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Objective: This study measured anatalline and nicotelline, two minor tobacco alkaloids, to discriminate between exclusive smokeless tobacco (SLT) use, exclusive electronic nicotine delivery systems (ENDS) use, exclusive cigarette use, dual SLT and cigarette use, and dual ENDS and cigarette use., Methods: N  = 664 urine samples from participants in the Population Assessment of Tobacco and Health Study were analyzed for anatalline and nicotelline. Geometric means and 95% confidence intervals were calculated for biomarker levels and their ratios. Non-parametric Receiver Operating Characteristic analyses were used to determine optimal cut-points of natural log-transformed biomarker ratios for distinguishing between tobacco use groups., Results: The anatalline/nicotelline ratio distinguished exclusive cigarette from exclusive SLT use (threshold = 18.1, sensitivity = 89.3%, specificity = 86.4%, AUC = 0.90), and exclusive SLT from exclusive ENDS use (threshold = 12.8, sensitivity = 96.4%, specificity = 76.3%, AUC = 0.90) very well, but had reduced sensitivity and specificity when distinguishing exclusive cigarette from exclusive ENDS or any dual use with cigarettes., Conclusions: This research fills a gap in understanding the public health consequences of SLT and ENDS use by providing objective measures that can signal use of these products alone or in combination with cigarettes.

Introduction: The Population Assessment of Tobacco and Health (PATH) Study is a longitudinal cohort study on tobacco use behavior, attitudes and beliefs, and tobacco-related health outcomes, including biomarkers of tobacco exposure in the U.S. population. In this report we provide a summary of urinary nicotine metabolite measurements among adult users and non-users of tobacco from Wave 1 (2013-2014) of the PATH Study., Methods: Total nicotine and its metabolites including cotinine, trans-3'-hydroxycotinine (HCTT), and other minor metabolites were measured in more than 11 500 adult participants by liquid chromatography tandem mass spectrometry methods. Weighted geometric means (GM) and least square means from statistical modeling were calculated for non-users and users of various tobacco products., Results: Among daily users, the highest GM concentrations of nicotine, cotinine and HCTT were found in exclusive smokeless tobacco users, and the lowest in exclusive e-cigarette users. Exclusive combustible product users had intermediate concentrations, similar to those found in users of multiple products (polyusers). Concentrations increased with age within the categories of tobacco users, and differences associated with gender, race/ethnicity and educational attainment were also noted among user categories. Recent (past 12 months) former users had GM cotinine concentrations that were more than threefold greater than never users., Conclusions: These urinary nicotine metabolite data provide quantification of nicotine exposure representative of the entire US adult population during 2013-2014 and may serve as a reference for similar analyses in future measurements within this study., Implications: Nicotine and its metabolites in urine provide perhaps the most fundamental biomarkers of recent nicotine exposure. This report, based on Wave 1 of the Population Assessment of Tobacco and Health (PATH) Study, provides the first nationally representative data describing urinary nicotine biomarker concentrations in both non-users, and users of a variety of tobacco products including combustible, e-cigarette and smokeless products. These data provide a urinary biomarker concentration snapshot in time for the entire US population during 2013-2014, and will provide a basis for comparison with future results from continuing, periodic evaluations in the PATH Study., (Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco 2021.)

Background: Determine the overall, sex-, and racially/ethnically-appropriate population-level cotinine and total nicotine equivalents (TNE-2, the molar sum of the two major nicotine metabolites) cut-points to distinguish tobacco users from nonusers across multiple definitions of use (e.g., exclusive vs. polytobacco, and daily vs. non-daily)., Methods: Using Wave 1 (2013-2014) of the U.S. Population Assessment of Tobacco and Health (PATH) Study, we conducted weighted Receiver Operating Characteristic (ROC) analysis to determine the optimal urinary cotinine and TNE-2 cut-points, stratified by sex and race/ethnicity., Results: For past 30-day exclusive cigarette users, the cotinine cut-point that distinguished them from nonusers was 40.5 ng/mL, with considerable variation by sex (male: 22.2 ng/mL; female: 43.1 ng/mL) and between racial/ethnic groups (non-Hispanic other: 5.2 ng/mL; non-Hispanic black: 297.0 ng/mL). A similar, but attenuated, pattern emerged when assessing polytobacco cigarette users (overall cut-point = 39.1 ng/mL, range = 5.5 ng/mL-80.4 ng/mL) and any tobacco users (overall cut-point = 39.1 ng/mL, range = 4.8 ng/mL-40.0 ng/mL). Using TNE-2, which is less impacted by racial differences in nicotine metabolism, produced a comparable pattern of results although reduced the range magnitude., Conclusions: Because of similar frequency of cigarette use among polytobacco users, overall cut-points for exclusive cigarette use were not substantially different from cut-points that included polytobacco cigarette use or any tobacco use. Results revealed important differences in sex and race/ethnicity appropriate cut-points when evaluating tobacco use status and established novel urinary TNE-2 cut-points., Impact: These cut-points may be used for biochemical verification of self-reported tobacco use in epidemiologic studies and clinical trials., (©2021 American Association for Cancer Research.)

Introduction: The tobacco-specific nitrosamines (TSNAs) are an important group of carcinogens found in tobacco and tobacco smoke. To describe and characterize the levels of TSNAs in the Population Assessment of Tobacco and Health (PATH) Study Wave 1 (2013-2014), we present four biomarkers of TSNA exposure: N'-nitrosonornicotine, N'-nitrosoanabasine, N'-nitrosoanatabine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) which is the primary urinary metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone., Methods: We measured total TSNAs in 11 522 adults who provided urine using automated solid-phase extraction coupled to isotope dilution liquid chromatography-tandem mass spectrometry. After exclusions in this current analysis, we selected 11 004 NNAL results, 10 753 N'-nitrosonornicotine results, 10 919 N'-nitrosoanatabine results, and 10 996 N'-nitrosoanabasine results for data analysis. Geometric means and correlations were calculated using SAS and SUDAAN., Results: TSNA concentrations were associated with choice of tobacco product and frequency of use. Among established, every day, exclusive tobacco product users, the geometric mean urinary NNAL concentration was highest for smokeless tobacco users (993.3; 95% confidence interval [CI: 839.2, 1147.3] ng/g creatinine), followed by all types of combustible tobacco product users (285.4; 95% CI: [267.9, 303.0] ng/g creatinine), poly tobacco users (278.6; 95% CI: [254.9, 302.2] ng/g creatinine), and e-cigarette product users (6.3; 95% CI: [4.7, 7.9] ng/g creatinine). TSNA concentrations were higher in every day users than in intermittent users for all the tobacco product groups. Among single product users, exposure to TSNAs differed by sex, age, race/ethnicity, and education. Urinary TSNAs and nicotine metabolite biomarkers were also highly correlated., Conclusions: We have provided PATH Study estimates of TSNA exposure among US adult users of a variety of tobacco products. These data can inform future tobacco product and human exposure evaluations and related regulatory activities., (Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco 2020.)

Background: Monitoring population-level toxicant exposures from smokeless tobacco (SLT) use is important for assessing population health risks due to product use. In this study, we assessed tobacco biomarkers of exposure (BOE) among SLT users from the Wave 1 (2013-2014) of the Population Assessment of Tobacco and Health (PATH) Study., Methods: Urinary biospecimens were collected from adults ages 18 and older. Biomarkers of nicotine, tobacco-specific nitrosamines (TSNA), polycyclic aromatic hydrocarbons (PAH), volatile organic compounds (VOC), metals, and inorganic arsenic were analyzed and reported among exclusive current established SLT users in comparison with exclusive current established cigarette smokers, dual SLT and cigarette users, and never tobacco users., Results: In general, SLT users ( n = 448) have significantly higher concentrations of BOE to nicotine, TSNAs, and PAHs compared with never tobacco users; significant dose-response relationships between frequency of SLT use and biomarker concentrations were also reported among exclusive SLT daily users. Exclusive SLT daily users have higher geometric mean concentrations of total nicotine equivalent-2 (TNE2) and TSNAs than exclusive cigarette daily smokers. In contrast, geometric mean concentrations of PAHs and VOCs were substantially lower among exclusive SLT daily users than exclusive cigarette daily smokers., Conclusions: Our study produced a comprehensive assessment of SLT product use and 52 biomarkers of tobacco exposure. Compared with cigarette smokers, SLT users experience greater concentrations of some tobacco toxicants, including nicotine and TSNAs., Impact: Our data add information on the risk assessment of exposure to SLT-related toxicants. High levels of harmful constituents in SLT remain a health concern., (©2020 American Association for Cancer Research.)

Background: Nicotine acts as major alkaloid of all tobacco products including smokeless tobacco (SLT) forms. The mode of SLT consumption is in the form of chewing under the cheek or lip and induced biochemical alterations in the plasma, saliva, and urine., Materials and Methods: The smokeless tobacco products like Raja or blue bull tobacco brands are widely consumed by human male volunteers under the age of 18-30 years for the period of 3 years consisting of 30g per day. The concentrations of nicotine and cotinine in samples of plasma, saliva, and urine are quantified by the method of HPLC. The remaining variables of plasma are evaluated by auto analyzer and spectrophotometric methods., Results: The analysis of results presented that significant increase in the levels of nicotine and cotinine in plasma, saliva, and urine of chewing tobacco users. The lipid profile (Cholesterol, triglycerides, HDL-C, and LDL-C), liver marker enzymes (SGOT, SGPT, and ALP), kidney markers (Creatinine, urea, and uric acid), glucose, and the remaining variables are present within normal range observed in SLT users. The lipid peroxidation (LPO), nitric oxide (NO) (NO2 and NO3), protein carbonyls (PCO), and peroxynitrites (ONOO-) are reported to be higher levels in the plasma of experimental subjects in comparison with normal controls. The various brands of tobacco varieties (Raja, madhu chhap, hans chhap, miraj, badshah, blue bull, and swagat gold tobacco) are presented., Conclusion: The chewing tobacco users exhibited greater amounts of nicotine and cotinine are at risk of cardiovascular due to nicotine has cardiovascular effects, and oral cancer disease complications in the future for chronic consumption of smokeless tobacco products  due to the presence of carcinogens of tobacco-specific N-nitrosamines.

Introduction: Reducing smoking in pregnancy was a primary outcome in our Building Blocks trial of the Family Nurse Partnership. We calibrated maternal reports of smoking using cotinine values derived from urine samples to assess tobacco use. This involves identifying the extent to which an individual accurately reports smoking and requires complete and synchronized data collection over time. However, some urine samples may be missed or collected at a different time from self-report (non-synchronized., Methods: We used statistical validation processes to address both non-synchronized and incomplete data. First, we examined consistency in reporting behaviors at baseline and follow-up for participants grouped by extent of non-synchronized time of collection. Second, we used data from complete cases to infer values for mothers with missing urine samples at follow-up. We then used Markov chain transition rate matrix constructed to assess the robustness of such inferences., Results: Maternal underreporting and overreporting of smoking were consistent across the 870 participants grouped by different levels of noncontemporary data collection (Breslow-Day test: p = .24; chi-square test: p = .69). Using participants' baseline reporting behaviors to infer their follow-ups provided comparable smoking outcomes (4.5 cigarettes/day with SD of 5.5) to the simulated counterparts (4.5 cigarettes/day with SD of 6.0)., Conclusion: We have demonstrated consistent reporting behavior over time and minimal impact due to nonaligned follow-up urine sample collection. For studies collecting smoking data, this proposed method provided a pragmatic solution to facilitate the calibration process of self-reported tobacco use and retain adequate power without introducing undue bias., Implications: Synchronized and completed data collection is essential but very often hard to achieve in smoking related studies. When violated, proper statistical validation process should be followed to minimize the potential bias and loss of power in trial analyses. For this purpose, we provided the Building Block trial as an example to demonstrate how to deal with the non-synchronization and incompleteness issues in data collection., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Cigarette smoking is associated with an increase in cardiovascular disease risk, attributable in part to reactive volatile organic chemicals (VOCs). However, little is known about the extent of VOC exposure due to the use of other tobacco products., Methods: We recruited 48 healthy, tobacco users in four groups: cigarette, smokeless tobacco, occasional users of first generation e-cigarette and e-cigarette menthol and 12 healthy nontobacco users. After abstaining for 48 h, tobacco users used an assigned product. Urine was collected at baseline followed by five collections over a 3-h period to measure urinary metabolites of VOCs, nicotine, and tobacco alkaloids., Results: Urinary levels of nicotine were ≃2-fold lower in occasional e-cigarette and smokeless tobacco users than in the cigarette smokers; cotinine and 3-hydroxycotinine levels were similar in all groups. Compared with nontobacco users, e-cigarette users had higher levels of urinary metabolites of xylene, cyanide, styrene, ethylbenzene, and benzene at baseline and elevated urinary levels of metabolites of xylene, N,N-dimethylformamide, and acrylonitrile after e-cigarette use. Metabolites of acrolein, crotonaldehyde, and 1,3-butadiene were significantly higher in smokers than in users of other products or nontobacco users. VOC metabolite levels in smokeless tobacco group were comparable to those found in nonusers with the exception of xylene metabolite-2-methylhippuric acid (2MHA), which was almost three fold higher than in nontobacco users., Conclusions: Smoking results in exposure to a range of VOCs at concentrations higher than those observed with other products, and first generation e-cigarette use is associated with elevated levels of N,N-dimethylformamide and xylene metabolites., Implications: This study shows that occasional users of first generation e-cigarettes have lower levels of nicotine exposure than the users of combustible cigarettes. Compared with combustible cigarettes, e-cigarettes, and smokeless tobacco products deliver lower levels of most VOCs, with the exception of xylene, N,N-dimethylformamide, and acrylonitrile, whose metabolite levels were higher in the urine of e-cigarette users than nontobacco users. Absence of anatabine in the urine of e-cigarette users suggests that measuring urinary levels of this alkaloid may be useful in distinguishing between users of e-cigarettes and combustible cigarettes. However, these results have to be validated in a larger cohortcomprised of users of e-cigarettes of multiple brands., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cigarette smoking (CS) and betel quid (BQ) chewing are two known risk factors that have synergistic potential for the enhancing the development of oral squamous cell carcinoma (OSCC) in Taiwan. Most mutagens and carcinogens are metabolically activated by cytochrome P450 (CYP450) to exert their mutagenicity or carcinogenicity. Previous studies have shown that metabolic activation of the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), by CYP2A6 activity determines NNK-induced carcinogenesis. In addition, safrole affects cytochrome P450 activity in rodents. However, the effect of BQ safrole on the metabolism of tobacco-specific NNK and its carcinogenicity remains elusive. This study demonstrates that safrole (1 mg/kg/d) induced CYP2A6 activity, reduced urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) levels, and increased NNK-induced DNA damage, including N7-methylguanine, 8-OH-deoxyguanosine and DNA strand breaks in a Syrian golden hamster model. Furthermore, altered NNK metabolism and increased NNK-induced DNA damage were also observed in healthy subjects with CS and BQ chewing histories compared to healthy subjects with CS histories. In conclusion, BQ containing safrole induced tobacco-specific NNK metabolic activation, resulting in higher NNK-induced genotoxicity. This study provides valuable insight into the synergistic mechanisms of CS- and BQ-induced OSCC., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Surveys have been instrumental in describing adolescent use of tobacco, electronic cigarettes (e-cigarettes), and marijuana. However, objective biomarker data are lacking. We compared adolescent self-reported use to urinary biomarkers., Methods: From April 2017 to April 2018, adolescents 12 to 21 years old completed an anonymous questionnaire regarding tobacco, e-cigarette, and marijuana use and provided a urine sample. Urine was analyzed for biomarkers cotinine, total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, and tetrahydrocannabinolic acid (THCA)., Results: Of 517 participants, 2.9% reported using tobacco, 14.3% e-cigarettes, and 11.4% marijuana in the past week. Only 2% reporting no smoking had total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol levels above cutoff (14.5 pg/mL); 2% of non-e-cigarette users had cotinine above cutoff (10 ng/mL); 2% of those denying marijuana use had THCA above cutoff (10 ng/mL). Daily e-cigarette users showed significantly higher median cotinine than nondaily users (315.4 [interquartile range (IQR) 1375.9] vs 1.69 ng/mL [IQR 28.2]; P < .003). Overall, 40% who reported using nicotine-free products had cotinine >10 ng/mL. Pod users' median cotinine was significantly higher than in nonpod users (259.03 [IQR 1267.69] vs 1.61 ng/mL [IQR 16.3]; P < .003). Median THCA among daily marijuana users was higher than in nondaily users (560.1 [IQR 1248.3] vs 7.2 ng/mL [IQR 254.9]; P = .04). Sixty-one percent of those with cotinine >10 ng/mL vs 39% of those with cotinine<10 ng/mL had THCA >10 ng/mL ( P < .001)., Conclusions: Adolescents' self-report correlated with measured urinary biomarkers, but subjects were unaware of their nicotine exposure. More frequent e-cigarette and pod use correlated with elevated biomarkers. Co-use of tobacco, e-cigarettes, and marijuana was corroborated by higher THCA in those with higher cotinine., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Goniewicz received a research grant from Pfizer and served as an advisory board member to Johnson & Johnson, pharmaceutical companies that manufacture smoking cessation medications. Additionally, Dr Goniewicz was a member of the National Academies of Sciences, Engineering, and Medicine Committee on the Review of the Health Effects of Electronic Nicotine Delivery Systems, which wrote the report; the report was funded by the US Food and Drug Administration, but the US Food and Drug Administration was not involved in the drafting or review of the National Academies of Sciences, Engineering, and Medicine report or this manuscript. The policy implications written in this article are the views of the authors and do not necessarily represent the views of the other members of the committee; the National Academies of Sciences, Engineering, and Medicine; or the US Food and Drug Administration; the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Background: Cotinine, a nicotine metabolite, is used to measure tobacco use and exposure, but recommended cut-offs to differentiate tobacco users from those exposed through the environment range from 3 to 58 ng/ml in serum, and 2.5 to 550 ng/ml in urine. Cut-offs may differ by ethnicity, sex and age. As data from adults in Africa are scarce, our aim was to evaluate cut-offs for serum and urine cotinine that best predict self-reported tobacco use in South African adults., Methods: Two datasets were explored: African-PREDICT (n = 941 black and white healthy young adults, 20-30 years, serum cotinine); and WHO SAGE Wave 2 (n = 604 adults, 18-102 years, urine cotinine). Population specific cut-offs (ROC analyses) were compared with published cut-offs and self-reported tobacco use., Results: Overall, 19% (293 of 1545) reported current tobacco use. The following cotinine cut-offs showed the highest sensitivity and specificity: serum ≥15 ng/ml in black and white men, and white women; serum ≥10 ng/ml in black women; urine ≥300 ng/ml for black, mixed ancestry, and older adults (50-plus years); urine ≥500 ng/ml for younger adults (18-49 years). Specificity was lower for urine than for serum cotinine., Conclusion: Our study suggests that a serum cotinine level of ≥15 ng/ml and a urine cotinine level of ≥300 ng/ml best distinguish current tobacco users from non-users generally in the South African adult population., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: How carcinogen exposure varies across users of different, particularly noncigarette, tobacco products remains poorly understood., Methods: We randomly selected 165 participants of the Golestan Cohort Study from northeastern Iran: 60 never users of any tobacco, 35 exclusive cigarette, 40 exclusive (78% daily) waterpipe, and 30 exclusive smokeless tobacco (nass) users. We measured concentrations of 39 biomarkers of exposure in 4 chemical classes in baseline urine samples: tobacco alkaloids, tobacco-specific nitrosamines (TSNA), polycyclic aromatic hydrocarbons (PAH), and volatile organic compounds (VOC). We also quantified the same biomarkers in a second urine sample, obtained 5 years later, among continuing cigarette smokers and never tobacco users., Results: Nass users had the highest concentrations of tobacco alkaloids. All tobacco users had elevated TSNA concentrations, which correlated with nicotine dose. In both cigarette and waterpipe smokers, PAH and VOC biomarkers were higher than never tobacco users and nass users, and highly correlated with nicotine dose. PAH biomarkers of phenanthrene and pyrene and two VOC metabolites (phenylmercapturic acid and phenylglyoxylic acid) were higher in waterpipe smokers than in all other groups. PAH biomarkers among Golestan never tobacco users were comparable to those in U.S. cigarette smokers. All biomarkers had moderate to good correlations over 5 years, particularly in continuing cigarette smokers., Conclusions: We observed two patterns of exposure biomarkers that differentiated the use of the combustible products (cigarettes and waterpipe) from the smokeless product. Environmental exposure from nontobacco sources appeared to contribute to the presence of high levels of PAH metabolites in the Golestan Cohort., Impact: Most of these biomarkers would be useful for exposure assessment in a longitudinal study., (©2019 American Association for Cancer Research.)

Objective: Foetuses and neonates of women who use tobacco are exposed to nicotine and tobacco-derived carcinogens. We determined the relationship between urine biomarkers of tobacco toxicant exposure postpartum and in the neonates of Alaska Native (AN) women, comparing smokers and smokeless tobacco (ST) users, including iqmik, a homemade ST product., Methods: AN women, including 36 smokers, 9 commercial ST and 16 iqmik users their neonates participated. Urine from the woman at the time of delivery and her neonate's first urine were analysed for cotinine, the major metabolite of nicotine, and 4-(methylnitrosamino)-1-(3) pyridyl-1-butanol (NNAL), a tobacco-specific carcinogen biomarker., Results: Maternal urine cotinine and neonatal urine cotinine were strongly correlated in all tobacco use groups (r from 0.83 to 0.9, p < 0.002). Correlations between maternal cotinine and neonatal NNAL were moderately strong for cigarettes and commercial smokeless but weaker for iqmik users (r 0.73, 0.6 and 0.36, respectively)., Conclusion: Correlations between maternal and neonatal biomarkers of tobacco toxicant exposure vary, dependent on tobacco product use., Significance: This study provides novel data on biomarkers of tobacco exposure among postpartum AN women and their neonates. The results could be useful to guide future epidemiological studies of health risks associated with use of various tobacco products during pregnancy.

Introduction: Tobacco smoke contains more than 7,000 chemicals, including known carcinogens, such as tobacco-specific nitrosamines (TSNAs). TSNA levels in cigarettes vary considerably within and across markets; however, the extent to which these different TSNA levels translate into differences in human exposure and risk remains unclear. The current study sought to examine TSNA exposure among Canadian tobacco users., Methods: Data from the 2007-2009 Canadian Health Measures Survey were used to measure levels of urinary NNAL [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol], a metabolite of the TSNA NNK [4-(methylnitrosamino-1-(3-pyridyl)-1-butanone], among tobacco users (n = 507). Geometric mean concentrations of total urinary NNAL and creatinine-corrected total urinary NNAL were calculated. A linear regression model was used to examine predictors of urinary levels of NNAL., Results: The mean population level of total urinary NNAL and creatinine-corrected total urinary NNAL was 71.2 pg/ml and 82.0 pg/mg creatinine, respectively. NNAL levels were higher among older respondents (p = .02), among females (p = .04), and among those with greater daily cigarette consumption (p < .0001), greater levels of urinary free cotinine (p < .0001), and greater levels of urinary creatinine (p < .0001). Overall, the mean level of urinary total NNAL among Canadian tobacco users was approximately one fourth that of their U.S. counterparts., Conclusions: The study findings provide the first nationally representative characterization of TSNA exposure among Canadian tobacco users. Although the findings indicate marked differences in TSNA exposure between Canadian and American populations of tobacco users, it is not known whether these differences in exposure translate into differences in risk., (© The Author 2014. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The purpose of this case-control study is to investigate the association between stress and periodontitis by determining stress biomarkers in saliva and urine and to determine whether oral hygiene, gingival inflammation, and tooth loss are correlated with stress biomarkers in patients with periodontitis., Methods: A total of 77 patients (41 cases [with periodontitis] and 36 controls) participated in this study. Periodontal examination findings included probing depth, clinical attachment loss, bleeding on probing (BOP), plaque index (PI), and tooth loss. Secretory immunoglobulin (sIg)A and cortisol were determined in saliva. Cortisol, creatinine-adjusted cortisol, metanephrine, normetanephrine, and total metanephrines were measured in urine., Results: Urinary metanephrine (P = 0.013) and total metanephrine (P = 0.023) levels were higher in the case group. In cases, salivary cortisol was correlated with PI (r = 0.464, P <0.01), BOP (r = 0.401, P <0.05), and tooth loss (r = 0.245, P <0.05). Urinary metanephrine levels above the median were associated with a 3.4-fold higher risk of periodontitis (95% confidence interval [CI] = 1.1 to 10.2; P = 0.029), with an 82% increase in risk for each increment of 0.05 µg/24 hours. Urinary total metanephrine levels above the median were associated with a five-fold higher risk of periodontitis (95% CI = 1.6 to 15.7; P = 0.006)., Conclusions: The present results offer new evidence of the association between urinary concentrations of catecholamine metabolites (metanephrine and total metanephrines) and chronic periodontitis. Salivary IgA level showed no statistical difference between the cases and controls. Salivary cortisol levels in the patients with periodontitis were correlated with worse PI, higher gingival inflammation, and greater tooth loss.