervention services?” Serum cotinine and urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) were utilized as acute and chronic exposure biomarkers of ETS, respectively. Participants with serum cotinine >0.015 ng/mL were considered as with acute ETS exposure, and participants with creatinine-adjusted NNAL >0.0006 ng/mL were considered as with chronic ETS exposure. A survey logistic regression model was used to estimate the association between ETS exposure biomarkers and DDs. Additive interaction was utilized to examine the interaction of gender and biomarkers of ETS. Overall, approximately 9% of children were defined as DDs, and 65% of children had serum cotinine and urinary NNAL levels above the limit of detection. In the adjusted models, the association of ETS exposure biomarkers with DDs was only observed in girls. Girls with low cotinine levels and high urinary NNAL levels had 2.074 (95% CI: 1.012–4.247) and 1.851 (95% CI: 1.049–3.265) times higher odds of being DDs than those without ETS exposure, respectively. However, the effects of boys and NNAL exposure on DDs have additively interacted. Our findings first provided strong evidence for gender differences in the association between two tobacco metabolites and DDs in children, disclosing the public health implications and economic burdens of environmental tobacco smoke exposure.

The purpose of this study was to determine the relationship between urinary cotinine and total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) concentrations in non-smoking staff and the indoor levels of fine particles (PM2.5) in hospitality venues that allow smoking, with respect to demographic and indoor environmental factors. We evaluated 62 hospitality venues that allowed smoking in Seoul, Korea. A real-time aerosol monitor was used to measure indoor PM2.5 concentrations. Field technicians recorded indoor environmental characteristics. One non-smoking staff member in each hospitality venue was tested for urinary cotinine and total NNAL concentrations. Demographic characteristics were obtained from self-reported staff questionnaires. Natural-log (ln)-transformed PM2.5 concentrations were significantly correlated with the ln-transformed cotinine (r = 0.31) and the total NNAL concentrations (r = 0.32). In multivariable regression analysis, the urinary cotinine concentrations of the staff members were significantly correlated with indoor PM2.5 concentrations; those with the highest concentrations were more likely to be women or staff members that worked in venues with a volume <375 m3. Total NNAL concentrations were significantly correlated only with indoor PM2.5 concentrations. Indoor PM2.5 may be used as an indicator for urinary cotinine and total NNAL concentrations in non-smoking staff members in hospitality venues that allow smoking.

High levels of NNAL, the tobacco smoke exposure (TSE) biomarker of the carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), indicate future cancer risk. A prior study of smokers’ children revealed NNAL levels as high as active smokers. Therefore, we conducted a case series to examine the sociodemographics, TSE and clinical patterns, and other TSE biomarker levels in 9 children with extreme NNAL levels of >200 pg/ml to generate hypotheses and explore potential causes and implications. We identified 0 to 4-year-olds who presented to an emergency setting and lived with ⩾1 smoker who were part of a parental tobacco cessation trial (n = 461). Of these children, 52 had urinary NNAL, cotinine, and N-oxides results (n = 52). Nine children (17.3%) had NNAL levels >200 pg/ml, ranging from 206.4 to 1399.0 pg/ml (Median (Mdn) = 489.2 pg/ml; Interquartile Range (IQR) = 222.7-1289.3 pg/ml). The cotinine Mdn (IQR) was 38.5 (10.3-102.2) ng/ml and the N-oxides Mdn (IQR) = 93.8 (24.7-109.6) pg/ml. While all biomarker levels were alarmingly high, these young children would not have been flagged for very high cancer risk based on urinary cotinine levels alone. This underscores the critical role of comprehensive TSE biomarker measurement in capturing different TSE exposure patterns and assessing children’s future risk for cancer and other TSE-related morbidities.

Carcinogenic tobacco-specific nitrosamines (TSNAs) such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are found only in tobacco and derived products. Food and Drug Administration of the United States (US FDA) lists NNK as one of the 93 harmful and potentially harmful constituents (HPHCs) found in tobacco products and tobacco smoke. The aim of this study was to use the urinary concentration of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a major metabolite of NNK, to quantitatively estimate exposure to NNK in the US general population. In 2011–2012, the Centers for Disease Control and Prevention’s National Health and Nutrition Examination Survey (NHANES) collected urine and serum samples from a representative sample of US residents. We used a serum cotinine cutoff of 10 ng/ml with combination of questionnaire data to select non-users from cigarette users and used self-reported data to determine different tobacco product user groups. We estimated the absorbed total daily dose of NNK using a probabilistic method based on a two-compartment model. The geometric mean (GM) for the daily dose of NNK among smokers aged 12–16 years was significantly higher than that for non-users at the same age stage exposed to second-hand smoke (SHS) ( P <0.001). Among those exposed to SHS, the GM for daily dose of NNK in young children (6–11 years) was nearly three times of those for adults in the age range 21–59 years. Among cigarette users, non-Hispanic Whites had the highest NNK daily dose and Mexican Americans had the lowest levels. Exclusive snuff or chewing product users had significantly higher daily dose of NNK than did cigarette smokers. Our study found that the maximum daily dose of NNK for children aged from 6 to 11 years and that for a significant percentage of cigarette users, chewing product and snuff users were higher than an estimated provisional “reference” risk level.

Home smoking bans can reduce tobacco smoke exposure, but little is known about the impact for Chinese American household pairs. In this study of 202 household pairs with low acculturation, 53.9% reported a home smoking ban, 31.7% had inconsistent reports, and 14.4% reported no ban. With decreasing home smoking ban enforcement, more nonsmokers had tobacco smoke exposure (66.1%–86.2%) as measured by the tobacco-specific nitrosamine biomarker urine NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol). Despite reported bans, about one-quarter of nonsmokers still reported tobacco smoke exposure at home (23.6%–30%) within the past 2 months and three-quarters reported outdoor exposure. In adjusted regression analyses of geometric mean NNAL ratios, nonsmokers in households with no ban had over two times higher levels than nonsmokers in households with a ban: adjusted log NNAL ratio = 2.70 (95% CI 1.21, 6.03). Higher smoker NNAL level and nonsmoker English fluency were also significantly associated with nonsmoker NNAL levels. Nonsmoker levels in households with an inconsistent ban were not significantly different compared to those with a ban. Although home smoking bans were generally associated with lower NNAL levels, tobacco smoke exposure in this immigrant population with low English proficiency was higher than that of the general population. From a health equity standpoint, there is a need for broader implementation and enforcement of comprehensive smoke-free policies.

Cigarette smoke can increase oxidative DNA damage. The main component in cigarette smoke is nicotine. Nicotine is metabolized to cotinine, which can be regarded as a biomarker for measuring exposure to tobacco smoke. A sensitive, simple, and robust method based on on-line solid-phase extraction liquid chromatography with tandem mass spectrometry (on-line SPE LC-MS/MS) has been developed and validated for the simultaneous determination of 8-OHdG and cotinine. The matrix effects of 8-OHdG and cotinine were measured at 97.1 and 91.7 %, with values for CV at 4.4 and 4.2 %, respectively. The limits of detection of 8-OHdG and cotinine were 10.0 and 5.5 pg mL −1 , and the limits of quantification were 40.0 and 20.0 pg mL −1 , respectively. The total run time was 12 min. We quantified 8-OHdG and cotinine in the urine of 80 male subjects. The results showed the levels of 8-OHdG and cotinine in smokers were significantly higher than that in non-smokers. Furthermore, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronide conjugate (defined as total NNAL) are the nitrosation metabolites of nicotine. In this study, urinary levels of 8-OHdG and cotinine were well correlated with urinary levels of total NNAL. This is also the first study to focus on the future risk of oxidative stress from exposure to cigarette smoke based on the relationship between 8-OHdG levels, cotinine levels, and total NNAL concentrations in the urine of humans. Graphical Abstract On-line SPE LC-MS/MS for the simultaneous determination of 8-OHdG and cotinine in human urine

Tobacco heating products (THPs) are a potentially safer alternative to combustible cigarette smoking. Through continued use, THPs may reduce smoking-related disease risk, whilst maintaining the sensorial experience and nicotine delivery sought by smokers. While literature evidence of the biological effects of THP aerosol exposure is increasing, there remains a knowledge gap with respect to substantiation of THP reduced risk potential in longer term real-life use. This randomized, multi-centre, controlled clinical study will test the hypotheses that following a switch from combustible cigarettes to a THP for 1 year, participants will experience a sustained reduction in exposure to tobacco-related toxicants that will lead to favourable changes in health effect indicators associated with smoking-related disease development. Changes in such indicators will be contextualized against smoking cessation and never-smoker cohorts. Up to 280 participants who do not intend to quit smoking will be randomized to continued combustible smoking (arm A, up to n = 80) or a commercially available THP (arm B n = 200). Furthermore, up to 190 participants with a high intent to quit smoking will undergo smoking cessation (arm D), and 40 never smokers will serve as a control group (arm E). Recruitment numbers were determined to be sufficient to achieve n = 50 in arms A, B and D, at study end. Enrolment started in March 2018 and the trial is scheduled to be completed in March 2020. Data from this study will be a valuable addition to the growing body of evidence in the field of understanding the individual and public health impact of THPs.Clinical Trial Registration: https://www.isrctn.com/ISRCTN81075760