Human cases of avian influenza virus (AIV) infections are associated with an age-specific disease burden. As the influenza virus N2 neuraminidase (NA) gene was introduced from avian sources during the 1957 pandemic, we investigate the reactivity of N2 antibodies against A(H9N2) AIVs. Serosurvey of healthy individuals reveal the highest rates of AIV N2 antibodies in individuals aged ≥65 years. Exposure to the 1968 pandemic N2, but not recent N2, protected against A(H9N2) AIV challenge in female mice. In some older adults, infection with contemporary A(H3N2) virus could recall cross-reactive AIV NA antibodies, showing discernable human- or avian-NA type reactivity. Individuals born before 1957 have higher anti-AIV N2 titers compared to those born between 1957 and 1968. The anti-AIV N2 antibodies titers correlate with antibody titers to the 1957 N2, suggesting that exposure to the A(H2N2) virus contribute to this reactivity. These findings underscore the critical role of neuraminidase immunity in zoonotic and pandemic influenza risk assessment.

Background: Volatile organic compounds (VOCs) are major components of air pollution and tobacco smoke, two known risk factors for cardiovascular diseases. VOCs are ubiquitous in the environment and originate from a wide range of sources, including the burning of biomass, fossil fuels, and consumer products. Direct evidence for associations between specific VOCs and ischemic heart disease (IHD) mortality in the general population is scarce. Methods: In a case-cohort study (stratified by age groups, sex, residence, and tobacco smoking), nested within the population-based Golestan cohort study (n = 50,045, 40–75 years, 58% women, enrollment: 2004–2008) in northeastern Iran, we measured urinary concentrations of 20 smoking-related VOC biomarkers using ultra high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. We calculated hazard ratio (HR) and 95% confidence interval (CI) for their associations with IHD mortality during follow-up to 2018, using Cox regression models adjusted for age, ethnicity, education, marital status, body mass index, physical activity, wealth, and urinary cotinine. Results: There were 575 non-cases from random subcohort and 601 participants who died from IHD, mean (standard deviation) age, 58.2 (9.3) years, with a median of 8.4 years follow-up. Significant associations [3rd vs. 1st tertile, HR (95% CI), P for trend] were observed between biomarkers of acrylamide [1.68(1.05,2.69), 0.025], acrylonitrile [2.06(1.14,3.72), 0.058], acrolein [1.98(1.30,3.01), 0.003 and 2.44(1.43,4.18), 0.002], styrene/ethylbenzene [1.83(1.19,2.84), 0.007 and 1.44(1.01,2.07), 0.046], dimethylformamide/methylisocyanate [2.15(1.33,3.50), 0.001], and 1,3butadiene [2.35(1.52,3.63),<0.001] and IHD mortality. These associations were independent of tobacco smoking, and they were only present in the non-smoking subgroup. Conclusion: Our findings provide direct evidence for associations between exposure to several VOCs with widespread household and commercial use and IHD mortality many years after these exposures. These results highlight the importance of VOC exposure in the general population as a risk factor for cardiovascular diseases and underline the importance of bio-monitoring non-tobacco VOC exposure. © 2024

Liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS-MS) with stable isotope-labeled internal standards (SIL-ISs) is the gold standard for quantitative analysis of drugs and metabolites in complex biological samples. Significant isotopic effects associated with deuterium labeling often cause the deuterated IS to elute at a different retention time from the target analyte, diminishing its capability to compensate for matrix effects. In this study, we systematically compared the analytical performance of deuterated (2H) SIL-IS to non-deuterated (13C and 15N) SIL-ISs for quantifying urinary 2-methylhippuric acid (2MHA) and 4-methylhippuric acid (4MHA), biomarkers of xylenes exposure, with an LC-ESI-MS-MS assay. Analytical method comparison between ISs demonstrated a quantitative bias for urinary 2MHA results, with concentrations generated with 2MHA-[2H7] on average 59.2% lower than concentrations generated with 2MHA-[13C6]. Spike accuracy, measured by quantifying the analyte-spiked urine matrix and comparing the result to the known spike concentration, determined that 2MHA-[2H7] generated negatively biased urinary results of -38.4%, whereas no significant bias was observed for 2MHA-[13C6]. Post-column infusion demonstrated that ion suppression experienced by 2MHA and 2MHA-[13C6] was not equally experienced by 2MHA-[2H7], explaining the negatively biased 2MHA results. The quantitation of urinary 4MHA results between ISs exhibited no significant quantitative bias. These results underscore the importance of the careful selection of ISs for targeted quantitative analysis in complex biological samples.

BACKGROUND: Infective endocarditis (IE) has increased in rural states such as West Virginia (WV) with high injection drug use. IE is medically managed with antimicrobial treatment alone or combined with surgical treatment. This study aimed to characterize the predictors associated with surgical treatment and rates of inpatient mortality and readmission among IE patients in WV's rural centers. METHODS: This retrospective review of electronic health records includes all adults hospitalized for IE at major rural tertiary cardiovascular centers in WV during 2014-2018. Descriptive statistics were presented on demographics, history of injection drug use, clinical characteristics, and hospital utilization by surgery status, and multivariable logistic regression examined the association of surgery with key predictor variables, generating odds ratios (OR). RESULTS: Of the 780 patients with IE, 38% had surgery, with a 26-fold increase in patients undergoing surgery between 2014-2018. Comparing surgery and non-surgery patients revealed significant differences. Surgery patients were significantly younger (median age 35.6 vs. 40.5 years; p<0.001); had higher rates of drug use history (80% vs. 65%; p<0.001), psychiatric disorders (57% vs. 31%; p<0.001), and readmissions (18% vs.12%; p = 0.015). Surgery patients had lower rates of discharge against medical advice (11% vs.17%; p = 0.028) and in-hospital mortality (5% vs.12%; p<0.001). In the multivariable logistic regression, surgery was associated with injection drug use (OR: 1.9; 95% CI:1.09-3. 3), indications for surgery (OR: 1.68; 95% CI:1.48-1.91), left-sided IE (OR: 2.14; 95%CI:1.43-3.19) and later years (OR:3.75; 95%CI:2.5-5.72). CONCLUSION: This study characterizes the predictors associated with surgical treatment and rates of inpatient mortality and readmission among IE patients across rural WV. The decision to perform cardiac surgery on IE patients is complex. Results with increased injection drug use-associated IE emphasize the importance of comprehensive care by a multidisciplinary team for optimal management of patients with IE.

Background. Benzene is a known human carcinogen. Human exposure to benzene can be assessed by measuring trans, trans-muconic acid (MUCA) in urine. Golestan Province in northeastern Iran has been reported to have high incidence of esophageal cancer linked to the use of tobacco products. This manuscript evaluates the urinary MUCA concentrations among the participants of the Golestan Cohort Study (GCS).Methods. We analyzed MUCA concentration in 177 GCS participants' urine samples and performed nonparametric pairwise multiple comparisons to determine statistically significant difference among six different product use groups. Mixed effects model was fitted on 22 participants who exclusively smoked cigarette and 51 participants who were classified as nonusers. The urinary MUCA data were collected at the baseline and approximately five years later, and intraclass correlation coefficient (ICC) was calculated from the model.Results. Compared with nonusers, tobacco smoking was associated with higher urinary MUCA concentrations. Based on the nonparametric test of pairwise multiple comparisons, MUCA concentrations among participants who smoked combusted tobacco products were statistically significantly higher compared to nonusers. Urinary MUCA collected five years apart from the same individuals showed moderate reliability (ICC = 0.41), which was expected given the relatively short half-life (∼6 hrs) of MUCA.Conclusion. Our study revealed that tobacco smoke was positively associated with increased levels of urinary MUCA concentration, indicating that it is a significant source of benzene exposure among GCS participants.

BACKGROUND: Studying carcinogens in tobacco and non-tobacco sources may be key to understanding the pathogenesis and geographic distribution of esophageal cancer. METHODS: Golestan Cohort Study (GCS) has been conducted since 2004 in a region with high rates of esophageal squamous cell carcinoma (ESCC). For this nested study, the cases comprised of all incident cases by Jan 1, 2018; controls were matched to the case by age, sex, residence, time in cohort, and tobacco use. We measured urinary concentrations of 33 exposure biomarkers of nicotine, polycyclic aromatic hydrocarbons (PAHs), volatile organic compounds (VOCs), and tobacco-specific nitrosamines (TSNAs). We used conditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (95%CI) for associations between the 90th versus the 10th percentiles of the biomarker concentrations and incident ESCC. RESULTS: Among individuals who did not currently use tobacco (148 cases/163 controls), two acrolein metabolites, two acrylonitrile metabolites, one propylene oxide metabolite and one 1,3-butadiene metabolite were significantly associated with incident ESCC (adjusted ORs between 1.8 and 4.3). Among tobacco users (57 cases/63 controls), metabolites of two other VOCs (styrene and xylene) were associated with ESCC (ORs= 6.2 and 9.0). In tobacco users, two TSNAs (NNN and N'-Nitrosoanatabine) were also associated with ESCC. Suggestive associations were seen with some PAHs (especially 2-hydroxynaphthalene) in non-users of tobacco products and other TSNAs in tobacco users. CONCLUSION: These novel associations based on individual-level data and samples collected many years before cancer diagnosis, from a population without occupational exposure, have important public health implications.

BACKGROUND: Biomarkers of exposure are tools for understanding the impact of tobacco use on health outcomes if confounders like demographics, use behavior, biological half-life and other sources of exposure are accounted for in the analysis. METHODS: We performed multiple regression analysis of longitudinal measures of urinary biomarkers of alkaloids, tobacco-specific nitrosamines, polycyclic aromatic hydrocarbons, volatile organic compounds (VOC), and metals to examine the sample-to-sample consistency in Waves 1 and 2 of the Population Assessment of Tobacco and Health Study including demographic characteristics and use behavior variables of persons who smoked exclusively. Regression coefficients, within- and between-person variance, and intra-class correlation coefficients were compared to biomarker smoking-nonsmoking population mean ratios and biological half-lives. RESULTS: Most biomarkers were similarly associated with sex, age, race/ethnicity, and product use behavior. The biomarkers with larger smoking-nonsmoking population mean ratios had greater regression coefficients related to recency of exposure. For VOC and alkaloid metabolites, longer biological half-life was associated with lower within-person variance. For each chemical class studied, there were biomarkers that demonstrated good intra-class correlation coefficients. CONCLUSIONS: For most of the biomarkers of exposure reported in the PATH Study, for people who smoke cigarettes exclusively, associations are similar between urinary biomarkers of exposure and demographic and use behavior covariates. Biomarkers of exposure within-subject consistency is likely associated with non-tobacco sources of exposure and biological half-life. IMPACT: Biomarkers measured in the PATH Study provide consistent sample-to-sample measures from which to investigate the association of adverse health outcomes with the characteristics of cigarettes and their use.

Assessing benzene exposure is a public health priority due to its deleterious health effects and ubiquitous industrial and environmental sources of exposure. Phenyl mercapturic acid (PhMA) is a commonly used urinary biomarker to assess benzene exposure. However, recent work has identified significant interlaboratory variation in urinary PhMA concentrations related to methodological differences. In this study, we present urinary 6-hydroxy-2,4-cyclohexadienyl mercapturic acid (pre-PhMA), a metabolite that undergoes acid-catalyzed dehydration to form PhMA, as a novel and specific urinary biomarker for assessing benzene exposure. We developed and validated the first quantitative liquid chromatography-tandem mass spectrometry assay for measuring urinary concentrations of pre-PhMA. The pH effect on the method of ruggedness testing determined that pre-PhMA is stable across the normal human urine pH range and that neutral conditions must be maintained throughout quantification for robust and accurate measurement of urinary pre-PhMA concentrations. The method exhibited below 2 ng/mL sensitivity for pre-PhMA, linearity over three orders of magnitude, and precision and accuracy within 10%. Urinary pre-PhMA concentrations were assessed in 369 human urine samples. Smoking individuals exhibited elevated levels of pre-PhMA compared to non-smoking individuals. Furthermore, the relationship between benzene exposure and urinary pre-PhMA levels was explored by examining the correlation of pre-PhMA with 2-cyanoethyl mercapturic acid, a smoke exposure biomarker. The urinary biomarkers exhibited a positive correlation (r = 0.720), indicating that pre-PhMA levels increased with benzene exposure. The results of this study demonstrate that urinary pre-PhMA is a rugged and effective novel biomarker of benzene exposure that can be widely implemented for future biomonitoring studies.

OBJECTIVE: Volatile organic compounds (VOCs) are used in the sterilization and manufacture of medical equipment. These compounds have high vapor pressures with low water solubility and are emitted as gases from solids or liquids. They can be mutagenic, neurotoxic, genotoxic, and/or carcinogenic. Safe limits of exposure are not known for neonates. This study examined determinants of exposure in newborns undergoing cardiac surgery. METHODS: Twenty metabolites of 16 VOCs (e.g., xylene, cyanide, acrolein, acrylonitrile, N, N-dimethylformamide, 1,3-butadiene, styrene, and benzene) were measured as metabolites in daily urine samples collected from 10 neonates undergoing cardiac operations (n = 150 samples). Metabolites were quantified using reversed-phase ultra-high performance liquid chromatography and electrospray ionization tandem mass spectrometry. Repeated measures ANOVA was performed for each metabolite to examine associations with use of medical devices. RESULTS: At least 3 metabolites were detected in every sample. The median number of metabolites detected in each sample was 14 (range: 3-15). In a model controlling for other factors, the use of extracorporeal membrane oxygenation was associated with significantly (p ≤ 0.05) higher metabolite levels of acrolein, acrylonitrile, ethylene oxide, propylene oxide, styrene, and ethylbenzene. Patients breathing ambient air had higher levels of metabolites of acrolein, xylene, N,N-dimethylformamide, methyl isocyanate, cyanide, 1,3-butadiene (all p≤ 0.05). CONCLUSIONS: Exposure to volatile organic compounds is pervasive in newborns undergoing cardiac surgery. Sources of exposure likely include medical devices and inhalation from the air in the intensive care unit. The contribution of VOC exposure during cardiac surgery in newborns to adverse outcomes warrants further evaluation.

Firefighters are at an increased risk of cancer due to their occupational exposure to combustion byproducts, especially when those compounds penetrate the firefighter personal protective equipment (PPE) ensemble. This has led to questions about the impact of base layers (i.e., shorts vs. pants) under PPE ensembles. This study asked 23 firefighters to perform firefighting activities while wearing one of three different PPE ensembles with varying degrees of protection. Additionally, half of the firefighters unzipped their jackets after the scenario while the other half kept their jackets zipped for five additional minutes. Several volatile organic compound (VOC) and naphthalene air concentrations outside and inside of hoods, turnout jackets, and turnout pants were evaluated; biological (urinary and exhaled breath) samples were also collected. VOCs and naphthalene penetrated the three sampling areas (hoods, jackets, pants). Significant (p-value < 0.05) increases from pre- to post-fire for some metabolites of VOCs (e.g., benzene, toluene) and naphthalene were found. Firefighters wearing shorts and short sleeves absorbed higher amounts of certain compounds (p-value < 0.05), and the PPE designed with enhanced interface control features appeared to provide more protection from some compounds. These results suggest that firefighters can dermally absorb VOCs and naphthalene that penetrate the PPE ensemble.

BACKGROUND: Evidence suggests that rates of occupational injuries in the US are decreasing. As several different occupational injury surveillance systems are used in the US, more detailed investigation of this trend is merited. Furthermore, studies of this decrease remain descriptive and do not use inferential statistics. The aim of this study was to provide both descriptive and inferential statistics of temporal trends of occupational injuries treated in US emergency departments (EDs) for 2012 to 2019. METHODS: Monthly non-fatal occupational injury rates from 2012 to 2019 were estimated using the national electronic injury surveillance system-occupational supplement (NEISS-Work) dataset, a nationally representative sample of ED-treated occupational injuries. Rates were generated for all injuries and by injury event type using monthly full-time worker equivalent (FTE) data from the US Current Population Survey as a denominator. Seasonality indices were used to detect seasonal variation in monthly injury rates. Trend analysis using linear regression adjusted for seasonality was conducted to quantify changes in injury rates from 2012 to 2019. RESULTS: Occupational injuries occurred at an average rate of 176.2 (95% CI =  ± 30.9) per 10,000 FTE during the study period. Rates were highest in 2012 and declined to their lowest level in 2019. All injury event types occurred at their highest rate in summer months (July or August) apart from falls, slips, and trips, which occurred at their highest rate in January. Trend analyses indicated that total injury rates decreased significantly throughout the study period (- 18.5%; 95% CI =  ± 14.5%). Significant decreases were also detected for injuries associated with contact with foreign object and equipment (- 26.9%; 95% CI =  ± 10.5%), transportation incidents (- 23.2%; 95% CI =  ± 14.7%), and falls, slips, and trips (- 18.1%; 95% CI =  ± 8.9%). CONCLUSIONS: This study supports evidence that occupational injuries treated in US EDs have decreased since 2012. Potential contributors to this decrease include increased workplace mechanization and automation, as well as changing patterns in US employment and health insurance access.

We developed surveillance guidance for COVID-19 in 9 temporary camps for displaced persons along the Thailand-Myanmar border. Arrangements were made for testing of persons presenting with acute respiratory infection, influenza-like illness, or who met the Thailand national COVID-19 Person Under Investigation case definition. In addition, testing was performed for persons who had traveled outside of the camps in outbreak-affected areas or who departed Thailand as resettling refugees. During the first 18 months of surveillance, May 2020-October 2021, a total of 6,190 specimens were tested, and 15 outbreaks (i.e., >1 confirmed COVID-19 cases) were detected in 7 camps. Of those, 5 outbreaks were limited to a single case. Outbreaks during the Delta variant surge were particularly challenging to control. Adapting and implementing COVID-19 surveillance measures in the camp setting were successful in detecting COVID-19 outbreaks and preventing widespread disease during the initial phase of the pandemic in Thailand.

While the thirdhand smoke (THS) residue from tobacco smoke has been recognized as a distinct public health hazard, there are currently no gold standard biomarkers to differentiate THS from secondhand smoke (SHS) exposure. This study used machine learning algorithms to assess which combinations of biomarkers and reported tobacco smoke exposure measures best differentiate children into three groups: no/minimal tobacco smoke exposure (NEG); predominant THS exposure (TEG); and mixed SHS and THS exposure (MEG). Participants were 4485 nonsmoking 3-17-year-olds from the National Health and Nutrition Examination Survey 2013-2016. We fitted and tested random forest models, and the majority (76%) of children were classified in NEG, 16% were classified in TEG, and 8% were classified in MEG. The final classification model based on reported exposure, biomarker, and biomarker ratio variables had a prediction accuracy of 95%. This final model had prediction accuracies of 100% for NEG, 88% for TEG, followed by 71% for MEG. The most important predictors were the reported number of household smokers, serum cotinine, serum hydroxycotinine, and urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). In the absence of validated biomarkers specific to THS, comprehensive biomarker and questionnaire data for tobacco smoke exposure can distinguish children exposed to SHS and THS with high accuracy.

BACKGROUND: The existing World Health Organization (WHO) pneumonia case management guidelines rely on clinical symptoms and signs for identifying, classifying, and treating pneumonia in children up to 5 years old. We aimed to collate an individual patient-level data set from large, high-quality pre-existing studies on pneumonia in children to identify a set of signs and symptoms with greater validity in the diagnosis, prognosis, and possible treatment of childhood pneumonia for the improvement of current pneumonia case management guidelines. METHODS: Using data from a published systematic review and expert knowledge, we identified studies meeting our eligibility criteria and invited investigators to share individual-level patient data. We collected data on demographic information, general medical history, and current illness episode, including history, clinical presentation, chest radiograph findings when available, treatment, and outcome. Data were gathered separately from hospital-based and community-based cases. We performed a narrative synthesis to describe the final data set. RESULTS: Forty-one separate data sets were included in the Pneumonia Research Partnership to Assess WHO Recommendations (PREPARE) database, 26 of which were hospital-based and 15 were community-based. The PREPARE database includes 285839 children with pneumonia (244323 in the hospital and 41516 in the community), with detailed descriptions of clinical presentation, clinical progression, and outcome. Of 9185 pneumonia-related deaths, 6836 (74%) occurred in children <1 year of age and 1317 (14%) in children aged 1-2 years. Of the 285839 episodes, 280998 occurred in children 0-59 months old, of which 129584 (46%) were 2-11 months of age and 152730 (54%) were males. CONCLUSIONS: This data set could identify an improved specific, sensitive set of criteria for diagnosing clinical pneumonia and help identify sick children in need of referral to a higher level of care or a change of therapy. Field studies could be designed based on insights from PREPARE analyses to validate a potential revised pneumonia algorithm. The PREPARE methodology can also act as a model for disease database assembly.

BACKGROUND: The US President's Emergency Plan for AIDS Relief's (PEPFAR) first implemented pre-exposure prophylaxis (PrEP) for HIV prevention through the Determined, Resilient, Empowered, AIDS-Free, Mentored and Safe (DREAMS) partnership in 2016. PrEP is a critical intervention to achieve the main objective of DREAMS, reducing new HIV infections among 15-14 year old adolescent girls and young women (AGYW) in 15 high HIV burdened countries. METHODS: We describe uptake of PrEP among AGYW in PEPFAR. Most PrEP programs screened persons who tested HIV-negative for eligibility and offered PrEP as part of combination prevention with follow-up, including repeat HIV testing and counseling, at 3-month intervals. Platforms providing comprehensive services for AGYW were also leveraged. We examined two PEPFAR monitoring indicators, using the FY20Q4 Monitoring, Evaluation, Reporting (MER) indicator dataset to assess progress in PrEP uptake, and descriptive narratives to understand successes and challenges from fiscal year 2017 to 2020. To assess coverage, we calculated the PrEP to Need ratio (PnR) using a published methodology. RESULTS: From FY2017 to FY2020, 576570 total clients initiated PrEP and the number of PEPFAR countries offering PrEP doubled from 12 to 24. Of 360073 (62% of total) initiations among women, 52% were among AGYW with steady increases from year to year. Among all AGYW, 20-24-year-old women represented a significantly higher proportion of PrEP initiators than adolescents (15-19years) (64 versus 36%, P  < 0.05). Of all 186985 PrEP initiations among AGYW, 99% were in DREAMS countries. Barriers, such as low demand and adherence, were addressed through outreach efforts, including mobile sites, use of technology to educate and support AGYW, media campaigns, and engaging peers in program implementation. We saw a 2.5-fold increase in PrEP uptake among AGYW from 2018 to 2019; by 2020, all DREAMS countries were implementing PrEP. However, PrEP coverage among AGYW in DREAMS countries remains low (PnR range: 0-4.1); only two have a PnR greater than 1 where there were more PrEP users than new HIV diagnoses. CONCLUSION: PrEP uptake among AGYW has grown since 2016; however, challenges remain. Tools to improve adherence are needed to improve PrEP persistence among AGYW. National policies to facilitate greater PrEP uptake among adolescents would be beneficial. A greater need for PrEP in DREAMS countries is evident and if realized, will contribute to epidemic control.

INTRODUCTION: Firefighters are exposed to volatile organic compounds (VOCs) during structural fire responses and training fires, several of which (e.g., benzene, acrolein, styrene) are known or probable carcinogens. Exposure studies have found that firefighters can absorb chemicals like benzene even when self-contained breathing apparatus (SCBA) are worn, suggesting that dermal absorption contributes to potentially harmful exposures. However, few studies have characterized VOC metabolites in urine from firefighters. OBJECTIVES: We quantified VOC metabolites in firefighters' urine following live firefighting activity across two field studies. METHODS: In two separate controlled field studies, spot urine was collected before and 3 h after firefighters and firefighter students responded to simulated residential and training fires. Urine was also collected from instructors from the training fire study before the first and 3 h after the last training scenario for each day (instructors led three training scenarios per day). Samples were analyzed for metabolites of VOCs to which firefighters may be exposed. RESULTS: In the residential fire study, urinary metabolites of xylenes (2MHA), toluene (BzMA), and styrene (MADA) increased significantly (at 0.05 level) from pre- to post-fire. In the training fire study, MADA concentrations increased significantly from pre- to post-fire for both firefighter students and instructors. Urinary concentrations of benzene metabolites (MUCA and PhMA) increased significantly from pre- to post-fire for instructors, while metabolites of xylenes (3MHA+4MHA) and acrolein (3HPMA) increased significantly for firefighter students. The two highest MUCA concentrations measured post-shift from instructors exceeded the BEI of 500 μg/g creatinine. CONCLUSIONS: Some of the metabolites that were significantly elevated post-fire are known or probable human carcinogens (benzene, styrene, acrolein); thus, exposure to these compounds should be eliminated or reduced as much as possible through the hierarchy of controls. Given stringent use of SCBA, it appears that dermal exposure contributes in part to the levels measured here.

Limited data are available for how biomarkers of tobacco exposure (BOE) change when cigarette smokers transition to using electronic nicotine delivery systems (ENDS). Using biomarker data from Waves 1 (20132014) and 2 (20142015) of the PATH Study, we examined how mean BOE concentrations, including metabolites of nicotine, tobacco-specific nitrosamines (TSNA), polycyclic aromatic hydrocarbons (PAH), and volatile organic compounds (VOCM) and metals, changed when 2475 adult smokers transitioned to using ENDS or quit tobacco products. Exclusive smokers who transitioned to dual use had a significant decrease in NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol), but not nicotine metabolites, most PAHs, metals, or VOCMs. Exclusive smokers who became dual users had significant reductions in total nicotine equivalents, NNAL, and 2CyEMA (acrylonitrile metabolite), but only in those who reduced cigarettes per day (CPD) by >=50%. Smokers who transitioned to exclusive ENDS use had significant reductions in most TSNAs, PAHs, and VOCMs; however, nicotine metabolites did not decrease in dual users who became exclusive ENDS users. Smokers who quit tobacco use had significant decreases in nicotine metabolites, all TSNAs, most PAHs, and most VOCMs. Cigarette smokers who became dual users did not experience significant reductions in most BOEs. Reductions were impacted by changes in CPD. However, transitioning from smoking to no tobacco or exclusive ENDS use was associated with reduced exposure to most BOEs measured. Future analyses could incorporate additional waves of PATH data and examine changes in biomarker exposure by ENDS device type and CPD. 2022 by the authors. Licensee MDPI, Basel, Switzerland.

2-carbamoylethyl mercapturic acid (2CaEMA, N-Acetyl-S-carbamoylethyl-L-cysteine) is a urinary metabolite and exposure biomarker of acrylamide, which is a harmful volatile organic compound found in cigarette smoke and in some foods. The goal of this study was to determine the association between cigarette smoking and urinary 2CaEMA concentrations among the U.S. population while considering potential dietary sources of acrylamide intake and demographics. We measured 2CaEMA concentrations in urine specimens collected during the National Health and Nutrition Examination Survey 2011-2012, 2013-2014, and 2015-2016 cycles from eligible participants 18 years and older (n=5443) using liquid chromatography/tandem mass spectrometry. We developed multiple regression models with urinary 2CaEMA concentrations as the dependent variable and sex, age, race/Hispanic origin, reported primary sources of dietary acrylamide intake, and cigarette smoke exposure as independent variables. This study demonstrates that cigarette smoking is strongly associated with urinary 2CaEMA, suggests that cigarette smoking is likely a primary source of acrylamide exposure, and provides a baseline measure for 2CaEMA in the U.S. population.

BACKGROUND: Cotinine is a widely used biomarker for classifying cigarette smoking status. However, cotinine does not differentiate between the use of combustible and noncombustible tobacco products. The increasing use of noncombustible tobacco drives the need for a complementary biomarker for distinguishing cigarette smokers from users of noncombustible tobacco products. METHODS: We evaluated the urinary acrylonitrile metabolite, 2CyEMA, as a biomarker of exposure to cigarette smoke in the U.S. population-representative data from the National Health and Nutritional Examination Survey (NHANES). Smoking status was categorized based on the recent tobacco use questionnaire. The receiver operating characteristic (ROC) curve analysis was performed to identify optimal cutoff concentrations by maximizing Youden's J index. The area under the curve (AUC) was used to compare 2CyEMA effectiveness with respect to serum cotinine. RESULTS: The overall cutoff concentration for the classification of cigarette smokers from nonsmokers was 7.32 ng/mL with high sensitivity and specificity (≥0.925). When stratified by demographic variables, the cutoff concentrations varied among subgroups based on age, sex, and race/Hispanic origin. Non-Hispanic Blacks had the highest cutoff concentration (15.3 ng/mL), and Hispanics had the lowest (4.63 ng/mL). Females had higher cutoff concentrations (8.80 ng/mL) compared to males (6.10 ng/mL). Among different age groups, the cutoff concentrations varied between 4.63 ng/mL (21 - 39 years old) and 10.6 ng/mL (for ≥60 years old). We also explored the creatinine adjusted cutoff values. CONCLUSIONS: 2CyEMA is an effective biomarker for distinguishing cigarette smokers from nonsmokers (users of noncombustible tobacco products or nonusers). IMPACT: Increasing use of noncombustible tobacco products, including e-cigarettes, complicates differentiating smokers from nonsmokers; we document that urinary 2CyEMA accurately differentiates cigarette smokers from the noncombustible tobacco product users and nonusers. Also, it is the first paper to report urinary 2CyEMA cutoff values based on U.S. representative population data.

Background: 2-Hydroxyethyl mercapturic acid (2HEMA, N-acetyl-S-(2-hydroxyethyl)-L-cysteine) is a urinary metabolite of several volatile organic compounds including acrylonitrile and ethylene oxide, which are found in cigarette smoke.Methods: We measured 2HEMA concentrations in urine specimens collected during the National Health and Nutrition Examination Survey (2011-2016) from eligible participants aged >12 years (N = 7,416). We developed two multiple linear regression models to characterize the association between cigarette smoking and 2HEMA concentrations wherein the dependent variable was 2HEMA concentrations among participants who exclusively smoked cigarettes at the time of specimen collection and the independent variables included sex, age, race/ethnicity, creatinine, diet, and either cigarettes smoked per day (CPD) or serum cotinine.Results: We detected 2HEMA in 85% of samples tested among exclusive cigarette smokers, and only 40% of specimens from nonsmokers. When compared to exclusive cigarette smokers who smoked 1-9 CPD, smoking 10-19 CPD was associated with 36% higher 2HEMA (p < 0.0001) and smoking >19 CPD was associated with 61% higher 2HEMA (p < 0.0001). Additionally, 2HEMA was positively associated with serum cotinine.Conclusions: This study demonstrates that cigarette smoking intensity is associated with higher urinary 2HEMA concentrations and is likely a major source of acrylonitrile and/or ethylene oxide exposure.

Biomarkers of tobacco exposure are known to be associated with disease risk but previous studies are limited in number and restricted to certain regions. We conducted a nested case–control study examining baseline levels and subsequent lung cancer incidence among current male exclusive cigarette smokers in the Golestan Cohort Study in Iran. We calculated geometric mean biomarker concentrations for 28 matched cases and 52 controls for the correlation of biomarker levels among controls and for adjusted odds’ ratios (ORs) for lung cancer incidence by biomarker concentration, accounting for demographic characteristics, smoking quantity and duration, and opium use. Lung cancer cases had higher average levels of most biomarkers including total nicotine equivalents (TNE-2), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and 3-hydroxyfluorene (3-FLU). Many biomarkers correlated highly with one another including TNE-2 with NNAL and N-Acetyl-S-(2-cyanoethyl)-L-cysteine (2CYEMA), and N-Acetyl-S-(4-hydroxy-2-buten-1-yl)-L-cysteine (t4HBEMA) with N-Acetyl-S-(3-hydroxypropyl-1-methyl)-L-cysteine (3HMPMA) and N-Acetyl-S-(4-hydroxy-2-methyl-2-buten-1-yl)-L-cysteine (4HMBEMA). Lung cancer risk increased with concentration for several biomarkers, including TNE-2 (OR = 2.22, 95% CI = 1.03, 4.78) and NNN (OR = 2.44, 95% CI = 1.13, 5.27), and estimates were significant after further adjustment for demographic and smoking characteristics for 2CYEMA (OR = 2.17, 95% CI = 1.03, 4.55), N-Acetyl-S-(2-carbamoylethyl)-L-cysteine (2CAEMA) (OR = 2.14, 95% CI = 1.01, 4.55), and N-Acetyl-S-(2-hydroxypropyl)-L-cysteine (2HPMA) (OR = 2.85, 95% CI = 1.04, 7.81). Estimates were not significant with adjustment for opium use. Concentrations of many biomarkers were higher at the baseline for participants who subsequently developed lung cancer than among the matched controls. Odds of lung cancer were higher for several biomarkers including with adjustment for smoking exposure for some but not with adjustment for opium use. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Hairdressers are exposed to volatile organic compounds (VOCs), many of which have been linked to acute and chronic health effects. Those hairdressers serving an ethnic clientele may potentially experience disproportionate exposures from frequent use of products containing VOCs or different VOC concentrations contained in products which are marketed to the specific needs of their clientele. However, no biomonitoring studies have investigated occupational exposures in this population. In the present pilot study, we sought to characterize concentrations and exposure determinants for 28 VOC biomarkers in post-shift urine samples among 23 hairdressers primarily serving an ethnic clientele. VOC biomarker concentrations among hairdressers of color were compared to concentrations among a comparison group of 17 office workers and a representative sample of women participating in the U.S. National Health and Nutrition Examination Survey. VOC biomarkers were detected in all hairdressers with higher concentrations observed among hairdressers serving a predominantly Black versus Latino clientele, and among hairdressers overall versus office workers and women in the U.S. general population. Median biomarker concentrations for acrolein,1,3-butadiene, and xylene in hairdressers were more than twice as high as those observed among office workers. Median concentrations for 1-bromopropane, acrolein and 1,3-butadiene were more than four times higher among all hairdressers compared to those reported among women in the U.S. general population. Select salon services (e.g., sister locs, flat ironing, permanent hair coloring, permanent waves or texturizing, Brazilian blowout or keratin treatment, etc.) were also associated with higher VOC biomarker concentrations among hairdressers. This pilot study represents the first biomonitoring analysis to characterize VOC exposures among women hairdressers of color and to provide evidence that this occupational population may experience elevated VOC exposures compared to women in the U.S. general population. Results from our study represent an important first step in elucidating occupational VOC exposures in this understudied occupational group. Larger studies among a racially and ethnically diverse cohort of hairdressers are warranted to confirm our findings and inform future exposure interventions in this understudied occupational population.

Increased interest in volatile organic compound (VOC) exposure has led to an increased need for consistent, systematic, and informative naming of VOC metabolites. As analytical methods have expanded to include many metabolites in a single assay, the number of acronyms in use for a single metabolite has expanded in an unplanned and inconsistent manner due to a lack of guidance or group consensus. Even though the measurement of VOC metabolites is a well-established means to investigate exposure to VOCs, a formal attempt to harmonize acronyms amongst investigators has not been published. The aim of this work is to establish a system of acronym naming that provides consistency in current acronym usage and a foundation for creating acronyms for future VOC metabolites.

1,3-Butadiene is a volatile organic compound with a gasoline-like odor that is primarily used as a monomer in the production of synthetic rubber. The International Agency for Research on Cancer has classified 1,3-butadiene as a human carcinogen. We assessed 1,3-butadiene exposure in the U.S. population by measuring its urinary metabolites N-acetyl-S-(3,4-dihydroxybutyl)-L-cysteine (34HBMA), N-acetyl-S-(1-hydroxymethyl-2-propenyl)-L-cysteine (1HMPEMA), N-acetyl-S-(2-hydroxy-3-butenyl)-L-cysteine (2HBEMA), and N-acetyl-S-(4-hydroxy-2-buten-1-yl)-L-cysteine (t4HBEMA). Urine samples from the 2011-2016 National Health and Nutrition Examination Survey were analyzed for 1,3-butadiene metabolites using ultrahigh-performance liquid chromatography/tandem mass spectrometry. 34HBMA and t4HBEMA were detected in >96% of the samples; 1HMPEMA and 2HBEMA were detected in 0.66% and 9.84% of the samples, respectively. We used sample-weighted linear regression models to examine the influence of smoking status (using a combination of self-reporting and serum-cotinine data), demographic variables, and diet on biomarker levels. The median t4HBEMA among exclusive smokers (31.5 µg/g creatinine) was higher than in non-users (4.11 µg/g creatinine). Similarly, the median 34HBMA among exclusive smokers (391 µg/g creatinine) was higher than in non-users (296 µg/g creatinine). Furthermore, smoking 1-10, 11-20, and >20 cigarettes per day (CPD) was associated with 475%, 849%, and 1,143% higher t4HBEMA (p < 0.0001), respectively. Additionally, smoking 1-10, 11-20, and >20 CPD was associated with 33%, 44%, and 102% higher 34HBMA (p < 0.0001). These results provide significant baseline data for 1,3-butadiene exposure in the U.S. population, and demonstrate that tobacco smoke is a major exposure source.

BACKGROUND: Acrylonitrile is a possible human carcinogen that is used in polymers and formed in tobacco smoke. We assessed acrylonitrile exposure in the US population by measuring its urinary metabolites N-acetyl-S-(4-hydroxy-2-methyl-2-buten-1-yl)-L-cysteine (2CYEMA) and N-acetyl-S-(1-cyano-2-hydroxyethyl)-L-cysteine (1CYHEMA) in participants from the 2011-2016 National Health and Nutrition Examination Survey. OBJECTIVE: To assessed acrylonitrile exposure using population-based biomonitoring data of the US civilian, non-institutionalized population. METHODS: Laboratory data for 8057 participants were reported for 2CYEMA and 1CYHEMA using ultrahigh-performance liquid chromatography/tandem mass spectrometry. Exclusive tobacco smokers were distinguished from non-users using a combination of self-reporting and serum cotinine data. We used multiple linear regression models to fit 2CYEMA concentrations with sex, age, race/Hispanic origin, and tobacco user group as predictor variables. RESULTS: The median 2CYEMA level was higher for exclusive cigarette smokers (145 µg/g creatinine) than for non-users (1.38 µg/g creatinine). Compared to unexposed individuals (serum cotinine ≤0.015 ng/ml) and controlling for confounders, presumptive second-hand tobacco smoke exposure (serum cotinine >0.015 to ≤10 ng/ml and 0 cigarettes per day, CPD) was significantly associated with 36% higher 2CYEMA levels (p < 0.0001). Smoking 1-10 CPD was significantly associated with 6720% higher 2CYEMA levels (p < 0.0001). SIGNIFICANCE: We show that tobacco smoke is an important source of acrylonitrile exposure in the US population and provide important biomonitoring data on acrylonitrile exposure.

Xylenes are aromatic hydrocarbons used for industrial applications such as the production of petrochemicals and plastics. Acute xylene exposures can negatively impact health through neurotoxicity and irritation of respiratory and dermal tissues. We quantified urinary biomarkers of xylene exposure [2-methylhippuric acid (2MHA) and a mixture of 3- and 4-methylhippuric acids (34MH)] in a representative sample of the U.S. population. Spot urine obtained during the National Health and Nutrition Examination Survey 2005-2006 and 2011-2016 was analyzed using ultra-high-performance liquid chromatography/tandem mass spectrometry. Exclusive smokers were distinguished from non-users using a combination of self-report and serum cotinine data. The median 2MHA and 34MH levels were higher for exclusive smokers (100 µg/g and 748 µg/g creatinine, respectively) than for non-users (27.4 µg/g and 168 µg/g creatinine, respectively). Participants who smoked cigarettes had significantly higher 2MHA and 34MH levels (p < 0.0001) than unexposed participants. Smoking 1-10, 11-20, and >20 cigarettes per day (CPD) was significantly associated with 181%, 339% and 393% higher 2MHA levels, respectively. For 34MH, smoking 1-10, 11-20, and >20 CPD was significantly associated with 201%, 398%, and 471% higher 34MH levels, respectively. We confirm that tobacco smoke is a significant source of xylene exposure as measured by urinary 2MHA and 34MH levels.

Benzene is a known genotoxic carcinogen linked to many hematological abnormalities. S-phenylmercapturic acid (PHMA, N-Acetyl-S-(phenyl)-L-cysteine, CAS# 4775-80-8) is a urinary metabolite of benzene and is used as a biomarker to assess benzene exposure. Pre-S-phenylmercapturic acid (pre-PHMA) is a PHMA precursor that dehydrates to PHMA at acidic pH. Published analytical methods that measure urinary PHMA adjust urine samples to a wide range of pH values using several types of acid, potentially leading to highly variable results depending on the concentration of pre-PHMA in a sample. Information is lacking on the variation in sample preparation among laboratories regularly measuring PHMA and the effect of those differences on PHMA quantitation in human urine samples. To investigate the differences in PHMA quantitation, we conducted an inter-laboratory comparison that included the analysis of 50 anonymous human urine samples (25 self-identified smokers, 25 self-identified non-smokers), quality control samples, and commercially available reference samples in five laboratories using different analytical methods to determine which sample preparation methods are currently in use and compare PHMA results. Observed urinary PHMA concentrations were proportionally higher at lower pH and results for anonymous urine samples varied widely among the methods. The method with the neutral preparation pH yielded results about 60% lower than the method using the most acidic conditions. Samples spiked with PHMA showed little variation, suggesting that the variability in results in human urine samples across methods is driven by the acid-mediated conversion of pre-PHMA to PHMA.

Volatile organic compounds (VOCs) are ubiquitous in the environment. In the United States (U.S.), tobacco smoke is the major non-occupational source of exposure to many harmful VOCs. Exposure to VOCs can be assessed by measuring their urinary metabolites (VOCMs). The Population Assessment of Tobacco and Health (PATH) Study is a U.S. national longitudinal study of tobacco use in the adult and youth civilian non-institutionalized population. We measured 20 VOCMs in urine specimens from a subsample of adults in Wave 1 (W1) (2013-2014) to characterize VOC exposures among tobacco product users and non-users. We calculated weighted geometric means (GMs) and percentiles of each VOCM for exclusive combustible product users (smokers), exclusive electronic cigarette (e-cigarette) users, exclusive smokeless product users, and tobacco product never users. We produced linear regression models for six VOCMs with sex, age, race, and tobacco user group as predictor variables. Creatinine-ratioed levels of VOCMs from exposure to acrolein, crotonaldehyde, isoprene, acrylonitrile, and 1,3-butadiene were significantly higher in smokers than in never users. Small differences of VOCM levels among exclusive e-cigarette users and smokeless users were observed when compared to never users. Smokers showed higher VOCM concentrations than e-cigarette, smokeless, and never users. Urinary VOC metabolites are useful biomarkers of exposure to harmful VOCs.

Isoprene is the 2-methyl analog of 1,3-butadiene and is a possible human carcinogen (IARC Group 2B). We assessed isoprene exposure in the general US population by measuring its urinary metabolite, N-acetyl-S-(4-hydroxy-2-methyl-2-buten-1-yl)-l-cysteine (IPM3) in participants (>/=3 year old) from the 2015-2016 National Health and Nutrition Examination Survey. Spot urine samples were analyzed for IPM3 using ultrahigh-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. Exclusive tobacco smokers were distinguished from non-users using a combination of self-reporting and serum cotinine data. IPM3 was detected in 80.2% of samples. The median IPM3 level was higher for exclusive cigarette smokers (39.8 mug/g creatinine) than for non-users (3.05 mug/g creatinine). Sample weighted regression analysis, controlling for creatinine, sex, age, race, body mass index, and diet, showed that IPM3 was positively and significantly associated with serum cotinine. Smoking 1-10 cigarettes per day (CPD, 0.5 pack) was significantly associated with an IPM3 increase of 596% (p < .0001), and smoking >20 CPD (>1 pack) was significantly associated with an IPM3 increase of 1640% (p < .0001), controlling for confounding variables. Drinking beer/ale at median and 90th percentile levels (compared to zero consumption) was associated (p < 0.05) with 0 and 2.9% increase in IPM3 in non-users, respectively. We conclude that tobacco smoke is a major source of isoprene exposure in the US population. This study provides important public health biomonitoring data on isoprene exposure in the general US population.

This study investigated the associations of baseline sleep onset latency, wake after sleep onset, longest wake episode, number of awakenings, sleep efficiency and sleep duration with incident hypertension during a 7-year follow-up (n = 161, 68% men) and the joint effect of insufficient sleep and obesity on incident hypertension. Sleep parameters were derived from 15-day actigraphy data. Relative risks and 95% confidence intervals were estimated using a robust Poisson regression model. Each 10-min increase in sleep onset latency was associated with an 89% higher risk of hypertension (95% confidence interval [CI] = 1.12-3.20). Each 10-min increase in longest wake episode was associated with a 23% higher risk of hypertension (95% CI = 1.01-1.50) and each 10% decrease in sleep efficiency was associated with a 50% higher risk of hypertension (95% CI = 1.02-2.22). These associations were independent of demographic and lifestyle characteristics, depressive symptoms, shift work, sleep duration and body mass index. Having <6 hr of sleep and a body mass index >/=30 kg/m(2) increased the risk of hypertension (relative risk = 2.81; 95% CI = 1.26-6.25) compared with having >/=6 hr of sleep and a body mass index <30 after controlling for confounders. Relative excess risk due to interaction was 3.49 (95% CI = -1.69-8.68) and ratio of relative risk was 3.21 (95% CI = 0.72-14.26). These results suggest that poor sleep quality is a risk factor for hypertension. Longitudinal studies with larger sample sizes are warranted to examine the joint effect of insufficient sleep and obesity on development of hypertension.