A Strong Dose-Response Relation Between Serum Concentrations of Persistent Organic Pollutants and Diabetes Results from the National Health and Examination Survey 1999 –2002 DUK-HEE LEE, MD, PHD 1 IN-KYU LEE, MD, PHD 2 KYUNGEUN SONG, MD, PHD 3 MICHAEL STEFFES, MD, PHD 4 WILLIAM TOSCANO, PHD 5 BETH A. BAKER, MD, PHD 5,6 DAVID R. JACOBS,JR., PHD 7,8 OBJECTIVE — Low-level exposure to some persistent organic pollutants (POPs) has recently become a focus because of their possible link with the risk of diabetes. RESEARCH DESIGN AND METHODS — Cross-sectional associations of the serum concentrations of POPs with diabetes prevalence were investigated in 2,016 adult participants in the National Health and Nutrition Examination Survey 1999 –2002. Six POPs (2,2',4,4',5,5'- hexachlorobiphenyl, 1,2,3,4,6,7,8-heptachlorodibenzo- p -dioxin, 1,2,3,4,6,7,8,9- octachlorodibenzo-p-dioxin, oxychlordane, p,p'-dichlorodiphenyltrichloroethane, and trans-nonachlor) were selected, because they were detectable in 80% of participants. RESULTS — Compared with subjects with serum concentrations below the limit of detection, after adjustment for age, sex, race and ethnicity, poverty income ratio, BMI, and waist circum- ference, diabetes prevalence was strongly positively associated with lipid-adjusted serum con- centrations of all six POPs. When the participants were classified according to the sum of category numbers of the six POPs, adjusted odds ratios were 1.0, 14.0, 14.7, 38.3, and 37.7 (P for trend  0.001). The association was consistent in stratified analyses and stronger in younger participants, Mexican Americans, and obese individuals. CONCLUSIONS — There were striking dose-response relations between serum concentra- tions of six selected POPs and the prevalence of diabetes. The strong graded association could offer a compelling challenge to future epidemiologic and toxicological research. Diabetes Care 29:1638 –1644, 2006 P ersistent organic pollutants (POPs) have become widespread environ- mental contaminants and now rep- resent a global problem (1). The toxicity of these pollutants in humans and wildlife is enhanced by their persistence in the en- vironment and their bioaccumulation po- tential in the tissues of animals and humans through the food chain (1). POPs include a variety of man-made chemicals. Some POPs, including polychlorinated dibenzo-p-dioxins (PCDDs), polychlori- nated dibenzofurans (PCDFs), poly- chlorinated biphenyls (PCBs), hexa- chlorobenzene (HCB), and several organochlorines used as pesticides have been highlighted by international organi- zations as being chemicals of concern (2). Low-level exposure to some POPs has recently been associated with an in- creased risk of diabetes (3). Prospective cohort studies of subjects exposed to 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD), the most potent dioxin congener of POPs, or other POPs in occupational or accidental settings have reported in- creased risk of diabetes, modified glucose metabolism, or insulin resistance (4 –10). The U.S. Department of Veterans Affairs added type 2 diabetes to the list of pre- sumptive diseases associated with the ex- posure to dioxin-containing Agent Orange in Vietnam (11). However, whether similar associa- tions exist in the general population with lifetime exposure to very low doses of a mixture of various POPs is not known. Given that almost everyone has measur- able amounts of POPs, the public health significance of a relation of mixed dioxins with diabetes may be substantial despite a relatively modest association with any in- dividual dioxin. TCDD-mediated diabetes might re- flect decreased expression of the insulin- responsive glucose transporter GLUT4. Several animal studies have demonstrated a TCDD-mediated decrease in glucose transport in vitro and in vivo (12–16). The stimulation of tumor necrosis fac- tor- expression by TCDD in adipose tis- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● From the 1 Department of Preventive Medicine and Health Promotion Research Center, School of Medicine, Kyungpook National University, Daegu, Korea; the 2 Department of Endocrinology, School of Medicine, Kyungpook National University, Daegu, Korea; the 3 Department of Clinical Pathology, School of Medicine, Kyungpook National University, Daegu, Korea; the 4 Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota; the 5 Division of Environmental Health Sciences, School of Public Health, University of Minnesota, Minneapolis, Minnesota; 6 Regions Hospital, Occupational and Environmental Medicine, St. Paul, Minnesota; the 7 Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, Minnesota; and the 8 Department of Nutrition, University of Oslo, Oslo, Norway. Address correspondence and reprint requests to Duk-Hee Lee, MD, PhD, Department of Preventive Medicine, School of Medicine, Kyungpook University, 101 Dongin-dong, Jung-gu, Daegu, Korea 700-422. E-mail: lee_dh@knu.ac.kr. Received for publication 10 March 2006 and accepted in revised form 5 April 2006. Abbreviations: AhR, aryl hydrocarbon receptor; DDE, p,p'-dichlorodiphenyltrichloroethane; HCB, hexachlorobenzene; HpCDD, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin; LOD, limit of detection; NHANES, National Health and Nutrition Examination Survey; OCDD, 1,2,3,4,6,7,8,9-octachlorodibenzo- p-dioxin; PCB, polychlorinated biphenyl; PCB153, 2,2',4,4',5,5'-hexachlorobiphenyl; PCDD, polychlori- nated dibenzo-p-dioxin; PCDF, polychlorinated dibenzofuran; POP, persistent organic pollutant; SUMPOP, sum of POP levels; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEF, toxic equivalency factor. A table elsewhere in this issue shows conventional and Syste `me International (SI) units and conversion factors for many substances. DOI: 10.2337/dc06-0543 © 2006 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Cardiovascular and Metabolic Risk O R I G I N A L A R T I C L E 1638 DIABETES CARE, VOLUME 29, NUMBER 7, JULY 2006 Downloaded from http://diabetesjournals.org/care/article-pdf/29/7/1638/656463/zdc00706001638.pdf by guest on 09 August 2023