{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T16:49:54Z","timestamp":1778172594449,"version":"3.51.4"},"reference-count":34,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2021,7,9]],"date-time":"2021-07-09T00:00:00Z","timestamp":1625788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>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\u2013control 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\u2019 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.<\/jats:p>","DOI":"10.3390\/ijerph18147349","type":"journal-article","created":{"date-parts":[[2021,7,9]],"date-time":"2021-07-09T10:50:38Z","timestamp":1625827838000},"page":"7349","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Associations between Biomarkers of Exposure and Lung Cancer Risk among Exclusive Cigarette Smokers in the Golestan Cohort Study"],"prefix":"10.3390","volume":"18","author":[{"given":"Brian L.","family":"Rostron","sequence":"first","affiliation":[{"name":"Center for Tobacco Products, Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Tobacco Products, Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arash","family":"Etemadi","sequence":"additional","affiliation":[{"name":"Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"name":"Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran 1411713135, Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sapna","family":"Thakur","sequence":"additional","affiliation":[{"name":"Center for Tobacco Products, Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanne T.","family":"Chang","sequence":"additional","affiliation":[{"name":"Center for Tobacco Products, Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deepak","family":"Bhandari","sequence":"additional","affiliation":[{"name":"Division of Laboratory Sciences, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julianne Cook","family":"Botelho","sequence":"additional","affiliation":[{"name":"Division of Laboratory Sciences, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4964-538X","authenticated-orcid":false,"given":"V\u00edctor R.","family":"De Jes\u00fas","sequence":"additional","affiliation":[{"name":"Division of Laboratory Sciences, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Feng","sequence":"additional","affiliation":[{"name":"Division of Laboratory Sciences, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitchell H.","family":"Gail","sequence":"additional","affiliation":[{"name":"Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0070-7829","authenticated-orcid":false,"given":"Maki","family":"Inoue-Choi","sequence":"additional","affiliation":[{"name":"Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9820-6335","authenticated-orcid":false,"given":"Reza","family":"Malekzadeh","sequence":"additional","affiliation":[{"name":"Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran 1411713135, Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akram","family":"Pourshams","sequence":"additional","affiliation":[{"name":"Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran 1411713135, Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hossein","family":"Poustchi","sequence":"additional","affiliation":[{"name":"Liver and Pancreaticobilliary Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran 1411713135, Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5494-0722","authenticated-orcid":false,"given":"Gholamreza","family":"Roshandel","sequence":"additional","affiliation":[{"name":"Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan 4917867439, Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meredith S.","family":"Shiels","sequence":"additional","affiliation":[{"name":"Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuesong","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Laboratory Sciences, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Baoyun","family":"Xia","sequence":"additional","affiliation":[{"name":"Division of Laboratory Sciences, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo","family":"Boffetta","sequence":"additional","affiliation":[{"name":"Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA"},{"name":"Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Brennan","sequence":"additional","affiliation":[{"name":"International Agency for Research on Cancer, 69372 Lyon, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian C.","family":"Abnet","sequence":"additional","affiliation":[{"name":"Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonia M.","family":"Calafat","sequence":"additional","affiliation":[{"name":"Division of Laboratory Sciences, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lanqing","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Laboratory Sciences, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4788-8169","authenticated-orcid":false,"given":"Benjamin C.","family":"Blount","sequence":"additional","affiliation":[{"name":"Division of Laboratory Sciences, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neal D.","family":"Freedman","sequence":"additional","affiliation":[{"name":"Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cindy M.","family":"Chang","sequence":"additional","affiliation":[{"name":"Center for Tobacco Products, Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1136\/bmj.2.6051.1525","article-title":"Mortality in relation to smoking: 20 years\u2019 observations on male British doctors","volume":"2","author":"Doll","year":"1976","journal-title":"Br. 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