A comparison of urinary biomarkers of tobacco and carcinogen exposure in smokers (original) (raw)
Related papers
Chemical Research in Toxicology, 2012
We determined the persistence at various times and 56 days) of eight tobacco smoke carcinogen and toxicant biomarkers in the urine of 17 smokers who stopped smoking. The biomarkers were 1-hydroxy-2-(N-acetylcysteinyl)-3-butene (1) and 1-(N-acetylcysteinyl)-2hydroxy-3-butene (2) [collectively called MHBMA for monohydroxybutyl mercapturic acid] and 1,2-dihydroxy-4-(N-acetylcysteinyl)butane (3) [DHBMA for dihydroxybutyl mercapturic acid], metabolites of 1,3-butadiene; 1-(N-acetylcysteinyl)-propan-3-ol (4, HPMA for 3-hydroxypropyl mercapturic acid), a metabolite of acrolein; 2-(N-acetylcysteinyl)butan-4-ol (5, HBMA for 4hydroxybut-2-yl mercapturic acid), a metabolite of crotonaldehyde; (N-acetylcysteinyl)benzene (6, SPMA for S-phenyl mercapturic acid), a metabolite of benzene; (N-acetylcysteinyl)ethanol (7, HEMA for 2-hydroxyethyl mercapturic acid), a metabolite of ethylene oxide; 1-hydroxypyrene (8) and its glucuronides (1-HOP), metabolites of pyrene; and 4-(methylnitrosamino)-1-(3-pyridyl)-1butanol (9) and its glucuronides (total NNAL), a biomarker of exposure to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These biomarkers represent some of the major carcinogens and toxicants in cigarette smoke: 1,3-butadiene, acrolein, crotonaldehyde, benzene, ethylene oxide, polycyclic aromatic hydrocarbons (PAH), and NNK. With the exception of DHBMA, levels of which did not change after cessation of smoking, all other biomarkers decreased significantly after 3 days of cessation (P<0.001). The decreases in MHBMA, HPMA, HBMA, SPMA, and HEMA were rapid, nearly reaching their ultimate levels (81 -91% reduction) after 3 days. The decrease in total NNAL was gradual, reaching 92% after 42 days, while reduction in 1-HOP was variable among subjects to about 50% of baseline. Since DHBMA did not change upon smoking cessation, there appear to be sources of this metabolite other than 1,3-butadiene. The results of this study demonstrate that the tobacco smoke carcinogen/toxicant biomarkers MHBMA, HPMA, HBMA, SPMA, HEMA, 1-HOP, and NNAL are related to smoking and are good indicators of the impact of smoking on human exposure to 1,3-butadiene, acrolein, crotonaldehyde, benzene, ethylene oxide, PAH and NNK.
Quantitation of Urinary Metabolites of a Tobacco-specific Lung Carcinogen after Smoking Cessation1
We quantified urinary levels of two metabolites of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in people who had stopped smoking: 4-(methylnitrosamino)-1-(3-pyridyl)- 1-butanol (NNAL) and its O-glucuronide, 4-((methylnitrosamino)-1-(3- pyridyl)but-1-yl)-b-O-D-glucosiduronic acid (NNAL-Gluc). Twenty-seven people completed the study. Thirteen used the nicotine patch starting at the quit date, whereas the others used no patch. Two 24-h urine samples were collected on 2 consecutive days before smoking cessation; blood was also obtained. Beginning at their quit date, subjects provided 24-h urine samples on days 7, 21, 42, 70, 98, and 126, and some subjects also provided samples at later times. The urine was analyzed for NNAL, NNAL-Gluc, nicotine plus nicotine-N-glucuronide, and cotinine plus cotinine-N-glucu- ronide. Some blood samples were also analyzed for NNAL. The decline of urinary NNAL and NNAL-Gluc after smoking cessation was much slow...
Quantitation of Urinary Metabolites of a Tobacco-specific Lung Carcinogen after Smoking Cessation
Cancer Research, 1999
We quantified urinary levels of two metabolites of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in people who had stopped smoking: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its O-glucuronide, 4-[(methylnitrosamino)-1-(3pyridyl)but-1-yl]--O-D-glucosiduronic acid (NNAL-Gluc). Twenty-seven people completed the study. Thirteen used the nicotine patch starting at the quit date, whereas the others used no patch. Two 24-h urine samples were collected on 2 consecutive days before smoking cessation; blood was also obtained. Beginning at their quit date, subjects provided 24-h urine samples on days 7, 21, 42, 70, 98, and 126, and some subjects also provided samples at later times. The urine was analyzed for NNAL, NNAL-Gluc, nicotine plus nicotine-N-glucuronide, and cotinine plus cotinine-N-glucuronide. Some blood samples were also analyzed for NNAL. The decline of urinary NNAL and NNAL-Gluc after smoking cessation was much slower than expected. This was clearly demonstrated by comparison with cotinine and nicotine levels in urine. One week after smoking cessation, 34.5% of baseline NNAL plus NNAL-Gluc was detected in urine, whereas the corresponding values for cotinine and nicotine were 1.1 and 0.5%, respectively. Even 6 weeks after cessation, 7.6% of the original levels of NNAL plus NNAL-Gluc remained. In some subjects, NNAL plus NNAL-Gluc were detected 281 days after cessation. The distribution half-life for NNAL and NNAL-Gluc was 3-4 days, whereas the elimination half-life was 40-45 days. Total body clearance of NNAL was estimated to be 61.4 ؎ 35.4 ml/min, and volume of distribution in the -phase was estimated to be 3800 ؎ 2100 liters, indicating substantial distribution into the tissues. Parallel studies in rats treated chronically or acutely with NNK in the drinking water support the conclusion that NNAL has a large volume of distribution. There was no effect of the nicotine patch on levels of NNAL plus NNAL-Gluc, indicating that NNK is not formed endogenously from nicotine. The results of this study demonstrate that NNAL and NNAL-Gluc are slowly cleared from the body after smoking cessation, indicating the presence of a high-affinity compartment where NNK, NNAL, and/or NNAL-Gluc are retained or sequestered and slowly released.
Cancer Epidemiology Biomarkers & Prevention
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.
Biomarkers, 2010
Intraindividual variability of measurements of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), nicotine, cotinine, and r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT) over time is uncertain. From 70 habitual smokers' plasma and urine sampled bimonthly for a year we analyzed plasma for NNAL, cotinine, and PheT; and urine for NNAL, cotinine, and nicotine. We estimated the intraclass correlation coefficients (ρ I ) for each measurement. Plasma and creatininecorrected urinary NNAL were stable (ρ I ≥ 70%); plasma PheT and plasma and urinary total cotinine were fairly stable (ρ I ≥ 50%), but urinary nicotine ρ I ≈ 40%.was not. Except for nicotine, single measurements from plasma or urine adequately represent individual mean exposure over time.
Relationships between Cigarette Consumption and Biomarkers of Tobacco Toxin Exposure
Cancer Epidemiology Biomarkers & Prevention, 2005
Epidemiologic studies show a dose-response relationship between cigarettes per day and health outcomes such as heart and lung disease, and health outcomes are related to some biomarkers of tobacco exposure. The objective of this study was to examine the relationships between cigarettes per day and levels of selected biomarkers of tobacco toxin exposure: carbon monoxide (CO), metabolites of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and polycyclic aromatic hydrocarbons [total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and 1-hydroxypyrene (1-HOP), respectively], and total cotinine (cotinine plus cotinine-N-glucuronide). We did a cross-sectional analysis of merged data from (a) two clinical trials and (b) two cohorts of light smokers (total n = 400). The mean age of participants was 50.4 years and the range of cigarette consumption was 1 to 100/d; however, few subjects smoked >45 cigarettes/d (n = 12).
Cancer Epidemiology Biomarkers & Prevention, 2010
Background: Smokers are exposed to significant doses of carcinogens, including tobacco-specific nitrosamines (TSNA). Previous studies have shown significant global differences in the levels of TSNAs in cigarette smoke because of the variation in tobacco blending and curing practices around the world. Methods: Mouth-level exposure to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) measured in cigarette butts and urinary concentrations of its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1butanol (NNAL) were examined among 126 daily smokers in four countries over a 24-hour study period. Results: As mouth-level exposure of NNK increased, the urinary NNAL increased even after adjustment for other covariates (β = 0.46, P = 0.004). The relationship between mouth-level exposure to nicotine and its salivary metabolite, cotinine, was not statistically significant (β = 0.29, P = 0.057), likely because of the very limited range of differences in mouth-level nicotine exposure in this population. Conclusions: We have shown a direct association between the 24-hour mouth-level exposure of NNK resulting from cigarette smoking and the concentration of its primary metabolite, NNAL, in the urine of smokers. Internal dose concentrations of urinary NNAL are significantly lower in smokers in countries that have lower TSNA levels in cigarettes such as Canada and Australia in contrast to countries that have high levels of these carcinogens in cigarettes, such as the United States. Impact: Lowering the levels of NNK in the mainstream smoke of cigarettes through the use of specific tobacco types and known curing practices can significantly affect the exposure of smokers to this known carcinogen. Cancer Epidemiol Biomarkers Prev; 19(6); 1389-98. ©2010 AACR.
Tobacco-smoke exposure indicators and urinary mutagenicity
Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 2002
In this study, the correlation of indicators of external (i.e. mean daily intake of condensate, nicotine, tobacco and tobacco proteins, and daily number of cigarettes smoked) and of internal tobacco-smoke exposure (i.e. urinary 1-pyrenol, nicotine and its metabolites and trans,trans-muconic acid) with urinary mutagenicity, detected on YG1024 Salmonella typhimurium strain with S9, were examined in 118 smokers.
Evaluation of Carcinogen Exposure in People Who Used "Reduced Exposure" Tobacco Products
JNCI Journal of the National Cancer Institute, 2004
Background: Although tobacco products with reportedly reduced carcinogen content are being marketed, carcinogen uptake in people who use these products has not been assessed systematically. Methods: Between June 2001 and November 2002, 54 users of smokeless tobacco and 51 cigarette smokers were randomly assigned to one of two groups. One used test products (Swedish snus for users of smokeless tobacco or OMNI cigarettes for smokers), while the other quit and used medicinal nicotine (the nicotine patch). All participants were assessed for urinary levels of total NNAL [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronide], metabolites of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Smokers were also assessed for levels of 1-hydroxypyrene (1-HOP), a biomarker of polycyclic aromatic hydrocarbon uptake. Assessments were made weekly during 2 weeks of baseline normal tobacco use and 4 weeks of treatment. Statistical tests were two-sided. Results: Primary data analyses were conducted on 41 users of smokeless tobacco and 38 cigarette smokers who met the inclusion criteria. Total NNAL levels were statistically significantly lower in users of smokeless tobacco after they switched to snus or to nicotine patch (P<.001 for both groups) than they were before the switch, although the overall mean total NNAL level among subjects who used the nicotine patch was statistically significantly lower than that among those who used snus (mean ؍ 1.2 and 2.0 pmol of NNAL/mg of creatinine, respectively; mean difference ؍ 0.9 pmol of NNAL/mg of creatinine, 95% confidence interval [CI] ؍ 0.2 to 1.5; P ؍ .008). Compared with baseline levels, total NNAL levels (P ؍ .003), but not 1-HOP levels, were statistically significantly reduced in cigarette smokers who switched to the OMNI cigarette, although both total NNAL levels and 1-HOP levels were statistically significantly reduced in smokers who switched to the nicotine patch (P<.001 for both). The overall mean total NNAL levels among smokers who used the nicotine patch was statistically significantly lower than that among smokers who used the OMNI cigarette (mean ؍ 1.2 and 1.9 pmol of NNAL/mg of creatinine, respectively; mean difference ؍ 0.6 pmol of NNAL/mg of creatinine, 95% CI ؍ 0.1 to 1.1; P ؍ .022). Conclusion: Switching to reduced-exposure tobacco products or medicinal nicotine can decrease levels of tobaccoassociated carcinogens, with greater reductions being observed with medicinal nicotine. Medicinal nicotine is a safer alternative than modified tobacco products. [J Natl Cancer Inst 2004;96:844 -52]
Cancer Research, 2009
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides (sum of which is denoted as total NNAL) are metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). NNK and NNAL can induce lung cancer in laboratory animals but human data are limited. The association between prediagnostic levels of urinary total NNAL and risk of lung cancer development was evaluated in two prospective cohorts of Chinese cigarette smokers. We conducted a nested case-control study involving 246 cases of incident lung cancer and 245 cohort controls who were individually matched to the index cases by age, gender, neighborhood of residence at cohort enrollment, and date of urine collection. Urinary levels of total NNAL were significantly associated with risk of lung cancer in a dose-dependent manner. Relative to the lowest tertile, risks associated with the second and third tertiles of total NNAL were 1.43 [95% confidence interval (95% CI), 0.86-2.37] and 2.11 (95% CI, 1.25-3.54), respectively (P for trend = 0.005) after adjustment for self-reported smoking history and urinary total cotinine. Smokers in the highest tertiles of urinary total NNAL and total cotinine exhibited a 8.5-fold (95% CI, 3.7-19.5) increased risk for lung cancer relative to smokers with comparable smoking history but possessing the lowest tertiles of urinary total NNAL and total cotinine. Findings of the present study directly link NNK exposure to lung cancer development in humans.