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1.  Biomarkers of Secondhand Smoke Exposure in Automobiles 
Tobacco control  2013;23(1):10.1136/tobaccocontrol-2012-050724.
Objectives
The objectives of this study were: (1) to characterize the exposure of nonsmokers exposed to secondhand smoke (SHS) in a vehicle using biomarkers, (2) to describe the time-course of the biomarkers over 24 h, and (3) to examine the relationship between tobacco biomarkers and airborne concentrations of SHS markers.
Methods
Eight nonsmokers were individually exposed to SHS in cars with fully open front windows and closed back windows over an hour from a smoker who smoked 3 cigarettes at 20 min intervals. The nonsmokers sat in the backseat-passenger side, while the smoker sat in the driver’s seat. Plasma cotinine and urine cotinine, 3-hydroxycotinine (3HC), and 4-(methylnitrosoamino)-(3-pyridyl)-1-butanol (NNAL) were compared in samples taken at baseline and several time-points after exposure. Nicotine, particulate matter (PM2.5), and carbon monoxide (CO) were measured inside and outside the vehicle and ventilation rates in the cars were measured.
Results
Average plasma cotinine and the molar sum of urine cotinine and 3HC (COT+3HC) increased 4-fold, urine cotinine increased 6-fold, and urine NNAL increased ~27 times compared to baseline biomarker levels. Plasma cotinine, urine COT+3HC and NNAL peaked at 4–8 hours post-exposure while urine cotinine peaked within 4 hours. Plasma cotinine was significantly correlated to PM2.5 (Spearman correlation (rs = 0.94) and CO (rs = 0.76) but not to air nicotine. The correlations between urine biomarkers, cotinine, COT+3HC, and NNAL and air nicotine, PM2.5, and CO were moderate but non-significant (rs range, 0.31 – 0.60).
Conclusion
Brief SHS exposure in cars resulted in substantial increases in levels of tobacco biomarkers in nonsmokers. For optimal characterization of SHS exposure, tobacco biomarkers should be measured within 4–8 h post-exposure. Additional studies are needed to better describe the relationship between tobacco biomarkers and environmental markers of SHS.
doi:10.1136/tobaccocontrol-2012-050724
PMCID: PMC3670969  PMID: 23349229
Cigarettes; Secondhand smoke; passive smoking; automobiles; motor vehicles; biomarkers; cotinine; tobacco-specific nitrosamines
2.  Urine nicotine metabolite concentrations in relation to plasma cotinine during low-level nicotine exposure 
Nicotine & Tobacco Research  2009;11(8):954-960.
Introduction
Plasma or saliva cotinine concentrations are used widely as biomarkers of secondhand smoke (SHS) exposure and have been associated with the risk of SHS-related disease. Concentrations of cotinine and other nicotine metabolites are considerably higher in urine than in plasma or saliva, making chemical analysis easier. In addition, urine is often more convenient to collect in some SHS exposure studies. The optimal use of nicotine metabolites in urine, singly or in combination, with or without correction for urine creatinine concentration, to estimate plasma cotinine concentration with low-level nicotine exposure has not been determined.
Methods
We dosed 36 nonsmokers with 100, 200, or 400 μg deuterium-labeled nicotine (simulating exposure to SHS) by mouth daily for 5 days and then measured plasma and urine cotinine and metabolites at various intervals over 24 hr.
Results
A plasma cotinine concentration of 1 ng/ml corresponds on average to a daily intake of 100 μg nicotine. Cotinine concentrations in urine averaged four to five times those in plasma. Correction of urine cotinine for creatinine concentration improved the correlation between urine and plasma cotinine. Measuring multiple cotinine metabolites in urine did not improve the correlation with plasma cotinine, compared with the use of urine cotinine alone.
Discussion
Measurement of urine cotinine corrected for creatinine concentration appears to be the best predictor of plasma cotinine.
doi:10.1093/ntr/ntp092
PMCID: PMC2734286  PMID: 19525206
3.  Stability of the Nicotine Metabolite Ratio in Smokers of Progressively Reduced Nicotine Content Cigarettes 
Nicotine & Tobacco Research  2013;15(11):1939-1942.
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 (12mg nicotine content) to the final test cigarette (1mg 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.
doi:10.1093/ntr/ntt065
PMCID: PMC3790625  PMID: 23674838
4.  Genetic and Pharmacokinetic Determinants of Response to Transdermal Nicotine in White, Black and Asian Non-Smokers 
Clinical pharmacology and therapeutics  2013;94(6):10.1038/clpt.2013.159.
The aim of the study was to examine genetic, pharmacokinetic and demographic factors that influence sensitivity to nicotine in never smokers. Sixty never smokers, balanced for gender and race (Caucasian, Blacks and Asian), wore 7 mg nicotine skin patches for up to 8 hours. Serial plasma nicotine concentrations and subjective and cardiovascular effects were measured, and genetic variation in the CYP2A6 gene, the primary enzyme responsible for nicotine metabolism, was assessed. Nicotine toxicity requiring patch removal developed in 9 subjects and was strongly associated with rate of rise and peak concentrations of plasma nicotine. Toxicity, subjective and cardiovascular effects of nicotine were associated with the presence of reduced function CYP2A6 alleles, presumably reflecting slow nicotine metabolic inactivation. This study has implications for understanding individual differences in responses to nicotine medications, particularly when the latter are used for treating medical conditions in non-smokers, and possibly in vulnerability to developing nicotine dependence.
doi:10.1038/clpt.2013.159
PMCID: PMC3834081  PMID: 23933970
5.  Determination of Tobacco Smoke Exposure by Plasma Cotinine Levels in Infants and Children Attending Urban Public Hospital Clinics 
Objective
To determine the prevalence of secondhand smoke (SHS) exposure among infants and young children who received preventive care at pediatric preventative care clinics associated with an urban public hospital. Cotinine, a metabolite of nicotine, has been used to study SHS exposure in population-based studies of children 3 years of age or older.
Design
Retrospective study using a convenience sample.
Setting
Urban county pediatric primary care clinics in San Francisco, California.
Participants
A total of 496 infants and children (mean [SD] age, 2.4 [1.9] years).
Interventions
Discarded plasma samples (which were routinely collected for lead screening) were tested, and medical records were reviewed, for SHS exposure.
Main Outcome Measure
Secondhand smoke exposure based on cotinine plasma level and history of exposure in the medical record.
Results
Thirteen percent of parents reported that their child was exposed to SHS, yet biochemical testing detected cotinine in 55% of samples, at a geometric mean (SD) of 0.23 (3.55) ng/mL. There were no significant sex or age differences. African American children had much higher mean cotinine levels than did Latino children (geometric mean difference, 6.07 ng/mL [95% CI, 4.37 to 8.43 ng/mL]).
Conclusion
In a city with a low smoking rate (12%) and public smoking bans, we documented 55% exposure among infants and young children, using a plasma biomarker, compared with 13% exposure reported by parents. Because SHS is associated with significant respiratory diseases and parents underreport exposure, routine biochemical screening should be considered as a tool to identify and reduce SHS exposure.
doi:10.1001/archpediatrics.2012.170
PMCID: PMC3997061  PMID: 22566513
6.  Racial differences in the relationship between tobacco dependence and nicotine and carcinogen exposure 
Addiction (Abingdon, England)  2012;108(3):607-617.
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.
doi:10.1111/j.1360-0443.2012.04077.x
PMCID: PMC3553231  PMID: 22971134
Tobacco dependence; nicotine addiction; carcinogen exposure; FTND; time to first cigarette (TFC); racial differences; NNAL; PAH
7.  Influence of CYP2B6 genetic variants on plasma and urine concentrations of bupropion and metabolites at steady state 
Pharmacogenetics and genomics  2013;23(3):135-141.
Background
Bupropion, an antidepressant and smoking cessation medication, is metabolized to hydroxybupropion (HB), an active metabolite, primarily by CYP2B6.
Objectives
To compare plasma concentrations of bupropion and metabolites at steady state in healthy volunteers with and without CYP2B6 genetic variants.
Methods
In a genotype-guided study of 42 healthy subjects we measured plasma and urine concentrations of bupropion and its metabolites, HB, threohydrobupropion (TB) and erythrohydrobupropion (EB) after 7 days of sustained release bupropion dosing.
Results
CYP2B6*6 and *18 gene variants were associated with approximately 33% reduced concentrations of HB, with no effects on concentrations of bupropion or other metabolites. We could account for 50% of the variation in HB concentrations in a model including genotype and sex.
Conclusions
Since HB is active and steady state concentrations of HB are more than 10 times higher than bupropion, CYP2B6 variants are likely to affect pharmacological activity. Due to the large individual variation within genotype group, the use of therapeutic drug monitoring for dose optimization may be necessary.
doi:10.1097/FPC.0b013e32835d9ab0
PMCID: PMC3763712  PMID: 23344581
8.  CYP2A6 Genotype but not Age Determines Cotinine Half-life in Infants and Children 
Clinical pharmacology and therapeutics  2013;94(3):10.1038/clpt.2013.114.
The formation of cotinine, the main proximate metabolite and a biomarker of nicotine exposure, is mediated primarily by CYP2A6. Our aim was to determine if higher cotinine levels in young children exposed to secondhand smoke (SHS) are a result of age-related differences in pharmacokinetics. Forty-nine participants, 2 to 84 months old, received oral deuterium-labeled cotinine, with daily urine samples for up to 10 days for cotinine half-life measurement. DNA from saliva was used for CYP2A6 genotyping. The estimate of half-life using a mixed effect model was 17.9 hrs (95%CI: 16.5, 19.3), similar to that reported in adults. There was no statistically significant effect of sex, race, age, or weight. Children with normal activity CYP2A6*1/*1 genotypes had a shorter half-life than those with 1–2 reduced activity variant alleles. Our data suggest that higher cotinine levels in SHS-exposed young children compared to adults are due to greater SHS exposure rather than different cotinine pharmacokinetics.
doi:10.1038/clpt.2013.114
PMCID: PMC3820275  PMID: 23714690
9.  Variation in Trans-3′-Hydroxycotinine Glucuronidation Does Not Alter the Nicotine Metabolite Ratio or Nicotine Intake 
PLoS ONE  2013;8(8):e70938.
Background
CYP2A6 metabolizes nicotine to its primary metabolite cotinine and also mediates the metabolism of cotinine to trans-3′-hydroxycotinine (3HC). The ratio of 3HC to cotinine (the “nicotine metabolite ratio”, NMR) is an in vivo marker for the rate of CYP2A6 mediated nicotine metabolism, and total nicotine clearance, and has been associated with differences in numerous smoking behaviors. The clearance of 3HC, which affects the NMR, occurs via renal excretion and metabolism by UGT2B17, and possibly UGT2B10, to 3HC-glucuronide. We investigated whether slower 3HC glucuronidation alters NMR, altering its ability to predict CYP2A6 activity and reducing its clinical utility.
Methods
Plasma NMR, three urinary NMRs, three urinary 3HC glucuronidation phenotypes and total nicotine equivalents were examined in 540 African American smokers. The UGT2B17 gene deletion and UGT2B10*2 were genotyped.
Results
The UGT2B17 gene deletion, but not UGT2B10*2 genotype, was associated with slower 3HC glucuronidation (indicated by three 3HC-glucuronidation phenotypes), indicating its role in this glucuronidation pathway. However, neither lower rates of 3HC glucuronidation, nor the presence of a UGT2B17 and UGT2B10 reduced function allele, altered plasma or urinary NMRs or levels of smoking.
Conclusions
Variation in 3HC glucuronidation activity, including these caused by UGT2B17 gene deletions, did not significantly alter NMR and is therefore unlikely to affect the clinical utility of NMR in smoking behavior and cessation studies. This study demonstrates that NMR is not altered by differences in the rate of 3HC glucuronidation, providing further support that NMR is a reliable indicator of CYP2A6 mediated nicotine metabolism.
doi:10.1371/journal.pone.0070938
PMCID: PMC3732272  PMID: 23936477
10.  Reproducibility of the Nicotine Metabolite Ratio in Cigarette Smokers 
Background
The nicotine metabolite ratio (NMR or 3-hydroxycotinine/cotinine) has been used to phenotype CYP2A6-mediated nicotine metabolism. Our objectives were to analyze (a) the stability of NMR in plasma, saliva, and blood in various storage conditions, (b) the relationship between NMRs derived from blood, plasma, saliva, and urine, and (c) the reproducibility of plasma NMR in ad libitum cigarette smokers.
Methods
We analyzed data from four clinical studies. In studies 1 and 2, we assessed NMR stability in saliva and plasma samples at room temperature (~22°C) over 14 days and in blood at 4°C for up to 72 hours. In studies 2 and 3, we used Bland-Altman analysis to assess agreement between blood, plasma, saliva, and urine NMRs. In study 4, plasma NMR was measured on 6 occasions over 44 weeks in 43 ad libitum smokers.
Results
Reliability coefficients for stability tests of NMR in plasma and saliva at room temperature were 0.97 and 0.98, respectively, and 0.92 for blood at 4°C. Blood NMR agreed consistently with saliva and plasma NMRs but showed more variability in relation to urine NMR. The reliability coefficient for repeated plasma NMR measurements in smokers was 0.85.
Conclusion
The NMR is stable in blood, plasma, and saliva at the conditions tested. Blood, plasma, and saliva NMRs are similar while urine NMR is a good proxy for these NMR measures. Plasma NMR was reproducible over time in smokers.
Impact
One measurement may reliably estimate a smoker’s NMR for use as an estimate of the rate of nicotine metabolism.
doi:10.1158/1055-9965.EPI-12-0236
PMCID: PMC3392523  PMID: 22552800
Nicotine metabolite ratio (NMR); cotinine; 3-hydroxycotinine; biological stability; chemical stability
11.  Exposure to Nicotine and Carcinogens among Southwestern Alaskan Native Cigarette Smokers and Smokeless Tobacco Users 
Background
The prevalence of tobacco use, both cigarette smoking and smokeless, including iqmik (homemade smokeless tobacco prepared with dried tobacco leaves mixed with alkaline ash), and of tobacco-related cancer is high in Alaskan Native people (AN). To investigate possible mechanisms of increased cancer risk we studied levels of nicotine and tobacco-specific nitrosamines (TSNA) in tobacco products and biomarkers of tobacco toxicant exposure in Southwestern AN people.
Methods
Participants included 163 cigarette smokers, 76 commercial smokeless tobacco, 20 iqmik, 31 dual cigarette smokers and smokeless tobacco, and 110 nontobacco users. Tobacco use history, samples of tobacco products used, and blood and urine samples were collected.
Results
Nicotine concentrations were highest in cigarette tobacco and TSNAs highest in commercial smokeless tobacco products. The AN participants smoked on average 7.8 cigarettes per day. Nicotine exposure, assessed by several biomarker measures, was highest in iqmik users, and similar in smokeless tobacco and cigarette smokers. TSNA exposure was highest in smokeless tobacco users, and polycyclic aromatic hydrocarbon exposure was highest in cigarette smokers.
Conclusions
Despite smoking fewer cigarettes per day, AN cigarette smokers had similar daily intake of nicotine compared to the general U.S. population. Nicotine exposure was greatest from iqmik, likely related to its high pH due to preparation with ash, suggesting high addiction potential compared to other smokeless tobacco products. TSNA exposure was much higher with smokeless tobacco than other product use, possibly contributing to the high rates of oral cancer.
Impact
Our data contribute to an understanding of the high addiction risk of iqmik use and of the cancer-causing potential of various forms of tobacco use among AN people.
doi:10.1158/1055-9965.EPI-11-1178
PMCID: PMC3444141  PMID: 22490317
12.  Smoking Behavior and Exposure to Tobacco Toxicants During 6 months of Smoking Progressively Reduced Nicotine Content Cigarettes 
Background
Recent federal legislation gives the FDA 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
135 healthy smokers were randomly assigned to one of two groups. A research group smoked their usual brand of cigarettes followed by 5 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, while 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.
doi:10.1158/1055-9965.EPI-11-0644
PMCID: PMC3348427  PMID: 22354905
13.  Racial Differences in the Relationship Between Number of Cigarettes Smoked and Nicotine and Carcinogen Exposure 
Nicotine & Tobacco Research  2011;13(9):772-783.
Introduction:
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.
Methods:
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.
Results:
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.
doi:10.1093/ntr/ntr072
PMCID: PMC3168241  PMID: 21546441
14.  Comparison of Urine Cotinine and the Tobacco-Specific Nitrosamine Metabolite 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol (NNAL) and Their Ratio to Discriminate Active From Passive Smoking 
Nicotine & Tobacco Research  2011;13(3):202-208.
Objectives:
Cotinine is the most widely used biomarker to distinguish active versus passive smoking. However, there is an overlap in cotinine levels when comparing light or occasional smokers versus heavily exposed passive smokers. 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is a tobacco-specific nitrosamine measurable in urine with a much longer half-life than cotinine. The aim of the study was to determine optimal cutoff points to discriminate active versus passive smokers and to compare sensitivity and specificity for the use of cotinine, NNAL, and the ratio of the NNAL/cotinine in urine.
Methods:
Cotinine and NNAL were measured in urine of 373 active smokers and 228 passive smokers.
Results:
Geometric mean cotinine levels were 2.03 ng/ml (interquartile interval: 0.43–8.60) and 1,043 ng/ml (658–2,251) and NNAL levels were 5.80 pg/ml (2.28–15.4) and 165 pg/ml (90.8–360) pg/ml in passive and active smokers, respectively. NNAL/cotinine ratio in urine was significantly higher for passive smokers when compared with active smokers (2.85 vs. 0.16, p < .01). The receiver operating characteristics analysis determined optimal cutoff points to discriminate passive versus active smokers: 31.5 ng/ml for cotinine (sensitivity: 97.1% and specificity: 93.9%), 47.3 pg/ml for NNAL (87.4% and 96.5%), and 0.74 × 10−3 for NNAL/cotinine ratio (97.3% and 87.3%).
Conclusions:
Both urine cotinine and NNAL are sensitive and specific biomarkers for discriminating the source of tobacco smoke exposure. Cotinine is the best overall discriminator when biomarkers are measured while a person has ongoing exposure to tobacco smoke. NNAL because of its long half-life would be particularly useful when there is a delay between exposure and biomarker measurement. The NNAL/cotinine ratio provides similar sensitivity but poorer specificity at discriminating passive versus active smokers when compared with NNAL alone.
doi:10.1093/ntr/ntq237
PMCID: PMC3045466  PMID: 21330276
15.  Urine Menthol as a Biomarker of Mentholated Cigarette Smoking 
Objectives
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1158/1055-9965.EPI-10-0706
PMCID: PMC3005539  PMID: 20962297
16.  Estimation of Nicotine Dose after Low Level Exposure Using Plasma and Urine Nicotine Metabolites 
Background
We sought to determine the optimal plasma and urine nicotine metabolites, alone or in combination, to estimate the systemic dose of nicotine after low level exposure.
Methods
We dosed 36 nonsmokers with 100, 200 or 400 μg deuterium-labeled nicotine (doses similar to exposure to secondhand smoke, SHS) by mouth daily for 5 days and then measured plasma and urine nicotine metabolites at various intervals over 24 hours.
Results
The strongest correlations with nicotine dose were seen for the sum of four [cotinine + cotinine-glucuronide + trans-3′-hydroxycotinine + 3HC-glucuronide] or six [ including also nicotine + nicotine-glucuronide] of the major nicotine metabolites in 24 hour urine collection (r = 0.96), with lesser correlations for these metabolites using spot urines corrected for creatinine at various times of day (r = 0.72 – 0.80). Plasma [cotinine + trans 3′ hydroxycotine] was more highly correlated with nicotine dose than plasma cotinine alone (r = 0.82 vs 0.75).
Conclusions
Our results provide guidance for selection of biomarkers to estimate the dose of nicotine taken in low level (SHS) tobacco exposure.
Impact
This is probably relevant to active smoking as well.
doi:10.1158/1055-9965.EPI-09-1303
PMCID: PMC2867075  PMID: 20447913
17.  Counseling to reduce children's secondhand smoke exposure and help parents quit smoking: A controlled trial 
Nicotine & Tobacco Research  2009;11(12):1383-1394.
Introduction:
We tested a combined intervention to reduce children's secondhand smoke exposure (SHSe) and help parents quit smoking.
Methods:
After baseline, mothers who exposed their children younger than 4 years to 10 or more cigarettes/week were randomized to the intervention (n = 76) or usual care control condition (n = 74). Outcomes were assessed at 3, 6, 12, and 18 months. Intervention families were offered 10 in-person at home and 4 telephone counseling sessions over 6 months, and additional pre- and postquit telephone sessions. Counseling procedures included behavioral contracting, self-monitoring, and problem solving.
Results:
Parents’ reports of their smoking and children's exposure showed moderate and significant correlations with children's urine cotinine levels and home air nicotine (r = .40–.78). Thirteen (17.1%) intervention group mothers and 4 (5.4%) controls reported that they quit smoking for 7 days prior to 1 or more study measurements, without biochemical contradiction (p = .024). Results of generalized estimating equations showed significantly greater decrease in reported SHSe and mothers’ smoking in the counseled group compared with controls. Reported indoor smoking and children's urine cotinine decreased, yet group differences for changes were not significant.
Discussion:
Nicotine contamination of the home and resulting thirdhand exposure may have contributed to the failure to obtain a differential decrease in cotinine concentration. Partial exposure to counseling due to dropouts and lack of full participation from all family members and measurement reactivity in both conditions may have constrained intervention effects. Secondhand smoke exposure counseling may have been less powerful when combined with smoking cessation.
doi:10.1093/ntr/ntp148
PMCID: PMC2784487  PMID: 19875762
18.  Elimination Kinetics of the Tobacco-Specific Biomarker and Lung Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol 
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is tobacco specific and has a longer half-life than other tobacco biomarkers studied thus far. An accurate measurement of the NNAL half-life is important for optimal use to assess exposure to tobacco smoke. We determined the half-life of NNAL in urine in eight daily smokers on a clinical research ward and in five occasional smokers in a real-life environment. Total NNAL in urine was monitored for 14 days in daily smokers after stopping smoking and for up to 60 days in occasional smokers. The average half-life for the terminal phase in the daily smoker group using a two-compartmental body model was 10.3 days (beta phase), and using a noncompartmental model, it was 9.1 days. In the occasional group, these values were 17.6 and 16.0 days, respectively. The alpha-phase half-lives were 14.3 and 27.8 hours for the two groups, respectively. The inter-subject coefficient of variation of the NNAL terminal half-life ranged from 14% to 30%, and the intra-subject coefficient of variation ranged from 3% to 18%. There was very good agreement between the plasma and urinary half-lives in two subjects with plasma analyses: 7.4 versus 7.9 days and 9.2 versus 10.7 days. Mean renal clearance of NNAL was 13 ± 2.3 mL/min. The terminal half-life of NNAL of 10 to 18 days indicates that this biomarker can be used to detect tobacco smoke exposure for 6 to 12 weeks after cessation of exposure and requires a similar time to assess the steady levels of NNAL after switching from one tobacco product to another.
doi:10.1158/1055-9965.EPI-09-0874
PMCID: PMC2804843  PMID: 19959691
19.  Interlaboratory comparability of serum cotinine measurements at smoker and nonsmoker concentration levels: A round-robin study 
Nicotine & Tobacco Research  2009;11(12):1458-1466.
Introduction:
Cotinine, the primary proximate metabolite of nicotine, is commonly measured as an index of exposure to tobacco in both active users of tobacco and nonsmokers with possible exposure to secondhand smoke (SHS). A number of laboratories have implemented analyses for measuring serum cotinine in recent years, but there have been few interlaboratory comparisons of the results. Among nonsmokers exposed to SHS, the concentration of cotinine in blood can be quite low, and extensive variability in these measurements has been reported in the past.
Methods:
In this study, a group of seven laboratories, all experienced in serum cotinine analysis, measured eight coded serum pools with concentrations ranging from background levels of about 0.05 ng/ml to relatively high concentrations in the active smokers range. All laboratories used either gas–liquid chromatography with nitrogen–phosphorus detection or liquid chromatography with mass spectrometric detection.
Results:
All seven laboratories reliably measured the cotinine concentrations in samples that were within the range of their methods. In each case, the results for the pools were correctly ranked in order, and no significant interlaboratory bias was observed at the 5% level of significance for results from any of the pools.
Discussion:
We conclude that present methods of chromatographic analysis of serum cotinine, as used by these experienced laboratories, are capable of providing accurate and precise results in both the smoker and the nonsmoker concentration range.
doi:10.1093/ntr/ntp161
PMCID: PMC3167685  PMID: 19933777
20.  Prevalence of Smoking Assessed Biochemically in an Urban Public Hospital: A Rationale for Routine Cotinine Screening 
American Journal of Epidemiology  2009;170(7):885-891.
Cotinine, a metabolite of nicotine, has been used to study tobacco smoke exposure in population studies, but the authors are unaware of its use to screen hospitalized patients. The authors measured serum cotinine levels in 948 patients admitted to an urban public hospital in San Francisco, California, between September 2005 and July 2006. On the basis of cotinine levels, they classified patients as active smokers (cotinine ≥ 14 ng/mL), recent smokers or significantly exposed to secondhand smoke (SHS) (0.5–13.9 ng/mL), lightly exposed to SHS (0.05–0.49 ng/mL), or unexposed (<0.05 ng/mL). In contrast to the 13% prevalence of smoking in the general population of San Francisco, 40% of patients were active smokers; 15% were recent smokers or heavily exposed to SHS; 25% had low-level exposure to SHS; and 20% were unexposed. Active smoking or heavy SHS exposure was particularly high among African Americans (77%), the uninsured (65%), self-reported alcohol drinkers (77%), and illicit drug users (90%). Of people who denied smoking, 32% were found to have had significant exposure. If serum cotinine measurement became part of routine screening at urban public hospitals, cotinine levels would be abnormal in many patients and would provide objective evidence of tobacco smoke exposure, probably resulting in more intensive intervention to encourage patients to stop smoking and avoid SHS.
doi:10.1093/aje/kwp215
PMCID: PMC2765360  PMID: 19713287
biological markers; cotinine; ethnic groups; hospitalization; smoking; tobacco; tobacco smoke pollution; vulnerable populations
21.  Longer term exposure to secondhand smoke and health outcomes in COPD: Impact of urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
Nicotine & Tobacco Research  2009;11(8):945-953.
Introduction
Secondhand smoke (SHS) contains respiratory irritants and has the potential to adversely affect adults with chronic obstructive pulmonary disease (COPD), but few studies have evaluated the impact of SHS on COPD.
Methods
We used data from 72 nonsmoking participants in a cohort study of COPD. Urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) was measured as an indicator of longer term SHS exposure, whereas urine cotinine was assessed as a measure of more recent exposure. The impact of SHS exposure on COPD-related health status was examined using multivariate linear regression (controlling for age, sex, race, educational attainment, and smoking history). Health status was measured using a validated COPD severity score, reported dyspnea, a standard health status measure (Short Form-12), and activity restriction.
Results
The urine NNAL-to-creatinine ratio (per interquartile increment) was associated with greater COPD severity (mean score increase 1.7 points; 95% CI 0.6–2.8; p = .0003). Higher urine NNAL was also related to greater dyspnea, poorer physical health status, and more restricted activity (p ≤ .05 in all cases). When considered simultaneously, longer term exposure (NNAL) had a greater negative impact on COPD status than shorter term exposure (cotinine).
Discussion
Urine NNAL can be used to estimate longer term SHS exposure and negatively affects a number of health outcomes among adults with COPD. Screening for and prevention of SHS exposure among persons with COPD may be beneficial.
doi:10.1093/ntr/ntp091
PMCID: PMC2711983  PMID: 19587064
22.  Progressive Commercial Cigarette Yield Reduction: Biochemical Exposure and Behavioral Assessment 
Background
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.
Methods
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.
Findings
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.
Implications
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.
doi:10.1158/1055-9965.EPI-08-0731
PMCID: PMC2802575  PMID: 19258480
23.  Withdrawal in adolescent light smokers following 24-hour abstinence 
Nicotine & Tobacco Research  2009;11(2):185-189.
Introduction:
Withdrawal is one of the most important symptoms of nicotine addiction. We examined the extent to which adolescent light smokers experienced withdrawal symptoms when deprived of nicotine for a 24-hr period.
Methods:
A total of 20 adolescents aged 13–17 years who smoked 1–5 cigarettes/day (CPD) refrained from smoking for a 24-hr period. Withdrawal scales were administered, and heart rate was measured at baseline, 12, and 24 hr. Neuropsychological testing was performed at baseline and 24 hr. Participants were divided into two groups: very light smokers (1–3 CPD) and light smokers (4–5 CPD).
Results:
At 12 hr, very light smokers experienced a decrease in withdrawal symptoms versus light smokers, who reported an increase in symptoms (−2.9 vs. 2.8, p = .02). Similarly, at 24 hr, very light smokers experienced a mean decrease in withdrawal score compared with a mean increase for the light smoker group (–2.2 vs. 5.8, p = .04). We did not find a significant change in heart rate or any differences in participants’ scores on the memory or concentration tasks.
Discussion:
Based on our findings in this controlled laboratory experiment, adolescent very light smokers did not appear to have significant withdrawal symptoms following abstinence from nicotine. Adolescent light smokers who smoke 4–5 CPD experienced subjective withdrawal symptoms but did not have objective signs of nicotine withdrawal. The stage of smoking in which adolescents are smoking 5 CPD or fewer appears to be a crucial time for studying development of nicotine addiction in teens as they may be transitioning from social smoking to early addiction.
doi:10.1093/ntr/ntn028
PMCID: PMC2658900  PMID: 19246428
24.  Rate of Nicotine Metabolism and Withdrawal Symptoms in Adolescent Light Smokers 
Pediatrics  2008;122(3):e643-e647.
OBJECTIVES
The rate of nicotine metabolism may contribute to vulnerability in adolescents’ transition from smoking initiation to addiction. The objectives of this study were to examine the associations between the rate of nicotine metabolism and cigarette consumption, addiction and withdrawal symptoms in a sample of adolescent light smokers.
PARTICIPANTS
Twenty adolescent smokers between 13 and 17 years-old, who smoked between 1 and 6 cigarettes daily for at least 6 months were recruited from several San Francisco Bay area schools and pediatric clinics from 2006–2007.
METHODS
Participants underwent 24 hours of supervised tobacco abstinence. Serum was collected at baseline and at 24 hours for measurement of the nicotine metabolites, cotinine and 3’-hydroxycotinine (3HC). Participants also completed self-report measures which included smoking behavior, nicotine dependence and withdrawal scales at baseline and 24 hours post baseline. The ratio of serum 3HC to cotinine (the nicotine metabolite ratio), a measure of the rate of nicotine metabolism, was computed using measurements from the 24 hour serum samples.
RESULTS
Participants were divided into two groups: faster metabolizers (3HC/Cotinine ratio ≥ 0.5; n=5) and slower metabolizers (3HC/Cotinine ratio < 0.5; n=15). Faster metabolizers reported greater withdrawal symptoms after 24 hours of abstinence compared with slower metabolizers even after adjusting for the number of cigarettes smoked per day (p=.03). The metabolite ratio was significantly correlated with self-described level of addiction (r=.50, p=.03).
CONCLUSIONS
This is the first study to report a significant relationship between the rate of nicotine metabolism and withdrawal symptoms and self-reported addiction in adolescent light smokers. Given the association between withdrawal symptoms and nicotine addiction, adolescent smokers who are faster metabolizers of nicotine may be at greater risk for becoming addicted to nicotine compared with slower metabolizers.
doi:10.1542/peds.2007-3679
PMCID: PMC2722964  PMID: 18762498
Adolescent smoking; nicotine metabolism; addiction; withdrawal
25.  Factors Associated with Discontinuation of Bupropion and Counseling among African American Light Smokers in a Randomized Clinical Trial 
Background
African Americans are at risk for inadequate adherence to smoking cessation treatment yet little is known about what leads to treatment discontinuation.
Purpose
Examine the factors associated with discontinuation of treatment in African American light smokers (≤10 cigarettes per day).
Methods
Bupropion plasma levels and counseling attendance were measured among 540 African American light smokers in a placebo-controlled randomized trial of bupropion.
Results
By Week 3, 28.0% of subjects in the bupropion arm had discontinued bupropion and only moderate associations were found between plasma levels and self-reported bupropion use (rs=0.38). By Week 16, 36.9% of all subjects had discontinued counseling. Males had greater odds of discontinuing medication (OR=2.02, 95% CI, 1.10–3.71, p=0.02) and older adults had lower odds of discontinuing counseling (OR=0.96, 95% CI, 0.94–0.97, p<0.0001).
Conclusions
Bupropion and smoking cessation counseling are underutilized even when provided within the context of a randomized trial. Future research is needed to examine strategies for improving treatment utilization among African American smokers.
doi:10.1007/s12160-013-9510-x
PMCID: PMC3815499  PMID: 23733379
Smoking cessation; discontinuation of treatment; African Americans

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