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Introduction The aims of this study were to characterize particle size in a thirdhand smoke (THS) aerosol and measure the effects of controlled inhalational exposure to THS on biomarkers of tobacco smoke exposure, inflammation, and oxidative stress in human subjects. Secondhand cigarette smoke changes physically and chemically after release into the environment. Some of the resulting chemicals persist indoors as thirdhand cigarette smoke. THS that is sorbed to surfaces can emit particles back into the air. Aims and Methods Smoke particle size was measured with a scanning mobility particle sizer and condensation particle counter. Using a crossover study design, 18 healthy nonsmokers received a 3-hour inhalational exposure to THS and to filtered, conditioned air. THS was generated with a smoking machine and aged overnight in a chamber. The chamber was flushed with clean air to create the THS aerosol. The tobacco smoke metabolites cotinine, 3-hydroxycotinine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) were measured in urine. Vascular endothelial growth factor and interleukin-6 in plasma, and 8-isoprostane in urine, were measured using enzyme-linked immunosorbent assay kits. Results Mean smoke particle size increased with aging (171 to 265 nm). We found significant increases in urinary cotinine and 3-hydroxycotinine after 3 hours of exposure to THS and no significant increases in NNAL, interleukin-6, vascular endothelial growth factor or 8-isoprostane. Conclusions Acute inhalational exposure to 22-hour old tobacco smoke aerosol caused increases in the metabolites of nicotine but not the metabolites of the tobacco-specific nitrosamine NNK (4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone). This corroborates the utility of cotinine and NNAL for secondhand and THS exposure screening. Implications This study shows that a 3-hour inhalational exposure to the tobacco smoke aerosol that forms in a room that has been smoked in and left unventilated overnight causes increases in urinary metabolites of nicotine, but not of the tobacco-specific nitrosamine NNK. This suggests that cleaning personnel and others who live and work in rooms polluted with aged or thirdhand cigarette smoke regularly may have inhalational exposures and potential health effects related to their exposure to nicotine and other smoke toxicants.

Author(s): Liu, Jia; Benowitz, Neal L.; Hatsukami, Dorothy K.; Havel, Christopher M.; Lazcano-Ponce, Eduardo; Strasser, Andrew A.; Jacob, Peyton | Abstract: In studies of tobacco toxicology, including comparisons of different tobacco products and exposure to secondhand or thirdhand smoke, exposure assessment using biomarkers is often useful. Some studies have indicated that most of the toxicity of tobacco smoke is due to gas-phase compounds. 3-Ethenylpyridine (3-EP) is a major nicotine pyrolysis product occurring in the gas phase of tobacco smoke. It has been used extensively as an environmental tracer for tobacco smoke. 3-EP would be expected to be a useful tobacco smoke biomarker as well, but nothing has been published about its metabolism and excretion in humans. In this Article we describe a solid-phase microextraction (SPME) GC-MS/MS method for determination of 3-EP in human urine and its application to the determination of 3-EP in the urine of smokers and people exposed to secondhand smoke. We conclude that 3-EP is a promising biomarker that could be useful in studies of tobacco smoke exposure and toxicology. We also point out the paucity of data on 3-EP toxicity and suggest that additional studies are needed.Graphical Abstract

ObjectiveIt is unclear why Black smokers in the United States have elevated risk of some tobacco-related diseases compared to White smokers. One possible causal mechanism is differential intake of tobacco toxicants, but results across studies are inconsistent. Thus, we examined racial differences in biomarkers of toxic volatile organic compounds (VOCs) present in tobacco smoke.MethodWe analyzed baseline data collected from 182 Black and 184 White adult smokers who participated in a randomized clinical trial in 2013-2014 at 10 sites across the United States. We examined differences in urinary levels of ten VOC metabolites, total nicotine equivalents (TNE), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), controlling for covariates such as cigarettes per day (CPD), as well as differences in VOCs per TNE to assess the extent to which tobacco exposure, and not metabolic factors, accounted for racial differences.ResultsConcentration of metabolites of acrolein, acrylonitrile, ethylene oxide, and methylating agents were significantly higher in Blacks compared to Whites when controlled for covariates. Other than the metabolite of methylating agents, VOCs per TNE did not differ between Blacks and Whites. Concentrations of TNE/CPD and VOCs/CPD were significantly higher in Blacks. Menthol did not contribute to racial differences in VOC levels.ConclusionsFor a given level of CPD, Black smokers likely take in higher levels of acrolein, acrylonitrile, and ethylene oxide than White smokers. Our findings are consistent with Blacks taking in more nicotine and toxicants per cigarette smoked, which may explain their elevated disease risk relative to other racial groups.

BackgroundHeated tobacco products (also called ‘heat-not-burn’ products) heat tobacco at temperatures below that of combustion, causing nicotine and other compounds to aerosolise. One such product, IQOS from Philip Morris International, is being marketed internationally with claims of harm reduction. We sought to determine whether exposure to IQOS aerosol impairs arterial flow-mediated dilation (FMD), a measure of vascular endothelial function that is impaired by tobacco smoke.MethodsWe exposed anaesthetised rats (n=8/group) via nose cone to IQOS aerosol from single HeatSticks, mainstream smoke from single Marlboro Red cigarettes or clean air for a series of consecutive 30 s cycles over 1.5–5 min. Each cycle consisted of 15 or 5 s of exposure followed by removal from the nose cone. We measured pre-exposure and postexposure FMD, and postexposure serum nicotine and cotinine.ResultsFMD was impaired comparably by ten 15 s exposures and ten 5 s exposures to IQOS aerosol and to cigarette smoke, but not by clean air. Serum nicotine levels were similar to plasma levels after humans have smoked one cigarette, confirming that exposure conditions had real-world relevance. Postexposure nicotine levels were ~4.5-fold higher in rats exposed to IQOS than to cigarettes, despite nicotine being measured in the IQOS aerosol at ~63% the amount measured in smoke. When IQOS exposure was briefer, leading to comparable serum nicotine levels to the cigarette group, FMD was still comparably impaired.ConclusionsAcute exposures to IQOS aerosol impairs FMD in rats. IQOS use does not necessarily avoid the adverse cardiovascular effects of smoking cigarettes.

BackgroundElectronic cigarettes (ECs) are nicotine delivery devices that produce aerosol without combustion of tobacco; therefore, they do not produce sidestream smoke. Nevertheless, many users exhale large clouds of aerosol that can result in passive exposure of non-users. Analogous to thirdhand cigarette smoke, the exhaled aerosol also settles on indoor surfaces where it can produce a residue. We refer to this residue as EC exhaled aerosol residue (ECEAR). Our objective was to determine if exhaled EC aerosol transferred from a vape shop in a multiple-tenant retail building, where it was produced, to a nearby business (field site) where it could deposit as ECEAR.MethodsWe examined the build-up of ECEAR in commonly used materials (cotton towel and paper towels) placed inside the field site across from the vape shop. Materials were subjected to short-term (days) and long-term (months) exposures. Nicotine, other alkaloids and tobacco-specific nitrosamines (TSNAs) were identified and quantified in controls and field site samples using analytical chemical techniques.ResultsNicotine and other alkaloids were detected after 1 day of exposure in the field site, and these chemicals generally increased as exposure times increased. TSNAs, which have been linked to carcinogenesis, were also detected in short-term and long-term exposed samples from the field site.ConclusionsIn a multiple-tenant retail building, chemicals in EC aerosol travelled from a vape shop into an adjacent business where they deposited forming ECEAR. Regulatory agencies and tenants occupying such buildings should be aware of this potential environmental hazard.

Thirdhand smoke (THS) is the fraction of cigarette smoke that persists in indoor environments after smoking. We investigated the effects of neonatal and adult THS exposure on bodyweight and blood cell populations in C57BL/6 J mice. At the end of neonatal exposure, THS-treated male and female mice had significantly lower bodyweight than their respective control mice. However, five weeks after neonatal exposure ended, THS-treated mice weighed the same as controls. In contrast, adult THS exposure did not change bodyweight of mice. On the other hand, both neonatal and adult THS exposure had profound effects on the hematopoietic system. Fourteen weeks after neonatal THS exposure ended, eosinophil number and platelet volume were significantly higher, while hematocrit, mean cell volume, and platelet counts were significantly lower compared to control. Similarly, adult THS exposure also decreased platelet counts and increased neutrophil counts. Moreover, both neonatal and adult THS exposure caused a significant increase in percentage of B-cells and significantly decreased percentage of myeloid cells. Our results demonstrate that neonatal THS exposure decreases bodyweight and that THS exposure induces persistent changes in the hematopoietic system independent of age at exposure. These results also suggest that THS exposure may have adverse effects on human health.

© 2016 Elsevier Ireland Ltd. Background: Rate of nicotine metabolism is an important factor influencing cigarette smoking behavior, dependence, and efficacy of nicotine replacement therapy. The current study examined the hypothesis that chronic alcohol abuse can accelerate the rate of nicotine metabolism. Nicotine metabolite ratio (NMR, a biomarker for rate of nicotine metabolism) and patterns of nicotine metabolites were assessed at three time points after alcohol cessation. Methods: Participants were 22 Caucasian men randomly selected from a sample of 165 smokers entering a 7-week alcohol dependence treatment program in Poland. Data were collected at three time points: baseline (week 1, after acute alcohol detoxification), week 4, and week 7. Urine was analyzed for nicotine and metabolites and used to determine the nicotine metabolite ratio (NMR, a biomarker for rate of nicotine metabolism), and total nicotine equivalents (TNE, a biomarker for total daily nicotine exposure). Results and conclusions: There was a significant decrease in urine NMR over the 7 weeks after alcohol abstinence (F(2,42)= 18.83, p < 0.001), indicating a decrease in rate of nicotine metabolism. On average NMR decreased 50.0% from baseline to week 7 (9.6 ± 1.3 vs 4.1 ± 0.6). There was no change in urine TNE across the three sessions, indicating no change daily nicotine intake. The results support the idea that chronic alcohol abuse may increase the rate of nicotine metabolism, which then decreases over time after alcohol cessation. This information may help to inform future smoking cessation interventions in this population.

© 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. The association between cigarette smoke exposure and the acute respiratory distress syndrome in patients with the most common acute respiratory distress syndrome risk factors of sepsis, pneumonia, and aspiration has not been well studied. The goal of this study was to test the association between biomarker-confirmed cigarette smoking and acute respiratory distress syndrome in a diverse cohort. Design: Prospective cohort. Setting: Tertiary care center. Patients: Four hundred twenty-six critically ill patients with acute respiratory distress syndrome risk factors (excluding trauma and transfusion) Interventions: None. Measurements and Main Results: We obtained smoking histories and measured urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (a biomarker of cigarette smoke exposure) on urine samples obtained at the time of study enrollment. The association between cigarette smoke exposure and acute respiratory distress syndrome differed based on acute respiratory distress syndrome risk factor (p < 0.02 for interaction). In patients with nonpulmonary sepsis as the primary acute respiratory distress syndrome risk factor (n = 212), 39% of those with acute respiratory distress syndrome were current smokers by history compared with 22% of those without acute respiratory distress syndrome (odds ratio, 2.28; 95% CI, 1.24-4.19; p = 0.008). Likewise, cigarette smoke exposure as measured by urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol was significantly associated with acute respiratory distress syndrome in this group. The increased risk of acute respiratory distress syndrome in nonpulmonary sepsis was restricted to patients with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol levels consistent with active smoking and was robust to adjustment for other acute respiratory distress syndrome predictors. Cigarette smoke exposure as measured by history or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol was not associated with acute respiratory distress syndrome in patients with other risk factors (e.g., pneumonia and aspiration). Conclusions: Cigarette smoking measured both by history and biomarker is associated with an increased risk of acute respiratory distress syndrome in patients with nonpulmonary sepsis. This finding has important implications for tobacco product regulation and for understanding the pathogenesis of acute respiratory distress syndrome.

Background: Volatile organic compounds (VOC) from tobacco smoke are associated with cancer, cardiovascular, and respiratory diseases. The objective of this study was to characterize the exposure of nonsmokers to VOCs from secondhand smoke (SHS) in vehicles using mercapturic acid metabolites. Methods: Fourteen nonsmokers were individually exposed in the backseat to one hour of SHS from a smoker seated in the driver's seat who smoked three cigarettes at 20-minute intervals in a stationary car with windows opened by 10 cm. Baseline and 0- to 8-hour postexposure mercapturic acid metabolites of nine VOCs were measured in urine. Air-to-urine VOC ratios were estimated on the basis of respirable particulate matter (PM2.5) or air nicotine concentration, and lifetime excess risk (LER) of cancer death from exposure to acrylonitrile, benzene, and 1,3-butadiene was estimated for adults. Results: The greatest increase in 0- to 8-hour postexposure concentrations of mercapturic acids from baseline was MHBMA-3 (parent, 1,3-butadiene; 2.1-fold), then CNEMA (acrylonitrile; 1.7-fold), PMA (benzene; 1.6-fold), MMA (methylating agents; 1.6-fold), and HEMA (ethylene oxide; 1.3-fold). The LER of cancer death from exposure to acrylonitrile, benzene, and 1,3-butadiene in SHS for 5 hours a week ranged from 15.5 × 10−6 to 28.1 × 10−6 for adults, using air nicotine and PM2.5 to predict air VOC exposure, respectively. Conclusion: Nonsmokers have significant intake of multiple VOCs from breathing SHS in cars, corresponding to health risks that exceed the acceptable level. Impact: Smoking in cars may be associated with increased risks of cancer, respiratory, and cardiovascular diseases among nonsmokers. Cancer Epidemiol Biomarkers Prev; 23(12); 2774–82. ©2014 AACR.

Secondhand smoke (SHS) is a confirmed lung carcinogen that introduces thousands of toxic chemicals into the lungs. SHS contains chemicals that have been implicated in causing oxidative DNA damage in the airway epithelium. Although DNA repair is considered a key defensive mechanism against various environmental attacks, such as cigarette smoking, the associations of individual repair enzymes with susceptibility to lung cancer are largely unknown. This study investigated the role of NEIL2, a DNA glycosylase excising oxidative base lesions, in human lung cells treated with sidestream smoke (SSS), the main component of SHS. To do so, we generated NEIL2 knockdown cells using siRNA-technology and exposed them to SSS-laden medium. Representative SSS chemical compounds in the medium were analyzed by mass spectrometry. An increased production of reactive oxygen species (ROS) in SSS-exposed cells was detected through the fluorescent detection and the induction of HIF-1α. The long amplicon-quantitative PCR (LA-QPCR) assay detected significant dose-dependent increases of oxidative DNA damage in the HPRT gene of cultured human pulmonary fibroblasts (hPF) and BEAS-2B epithelial cells exposed to SSS for 24 h. These data suggest that SSS exposure increased oxidative stress, which could contribute to SSS-mediated toxicity. siRNA knockdown of NEIL2 in hPF and HEK 293 cells exposed to SSS for 24 h resulted in significantly more oxidative DNA damage in HPRT and POLB than in cells with control siRNA. Taken together, our data strongly suggest that decreased repair of oxidative DNA base lesions due to an impaired NEIL2 expression in non-smokers exposed to SSS would lead to accumulation of mutations in genomic DNA of lung cells over time, thus contributing to the onset of SSS-induced lung cancer. © 2014 Sarker et al.

Particulate matter (PM) derived from tobacco smoke contains numerous toxic substances. Since the PM and gas phase of tobacco smoke may distribute differently in the environment and substances in them may have different human bioavailability, multiple tracers and biomarkers for tobacco smoke constituents are desirable. Nicotelline is a relatively nonvolatile alkaloid present in tobacco smoke, and therefore, it has the potential to be a suitable tracer and biomarker for tobacco smoke-derived PM. We describe experiments demonstrating that nicotelline is present almost entirely in the PM, in both freshly generated cigarette smoke and aged cigarette smoke. An excellent correlation between the mass of nicotelline and the mass of the PM in aged cigarette smoke was found. We also describe experiments suggesting that the main source of nicotelline in tobacco smoke is dehydrogenation of another little-studied tobacco alkaloid, anatalline, during the burning process. We show that nicotelline metabolites can be measured in the urine of smokers and that nicotelline can be measured in house dust from homes of smokers and nonsmokers. We conclude that nicotelline should be useful as a tracer and biomarker for PM derived from tobacco smoke. © 2013 American Chemical Society.

Introduction: The nicotine metabolite ratio (NMR), the ratio of trans-3'-hydroxycotinine (3-HC) to cotinine, has been used as a biomarker of the rate of CYP2A6-mediated nicotine metabolism. While stable in smokers who maintain constant smoking consumption, since smoking has been shown to inhibit nicotine metabolism and this inhibition could be mediated by the nicotine in the smoke, NMR could change during nicotine reduction. The objective of this study was to determine the reproducibility (or stability) of plasma NMR in smokers of progressively reduced nicotine content (RNC) cigarettes. Methods: We analyzed data from subjects in a clinical trial of smoking progressively RNC cigarettes. Plasma NMR in 30 smokers whose plasma cotinine levels had decreased by at least 50% from the use of the first test cigarette (12 mg nicotine content) to the final test cigarette (1 mg nicotine content) was measured on 4 occasions over a period of 24 weeks. Results: Plasma cotinine and 3-HC decreased by an average of 85% and 84%, respectively, following the use of the first type of RNC cigarette to the last type. Plasma NMR had an average absolute change of 28.5% over the same period. Using repeated measures analysis, changes in plasma NMR over time were not significant with or without controlling for the effects of age, body mass index, gender, and race (p = .24 and p = .23, respectively). The reliability coefficient for repeated measurements of plasma NMR was .72. The average within-subject coefficient of variation for plasma NMR was 21.6% (SD = 12.0%). Conclusion: The plasma NMR is relatively stable over time as nicotine levels decline in smokers of progressively RNC cigarettes. © The Author 2013. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco.

Background: Recent federal legislation gives the U.S. Food and Drug Administration authority to regulate the nicotine content of cigarettes. A nationwide strategy for progressive reduction of the nicotine content of cigarettes is a potential way to reduce the addictiveness of cigarettes, to prevent new smokers from becoming addicted, and to facilitate quitting in established smokers. We conducted a trial of progressive nicotine content tapering over 6 months to determine the effects on smoking behaviors and biomarkers of tobacco smoke exposure and cardiovascular effects. Methods: One hundred and thirty-five healthy smokers were randomly assigned to one of two groups. A research group smoked their usual brand of cigarettes followed by five types of research cigarettes with progressively lower nicotine content, each smoked for one month. A control group smoked their own brand of cigarettes for the same period of time. Results: Nicotine intake, as indicated by plasma cotinine concentration, declined progressively as the nicotine content of cigarettes was reduced. Cigarette consumption and markers of exposure to carbon monoxide and polycyclic aromatic hydrocarbons, as well as cardiovascular biomarkers remained stable, whereas urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) excretion decreased. No significant changes in biomarkers of exposure or cardiovascular effects were observed in controls. Conclusions: Our data support the proposition that the intake of nicotine from cigarettes of smokers can be substantially lowered without increasing exposure to other tobacco smoke toxins. Impact: These findings support the feasibility and safety of gradual reduction of the nicotine content in cigarettes. Cancer Epidemiol Biomarkers Prev; 21(5); 761–9. ©2012 AACR.