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ABSTRACT: AIMS: To investigate the relationships between tobacco dependence, biomarkers of nicotine and carcinogen exposure, and biomarkers of nicotine and carcinogen exposure per cigarette in Black and White smokers. DESIGN AND PARTICIPANTS: 204 healthy Black (n=69) and White (n=135) smokers were enrolled in two clinical studies. MEASUREMENT: Nicotine equivalents (nicotine and its metabolites), 4-(methylnitrosamino)-1-(3)pyridyl-1-butanol (NNAL), and polycyclic aromatic hydrocarbon (PAH) metabolites were measured in urine. The Fagerström Test for Nicotine Dependence (FTND) and time to first cigarette (TFC) measured tobacco dependence. FINDINGS: Average TFC and FTND for Blacks and Whites were not significantly different. Urine NNAL and nicotine equivalents increased with increasing FTND in Whites but did not increase in Blacks (race x FTND interaction, both p<0.031). The interaction term was not significant for PAHs. An inverse relationship was seen between FTND and nicotine equivalents, NNAL, and PAH metabolites per cigarette in Blacks but remained flat in Whites (race x FTND interaction, all p≤0.039). Regardless of dependence (low dependence, TFC>15 minutes; high dependence, TFC≤15 minutes), FTND and TFC were not significantly correlated with urine nicotine equivalents and carcinogen exposure in Blacks. We found moderate correlations between FTND and TFC and nicotine equivalents and carcinogen exposure among Whites of low dependence and non-significant correlations among Whites of high dependence. CONCLUSION: In the US, tobacco dependence measures were linearly related to nicotine intake and carcinogen exposure in White but not in Black smokers. The relationship between dependence measures and tobacco biomarkers in Black smokers regardless of level of dependence resembled highly dependent White smokers.
Addiction 09/2012; · 4.31 Impact Factor
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ABSTRACT: Our study objectives were (1) to investigate the selectivity of polycyclic aromatic hydrocarbon (PAH) metabolites for tobacco smoke exposure and (2) to determine half-lives of PAH metabolites in smokers. There were 622 participants from the United States (US) and Poland, and of these, 70% were smokers. All subjects provided spot urine samples, and 125 smokers provided blood samples. Urinary PAH metabolite half-lives were determined in 8 smokers. In controlled hospital studies of 18 smokers, the associations between various measures of nicotine intake and urinary excretion of PAH metabolites were investigated. Plasma nicotine was measured by GC. LC-MS/MS was used to measure the plasma levels of cotinine and trans-3'-hydroxycotinine, and urine levels of nicotine and its metabolites, total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and PAH metabolites (2-naphthol, 1-, 2-, and 3-hydroxyfluorenes, 1-, 2-, 3-, and 4-hydroxyphenanthrenes, and 1-hydroxypyrene). Regardless of smoking status, PAH metabolite excretion was higher in Polish subjects than in US subjects (p-values <0.001). 1-Hydroxyfluorene exhibited the greatest difference between smokers and nonsmokers, with a 5-fold difference in Polish subjects and a 25-fold difference in US subjects, followed by 3- and 2-hydroxyfluorenes, 2-naphthol, and 1-hydroxypyrene. The differences for hydroxyphenanthrenes were small or nonsignificant. 1-Hydroxyfluorene had the highest correlation with urine nicotine equivalents (r = 0.77) and urine NNAL (r = 0.64). While the half-lives of PAH metabolites were <10 h in smokers, 1-hydroxyfluorene had the largest ratio of initial to terminal urine concentration (58.4 ± 38.6, mean ± SD) after smoking. Receiver Operating Characteristic (ROC) analysis of PAHs among Polish and US subjects further showed that hydroxyfluorenes are most highly discriminative of smokers from nonsmokers followed by 2-naphthol and 1-hydroxypyrene. In conclusion, hydroxyfluorenes, particularly 1-hydroxyfluorene, and 2-naphthol are more selective of tobacco smoke than 1-hydroxypyrene and hydroxyphenanthrenes. Characterization of hydroxyfluorene and 2-naphthol metabolites in urine may improve the characterization of PAHs from tobacco smoke and related disease risks among smokers and nonsmokers.
Chemical Research in Toxicology 03/2012; 25(4):952-64. · 3.78 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
These findings support the feasibility and safety of gradual reduction of the nicotine content in cigarettes.
Cancer Epidemiology Biomarkers & Prevention 02/2012; 21(5):761-9. · 4.12 Impact Factor
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ABSTRACT: Black smokers are reported to have higher lung cancer rates and greater tobacco dependence at lower levels of cigarette consumption compared to non-Hispanic White smokers. We studied the relationship between cigarettes per day (CPD) and biomarkers of nicotine and carcinogen exposure in Black and White smokers.
In 128 Black and White smokers, we measured plasma nicotine and its main proximate metabolite cotinine, urine nicotine equivalents, 4-(methylnitrosamino)-1-(3)pyridyl-1-butanol (NNAL), and polycyclic aromatic hydrocarbon (PAH) metabolites.
The dose-response between CPD and nicotine equivalents, and NNAL and PAH was flat for Black but positive for White smokers (Race × CPD interaction, all ps < .05). Regression estimates for the Race × CPD interactions were 0.042 (95% CI 0.013-0.070), 0.054 (0.023-0.086), and 0.028 (0.004-0.052) for urine nicotine equivalents, NNAL, and PAHs, respectively. In contrast there was a strong correlation between nicotine equivalents and NNAL and PAH independent of race. Nicotine and carcinogen exposure per individual cigarette was inversely related to CPD. This inverse correlation was stronger in Black compared to White smokers and stronger in menthol compared to regular cigarette smokers (not mutually adjusted). Conclusions: Our data indicate that Blacks on average smoke cigarettes differently than White smokers such that CPD predicts smoke intake more poorly in Black than in White smokers.
Nicotine & Tobacco Research 05/2011; 13(9):772-83. · 2.58 Impact Factor
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ABSTRACT: The objective of this study was to analyse environmental tobacco smoke (ETS) and PAH metabolites in urine samples of non-occupationally exposed non-smoker adult subjects and to establish relationships between airborne exposures and urinary concentrations in order to (a) assess the suitability of the studied metabolites as biomarkers of PAH and ETS, (b) study the use of 3-ethenypyridine as ETS tracer and (c) link ETS scenarios with exposures to carcinogenic PAH and VOC. Urine samples from 100 subjects were collected and concentrations of monophenolic metabolites of naphthalene, fluorene, phenanthrene, and pyrene and the nicotine metabolites cotinine and trans-3'-hydroxycotinine were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to assess PAH and ETS exposures. Airborne exposures were measured using personal exposure samplers and analysed using GC-MS. These included 1,3-butadiene (BUT), 3-ethenylpyridine (3-EP) (a tobacco-specific tracer derived from nicotine pyrolysis) and PAHs. ETS was reported by the subjects in 30-min time-activity questionnaires and specific comments were collected in an ETS questionnaire each time ETS exposure occurred. The values of 3-EP (>0.25 microg/m(3) for ETS) were used to confirm the ETS exposure status of the subject. Concentrations as geometric mean, GM, and standard deviation (GSD) of personal exposures were 0.16 (5.50)microg/m(3) for 3-EP, 0.22 (4.28)microg/m(3) for BUT and 0.09 (3.03)ng/m(3) for benzo(a)pyrene. Concentrations of urinary metabolites were 0.44 (1.70)ng/mL for 1-hydroxypyrene and 0.88 (5.28)ng/mL for cotinine. Concentrations of urinary metabolites of nicotine were lower than in most previous studies, suggesting very low exposures in the ETS-exposed group. Nonetheless, concentrations were higher in the ETS population for cotinine, trans-3'hydroxycotinine, 3-EP, BUT and most high molecular weight PAH, whilst 2-hydroxyphenanthrene, 3+4-hydroxyphenanthrene and 1-hydroxyphenanthrene were only higher in the high-ETS subpopulation. There were not many significant correlations between either personal exposures to PAH and their urinary metabolites, or of the latter with ETS markers. However, it was found that the urinary log cotinine concentration showed significant correlation with log concentrations of 3-EP (R=0.75), BUT (R=0.47), and high molecular weight PAHs (MW>200), especially chrysene (R=0.55) at the p=0.01 level. On the other hand, low correlation was observed between the PAH metabolite 2-naphthol and the parent PAH, gas-phase naphthalene. These results suggest that (1) ETS is a significant source of inhalation exposure to the carcinogen 1,3-butadiene and high molecular weight PAHs, many of which are carcinogenic, and (2) that for lower molecular weight PAHs such as naphthalene, exposure by routes other than inhalation predominate, since metabolite levels correlated poorly with personal exposure air sampling.
Environment international 10/2010; 36(7):763-71. · 4.79 Impact Factor
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ABSTRACT: Menthol cigarettes are smoked by 27% of U.S. smokers, and there are concerns that menthol might enhance toxicity of cigarette smoking by increasing systemic absorption of smoke toxins. We measured urine menthol concentrations in relation to biomarkers of exposure to nicotine and tobacco carcinogens.
Concentrations of menthol glucuronide (using a novel analytical method), nicotine plus metabolites (nicotine equivalents, NE), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and polycyclic aromatic hydrocarbon (PAH) metabolites were measured in the urine of 60 menthol and 67 regular cigarette smokers.
Urine menthol was measurable in 82% of menthol and 54% in regular cigarette smokers. Among menthol smokers, urine menthol was highly correlated with NE, NNAL, and PAHs. In a multiple regression model NE but not menthol was significantly associated with NNAL and PAHs.
Urine menthol concentration is a novel biomarker of exposure in menthol cigarette smokers, and is highly correlated with exposure to nicotine and carcinogens. Menthol is not independently associated with carcinogen exposure when nicotine intake is considered.
Cancer Epidemiology Biomarkers & Prevention 10/2010; 19(12):3013-9. · 4.12 Impact Factor
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ABSTRACT: Mandated reduction of exposure to nicotine and other cigarette toxins has been proposed as a possible national regulatory strategy. However, tapering using lower yield commercial cigarettes may not be effective in reducing nicotine or tar exposure due to compensatory smoking behavior. We examined the effects of gradual reduction of nicotine yield in commercial cigarettes on smoking behavior, with an assessment of nicotine intake and exposure to tobacco smoke toxins.
This 10-week longitudinal study of 20 smokers involved smoking the usual brand followed by different brands with progressively lower machine-determined yields, ranging from 0.9 to 0.1 mg nicotine, each smoked for 1 week. Subjects were followed for 4 weeks after returning to smoking the usual brand (or quitting). Smoking behaviors, biomarkers of tobacco smoke exposure, and cardiovascular effects were measured.
Cotinine and other biomarkers of smoke exposure remained unchanged comparing the usual brand with the 0.4 mg nicotine brands. A 30% to 40% decrease in nicotine, carbon monoxide, and carcinogen exposure comparing 0.1 mg nicotine cigarettes with baseline was observed. Self-efficacy was significantly increased and dependence decreased after tapering.
We confirm prior cross-sectional population and experimental studies showing complete compensation for cigarettes down to the 0.4 mg nicotine range. Nicotine and tobacco toxin exposure were substantially reduced while smoking 0.1 mg nicotine cigarettes. Our data suggest that the degree of nicotine dependence of smokers may be lowered with progressive yield tapering. Gradual tapering of smokers from regular to ultralow nicotine yield commercial cigarettes might facilitate smoking cessation and warrants future research.
Cancer Epidemiology Biomarkers & Prevention 04/2009; 18(3):876-83. · 4.12 Impact Factor
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ABSTRACT: Reducing the nicotine content of cigarettes to make them non-addictive has been widely discussed as a potential strategy for tobacco regulation. A major concern with nicotine reduction is that smokers will compensate for reduced nicotine by smoking more cigarettes and/or smoking more intensively, thereby increasing their exposure to tobacco smoke toxins. This study examined whether gradual reduction in nicotine exposure increases exposure to tobacco smoke toxins.
This 10-week longitudinal study of 20 healthy smokers involved smoking their usual brand followed by different types of research cigarettes with progressively lower nicotine content, each smoked for 1 week. Subjects were followed for 4 weeks after returning to smoking their usual brand (or quitting). Smoking behaviors, chemical biomarkers of tobacco smoke exposure, and cardiovascular effect biomarkers were measured.
Intake of nicotine declined progressively as the nicotine content of cigarettes was reduced, with little evidence of compensation. 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 excretion decreased. Twenty-five percent of participants had spontaneously quit smoking 4 weeks after completing the research cigarette taper.
Our findings with reduced nicotine content cigarettes differ from those of commercial low yields for which compensatory smoking for lower nicotine delivery is substantial. Our data suggest that the degree of nicotine dependence of smokers can be lowered without increasing their exposure to tobacco smoke toxins. Gradual reduction of nicotine content of cigarettes seems to be feasible and should be further evaluated as a national tobacco regulatory strategy.
Cancer Epidemiology Biomarkers & Prevention 12/2007; 16(11):2479-85. · 4.12 Impact Factor
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ABSTRACT: Recently, we developed sensitive and quantitative methods for analysis of the biomarkers of tobacco smoke exposure nicotine, cotinine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in human toenails. In this study, we further evaluated the newly developed toenail biomarkers by investigating their relationship to demographic factors, reported exposure, plasma nicotine, cotinine, and trans-3'-hydroxycotinine, and urinary NNAL. Toenails of 105 smokers, mean age 38.9 years (range, 19-68), were analyzed. Fifty-five (53.4%) were male, with approximately equal numbers of Whites and African-Americans. The average number of cigarettes smoked per day was 18 (range, 5-50). There was no effect of age or gender on the toenail biomarkers. Toenail NNAL was higher in White than in African-American participants (P = 0.019). Toenail nicotine and toenail cotinine correlated significantly with cigarettes smoked per day (r = 0.24; P = 0.015 and r = 0.26; P = 0.009, respectively). Toenail nicotine correlated with plasma nicotine (r = 0.39; P < 0.001); toenail cotinine correlated with plasma cotinine (r = 0.45; P < 0.001) and plasma trans-3'-hydroxycotinine (r = 0.30; P = 0.008); and toenail NNAL correlated with urine NNAL (r = 0.53; P = 0.005). The results of this study provide essential validation data for the use of toenail biomarkers in investigations of the role of chronic tobacco smoke exposure in human cancer.
Cancer Epidemiology Biomarkers & Prevention 08/2007; 16(7):1382-6. · 4.12 Impact Factor
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ABSTRACT: Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants, and a number of them are carcinogenic. One approach for measuring exposure to them is to determine the concentrations of metabolites in urine. The pyrene metabolite 1-hydroxypyrene has been used as a biomarker for exposure in numerous studies. However, determination of exposure to several PAHs may be advantageous, since the relative amounts may vary depending upon the exposure source. We developed a liquid chromatography-tandem mass spectrometry method for the determination of phenolic metabolites of naphthalene, fluorene, phenanthrene, and pyrene in human urine. Following enzymatic cleavage of the glucuronide and sulfate conjugates, the phenolic metabolites are extracted from urine and converted to pentafluorobenzyl ethers. These derivatives greatly enhance the sensitivity of detection by atmospheric pressure chemical ionization in the negative ion mode. Lower limits of quantitation range from 0.01 to 0.5 ng/mL. Stable isotope-labeled internal standards were synthesized or obtained commercially. Data on urinary excretion of several PAH metabolites in urine of smokers and nonsmokers are presented.
Analytical Chemistry 02/2007; 79(2):587-98. · 5.86 Impact Factor
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ABSTRACT: "Light" cigarettes are extremely popular and are perceived by many smokers as less hazardous than higher-yield cigarettes. The objectives of this study were (a) to assess a battery of biomarkers of tobacco smoke exposure that includes tobacco smoke carcinogens, (b) to examine the behavioral nature of compensation, and (c) to examine the consistency of an individual's tobacco smoke exposure when smoking the same cigarette at different times.
The study was a 3-week crossover study in which smokers smoked their usual cigarettes during weeks 1 and 3, and a light cigarette, with a machine-determined nicotine yield of about 50% of the usual cigarette, during week 2. Blood and urine biomarkers of exposure and subjective questionnaires were collected weekly.
Based on cotinine and carboxyhemoglobin levels, compensation averaged 78% and 83%, respectively. Urinary excretion of 4-(methylnitrosamino)-1-(3-pyridyl)-butanol, a metabolite of the tobacco specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-butanone, and a number of polycyclic aromatic hydrocarbon metabolites was similar in all conditions. Compensation was accomplished both by smoking cigarettes more intensively and by smoking more cigarettes per day. Exposures to various tobacco smoke constituents while smoking the usual brand of cigarette in weeks 1 and 3 were highly correlated.
Our findings support the idea that smokers compensate to a high degree when switched from their usual brand to a light cigarette. Short-term switching resulted in no significant reduction in carcinogen exposure. Our assessment, based on measures of biochemical exposures, supports the idea that switching to light cigarettes is unlikely to reduce the health risks of cigarette smoking.
Cancer Epidemiology Biomarkers & Prevention 07/2005; 14(6):1376-83. · 4.12 Impact Factor
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ABSTRACT: A major metabolite of norepinephrine (NE) in brain is 4-hydroxy-3-methoxyphenylethylene glycol (MHPG). In many species, a large fraction of MHPG formed in brain is converted to the sulfate conjugate. Consequently, MHPG sulfate has been proposed as a biomarker for NE metabolism in the central nervous system. As part of the clinical trials of the monoamine oxidase inhibitor selegiline for treating cocaine addiction, we required a method for measuring urine concentrations of MHPG sulfate. Using a deuterium-labeled analogue as an internal standard, we developed a liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/ MS) method for determination of MHPG sulfate in human urine. Sample preparation involves simply diluting 50 microL of urine with 1 mL of ammonium formate buffer and adding the internal standard. The sample is centrifuged, the supernate is transferred to an autosampler vial, and 10 microL is injected into the LC-MS/MS system. Standard curves from 50 to 10,000 ng/mL are generated. Only one sample of 277 clinical samples analyzed had a concentration outside of this range. Precision (coefficient of variation) ranged from 1.9 to 9.7%, and accuracy ranged from 97 to 103% of expected values for controls prepared by spiking sulfatase-treated urine with MHPG sulfate.
Analytical Chemistry 11/2002; 74(20):5290-6. · 5.86 Impact Factor
