Urine cotinine underestimates exposure to the tobacco-derived lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in passive compared to active smokers Neal Benowitz, MD 1,2 , Maciej Lukasz Goniewicz, PhD 1,2,3 , Mark D. Eisner, MD,MPH 4 , Eduardo Lazcano-Ponce, D.Sc. 5 , Wioleta Zielinska-Danch, PhD 3 , Bartosz Koszowski, M.Sc. 3 , Andrzej Sobczak, PhD 3 , Christopher Havel 1 , and Peyton Jacob III, PhD 1 1 Center for Tobacco Control Research and Education, University of California, San Francisco, USA 2 Division of Clinical Pharmacology and Experimental Therapeutics, Departments of Medicine and Bioengineering and Therapeutic Sciences, University of California, San Francisco, USA 3 Department of General and Analytical Chemistry, Medical University of Silesia, Sosnowiec, Poland 4 Division of Occupational and Environmental Medicine & Division of Pulmonary and Critical Care Medicine, University of California San Francisco, USA 5 Centro de Investigación en Salud Poblacional, Instituto Nacional de Salud Pública de México, México, D.F., Mexico Abstract Objectives—Cotinine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) are widely used biomarkers for tobacco-derived nicotine and the lung carcinogen 4-(methylnitrosamino)-1-(3- pyridyl)-1-butanone (NNK), respectively. The discrepancy between cotinine levels in relation to disease risk comparing active vs. passive smoking suggests a non-linear tobacco smoke dose- response and/or that cotinine is not providing an accurate measure of exposure to tobacco smoke toxic constituents from secondhand smoke. Methods—Cotinine and NNAL were measured in urine of 373 active smokers and 228 passive smokers. Results—Average cotinine levels were 1,155 (IQR 703-2,715) for active smokers and 1.82 (0.45-7.33) ng/mg creatinine for passive smokers. Average NNAL levels were 183 (103-393) and 5.19 (2.04-11.6) pg/mg creatinine, respectively. NNAL/cotinine ratio in urine was significantly higher for passive smokers when compared to active smokers (2.85×10 3 vs. 0.16×10 3 , p<0.0001). Conclusions—Passive smoking is associated with a much higher ratio of NNAL/cotinine in the urine compared to active smoking. Impact—Cotinine measurement leads to an underestimation of exposure to the carcinogen NNK from second-hand smoke when compared with active smoking. Keywords cotinine; NNAL; smokers; tobacco smoke; exposure Copyright © 2010 American Association for Cancer Research Corresponding Author: Neal L. Benowitz, MD Chief, Division of Clinical Pharmacology and Experimental Therapeutics University of California, San Francisco, Box 1220 San Francisco, California 94143-1220 Tel. (415) 206-8324 Fax (415) 206-4956 NBenowitz@MedSFGH.ucsf.edu. NIH Public Access Author Manuscript Cancer Epidemiol Biomarkers Prev. Author manuscript; available in PMC 2011 November 1. Published in final edited form as: Cancer Epidemiol Biomarkers Prev. 2010 November ; 19(11): 2795–2800. doi: 10.1158/1055-9965.EPI-10-0497. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript