Publications by authors named "Cindy M Chang"

37 Publications

Associations between Biomarkers of Exposure and Lung Cancer Risk among Exclusive Cigarette Smokers in the Golestan Cohort Study.

Int J Environ Res Public Health 2021 07 9;18(14). Epub 2021 Jul 9.

Center for Tobacco Products, Food and Drug Administration, Silver Spring, MD 20993, USA.

Biomarkers of tobacco exposure are known to be associated with disease risk but previous studies are limited in number and restricted to certain regions. We conducted a nested case-control study examining baseline levels and subsequent lung cancer incidence among current male exclusive cigarette smokers in the Golestan Cohort Study in Iran. We calculated geometric mean biomarker concentrations for 28 matched cases and 52 controls for the correlation of biomarker levels among controls and for adjusted odds' ratios (ORs) for lung cancer incidence by biomarker concentration, accounting for demographic characteristics, smoking quantity and duration, and opium use. Lung cancer cases had higher average levels of most biomarkers including total nicotine equivalents (TNE-2), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and 3-hydroxyfluorene (3-FLU). Many biomarkers correlated highly with one another including TNE-2 with NNAL and N-Acetyl-S-(2-cyanoethyl)-L-cysteine (2CYEMA), and N-Acetyl-S-(4-hydroxy-2-buten-1-yl)-L-cysteine (t4HBEMA) with N-Acetyl-S-(3-hydroxypropyl-1-methyl)-L-cysteine (3HMPMA) and N-Acetyl-S-(4-hydroxy-2-methyl-2-buten-1-yl)-L-cysteine (4HMBEMA). Lung cancer risk increased with concentration for several biomarkers, including TNE-2 (OR = 2.22, 95% CI = 1.03, 4.78) and NNN (OR = 2.44, 95% CI = 1.13, 5.27), and estimates were significant after further adjustment for demographic and smoking characteristics for 2CYEMA (OR = 2.17, 95% CI = 1.03, 4.55), N-Acetyl-S-(2-carbamoylethyl)-L-cysteine (2CAEMA) (OR = 2.14, 95% CI = 1.01, 4.55), and N-Acetyl-S-(2-hydroxypropyl)-L-cysteine (2HPMA) (OR = 2.85, 95% CI = 1.04, 7.81). Estimates were not significant with adjustment for opium use. Concentrations of many biomarkers were higher at the baseline for participants who subsequently developed lung cancer than among the matched controls. Odds of lung cancer were higher for several biomarkers including with adjustment for smoking exposure for some but not with adjustment for opium use.
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http://dx.doi.org/10.3390/ijerph18147349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306295PMC
July 2021

Biomarkers of Inflammation and Oxidative Stress among Adult Former Smoker, Current E-Cigarette Users-Results from Wave 1 PATH Study.

Cancer Epidemiol Biomarkers Prev 2021 Oct 21;30(10):1947-1955. Epub 2021 Jul 21.

Office of Science, Center for Tobacco Products, FDA, Silver Spring, Maryland.

Background: Former smokers who currently use e-cigarettes have lower concentrations of biomarkers of tobacco toxicant exposure than current smokers. It is unclear whether tobacco toxicant exposure reductions may lead to health risk reductions.

Methods: We compared inflammatory biomarkers (high-sensitivity C-reactive protein, IL6, fibrinogen, soluble intercellular adhesion molecule-1) and an oxidative stress marker (F2-isoprostane) among 3,712 adult participants in Wave 1 (2013-2014) of the Population Assessment of Tobacco and Health Study by tobacco user groups: dual users of cigarettes and e-cigarettes; former smokers who currently use e-cigarettes-only; current cigarette-only smokers; former smokers who do not currently use any tobacco; and never tobacco users. We calculated geometric means (GM) and estimated adjusted GM ratios (GMR).

Results: Dual users experienced greater concentration of F2-isoprostane than current cigarette-only smokers [GMR 1.09 (95% confidence interval, CI, 1.03-1.15)]. Biomarkers were similar between former smokers who currently use e-cigarettes and both former smokers who do not use any tobacco and never tobacco users, but among these groups most biomarkers were lower than those of current cigarette-only smokers. The concentration of F2-isoprostane decreased by time since smoking cessation among both exclusive e-cigarette users ( = 0.03) and former smokers who do not currently use any tobacco ( = 0.0001).

Conclusions: Dual users have greater concentration of F2-isoprostane than smokers. Exclusive e-cigarette users have biomarker concentrations that are similar to those of former smokers who do not currently use tobacco, and lower than those of exclusive cigarette smokers.

Impact: This study contributes to an understanding of the health effects of e-cigarettes.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500540PMC
October 2021

Biomarkers of Potential Harm among Adult Cigarette and Smokeless Tobacco Users in the PATH Study Wave 1 (2013-2014): A Cross-sectional Analysis.

Cancer Epidemiol Biomarkers Prev 2021 07 4;30(7):1320-1327. Epub 2021 May 4.

Center for Tobacco Products, U.S. Food and Drug Administration, Silver Spring, Maryland.

Background: While smokeless tobacco (ST) causes oral cancer and is associated with cardiovascular diseases, less is known about how its effects differ from other tobacco use. Biomarkers of potential harm (BOPH) can measure short-term health effects such as inflammation and oxidative stress.

Methods: We compared BOPH concentrations [IL6, high-sensitivity C-reactive protein, fibrinogen, soluble intercellular adhesion molecule-1 (sICAM-1), and F2-isoprostane] across 3,460 adults in wave 1 of the Population Assessment of Tobacco and Health study (2013-2014) by tobacco use groups: primary ST users (current exclusive ST use among never smokers), secondary ST users (current exclusive ST use among former smokers), exclusive cigarette smokers, dual users of ST and cigarettes, former smokers, and never tobacco users. We estimated geometric mean ratios using never tobacco users, cigarette smokers, and former smokers as referents, adjusting for demographic and health conditions, creatinine (for F2-isoprostane), and pack-years in smoker referent models.

Results: BOPH levels among primary ST users were similar to both never tobacco users and former smokers. Most BOPH levels were lower among ST users compared with current smokers. Compared with never tobacco users, dual users had significantly higher sICAM-1, IL6, and F2-isoprostane. However, compared with smokers, dual users had similar biomarker levels. Former smokers and secondary ST users had similar levels of all five biomarkers.

Conclusions: ST users have lower levels of inflammatory and oxidative stress biomarkers than smokers.

Impact: ST use alone and in combination with smoking may result in different levels of inflammatory and oxidative stress levels.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254764PMC
July 2021

ENDS Flavor Preference by Menthol Cigarette Smoking Status among US Adults, 2018-2019.

Int J Environ Res Public Health 2020 12 31;18(1). Epub 2020 Dec 31.

Center for Tobacco Products, US Food and Drug Administration, Silver Spring, MD 20993, USA.

E-cigarette flavor preference may differ among smokers using e-cigarettes, but little information is available on preferences by menthol cigarette status. Using nationally representative data for US adults from the 2018-2019 Tobacco Use Supplement to the Current Population Survey, we analyzed e-cigarette flavor preference by menthol cigarette status and e-cigarette device type for dual-cigarette and e-cigarette users and e-cigarette users who had recently quit smoking by trying to switch to e-cigarettes ("switchers"). Approximately half (52.2%) of dual users of menthol cigarettes and e-cigarettes reported using menthol/mint-flavored e-cigarettes as did 41.4% of "switchers" who had smoked menthol cigarettes; exclusive menthol/mint flavor use was 13.1% for dual users and 21.3% for "switchers." A similar proportion (45.1%) of dual users who smoked nonmenthol cigarettes used tobacco-flavored e-cigarettes, but only 26.7% of "switchers" who had smoked nonmenthol cigarettes used tobacco-flavored e-cigarettes. Approximately 60% of dual users and "switchers" used fruit/other flavors, regardless of menthol cigarette use. By device type, 63.9% of dual users of cartridge-based e-cigarettes and menthol cigarettes used menthol/mint-flavored e-cigarettes. Approximately 75% of dual users and 85% of "switchers" who used tank or mod systems used fruit/other flavors. Menthol cigarette smokers may be particularly likely to use menthol/mint e-cigarettes, and a majority of dual users and "switchers" used fruit/other flavors. These results can inform policy measures concerning flavored electronic nicotine delivery system products.
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http://dx.doi.org/10.3390/ijerph18010240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796212PMC
December 2020

National Estimates of ENDS Liquid Nicotine Exposures, U.S., 2013-2017.

Am J Prev Med 2020 11 18;59(5):742-745. Epub 2020 Aug 18.

Center for Tobacco Products, U.S. Food and Drug Administration, Silver Spring, Maryland.

Introduction: Increased use of ENDS in the U.S. is related to acute adverse events from liquid nicotine exposure. This paper provides national estimates of U.S. hospital emergency department visits for exposures from liquid nicotine exposure in individuals aged ≥5 years.

Methods: In 2018-2019, data from the 2013-2017 National Electronic Injury Surveillance System All Injury Program were used to identify cases of liquid nicotine-related exposures in individuals aged ≥5 years. National estimates of exposures related to liquid nicotine exposure in ENDS for those aged ≥5 years by demographic characteristics, symptoms, diagnoses, and treatment dispositions were calculated.

Results: From 2013 to 2017, an estimated 2,718 cases related to liquid nicotine among those aged ≥5 years were treated in U.S. hospital emergency departments. Most exposures occurred among those who were aged ≥25 years (51.7%), white (74.1%), and male (51.9%). Most case patients were treated and released from the hospitals, and 7.5% were admitted. Poisoning was the most common diagnosis of these exposures (82.7%). The most common symptoms were cardiovascular (29.7%).

Conclusions: This study provides national estimates of emergency department visits for injury and poisoning cases related to nicotine exposure from ENDS among individuals aged ≥5 years. Although long-term health outcome studies of liquid nicotine exposure are not available, these estimates provide some insight into the acute health effects. Findings from this study may inform education programs aimed at preventing exposures related to ENDS products.
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http://dx.doi.org/10.1016/j.amepre.2020.05.027DOI Listing
November 2020

Cigarette Smoking Reduction and Health Risks: A Systematic Review and Meta-analysis.

Nicotine Tob Res 2021 03;23(4):635-642

Center for Tobacco Products, US Food and Drug Administration, Silver Spring, MD.

Introduction: Studies have shown the health benefits of cigarette smoking cessation. However, the literature remains unclear about the relationship between smoking reduction and health risks. This comprehensive review and meta-analysis updates previous reviews with the newest estimates.

Aims And Methods: We conducted a systematic review and meta-analysis evaluating the association between smoking reduction and some health risks in observational studies. We defined the following smoking categories: heavy smokers smoked ≥15-20 cigarettes per day (CPD), moderate smokers smoked 10-19 CPD, and light smokers smoked <10 CPD. The relative risks (RRs) and 95% confidence intervals (CIs) were estimated using random-effect models.

Results: We identified 19 studies including four case-control and 15 cohort studies. Compared with continuing heavy smokers, we found decreased lung cancer risk for those who reduced CPD by more than 50% (RR = 0.72, 95% CI: 0.52, 0.91), from heavy to moderate (RR = 0.66, 95% CI: 0.46, 0.85), and from heavy to light (RR = 0.60, 95% CI: 0.49, 0.72). We also found lower risk of cardiovascular disease (CVD) for those who reduced from heavy to light smoking (RR = 0.78, 95% CI: 0.67, 0.89) but not those who reduced by more than 50% and reduced smoking from heavy to moderate. We did not find any significant difference in all-cause mortality, all-cancer risks, and smoking-/tobacco-related cancer risk among those who reduced.

Conclusions: Substantial smoking reduction may decrease lung cancer risk but results on CVD (coronary heart disease and stroke combined) risk were mixed. The relationships between smoking reduction and other endpoints examined were not significant.

Implications: This meta-analysis helps clarify our understanding of various smoking reduction levels on some health risks. While smoking reduction may decrease risks of lung cancer, the relationships between smoking reduction and other endpoints, including all-cause mortality and cardiovascular disease, remain unclear. Although smoking reduction may decrease lung cancer risks, the magnitude of lung cancer risk remain high. Among smokers, complete cessation remains the most effective approach for cancer and CVD prevention.
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http://dx.doi.org/10.1093/ntr/ntaa156DOI Listing
March 2021

Nicotine Exposure by Device Type among Adult Electronic Nicotine Delivery System Users in the Population Assessment of Tobacco and Health Study, 2015-2016.

Cancer Epidemiol Biomarkers Prev 2020 10 29;29(10):1968-1972. Epub 2020 Jul 29.

Center for Tobacco Products, U.S. Food and Drug Administration, Silver Spring, Maryland.

Background: Previous studies have examined the characteristics of open and closed system electronic nicotine delivery system (ENDS) users, but population-level information on nicotine exposure among these users has not been available.

Methods: We analyzed nicotine biomarker and survey data from Wave 3 of the Population Assessment of Tobacco and Health (PATH) study collected from October 2015 to October 2016. We identified 277 exclusive ENDS users and 468 dual cigarette and ENDS users and analyzed concentrations of nicotine and its metabolites obtained from urine samples by device type and other characteristics, such as frequency of use and e-liquid flavor.

Results: Among exclusive ENDS users, open system users had higher levels of total nicotine exposure (TNE-2) than closed system users [8.8 μmol/g creatinine (95% confidence interval [CI] = 5.3-14.8 μmol/g vs. 2.0 μmol/g (95% CI = 0.7-5.4 μmol/g)]. However, TNE-2 concentrations were similar when open and closed system users were stratified as daily [26.4 μmol/g (95% CI = 20.1-34.7 μmol/g) vs. 27.1 μmol/g (95% CI = 16.4-44.9 μmol/g)] and nondaily [0.5 μmol/g (95% CI = 0.1-1.9 μmol/g) vs. 0.2 μmol/g (95% CI = 0.0-0.7 μmol/g)] ENDS users. Dual users generally had higher nicotine exposure than exclusive users.

Conclusions: Nicotine exposure was observed to be higher among exclusive open system ENDS users compared with closed system users, but levels were similar when users were stratified by frequency of use.

Impact: These results suggest that exclusive ENDS users with similar use patterns receive comparable levels of nicotine, regardless of whether they use open or closed system devices.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541662PMC
October 2020

Tobacco-Specific Nitrosamines (NNAL, NNN, NAT, and NAB) Exposures in the US Population Assessment of Tobacco and Health (PATH) Study Wave 1 (2013-2014).

Nicotine Tob Res 2021 02;23(3):573-583

Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA.

Introduction: The tobacco-specific nitrosamines (TSNAs) are an important group of carcinogens found in tobacco and tobacco smoke. To describe and characterize the levels of TSNAs in the Population Assessment of Tobacco and Health (PATH) Study Wave 1 (2013-2014), we present four biomarkers of TSNA exposure: N'-nitrosonornicotine, N'-nitrosoanabasine, N'-nitrosoanatabine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) which is the primary urinary metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

Methods: We measured total TSNAs in 11 522 adults who provided urine using automated solid-phase extraction coupled to isotope dilution liquid chromatography-tandem mass spectrometry. After exclusions in this current analysis, we selected 11 004 NNAL results, 10 753 N'-nitrosonornicotine results, 10 919 N'-nitrosoanatabine results, and 10 996 N'-nitrosoanabasine results for data analysis. Geometric means and correlations were calculated using SAS and SUDAAN.

Results: TSNA concentrations were associated with choice of tobacco product and frequency of use. Among established, every day, exclusive tobacco product users, the geometric mean urinary NNAL concentration was highest for smokeless tobacco users (993.3; 95% confidence interval [CI: 839.2, 1147.3] ng/g creatinine), followed by all types of combustible tobacco product users (285.4; 95% CI: [267.9, 303.0] ng/g creatinine), poly tobacco users (278.6; 95% CI: [254.9, 302.2] ng/g creatinine), and e-cigarette product users (6.3; 95% CI: [4.7, 7.9] ng/g creatinine). TSNA concentrations were higher in every day users than in intermittent users for all the tobacco product groups. Among single product users, exposure to TSNAs differed by sex, age, race/ethnicity, and education. Urinary TSNAs and nicotine metabolite biomarkers were also highly correlated.

Conclusions: We have provided PATH Study estimates of TSNA exposure among US adult users of a variety of tobacco products. These data can inform future tobacco product and human exposure evaluations and related regulatory activities.
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http://dx.doi.org/10.1093/ntr/ntaa110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885786PMC
February 2021

Correction to: Infectious mononucleosis, immune genotypes, and non-Hodgkin lymphoma (NHL): an InterLymph Consortium study.

Cancer Causes Control 2020 06;31(6):607

Department of Preventive Medicine, Center for Genetic Epidemiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Unfortunately, the word "Group" is missed in the article title of the original publication. It has been corrected by this erratum.
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http://dx.doi.org/10.1007/s10552-020-01297-xDOI Listing
June 2020

Changes in Cigarettes per Day and Biomarkers of Exposure Among US Adult Smokers in the Population Assessment of Tobacco and Health Study Waves 1 and 2 (2013-2015).

Nicotine Tob Res 2020 10;22(10):1780-1787

Center for Tobacco Products, Food and Drug Administration, Silver Spring, MD.

Introduction: Some studies have found some reduction in tobacco exposure and tobacco-related disease risk with decreased numbers of cigarettes smoked per day (CPD), but biomarker of exposure estimates by change in CPD are generally unavailable for the US population.

Methods: We analyzed biomarker of exposure data by smoking status from over 1100 adult exclusive daily cigarette smokers in Wave 1 of the Population Assessment of Tobacco and Health (PATH) Study who were either exclusive daily smokers or had quit tobacco use entirely at Wave 2. Wave 1 smoking categories consisted of "very light" (1-4 CPD), "light" (5-9 CPD), "moderate" (10-19 CPD), and "heavy" (20+ CPD), and Wave 2 categories were "quitters" (stopped smoking entirely), exclusive cigarette "reducers" (CPD decreased ≥ 50%), "maintainers" (CPD within 50%-150% of Wave 1 value), and "increasers" (CPD increased ≥ 50%).

Results: Complete quitters had significantly lower levels of TNE-2, NNAL, NNN, 2-Fluorene, HPMA, CYMA, and MHB3 at Wave 2 for all Wave 1 CPD categories, and decreases were often large. Moderate "reducers" had lower levels of NNAL and 1-Hydroxypyrene at Wave 2, and heavy "reducers" had lower levels of NNAL, 2-Fluorene, and MHB3. Light "increasers" had higher levels of TNE-2, NNAL, 2-Fluorene, CYMA, and cadmium at Wave 2, and heavy "increasers" had higher levels of NNAL and HPMA.

Conclusions: Smoking "reducers" and "increasers" had changes in some biomarker of tobacco exposure levels, but reductions were much greater and more consistent for complete quitters.

Implications: PATH longitudinal cohort study data show that some exclusive daily cigarette smokers increase or decrease CPD over time. These differences may result in moderate changes in the levels of some biomarkers such as NNAL. Even so, however, reductions in biomarker levels are much greater with complete smoking cessation.
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http://dx.doi.org/10.1093/ntr/ntaa038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542633PMC
October 2020

Infectious mononucleosis, immune genotypes, and non-Hodgkin lymphoma (NHL): an InterLymph Consortium study.

Cancer Causes Control 2020 05 2;31(5):451-462. Epub 2020 Mar 2.

Department of Preventive Medicine, Center for Genetic Epidemiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Purpose: We explored the interaction between non-Hodgkin lymphoma (NHL), infectious mononucleosis (IM) history, and immune-related genotypes in a pooled case-control analysis.

Methods: A total of 7,926 NHL patients and 10,018 controls from 12 case-control studies were included. Studies were conducted during various time periods between 1988 and 2008, and participants were 17-96 years of age at the time of ascertainment/recruitment. Self-reported IM history and immune response genotypes were provided by the InterLymph Data Coordinating Center at Mayo Clinic. Odds ratios (OR) were estimated using multivariate logistic regression, and interactions were estimated using the empirical Bayes method. P was used to account for multiple comparisons.

Results: There was evidence of an interaction effect between IM history and two variants on T-cell lymphoma (TCL) risk: rs1143627 in interleukin-1B (IL1B) (p = 0.04, OR = 0.09, 95% confidence interval [CI] 0.01, 0.87) and rs1800797 in interleukin-6 (IL6) (p = 0.03, OR = 0.08, 95% CI 0.01, 0.80). Neither interaction effect withstood adjustment for multiple comparisons. There were no statistically significant interactions between immune response genotypes and IM on other NHL subtypes.

Conclusions: Genetic risk variants in IL1B and IL6 may affect the association between IM and TCL, possibly by influencing T-cell activation, growth, and differentiation in the presence of IM, thereby decreasing risk of immune cell proliferation.
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http://dx.doi.org/10.1007/s10552-020-01266-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534692PMC
May 2020

Evaluation of Tobacco Smoke and Diet as Sources of Exposure to Two Heterocyclic Aromatic Amines for the U.S. Population: NHANES 2013-2014.

Cancer Epidemiol Biomarkers Prev 2020 01 1;29(1):103-111. Epub 2019 Oct 1.

Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia.

Background: Heterocyclic aromatic amines (HAA) are a group of hazardous substances produced during combustion of tobacco or high-temperature cooking of meats. 2-Amino-9H-pyrido[2,3-b]indole (AαC) is a major carcinogenic HAA in tobacco smoke.

Methods: Urinary AαC, used as a marker of AαC exposure, was analyzed on spot urine samples from adult participants of the 2013-2014 cycle of the National Health and Nutrition Examination Survey ( = 1,792). AαC was measured using isotope-dilution liquid chromatography-tandem mass spectrometry. Exclusive combusted tobacco smokers were differentiated from nonusers of tobacco products through both self-report and serum cotinine data.

Results: Among exclusive smokers, sample-weighted median urinary AαC was 40 times higher than nonusers. Sample-weighted regression models showed that urinary AαC increased significantly with serum cotinine among both exclusive tobacco users and nonusers with secondhand smoke exposure. Among nonusers, eating beef cooked at high temperature was associated with a significant increase in urinary AαC, whereas consuming vegetables was associated with decreased AαC. In addition, smoking one-half pack of cigarettes per day was associated with a significant increase of 23.6 pg AαC/mL calculated at geometric mean of AαC, controlling for potential confounders. In comparison, increase in AαC attributable to consuming the 99th percentile of beef cooked at high temperature was 0.99 pg AαC/mL.

Conclusions: Both exclusive smokers and nonusers of tobacco in the general U.S. population are exposed to AαC from tobacco smoke, with additional, lesser contributions from certain dietary components.

Impact: AαC is an important biomarker that is associated with tobacco smoke exposure.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954285PMC
January 2020

National estimates of poisoning events related to liquid nicotine in young children treated in US hospital emergency departments, 2013-2017.

Inj Epidemiol 2019 1;6:10. Epub 2019 Apr 1.

Center for Tobacco Products, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993 USA.

Background: An estimated 2 million youth (in 2017) and 7.9 million adults (in 2015) reported currently using electronic nicotine delivery systems (ENDS). Reports of poisoning events related to liquid nicotine (e-liquids) in ENDS have been on the rise, but current, nationally-representative estimates of hospital-treated poisoning cases related to e-liquid nicotine exposure in the United States (US) are lacking.

Findings: We used National Electronic Injury Surveillance System (NEISS) data from 2013 to 2017 to calculate national estimates with 95% confidence intervals (CIs) of poisoning incidents related to e-liquid nicotine exposure. From 2013 to 2017, an estimated 4745 poisoning cases related to e-liquids among children under age five were treated in US hospital emergency departments; the number of cases increased from 181 (95% CI: 0-369) in 2013 to 1736 (95% CI, 871-2602) in 2015 and then decreased to 411 (95% CI, 84-738) in 2017. Most of the cases were treated and released; 4.1% were admitted to the hospital. The most common route of exposure was through ingestion (96.9%), and 2.6% of the cases were through dermal exposure. The highest amounts of e-liquids or nicotine ingested were 118.2mL, 1 bottle, and 100 mg, and the most common symptoms (63.6%) related to nicotine poisoning were nausea and vomiting.

Conclusions: This study provides national estimates of poisoning cases associated with nicotine exposure from e-liquids among children under age five. Findings on e-liquid volume or nicotine dose, when available, provide important insights into exposures associated with toxicity in children. Since NEISS data do not include product codes specific to ENDS or provide information on poisoning severity, we used general keywords to capture these events, which might underestimate the population burden. Information from this study may complement efforts, such as public education, to prevent unintended exposure to nicotine in e-liquids among children.
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http://dx.doi.org/10.1186/s40621-019-0188-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582692PMC
April 2019

Associations of Cigarettes Smoked Per Day with Biomarkers of Exposure Among U.S. Adult Cigarette Smokers in the Population Assessment of Tobacco and Health (PATH) Study Wave 1 (2013-2014).

Cancer Epidemiol Biomarkers Prev 2019 09 25;28(9):1443-1453. Epub 2019 Jun 25.

Center for Tobacco Products, Food and Drug Administration, Silver Spring, Maryland.

Background: The dose-response relationships between number of cigarettes smoked per day (CPD) and health outcomes, such as cancer and heart disease, are well established, but much less is known about the relationships between CPD and biomarkers of exposure.

Methods: We analyzed biomarker data by CPD from more than 2,700 adult daily cigarette smokers in Wave 1 of the Population Assessment of Tobacco and Health Study. Tobacco use categories consisted of exclusive cigarette smokers, dual cigarette and e-cigarette users, and dual cigarette and smokeless tobacco users.

Results: Biomarker concentrations consistently increased with CPD for each tobacco user group, although concentrations tended to level off at high smoking levels, such as those at and above 20 CPD. Dual cigarette and e-cigarette users had higher levels of some biomarkers such as Total Nicotine Equivalents-2 ( = 0.0036) than exclusive cigarette smokers, and dual cigarette and smokeless tobacco users had higher levels of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol ( < 0.0001) and N'-nitrosonornicotine ( = 0.0236) than exclusive cigarette smokers.

Conclusions: Among daily smokers, exposure to tobacco toxicants and constituents exhibits a dose-response relationship by number of cigarettes smoked, but the relationship is not necessarily linear in form. Dual users of cigarettes with either e-cigarettes or smokeless tobacco are exposed to higher levels of certain toxicants and carcinogens than exclusive cigarette smokers.

Impact: Availability of biomarker data by CPD may aid in comparisons between cigarette smoking and use of new and potentially reduced exposure tobacco products, which may result in different levels of constituent and toxicant exposure.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726522PMC
September 2019

Biomarkers of Exposure among U.S. Adult Cigar Smokers: Population Assessment of Tobacco and Health (PATH) Study Wave 1 (2013-2014).

Cancer Epidemiol Biomarkers Prev 2019 05 7;28(5):943-953. Epub 2019 Feb 7.

Center for Tobacco Products, Food and Drug Administration, Silver Spring, Maryland.

Background: Given the diverse cigar market and limited data on biomarker patterns by cigar type, we compared biomarkers of nicotine and tobacco toxicants among cigar smokers and other groups.

Methods: Using Wave 1 urinary biomarker data from 5,604 adults in the Population Assessment of Tobacco and Health (PATH) Study, we compared geometric mean concentrations among cigar-only smokers (all cigars and separately for traditional, cigarillo, and filtered cigars), cigarette-only smokers, dual cigar/cigarette smokers, and never users of tobacco. We calculated geometric mean ratios comparing groups with never users adjusting for sex, age, race/ethnicity, education and creatinine.

Results: Some day cigar-only smokers had lower biomarker concentrations than every day cigar-only smokers, but higher than never users. Every day cigar-only smokers ( = 61) had lower TNE-2 (cotinine+trans-3'-hydroxycotinine) compared to every day cigarette-only ( = 2217; < 0.0001) and dual cigar/cigarette smokers ( = 601; < 0.0001). Several biomarkers, including NNAL (NNK metabolite) and CYMA (metabolite of acrylonitrile), were comparable in these groups. In exploratory analyses, every day filtered cigar-only ( = 7) smokers had higher biomarker concentrations compared with every day traditional cigar-only smokers ( = 12) and cigarillo-only smokers ( = 24). Every day smokers of each cigar type were similar to exclusive cigarette smokers. For some biomarkers, particularly for every day filtered cigar-only smokers, concentrations were higher.

Conclusions: For some biomarkers, every day cigar-only smokers were comparable with every day cigarette-only smokers. Exploratory analyses suggest that biomarkers vary by cigar type with every day filtered cigar-only smokers having the highest concentrations.

Impact: High exposure to harmful constituents among cigar smokers is a continuing health issue.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-0539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500461PMC
May 2019

Urinary Biomarkers of Carcinogenic Exposure among Cigarette, Waterpipe, and Smokeless Tobacco Users and Never Users of Tobacco in the Golestan Cohort Study.

Cancer Epidemiol Biomarkers Prev 2019 02 8;28(2):337-347. Epub 2019 Jan 8.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland.

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.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-0743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935158PMC
February 2019

Loss of Gut Microbiota Alters Immune System Composition and Cripples Postinfarction Cardiac Repair.

Circulation 2019 01;139(5):647-659

Program in Molecular Medicine, National Yang Ming University and Academia Sinica, Taipei, Taiwan (T.W.H.T., P.C.C.H.).

Background: The impact of gut microbiota on the regulation of host physiology has recently garnered considerable attention, particularly in key areas such as the immune system and metabolism. These areas are also crucial for the pathophysiology of and repair after myocardial infarction (MI). However, the role of the gut microbiota in the context of MI remains to be fully elucidated.

Methods: To investigate the effects of gut microbiota on cardiac repair after MI, C57BL/6J mice were treated with antibiotics 7 days before MI to deplete mouse gut microbiota. Flow cytometry was applied to examine the changes in immune cell composition in the heart. 16S rDNA sequencing was conducted as a readout for changes in gut microbial composition. Short-chain fatty acid (SCFA) species altered after antibiotic treatment were identified by high-performance liquid chromatography. Fecal reconstitution, transplantation of monocytes, or dietary SCFA or Lactobacillus probiotic supplementation was conducted to evaluate the cardioprotective effects of microbiota on the mice after MI.

Results: Antibiotic-treated mice displayed drastic, dose-dependent mortality after MI. We observed an association between the gut microbiota depletion and significant reductions in the proportion of myeloid cells and SCFAs, more specifically acetate, butyrate, and propionate. Infiltration of CX3CR1+ monocytes to the peri-infarct zone after MI was also reduced, suggesting impairment of repair after MI. Accordingly, the physiological status and survival of mice were significantly improved after fecal reconstitution, transplantation of monocytes, or dietary SCFA supplementation. MI was associated with a reorganization of the gut microbial community such as a reduction in Lactobacillus. Supplementing antibiotic-treated mice with a Lactobacillus probiotic before MI restored myeloid cell proportions, yielded cardioprotective effects, and shifted the balance of SCFAs toward propionate.

Conclusions: Gut microbiota-derived SCFAs play an important role in maintaining host immune composition and repair capacity after MI. This suggests that manipulation of these elements may provide opportunities to modulate pathological outcome after MI and indeed human health and disease as a whole.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.035235DOI Listing
January 2019

Smokeless tobacco use and circulatory disease risk: a systematic review and meta-analysis.

Open Heart 2018;5(2):e000846. Epub 2018 Oct 8.

Center for Tobacco Products, Food and Drug Administration, Silver Spring, Maryland, USA.

Objective: Smokeless tobacco use is a public health issue throughout the world, but reviews and analyses of circulatory disease risks associated with smokeless tobacco use may be outdated or incomplete. This study provides a thorough and comprehensive review and meta-analysis of circulatory disease risks in high-income countries, including recently published study estimates.

Methods: We conducted a systematic review of studies of circulatory disease risks associated with smokeless tobacco use in Europe and North America that were identified from electronic databases and reference lists. Study estimates were extracted by region, smokeless tobacco use status, cigarette smoking status, and circulatory condition and combined in meta-analysis using a random-effects model. We used the Newcastle-Ottawa scale to assess study quality and risk of bias.

Results: We identified 17 relevant cohort studies, two pooled analyses, five case-control studies and one cross-sectional analysis. We found increased risk of heart disease (relative risk (RR) 1.17, 95% CI 1.09 to 1.27) and stroke (RR 1.28, 95% CI 1.01 to 1.62) among US smokeless tobacco users compared with non-users. Increased circulatory disease risk was not observed among Swedish smokeless tobacco users.

Conclusion: US smokeless tobacco users were found to have increased risk of heart disease and stroke.
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http://dx.doi.org/10.1136/openhrt-2018-000846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196954PMC
October 2018

Biomarkers of Potential Harm: Summary of an FDA-Sponsored Public Workshop.

Nicotine Tob Res 2019 01;21(1):3-13

Department of Psychiatry, Tobacco Research Programs, University of Minnesota, Minneapolis, MN.

Introduction: Since 2009, the United States (US) Food and Drug Administration (FDA) Center for Tobacco Products (CTP) has had the authority to regulate the manufacture, distribution, and marketing of tobacco products in order to reduce the death and disease caused by tobacco use. Biomarkers could play an important role across a number of FDA regulatory activities, including assessing new and modified risk tobacco products and identifying and evaluating potential product standards.

Methods: On April 4-5, 2016, FDA/CTP hosted a public workshop focused on biomarkers of potential harm (BOPH) with participants from government, industry, academia, and other organizations. The workshop was divided into five sessions focused on: (1) overview of BOPH; (2) cardiovascular disease (CVD); (3) chronic obstructive pulmonary disease (COPD); (4) cancer; and (5) new areas of research.

Results And Conclusions: The deliberations from the workshop noted some promising BOPH but also highlighted the lack of systematic effort to identify BOPH that would have utility and validity for evaluating tobacco products. Research areas that could further strengthen the applicability of BOPH to tobacco regulatory science include the exploration of composite biomarkers as predictors of disease risk, "omics" biomarkers, and examining biomarkers using existing cohorts, surveys, and experimental studies.

Implications: This paper synthesizes the main findings from the 2016 FDA-sponsored workshop focused on BOPH and highlights research areas that could further strengthen the science around BOPH and their applicability to tobacco regulatory science.
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http://dx.doi.org/10.1093/ntr/ntx273DOI Listing
January 2019

Biomarkers of Tobacco Exposure: Summary of an FDA-Sponsored Public Workshop.

Cancer Epidemiol Biomarkers Prev 2017 03 9;26(3):291-302. Epub 2016 Nov 9.

Department of Psychiatry, Tobacco Research Programs, University of Minnesota, Minneapolis, Minnesota.

Since 2009, the FDA Center for Tobacco Products (CTP) has had the authority to regulate the manufacturing, distribution, and marketing of tobacco products in order to reduce the death and disease caused by tobacco use. Biomarkers of exposure pertain to actual human exposure to chemicals arising from tobacco use and could play an important role across a number of FDA regulatory activities, including assessing new and modified-risk tobacco products and identifying and evaluating potential product standards. On August 3-4, 2015, FDA/CTP hosted a public workshop focused on biomarkers of exposure with participants from government, industry, academia, and other organizations. The workshop was divided into four sessions focused on: (i) approaches to evaluating and selecting biomarkers; (ii) biomarkers of exposure and relationship to disease risk; (iii) currently used biomarkers of exposure and biomarkers in development; and (iv) biomarkers of exposure and the assessment of smokeless tobacco and electronic nicotine delivery systems. This article synthesizes the main findings from the workshop and highlights research areas that could further strengthen the science around biomarkers of exposure and help determine their application in tobacco product regulation. .
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http://dx.doi.org/10.1158/1055-9965.EPI-16-0675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5336443PMC
March 2017

Nicotine and Toxicant Exposure among U.S. Smokeless Tobacco Users: Results from 1999 to 2012 National Health and Nutrition Examination Survey Data.

Cancer Epidemiol Biomarkers Prev 2015 Dec;24(12):1829-37

Tobacco and Volatiles Branch, Division of Laboratory Sciences, Centers for Disease Control and Prevention, Atlanta, Georgia.

Background: It has been suggested that smokeless tobacco users have high nicotine and toxicant exposure, but studies with nationally representative data have been limited.

Methods: We analyzed biomarkers of tobacco exposure for 23,684 adult participants from the National Health and Nutrition Examination Survey from 1999 to 2012. The biomarkers analyzed were serum cotinine, urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), blood lead, blood cadmium, blood mercury, urinary arsenic, and urinary N-acetyl-S-(2-cyanoethyl)-L-cysteine. We calculated geometric mean concentrations for each biomarker by tobacco use category and geometric mean ratios adjusting for demographic factors.

Results: Exclusive smokeless tobacco users had higher geometric mean concentrations of serum cotinine [178.9 ng/mL, 95% confidence interval (CI), 145.5-220.0] and NNAL (583.0 pg/mg creatinine, 95% CI, 445.2-763.5) than exclusive cigarette smokers (130.6 ng/mL, 95% CI, 122.3-139.6 and 217.6 pg/mg creatinine, 95% CI, 193.0-245.2, respectively). Smokeless tobacco users also had higher concentrations of blood lead compared with nontobacco users (adjusted geometric mean ratio = 1.30, 95% CI, 1.21-1.38). Based on limited sample sizes, NNAL concentrations for smokeless tobacco users appear to have declined from 2007 to 2008 (geometric mean = 1013.7 pg/mg creatinine, 95% CI, 738.9-1390.8) to 2011 to 2012 (geometric mean = 325.7 pg/mg creatinine, 95% CI, 159.6-664.9).

Conclusions: Exclusive smokeless tobacco users have higher observed levels of exposure to nicotine and carcinogenic tobacco-specific nitrosamines, as measured by cotinine and NNAL biomarker concentrations, than exclusive cigarette smokers. These patterns in NNAL levels for smokeless tobacco users may be changing over time.

Impact: High exposure to harmful constituents among smokeless tobacco users is a continuing health issue.
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http://dx.doi.org/10.1158/1055-9965.EPI-15-0376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5134927PMC
December 2015

Systematic review of cigar smoking and all cause and smoking related mortality.

BMC Public Health 2015 Apr 24;15:390. Epub 2015 Apr 24.

Office of Science, Center for Tobacco Products, Food and Drug Administration, Document Control Center, Building 71, Room G335, 10903 ,New Hampshire Avenue, Silver Spring, MD, 20993-0002, USA.

Background: Cigars are a growing public health concern, given the changes in cigar use patterns in the US and elsewhere since the 1960s. We conducted a systematic review of published studies on current cigar smoking and all-cause and cause-specific mortality risks to inform potential regulatory approaches and future research that would strengthen the body of evidence.

Methods: Using 3 different databases and handsearching, we identified epidemiological studies published prior to June 2014 that examined the association between cigar smoking and all-cause mortality and smoking-related mortality. Detailed study characteristics as well as association-level characteristics, including effect estimates and 95% confidence intervals, were abstracted or calculated from each selected study.

Results: A total of 22 studies from 16 different prospective cohorts were identified. Primary cigar smoking (current, exclusive cigar smoking with no history of previous cigarette or pipe smoking) was associated with all cause-mortality, oral cancer, esophageal cancer, pancreatic cancer, laryngeal cancer, lung cancer, coronary heart disease (CHD), and aortic aneurysm. Strong dose trends by cigars per day and inhalation level for primary cigar smoking were observed for oral, esophageal, laryngeal, and lung cancers. Among primary cigar smokers reporting no inhalation, relative mortality risk was still highly elevated for oral, esophageal, and laryngeal cancers.

Conclusions: In summary, cigar smoking carries many of the same health risks as cigarette smoking. Mortality risks from cigar smoking vary by level of exposure as measured by cigars per day and inhalation level and can be as high as or exceed those of cigarette smoking. The body of evidence would be strengthened by future studies that focus on the health effects of primary cigar smoking and incorporate more contemporary and diverse study populations to better reflect the current patterns of cigar use in the US. Ideally, these studies would also collect detailed information on cigar type, exposure level, and biomarkers of exposure and potential harm.
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http://dx.doi.org/10.1186/s12889-015-1617-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408600PMC
April 2015

Estimation of cigarette smoking-attributable morbidity in the United States.

JAMA Intern Med 2014 Dec;174(12):1922-8

Office on Smoking and Health, Centers for Disease Control and Prevention, Atlanta, Georgia.

Importance: Cigarette smoking has been found to harm nearly every bodily organ and is a leading cause of preventable disease, but current estimates of smoking-attributable morbidity by condition for the United States are generally unavailable.

Objective: To estimate the burden of major medical conditions attributable to cigarette smoking in the United States.

Design, Setting, And Participants: The disease burden of smoking was estimated using population-attributable risk calculations, taking into account the uncertainty of estimates. Population estimates came from 2009 US Census Bureau data and smoking prevalence, disease prevalence, and disease relative risk estimates came from National Health Interview Survey data for surveyed adults from 2006 through 2012. National Health and Nutrition Examination Survey spirometry data obtained from medical examination of surveyed adults from 2007 through 2010 was used to adjust for underreporting of chronic obstructive pulmonary disease.

Exposures: Smoking status was assessed from self-reported National Health Interview Survey data.

Main Outcomes And Measures: The number of adults 35 years and older who had had a major smoking-attributable disease by sex and condition and the total number of these conditions were estimated for the United States in 2009.

Results: Using National Health Interview Survey data, we estimated that 6.9 million (95% CI, 6.5-7.4 million) US adults had had a combined 10.9 million (95% CI, 10.3-11.5 million) self-reported smoking-attributable medical conditions. Using chronic obstructive pulmonary disease prevalence estimates obtained from National Health and Nutrition Examination Survey self-reported and spirometry data, we estimated that US adults had had a combined 14.0 million (95% CI, 12.9-15.1 million) smoking-attributable conditions in 2009.

Conclusions And Relevance: We estimate that US adults have had approximately 14 million major medical conditions that were attributable to smoking. This figure is generally conservative owing to the existence of other diseases and medical events that were not included in these estimates. Cigarette smoking remains a leading cause of preventable disease in the United States, underscoring the need for continuing and vigorous smoking-prevention efforts.
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http://dx.doi.org/10.1001/jamainternmed.2014.5219DOI Listing
December 2014

Cigarette smoking and variations in systemic immune and inflammation markers.

J Natl Cancer Inst 2014 Nov 1;106(11). Epub 2014 Oct 1.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD (MSS, HAK, NDF, MPP, NW, BT, CMK, JJG, EAE, NEC, AH, ANK); Information Management Services, Inc, Rockville, MD (MF); Joint Program for Survey Methodology, University of Maryland, College Park, MD (YL); Leidos Biomedical Research, Inc., Frederick, MD (TJK, LAP); Center for Tobacco Products, Food and Drug Administration, Rockville, MD (CMC).

Background: A comprehensive characterization of the effects of cigarette smoke on systemic soluble immune/inflammatory markers may provide insight into the mechanisms through which smoking causes disease.

Methods: Levels of 78 inflammation, immune, and metabolic markers were measured using multiplex immune assays in 1819 Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) participants aged 55 to 74 years from three existing nested case-control studies. These data were made representative of the entire PLCO screening arm through reweighting with weights estimated in logistic regression models. We assessed associations between smoking status, cigarettes smoked per day, and time since quitting with dichotomized marker levels using adjusted weighted logistic regression models.

Results: Current smoking was associated with 10 inflammation markers after correcting for multiple testing, encompassing several components of the immune/inflammation response. Levels of seven of these markers (interleukin [IL]-15, IL-1RA, IL-1β, IL-16, stem cell factor, soluble interleukin 6 receptor, and soluble vascular endothelial growth factor receptor 3) were lower among current smokers (n = 414) when compared with never smokers (n = 548), with odds ratios (ORs) ranging from 0.44 to 0.27, while levels of CC motif ligand (CCL)/thymus and activation regulated chemokine (CCL17/TARC) (OR = 4.08, 95% confidence interval [CI] = 2.01 to 8.25), CCL11/EOTAXIN (OR = 2.57, 95% CI = 1.45 to 4.55), and C-reactive protein (CRP) (OR = 2.54, 95% CI = 1.29 to 4.98) were elevated. These markers were not associated with cigarettes per day among current smokers, but there were trends in IL-15, IL-1RA, IL-1β, CCL17/TARC, CCL11/EOTAXIN, and CRP levels across categories of years since quitting smoking.

Conclusions: Smoking is associated with a broad range of alterations in systemic immune and inflammation marker levels among older, long-term smokers. Smoking cessation may result in marker levels reverting back to those of never smokers over time.
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http://dx.doi.org/10.1093/jnci/dju294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200029PMC
November 2014

GBV-C infection and risk of NHL among U.S. adults.

Cancer Res 2014 Oct 12;74(19):5553-60. Epub 2014 Aug 12.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.

Some retrospective studies suggest an association between infection with GB virus-C (GBV-C) and non-Hodgkin lymphoma (NHL). We evaluated this association prospectively in a nested case-control study within the U.S. Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Cases (N = 658) and controls (N = 1,316) were individually matched by age, sex, race/ethnicity, timing of study entry, and sample selection. Prediagnostic PLCO serum samples were tested for GBV-C RNA (as a measure of active infection) and E2 antibody (active or resolved infection). Logistic regression was used to estimate odds ratios (OR) for the association between GBV-C and NHL overall and NHL subtypes. Twelve cases (1.8%) and seven controls (0.5%) were GBV-C RNA-positive. GBV-C RNA positivity was associated with NHL overall [OR, 3.43; 95% confidence interval (CI), 1.35-8.71] and, based on small numbers, diffuse large B-cell lymphoma (OR, 5.31; 95% CI, 1.54-18.36). The association with NHL persisted when the interval between testing and selection was greater than 4 years (OR, 6.00; 95% CI, 1.21-29.73). In contrast, E2 antibody positivity was not associated with NHL risk (OR, 1.08; 95% CI, 0.74-1.58). Our study demonstrates that GBV-C infection precedes development of NHL. GBV-C infection may play an etiologic role in a small proportion of NHL cases, perhaps by causing chronic immune stimulation or impaired immunosurveillance.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-0209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184918PMC
October 2014

Exposure to tobacco coupons among U.S. middle and high school students.

Am J Prev Med 2014 Aug;47(2 Suppl 1):S61-8

Office of Science, Center for Tobacco Products, Food and Drug Administration, Rockville, Maryland.

Background: Tobacco marketing contributes to increased tobacco use susceptibility and sustained use. There are limited data on youth exposure to tobacco coupons, a type of pro-tobacco promotion.

Purpose: To explore channels through which youth report exposure to coupons and characteristics associated with this exposure. This may help inform efforts aimed at decreasing youth exposure to advertising and promotion.

Methods: Data from the 2012 National Youth Tobacco Survey were analyzed in 2013 to estimate the self-reported prevalence of U.S. middle and high school student exposure to coupons through various channels. Associations among exposure to coupons and demographics, tobacco use, living with a tobacco user, and receptivity to tobacco marketing were examined using multivariate logistic regression models.

Results: Approximately 13% of students reported exposure to tobacco coupons in the past 30 days through mail, digital communications, or tobacco packages. Prevalence was greatest among current tobacco users (34.0%) and those receptive to tobacco marketing (23.4%) compared to non-tobacco users (9.3%) and those not receptive to tobacco marketing (8.2%), respectively. Coupon exposure varied by sex, grade, and race/ethnicity. In adjusted models, current tobacco use (AOR=3.4, 95% CI=3.0, 3.9); living with a tobacco user (AOR=2.1, 95% CI=1.9, 2.4); and receptivity to tobacco marketing (AOR=2.3, 95% CI=2.0, 2.7) were independently associated with coupon exposure.

Conclusions: Findings from this study indicate that despite restrictions on marketing to youth, youth are still being exposed to tobacco promotions such as coupons. Efforts to limit youth exposure may be valuable in reducing curiosity, susceptibility, and initiation.
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http://dx.doi.org/10.1016/j.amepre.2014.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624109PMC
August 2014

Innate immunity gene polymorphisms and the risk of colorectal neoplasia.

Carcinogenesis 2013 Nov 26;34(11):2512-20. Epub 2013 Jun 26.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD 20892, USA.

Inherited variation in genes that regulate innate immunity and inflammation may contribute to colorectal neoplasia risk. To evaluate this association, we conducted a nested case-control study of 451 colorectal cancer cases, 694 colorectal advanced adenoma cases and 696 controls of European descent within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. A total of 935 tag single-nucleotide polymorphisms (SNPs) in 98 genes were evaluated. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association with colorectal neoplasia. Sixteen SNPs were associated with colorectal neoplasia risk at P < 0.01, but after adjustment for multiple testing, only rs2838732 (ITGB2) remained suggestively associated with colorectal neoplasia (OR(per T allele) = 0.68, 95% CI: 0.57-0.83, P = 7.7 × 10(-5), adjusted P = 0.07). ITGB2 codes for the CD18 protein in the integrin beta chain family. The ITGB2 association was stronger for colorectal cancer (OR(per T allele) = 0.41, 95% CI: 0.30-0.55, P = 2.4 × 10(-) (9)) than for adenoma (OR(per T allele) = 0.84, 95%CI: 0.69-1.03, P = 0.08), but it did not replicate in the validation study. The ITGB2 rs2838732 association was significantly modified by smoking status (P value for interaction = 0.003). Among never and former smokers, it was inversely associated with colorectal neoplasia (OR(per T allele) = 0.5, 95% CI: 0.37-0.69 and OR(per T allele) = 0.72, 95% CI: 0.54-0.95, respectively), but no association was seen among current smokers. Other notable findings were observed for SNPs in BPI/LBP and MYD88. Although the results need to be replicated, our findings suggest that genetic variation in inflammation-related genes may be related to the risk of colorectal neoplasia.
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http://dx.doi.org/10.1093/carcin/bgt228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3810838PMC
November 2013

Chronic fatigue syndrome and subsequent risk of cancer among elderly US adults.

Cancer 2012 Dec 30;118(23):5929-36. Epub 2012 May 30.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland 20892, USA.

Background: The cause of chronic fatigue syndrome (CFS) is unknown but is thought to be associated with immune abnormalities or infection. Because cancer can arise from similar conditions, associations between CFS and cancer were examined in a population-based case-control study among the US elderly.

Methods: Using linked Surveillance, Epidemiology, and End Results (SEER)-Medicare registry data, approximately 1.2 million cancer cases and 100,000 controls (age range, 66-99 years; 1992-2005) were evaluated. CFS was identified in the period more than 1 year prior to selection, using linked Medicare claims. Unconditional logistic regression was used to estimate the odds ratios (ORs) comparing the CFS prevalence in cases and controls, adjusting for age, sex, and selection year. All statistical tests were 2-sided.

Results: CFS was present in 0.5% of cancer cases overall and 0.5% of controls. CFS was associated with an increased risk of non-Hodgkin lymphoma (NHL) (OR = 1.29, 95% confidence interval [CI] = 1.16-1.43, P = 1.7 × 10(-6) ). Among NHL subtypes, CFS was associated with diffuse large B cell lymphoma (OR = 1.34, 95% CI = 1.12-1.61), marginal zone lymphoma (OR = 1.88, 95% CI = 1.38-2.57), and B cell NHL not otherwise specified (OR = 1.51, 95% CI = 1.03-2.23). CFS associations with NHL overall and NHL subtypes remained elevated after excluding patients with medical conditions related to CFS or NHL, such as autoimmune conditions. CFS was also associated, although not after multiple comparison adjustment, with cancers of the pancreas (OR = 1.25, 95% CI = 1.07-1.47), kidney (OR = 1.27, 95% CI = 1.07-1.49), breast (OR = 0.85, 95% CI = 0.74-0.98), and oral cavity and pharynx (OR = 0.70, 95% CI = 0.49-1.00).

Conclusions: Chronic immune activation or an infection associated with CFS may play a role in explaining the increased risk of NHL.
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http://dx.doi.org/10.1002/cncr.27612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3434293PMC
December 2012

Risk factors for non-Hodgkin lymphoma subtypes defined by histology and t(14;18) in a population-based case-control study.

Int J Cancer 2011 Aug 23;129(4):938-47. Epub 2010 Nov 23.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Rockville, MD 20892, USA.

The t(14;18) chromosomal translocation is the most common cytogenetic abnormality in non-Hodgkin lymphoma (NHL), occurring in 70-90% of follicular lymphomas (FL) and 30-50% of diffuse large B-cell lymphomas (DLBCL). Previous t(14;18)-NHL studies have not evaluated risk factors for NHL defined by both t(14;18) status and histology. In this population-based case-control study, t(14;18) status was determined in DLBCL cases using fluorescence in situ hybridization on paraffin-embedded tumor sections. Polytomous logistic regression was used to evaluate the association between a wide variety of exposures and t(14;18)-positive (N=109) and -negative DLBCL (N=125) and FL (N=318), adjusting for sex, age, race, and study center. Taller height, more lifetime surgeries, and PCB180 exposure were associated with t(14;18)-positivity. Taller individuals (third tertile vs. first tertile) had elevated risks of t(14;18)-positive DLBCL (odds ratio [OR] = 1.8, 95% confidence interval [CI] 1.1-3.0) and FL (OR=1.4, 95%CI 1.0-1.9) but not t(14;18)-negative DLBCL. Similar patterns were seen for individuals with more lifetime surgeries (13+ vs. 0-12 surgeries; t(14;18)-positive DLBCL OR=1.4, 95%CI 0.7-2.7; FL OR=1.6, 95%CI 1.1-2.5) and individuals exposed to PCB180 greater than 20.8 ng/g (t(14;18)-positive DLBCL OR=1.3, 95%CI 0.6-2.9; FL OR=1.7, 95%CI 1.0-2.8). In contrast, termite treatment and high alpha-chlordane levels were associated with t(14;18)-negative DLBCL only, suggesting that these exposures do not act through t(14;18). Our findings suggest that putative associations between NHL and height, surgeries, and PCB180 may be t(14;18)-mediated and provide support for case-subtyping based on molecular and histologic subtypes. Future efforts should focus on pooling data to confirm and extend previous research on risk factors for t(14;18)-NHL subtypes.
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http://dx.doi.org/10.1002/ijc.25717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3125462PMC
August 2011
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