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1.  Validation of a LC-MS/MS Method for Quantifying Urinary Nicotine, Six Nicotine Metabolites and the Minor Tobacco Alkaloids—Anatabine and Anabasine—in Smokers' Urine 
PLoS ONE  2014;9(7):e101816.
Tobacco use is a major contributor to premature morbidity and mortality. The measurement of nicotine and its metabolites in urine is a valuable tool for evaluating nicotine exposure and for nicotine metabolic profiling—i.e., metabolite ratios. In addition, the minor tobacco alkaloids—anabasine and anatabine—can be useful for monitoring compliance in smoking cessation programs that use nicotine replacement therapy. Because of an increasing demand for the measurement of urinary nicotine metabolites, we developed a rapid, low-cost method that uses isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) for simultaneously quantifying nicotine, six nicotine metabolites, and two minor tobacco alkaloids in smokers' urine. This method enzymatically hydrolyzes conjugated nicotine (primarily glucuronides) and its metabolites. We then use acetone pretreatment to precipitate matrix components (endogenous proteins, salts, phospholipids, and exogenous enzyme) that may interfere with LC-MS/MS analysis. Subsequently, analytes (nicotine, cotinine, hydroxycotinine, norcotinine, nornicotine, cotinine N-oxide, nicotine 1′-N-oxide, anatabine, and anabasine) are chromatographically resolved within a cycle time of 13.5 minutes. The optimized assay produces linear responses across the analyte concentrations typically found in urine collected from daily smokers. Because matrix ion suppression may influence accuracy, we include a discussion of conventions employed in this procedure to minimize matrix interferences. Simplicity, low cost, low maintenance combined with high mean metabolite recovery (76–99%), specificity, accuracy (0–10% bias) and reproducibility (2–9% C.V.) make this method ideal for large high through-put studies.
doi:10.1371/journal.pone.0101816
PMCID: PMC4094486  PMID: 25013964
2.  Prenatal Tobacco Smoke Exposure and Early Childhood BMI 
Summary
Maternal smoking during pregnancy is associated with increased risk of childhood overweight body mass index (BMI). Less is known about the association between prenatal secondhand tobacco smoke (SHS) exposure and childhood BMI. We followed 292 mother-child dyads from early pregnancy to 3 years of age. Prenatal tobacco smoke exposure during pregnancy was quantified using self-report and serum cotinine biomarkers. We used linear mixed models to estimate the association between tobacco smoke exposure and BMI at birth, 4 weeks, and 1, 2, and 3 years. During pregnancy, 15% of women reported SHS exposure and 12% reported active smoking, but 51% of women had cotinine levels consistent with SHS exposure and 10% had cotinine concentrations indicative of active smoking. After adjustment for confounders, children born to active smokers had higher BMI at 2 and 3 years of age (self-report or serum cotinine), compared to unexposed children. Children born to women with prenatal serum cotinine concentrations indicative of SHS exposure had higher BMI at 2 (Mean Difference [MD]:0.3; 95% confidence interval [CI]:−0.1, 0.7) and 3 (MD:0.4; [0, 0.8]) years compared to unexposed children. Using self-reported prenatal exposure resulted in non-differential exposure misclassification of SHS exposures that attenuated the association between SHS exposure and BMI compared to serum cotinine concentrations. These findings suggest active and secondhand prenatal tobacco smoke exposure may be related to an important public health problem in childhood and later life. In addition, accurate quantification of prenatal secondhand tobacco smoke exposures is essential to obtaining valid estimates.
doi:10.1111/j.1365-3016.2010.01146.x
PMCID: PMC3509191  PMID: 20955230
Body Mass Index; Children; Cotinine; Growth; Prenatal; Tobacco Smoke
3.  Household Smoking Behavior: Effects on Indoor Air Quality and Health of Urban Children with Asthma 
Maternal and child health journal  2011;15(4):460-468.
The goal of the study was to examine the association between biomarkers and environmental measures of second hand smoke (SHS) with caregiver, i.e. parent or legal guardian, report of household smoking behavior and morbidity measures among children with asthma. Baseline data were drawn from a longitudinal intervention for 126 inner city children with asthma, residing with a smoker. Most children met criteria for moderate to severe persistent asthma (63%) versus mild intermittent (20%) or mild persistent (17%). Household smoking behavior and asthma morbidity were compared with child urine cotinine and indoor measures of air quality including fine particulate matter (PM2.5) and air nicotine (AN). Kruskal–Wallis, Wilcoxon rank-sum and Spearman rho correlation tests were used to determine the level of association between biomarkers of SHS exposure and household smoking behavior and asthma morbidity. Most children had uncontrolled asthma (62%). The primary household smoker was the child's caregiver (86/126, 68%) of which 66 (77%) were the child's mother. Significantly higher mean PM2.5, AN and cotinine concentrations were detected in households where the caregiver was the smoker (caregiver smoker: PM2.5 μg/m3: 44.16, AN: 1.79 μg/m3, cotinine: 27.39 ng/ml; caregiver non-smoker: PM2.5: 28.88 μg/m3, AN: 0.71 μg/m3, cotinine:10.78 ng/ml, all P ≤ 0.01). Urine cotinine concentrations trended higher in children who reported 5 or more symptom days within the past 2 weeks (>5 days/past 2 weeks, cotinine: 28.1 ng/ml vs. <5 days/past 2 weeks, cotinine: 16.2 ng/ml; P = 0.08). However, environmental measures of SHS exposures were not associated with asthma symptoms. Urban children with persistent asthma, residing with a smoker are exposed to high levels of SHS predominantly from their primary caregiver. Because cotinine was more strongly associated with asthma symptoms than environmental measures of SHS exposure and is independent of the site of exposure, it remains the gold standard for SHS exposure assessment in children with asthma.
doi:10.1007/s10995-010-0606-7
PMCID: PMC3113654  PMID: 20401688
Asthma; Children; Cotinine; Particulate matter; Air Nicotine
4.  Variability and Predictors of Urinary Bisphenol A Concentrations during Pregnancy 
Environmental Health Perspectives  2010;119(1):131-137.
Background
Prenatal bisphenol A (BPA) exposure may be associated with developmental toxicity, but few studies have examined the variability and predictors of urinary BPA concentrations during pregnancy.
Objective
Our goal was to estimate the variability and predictors of serial urinary BPA concentrations taken during pregnancy.
Methods
We measured BPA concentrations during pregnancy and at birth in three spot urine samples from 389 women. We calculated the intraclass correlation coefficient (ICC) to assess BPA variability and estimated associations between log10-transformed urinary BPA concentrations and demographic, occupational, dietary, and environmental factors, using mixed models.
Results
Geometric mean (GM) creatinine-standardized concentrations (micrograms per gram) were 1.7 (16 weeks), 2.0 (26 weeks), and 2.0 (birth). Creatinine-standardized BPA concentrations exhibited low reproducibility (ICC = 0.11). By occupation, cashiers had the highest BPA concentrations (GM: 2.8 μg/g). Consuming canned vegetables at least once a day was associated with higher BPA concentrations (GM = 2.3 μg/g) compared with those consuming no canned vegetables (GM = 1.6 μg/g). BPA concentrations did not vary by consumption of fresh fruits and vegetables, canned fruit, or store-bought fresh and frozen fish. Urinary high-molecular-weight phthalate and serum tobacco smoke metabolite concentrations were positively associated with BPA concentrations.
Conclusions
These results suggest numerous sources of BPA exposure during pregnancy. Etiological studies may need to measure urinary BPA concentrations more than once during pregnancy and adjust for phthalates and tobacco smoke exposures.
doi:10.1289/ehp.1002366
PMCID: PMC3018492  PMID: 21205581
bisphenol A; dietary; occupational; predictors; pregnancy; prenatal; variability
5.  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
6.  Determinants of serum cotinine and hair cotinine as biomarkers of childhood secondhand smoke exposure 
Understanding the determinants of childhood secondhand smoke (SHS) exposure is important in measuring and preventing exposure to this widespread environmental contaminant. We evaluated the ability of a broad set of factors to explain variability in serum cotinine, reflecting recent exposure, and hair cotinine, reflecting longer-term exposure. We included repeated measures from 223 elementary-school-age asthmatic children residing with a smoker. We used a manual model-building approach and likelihood ratio tests to select a model predicting each biomarker, and also compared the predictive ability of determinants using Akaike Information Criteria. Potential determinants included a comprehensive parent questionnaire, household nicotine, home ventilation characteristics, exposure in vehicles and others’ homes, child demographics, and family social class. Variables in each of these categories remained in the final model for both serum (R2 of 0.61) and hair cotinine (R2 of 0.45). A comprehensive set of factors was required to best predict cotinine. Studies should use biomarkers for the best quantitative assessment of SHS exposure. Hair cotinine may be a problematic measure because it was highly influenced by racial differences that were unexplained by SHS exposure. When biospecimen collection is not possible, a household nicotine measurement is warranted. If only questionnaires are available, multiple questions are required to best characterize exposure, such as number of cigarettes, hours spent in a room with concurrent smoking, maternal smoking, and approximate home size.
doi:10.1038/jes.2010.7
PMCID: PMC2972673  PMID: 20237497
cotinine; secondhand smoke; questionnaire; nicotine dosimeter
7.  Low-Level Prenatal Exposure to Nicotine and Infant Neurobehavior 
Neurotoxicology and teratology  2009;31(6):356-363.
Objective
To examine the association between prenatal exposure to nicotine from tobacco smoke and infant neurobehavior using tobacco biomarkers and a sensitive and comprehensive measure of infant neurobehavior.
Study design
Participants were 318 infants (206 White, 95 Black, 17 Other) and their mothers. Prenatal tobacco smoke exposure was measured twice during pregnancy and once at delivery using maternal serum cotinine. Infant neurobehavior was assessed with the NICU Network Neurobehavioral Scale at approximately five weeks after birth.
Results
Prenatal tobacco smoke exposure was significantly associated with infant neurobehavior after controlling for important covariates, but the specific behaviors associated with exposure varied by race. In White infants, higher cotinine was associated with increased arousal (p=.030) and excitability (p=.034), and decreased self-regulation (p=.010). In contrast, among Black infants, higher cotinine was associated with decreased arousal (p=.001), excitability (p=.021), and special handling required to complete the assessment (p=.003), and increased self-regulation (p=.021) and hypotonicity (p=.016). In secondary analyses, we found racial differences in the effects of postnatal exposure to second hand smoke and low-level prenatal exposure.
Conclusions
Low-level prenatal tobacco smoke exposure is associated with infant neurobehavior at five weeks of age, but the specific effects differ by race. These effects may reflect racial differences in nicotine metabolism that are similar to differences reported in adult and child studies of tobacco.
doi:10.1016/j.ntt.2009.07.004
PMCID: PMC2761996  PMID: 19619640
tobacco smoke; prenatal exposure; infant neurobehavior
8.  A prospective cohort study of biomarkers of prenatal tobacco smoke exposure: the correlation between serum and meconium and their association with infant birth weight 
Environmental Health  2010;9:53.
Background
The evaluation of infant meconium as a cumulative matrix of prenatal toxicant exposure requires comparison to established biomarkers of prenatal exposure.
Methods
We calculated the frequency of detection and concentration of tobacco smoke metabolites measured in meconium (nicotine, cotinine, and trans-3'-hydroxycotinine concentrations) and three serial serum cotinine concentrations taken during the latter two-thirds of pregnancy among 337 mother-infant dyads. We estimated the duration and intensity of prenatal tobacco smoke exposure using serial serum cotinine concentrations and calculated geometric mean meconium tobacco smoke metabolite concentrations according to prenatal exposure. We also compared the estimated associations between these prenatal biomarkers and infant birth weight using linear regression.
Results
We detected nicotine (80%), cotinine (69%), and trans-3'-hydroxycotinine (57%) in most meconium samples. Meconium tobacco smoke metabolite concentrations were positively associated with serum cotinine concentrations and increased with the number of serum cotinine measurements consistent with secondhand or active tobacco smoke exposure. Like serum cotinine, meconium tobacco smoke metabolites were inversely associated with birth weight.
Conclusions
Meconium is a useful biological matrix for measuring prenatal tobacco smoke exposure and could be used in epidemiological studies that enroll women and infants at birth. Meconium holds promise as a biological matrix for measuring the intensity and duration of environmental toxicant exposure and future studies should validate the utility of meconium using other environmental toxicants.
doi:10.1186/1476-069X-9-53
PMCID: PMC2944243  PMID: 20799929
9.  Trends in the Exposure of Nonsmokers in the U.S. Population to Secondhand Smoke: 1988–2002 
Environmental Health Perspectives  2006;114(6):853-858.
The objective of this study was to describe the exposure of nonsmokers in the U.S. population to secondhand smoke (SHS) using serum cotinine concentrations measured over a period of 14 years, from October 1988 through December 2002. This study consists of a series of National Health and Nutrition Examination Surveys (NHANES) measuring serum cotinine as an index of SHS exposure of participants. Study participants were individuals representative of the U.S. civilian, noninstitutionalized population, ≥ 4 years of age. We analyzed serum cotinine and interview data from NHANES obtained during surveys conducted during four distinct time periods. Our results document a substantial decline of approximately 70% in serum cotinine concentrations in non-smokers during this period. This decrease was reflected in all groups within the population regardless of age, sex, or race/ethnicity. The large decrease that we observed in serum cotinine concentrations suggests a substantial reduction in the exposure of the U.S. population to SHS during the 1990s. The exposure of nonsmokers to SHS represents an important public health concern. Our findings suggest that recent public health efforts to reduce such exposures have had an important effect, although children and non-Hispanic black nonsmokers show relatively higher levels of serum cotinine.
doi:10.1289/ehp.8850
PMCID: PMC1480505  PMID: 16759984
biomarker; cotinine; environmental tobacco smoke; ETS; health and nutrition examination survey; NHANES; secondhand smoke; SHS; tandem mass spectrometry
10.  Molecular evidence of an interaction between prenatal environmental exposures and birth outcomes in a multiethnic population. 
Environmental Health Perspectives  2004;112(5):626-630.
Inner-city, minority populations are high-risk groups for adverse birth outcomes and also are more likely to be exposed to environmental contaminants, including environmental tobacco smoke (ETS), benzo[a]pyrene (BaP), and other polycyclic aromatic hydrocarbons (PAHs) found in urban air. In a sample of nonsmoking African-American and Dominican women, we evaluated the effects on birth outcomes of prenatal exposure to ETS, using questionnaire data and plasma cotinine as a biomarker of exposure, and environmental PAHs using BaP-DNA adducts as a molecular dosimeter. We previously reported that among African Americans, high prenatal exposure to PAHs estimated by prenatal personal air monitoring was associated with lower birth weight (p = 0.003) and smaller head circumference (p = 0.01) after adjusting for potential confounders. In the present analysis, self-reported ETS was associated with decreased head circumference (p = 0.04). BaP-DNA adducts were not correlated with ETS or dietary PAHs. There was no main effect of BaP-DNA adducts on birth outcomes. However, there was a significant interaction between the two pollutants such that the combined exposure to high ETS and high adducts had a significant multiplicative effect on birth weight (p = 0.04) and head circumference (p = 0.01) after adjusting for ethnicity, sex of newborns, maternal body mass index, dietary PAHs, and gestational age. This study provides evidence that combined exposure to environmental pollutants at levels currently encountered in New York City adversely affects fetal development.
PMCID: PMC1241932  PMID: 15064172

Results 1-10 (10)