ORIGINAL ARTICLE Association Between Dioxin and Metabolic Syndrome by Age and Sex in an Endemic Area of Exposure in Taiwan Chien-Yuan Huang,a,b Ching-Chang Lee,a,c Jung-Wei Chang,a,c Ya-Yun Cheng,a Yau-Chang Kuo,d,e How-Ran Guo,a,d,e,f and Chen-Long Wud,e Background: Some of the effects of dioxins seem to be different between men and women, and exposures starting at an early age seem to have more prominent effects. Therefore, we conducted a study in Taiwan to evaluate the associations between exposure to polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and metabolic syndrome (MetS) starting at different ages in both sexes. Methods: We recruited participants from an area where residents were exposed to PCDD/Fs released from a factory and defined serum PCDD/Fs levels ≥20 pg WHO98-TEQDF/g lipid as high dioxin levels. MetS was defined as meeting three of the following criteria: fasting glucose ≥100 mg/dl or under treatment for diabetes, waist circumference ≥90 cm in men or ≥80 cm in women, triglycerides ≥150 mg/dl or under treatment for elevated triglycerides, high-density lipoprotein <40 mg/dl in men or <50 mg/dl in women, and blood pressures ≥130/85 mmHg or under treatment for hypertension. Results: Of the 2758 participants, 785 patients with MetS were identified, and we observed positive associations between a high dioxin level and MetS. After adjusting for sex, age, and age at starting exposure, we found that a high dioxin level was an independent predictor for MetS (adjusted odds ratio =1.38; 95% confidence interval = 1.11, 1.72). When we stratified the participants by gender, we found that a high dioxin level remained an independent predictor of MetS in men, but not in women, regardless of the age at starting exposure. Conclusions: Exposure to PCDD/Fs was associated with MetS in men, independent of age and age at starting exposure. Submitted 27 February 2017; accepted 11 May 2017. From the aDepartment of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan; bTainan Science Park Clinic, Chi-Mei Medical Center, Tainan 744, Taiwan; cResearch Center for Environmental Trace Toxic Substances, National Cheng Kung University, Tainan 704, Taiwan; dDepartment of Occupational and Environmental Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan; eDepartment of Occupational and Environmental Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan; and fOccupational Safety, Health, and Medicine Research Center, National Cheng Kung University, Tainan 704, Taiwan. Supported by grants from Tainan City Government. H.-R.G. and C.-L.W. contributed equally to this work. The authors report no conflicts of interest. Correspondence: Chen-Long Wu, Department of Occupational and Environmental Medicine, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan 70428, Taiwan. E-mail: firstname.lastname@example.org. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1044-3983/17/2806-0S82 DOI: 10.1097/EDE.0000000000000697 S82 | www.epidem.com 研究目的：有些戴奧辛的效應在男女性之間似乎有差異，而年 輕時的暴露似乎有較明顯的效應。因此，我們在臺灣進行一項 研究，分別探討在男女兩性身上不同年齡開始的多氯戴奧辛/呋 喃暴露與代謝症候群的相關性。 研究方法：我們由一個因工廠排放戴奧辛而遭到汙染的地 區招募居民為研究對象，將血清中戴奧辛濃度≥20 pg WHO98TEQDF/g lipid定義為高暴露。代謝症候群則定義為下列五項中 至少符合三項：空腹血糖 ≥100 mg/dl或正接受糖尿病治療、腰 圍男性≥90 cm或女性≥80 cm、三酸甘油脂 ≥150 mg/dl或因三酸 甘油脂過高正接受治療、高密度膽固醇男性<40 mg/dl 或女性<50 mg/dl、及血壓 ≥130/85 mmHg或正接受高血壓治療。 研究結果：在2,758位研究對象中，有785位罹患代謝症候群， 而高戴奧辛暴露與代謝症候群呈正相關。在校正性別、 年齡及開始暴露的年齡後，高戴奧辛暴露仍然為代謝症 候群的獨立危險因子 (校正勝算比=1.38，95%信賴區間：1.11– 1.72)。以性別分層分析，我們發現不論開始暴露的 年齡早晚，高戴奧暴露在男性是代謝症候群的獨立危險因子， 但在女性不是。. 結論：戴奧辛暴露與男性的代謝症候群有關，而此相關性獨立 於開始暴露的年齡及觀察時的年紀。 (Epidemiology 2017;28: S82–S88) D ioxins are widely distributed environmental contaminants that were found to be related to some metabolic disorders such as diabetes mellitus (DM) and thyroid diseases.1–3 For example, a study of U.S. veterans who were exposed to Agent Orange and its contaminant 2,3,7,8-tetrach lorodibenzo-p-dioxin (TCDD) during the Vietnam War found higher prevalence of DM.2 Likewise, after a chemical explosion, a large population in Seveso, Italy, were exposed to relatively pure TCDD, and a study found an excess mortality from DM.3 In addition, a study of 158 male employees who were exposed to TCDD in another chemical accident found a higher frequency of thyroid disease than the comparison population. Furthermore, polychlorinated dibenzo-p-dioxin and dibenzofurans (PCDD/Fs) were found to be associated with insulin resistance,4 an important mechanism of metabolic syndrome (MetS). In fact, a follow-up study of women in Seveso found that the exposure level of TCDD was associated with the occurrence of MetS.5 Epidemiology • Volume 28, Suppl 1, October 2017 Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Epidemiology • Volume 28, Suppl 1, October 2017 However, some of the endocrine disrupting effects of dioxins seem to be different between men and women. For example, a study in Seveso observed excess mortality from DM in women, but not in men.3 Likewise, a follow-up of the Yucheng (oil disease) cohort in Taiwan, who were exposed to dioxin through ingestion of rice oil contaminated with polychlorinated biphenyls (PCBs), found an association between the dioxin level and the occurrence of DM in women, but not in men.6 In addition, exposures starting at an early age seem to have more prominent effects. For example, a study of women in Seveso found an association between the exposure level of TCDD and MetS, but only in women ≤12 years old at the time of the accident.5 However, the study did not include men. Therefore, we conducted a study to evaluate the associations between dioxin exposure and MetS and to determine whether the associations are different between men and women and whether the associations depend on the age at starting exposure. METHODS Study Population This study was carried out in the Annan District of the Tainan City in southwestern Taiwan, where a factory produced pentachlorophenol (PCP) between 1965 and 1979. Residents living in the vicinity of the deserted factory were found to have high intake of PCDD/Fs from food, especially seafood,7,8 and have an average serum PCDD/F level three times higher than that in people living in nonpolluted areas (62.5 vs. 19.7 pg WHO98-TEQDF/g lipid).9 We recruited participants from residents of the exposure area, which covers three of the 51 administrative subdivisions (called “Li” in Taiwan) of the Annan District: Hsien-Gong, Lu-Erh, and Ssu-Tsao. All the residents above 18 years old were invited to participate, and 2,898 have complete measurements of serum PCDD/Fs levels, which were made by the Tainan city government between 2005 and 2007 using isotope dilution high-resolution gas chromatography/high-resolution mass spectrometry. The detailed methodology of the measurements has been described in previous reports.4,8,9 The study protocol was approved by the Human Experiment and Ethics Committee of National Cheng Kung University Hospital. Definitions of Exposure and Outcome Previous studies have shown that the serum PCDD/Fs level in the general population of Taiwan typically ranged from 15 to 20 pg WHO98-TEQDF/g lipid,10 and therefore, we defined a “high dioxin level” as serum PCDD/Fs ≥20 pg WHO98-TEQDF/g lipid. In addition to the measurement of serum PCDD/Fs levels, a health examination was offered to each participant. According to the results, we defined MetS as meeting three of the following criteria: fasting glucose ≥100 mg/dl or under treatment for DM, waist circumference ≥90 cm in men or ≥80 cm in women, triglycerides ≥150 mg/dl or under drug treatment © 2017 Wolters Kluwer Health, Inc. All rights reserved. Dioxin and Metabolic Syndrome for elevated triglycerides, high-density lipoprotein (HDL) <40 mg/dl in men or <50 mg/dl in women, and blood pressures ≥130/85 mmHg or under treatment for hypertension. The criteria are implemented by the Taiwan government in concordance with the newly developed harmonized definition of MetS,11,12 including the use of “population- and country-specific definitions” for “elevated waist circumference.” Furthermore, we defined DM as having fasting blood sugar >126 mg/dl or under treatment of DM and defined hypertension as having blood pressures ≥140/90 mmHg or under treatment of hypertension. To control effects of potential confounders, we collected data on demographic characteristics through a self-administrated questionnaire. In addition to medical history, participants were also asked to provide residential history. Data Analysis To evaluate the effects of potential risk factors for MetS, we performed univariate logistic regressions. In addition, we performed multiple logistic regressions and included all predictors identified from the univariate logistic regressions in the models to identify independent predictors of MetS and evaluate their effects. To assess the possible differences in the effects on men and women, we conducted separate analyses by sex. Likewise, to assess the possible differences in the effects introduced by the age at starting exposure, we conducted separate analyses using 12 years old as the cutoff according to a study in Seveso, Italy.5 The age before 12 is generally considered as before puberty in most countries, and the hypothalamic-pituitary-thyroid axis is known to be particularly sensitive to endocrine modulation before puberty.13 Therefore, there are biological bases for using 12 years old as the cutoff. We conducted all the data analyses using SPSS version 15.0 (SPSS Inc., Chicago, IL). RESULTS Of the 2898 participants who had measurement data on dioxin levels, 2,758 (90.9%) had completed the health examination and provided sufficient information on other potential predictors of MetS. Of them, 1,428 had high dioxin levels, and they were more likely to be women and older, have MetS, DM, and hypertension, and were exposed starting after 12 years old (Table 1). A total of 785 participants fit the diagnostic criteria of MetS. The risks of MetS, DM, and hypertension increased with age in both sexes (Table 3). In those below 65 years old, men generally had higher incidence rates of those diseases. However, in those who were older, men had a lower incidence rate of MetS, while they had similar rates of DM and hypertension (Table 2). In comparison with those who did not have MetS, men were more likely to have a high dioxin level (18.8% vs. 39.2%), be older, and start having exposure after 12 years old (20.6% vs. 45.8%) (Table 3). In the univariate logistic regression analyses, we found that a high dioxin level was associated with an OR of 2.79 www.epidem.com | S83 Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Epidemiology • Volume 28, Suppl 1, October 2017 Huang et al. TABLE 1. Comparisons Between Participants With and Without a High Dioxin Level TABLE 3. Comparisons Between Participants With and Without Metabolic Syndromea PCDD/Fs (pg WHO98TEQDF/g Lipid) Variables Sex Men Women Age, year <40 40–64 ≥65 Metabolic syndromea No Yes Diabetes mellitusb No Yes Hypertensionc No Yes Age at starting exposure, year ≤12 >12 <20, N (%) ≥20, N (%) 870 (56.3) 601 (44.5) 676 (43.7) 751 (55.5) 972 (86.5) 429 (36.1) 70 (11.9) 152 (13.5) 759 (63.9) 516 (88.1) 1,179 (59.8) 273 (34.8) 794 (40.2) 512 (65.2) 1,385 (56.0) 86 (20.2) 1,088 (44.0) 339 (79.8) 1,063 (63.9) 406 (33.0) 601 (36.1) 823 (67.0) 1,345 (68.5) 126 (13.5) 618 (31.5) 809 (86.5) a Defined as meeting three of the following criteria: fasting glucose ≥100 mg/dL or under treatment for diabetes, waist circumference ≥90 cm in men or ≥80 cm in women, triglycerides ≥150 mg/dL or under treatment for elevated triglycerides, high-density lipoprotein <40 mg/ dL in men or <50 mg/dL in women, and blood pressures ≥130/85 mmHg or under treatment for hypertensive; data not available on 140 participants without a high dioxin level. b Defined as fasting glucose >126 mg/dL or under treatment for diabetes. c Defined as having blood pressures ≥140/90 mmHg or under treatment for hypertension. TABLE 2. Distributions of Age, Metabolic Syndrome, Diabetes Mellitus, and Hypertension in Men and Women Age, year <40 40–64 ≥65 Outcome Metabolic syndrome <40 40–64 ≥65 Hypertension <40 40–64 ≥65 Diabetes mellitus <40 40–64 ≥65 S84 | www.epidem.com Men, N (%) Women, N (%) 585 (40.3) 595 (40.9) 273 (18.8) 535 (41.0) 494 (37.9) 276 (21.1) 103 (17.6) 224 (37.6) 104 (38.1) 45 (8.4) 152 (30.8) 157 (56.9) 151 (25.8) 282 (47.4) 224 (82.1) 59 (11.0) 220 (44.5) 226 (81.9) 26 (4.4) 105 (17.6) 84 (30.8) 15 (2.8) 73 (14.8) 96 (34.8) PCDD/Fs (pg WHO98TEQDF/g lipid) <20 ≥20 Sex Men Women Age, year <40 40–64 ≥65 Age at starting exposure, year ≤12 >12 Without Metabolic Syndrome, N (%) With Metabolic Syndrome, N (%) 1,179 (81.2) 794 (60.8) 273 (18.8) 512 (39.2) 1,022 (70.3) 951 (72.9) 431 (29.7) 354 (27.1) 972 (86.8) 713 (65.5) 288 (52.5) 148 (13.2) 376 (34.5) 261 (47.5) 1,508 (79.4) 465 (54.2) 392 (20.6) 393 (45.8) a Defined as meeting three of the following criteria: fasting glucose ≥100 mg/dL or under treatment for diabetes, waist circumference ≥90 cm in men or ≥80 cm in women, triglycerides ≥150 mg/dL or under treatment for elevated triglycerides, HDL <40 mg/dL in men or <50 mg/dL in women, and blood pressures ≥130/85 mmHg or under treatment for hypertensive; data not available on 140 participants without high dioxin levels. (95% CI = 2.34, 3.31), and sex, age, and age when exposure started were predictors of MetS (Table 4). Therefore, the multivariate model included high dioxin level (PCDD/Fs, ≥20 pg WHO98-TEQDF/g lipid), sex, age (<40, 40–64, and ≥65), and older exposure age (age at starting exposure, >12 years). After adjusting for other predictors in the multiple logistic regressions, we found that a high dioxin level was an independent predictor of MetS, with an AOR of 1.38 (95% CI = 1.11, 1.72). Sex, age, and age at starting exposure were all also independent predictors of MetS (Table 4). In the stratified analyses by sex, the models included high dioxin level (PCDD/Fs, ≥20 pg WHO98-TEQDF/g lipid), age (<40, 40–64, and ≥65), and older exposure age (age at starting exposure, >12 years). We found that a high dioxin level was associated with MetS in men (AOR = 1.59; 95% CI = 1.22, 2.08) (Table 5). But in women, a high dioxin level was not associated with MetS (AOR = 1.16; 95% CI = 0.80, 1.68). In both men and women, age and age at starting exposure were predictors of MetS, independent of the dioxin level (Table 5). We performed the Omnibus test and the Hosmer– Lemeshow test for the goodness-of-fit of the multivariate models and found that the models had good fit. When we stratified the population further by the age at starting exposure, the multivariate models that included high dioxin level (PCDD/Fs, ≥20 pg WHO98-TEQDF/g lipid), sex, and age (<40, 40–64, and ≥65) showed that a high dioxin level remained to be a predictor of MetS in men (AOR = 1.59; 95% CI = 1.22, 2.08), but not in women (data not shown in tables). © 2017 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Epidemiology • Volume 28, Suppl 1, October 2017 TABLE 4. The Predictors of Metabolic Syndrome Univariate Analyses OR (95% CI) Variables PCDD/Fs (pg WHO98-TEQDF/g lipid) <20 ≥20 Sex Women Men Age, year <40 40–64 ≥65 Age at starting exposure, year ≤12 >12 Multivariate Analyses AOR (95% CI) Reference Reference 2.79 (2.34, 3.31) 1.38 (1.11, 1.72) Reference Reference 1.13 (0.96, 1.34) 1.22 (1.02, 1.46) Reference Reference 3.46 (2.79, 4.29) 2.61 (2.04, 3.34) 5.95 (4.68, 7.57) 3.13 (2.15, 4.56) Reference Reference 3.25 (2.73, 3.87) 1.51 (1.15, 1.99) The full model included PCDD/Fs, sex, age, and age at starting exposure. AOR indicates adjusted odds ratio; CI, confidence interval; OR, odds ratio. TABLE 5. Predictors of Metabolic Syndrome by Sex PCDD/Fs (pg WHO98-TEQDF/g lipid) <20 ≥20 Age, year <40 40–64 ≥65 Age at starting exposure, year ≤12 >12 Men AOR (95% CI) Women AOR (95% CI) Reference 1.59 (1.22, 2.08) Reference 1.16 (0.80, 1.68) Reference 2.30 (1.70, 3.12) 2.05 (1.24, 3.40) Reference 3.66 (2.37, 5.65) 5.86 (3.21, 10.71) Reference 3.63 (2.81, 4.70) Reference 2.59 (1.70, 3.93) The model included PCDD/Fs, age, and age at starting exposure. AOR indicates adjusted odds ratio; CI, confidence interval. DISCUSSION In this study, we found that a high dioxin level was a predictor of MetS in men, independent of age, sex, and age at starting exposure. Combining “metabolic syndrome” and “dioxin” as keywords to search literature indexed in the PubMed, we identified 30 articles, of which six were original articles on epidemiology studies. Of the six articles, four had data on dioxins and MetS, but some were on the same population (Table 6).5,14–16 The Seveso Women’s Study found that MetS was related to a 10-fold increase in TCDD in women ≤12 years old at starting exposure (AOR = 2.03; 95% CI = 1.25, 3.30), but not in those who started exposure after 12 years old.5 The other three cross-sectional studies also observed associations © 2017 Wolters Kluwer Health, Inc. All rights reserved. Dioxin and Metabolic Syndrome between exposures to certain types of dioxins and MetS.14–16 In particular, a study in Japan found positive associations with MetS for both polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs),16 which is compatible with our findings. However, those studies did not evaluate the differences in effects by sex or age at starting exposure. Most toxic effects of dioxins and dioxin-like PCB congeners are mainly mediated by the aryl hydrocarbon receptor (AhR), and this is also a possible mechanism through which dioxins cause MetS.17 Dioxin can activate the AhR and then suppress the function of peroxisome proliferator-activated receptor (PPAR) γ, which may lead to insulin resistance.18 PPARs are ligand-activated transcription factors that control lipid metabolism and promote differentiation of adipocytes and translation of the glucose transporter protein 4 (GLUT4).19,20 Dioxins may progressively lower the translation of GLUT4 and then cause metabolic effect like insulin resistance and hyperglycemia. In addition to the association between PCDD/Fs and insulin resistance observed in humans,4 an animal study found that low-dose human serum AhR ligands can reduce the function of mitochondria in tissues by significant increases in TCDD, leading to weight gain, glucose intolerance, and other components of MetS.21 MetS is highly related to age. A study of MetS in the U.S. adult found that the prevalence increased from 6.7% in the 20–29-year-old group to 43.5% in the 60–69-year-old group.22 Another study in the United States using National Health and Nutrition Examination Survey (NHANES) 1999–2002 data also found that the prevalence of MetS increased from 18.9% in the 20–39-year-old group to 39% in the 40–59-year-old group and 54.8% in the >60-year-old group.23 In a study in Europe, the prevalence of MetS was found to increase with age in both men (13.2% in the 30–39-year-old group to 44.5% in the 70–74-year-old group, and 39.4% in the 75–89-yearold group) and women (10.3% in the 30–39-year-old group to 58.4% in the 75–89-year-old group).24 In a study in China, the prevalence of MetS increased from 39% in the 20–39-year-old group to 68.2% in the >60-year-old group.25 In the Nutrition and Health Survey in Taiwan (NAHSIT), the prevalence of MetS in the study cohort elevated from 13.6% in 1993–1996 to 25.5% in 2005–2008.26 In each individual survey period, the prevalence increased from 4% in the 19–30-year-old group to 48.7% in the ≥65-year-old group in the 1993–1996 NAHSIT and from 6.4% in the 19–30-year-old group to 62.5% in the age ≥65-year-old group in the 2005–2008 NAHSIT. Our study found that the prevalence increased from 13.2% in the <40-year-old group to 34.6% in the 40–64-year-old group and 47.5% in the >65-year-old group, and the findings are compatible with those in the previous studies. In the multiple logistic regression analyses, we found that the risk of developing MetS increased with age, which is compatible with the findings in previous studies. In our study population, there were more women in the high exposure group. Dioxin is highly lipophilic, and because women generally have more adipose tissue than men, they are www.epidem.com | S85 Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Epidemiology • Volume 28, Suppl 1, October 2017 Huang et al. TABLE 6. Summary of Epidemiology Studies on Dioxin and Metabolic Syndrome Study (Country) Chemicals (Unit) Warner et al5 (Italy) Lee et al14 (United States) Uemura et al16 (Japan) Chang et al15 (Taiwan) TCDD (ppt; a 10-fold increase) HPcDD, OCDD (by quartiles) PCDDs, PCDFs (pg WHO-TEQ/g lipid) PCDD/Fs (pg WHOTEQ/g lipid) Population, Study Design Seveso Women’s Study, Cohort NHANES 1999–2002, Cross-sectional General inhabitants, Cross-sectional Residents in contaminated, Cross-sectional Adjusted Odds Ratio (95% CI) By age at starting exposure: ≤12 years: 2.03 (1.25, 3.30); >12 years: 0.96 (0.68, 1.10) D03 Q1: 0.8 (0.5, 1.5); Q2: 1.0 (0.6, 1.7); Q3: 1.4 (0.8, 2.3); Q4: 0.6 (0.3, 1.1) D05 Q1: 1.5 (0.7, 3.0); Q2: 2.0 (1.0, 4.0); Q3: 1.5 (0.7, 3.1); Q4: 2.0 (0.9, 4.1) D07 Q1: 1.3 (0.7, 2.3); Q2: 1.6 (0.9, 2.9); Q3: 1.1 (0.6, 2.1); Q4: 1.3 (0.7, 2.5) F03 Q1: 1.7 (1.0, 3.0); Q2: 1.4 (0.8, 2.4); Q3: 1.4 (0.8, 2.6); Q4: 1.0 (0.5, 1.8) F04 Q1: 1.6 (0.9, 2.8); Q2: 1.9 (1.1, 3.4); Q3: 2.1 (1.2, 3.8); Q4: 2.0 (1.1, 3.6) F08 Q1: 1.2 (0.7, 2.1); Q2: 0.9 (0.5, 1.6); Q3: 1.1 (0.6, 2.0); Q4: 1.0 (0.6, 1.7) PCDDs 4.60–7.39: 2.2 (1.2, 4.4); 7.39–11.20: 2.1 (1.1, 4.3); ≥11.20: 3.2 (1.6, 6.7) PCDFs 2.90–4.50: 4.0 (1.9, 9.3); 4.50–6.80: 4.1 (1.9, 9.7); ≥6.80: 4.4 (2.0, 1.1) Quintile 1 as the reference; quintile 2: 1.3 (0.8, 2.2); quintile 3: 1.2 (0.7, 2.0); quintile 4: 2.2 (1.3, 3.7); quintile 5: 2.3 (1.3, 3.9) CI indicates confidence interval; HPcDD, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin; OCDD, 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin. more likely to accumulate dioxin in their bodies. In a study in Seveso, the association between the serum dioxin level and DM was observed in women, but not in men.3 But, we found an association between dioxin with MetS in men, not in women. In addition to the fact that DM is only one of the five components of MetS and that there are factors that may affect mortality other than incidence of DM, in the Seveso study, no case was observed in the high exposure group, with an expected value of only 0.6. Therefore, the lack of study power might also contribute the difference in the findings. We found that men had a higher risk of MetS than women, after adjusting for age and dioxin exposure. This finding is compatible with those in previous studies in Taiwan. A population-based survey found a prevalence rate of 20.4% in men, while it was only 15.3% in women, and the prevalent age of MetS appeared to be earlier in men (51.3 vs. 56.2 years old).27 Another study of MetS with abdominal obesity in a Chinese population found that the age-standardized S86 | www.epidem.com prevalence of men was higher (73.7% vs. 36.9%).24 But, in a study of adults in the United States, no differences in agestandardized prevalence were found between men and women (24.0% vs. 23.4%).22 Further studies need to explore the differences in findings observed across countries. In the Seveso Women’s Study, an association between the TCDD exposure level and MetS was observed, but only in those who were <12 years old at exposure.5 However, we did not observe an association between the PCDD/Fs exposure level and MetS in either age group in women. In addition to the fact that PCDD/Fs and TCDD might have different effects on MetS, in the Seveso Women’s’ Study, there were only 16 cases with an age of 12 years old or younger at starting exposure, but there were 130 in the current study. A small number of cases is more likely to generate unreliable risk estimates, which can lead to not only underestimation, but also overestimation as well. In fact, when the components of MetS were examined individually in the Seveso Women’s Study, the © 2017 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Epidemiology • Volume 28, Suppl 1, October 2017 AORs ranged from 0.63 to 1.45, but the AOR associated with MetS was as high as 2.03. Nonetheless, further studies are needed to evaluate the difference in the effects between men and women. Our study had some limitations. In particular, we used a one-time measurement of dioxin level in the blood as the exposure indicator and did not have exact data on the cumulative exposure dose. However, because PCDD/Fs have a long halflife in the serum, 7 years28,29 or longer,30,31 and the environmental sources of the contamination remained similar during the study period, we believe the level should have remained similar in the participants over the years. In fact, from our review of literature, we found that most of the previous studies on the health effects of dioxin also had only one measurement over the study period. On the other hand, our study has some unique features in comparison with previous studies. With a large population and a large number of MetS patients, we could obtain more reliable estimates of the risks and conduct stratified analyses. Specifically, stratifications by sex and the age at starting exposure were performed, which can help evaluate the possible effect modifications of these factors. In addition, with the actual measurement of the dioxin level on each participant in such a large population, we could obtain more accurate estimates of the risks than the previous studies. CONCLUSIONS A high serum dioxin level is a predictor of MetS in men, independent of age and age at starting exposure, but not in women. Age at starting exposure and sex are also predictors of MetS in both men and women. Therefore, screening and intervention programs should be considered in endemic areas of exposure to dioxin. ACKNOWLEDGMENTS We would like to thank the colleagues in the Department of Environmental and Occupational Health and the Research Center for Environmental Trace Toxic Substances of the National Cheng Kung University as well as the Tainan City Government for helping us completing this study. REFERENCES 1. Zober A, Ott MG, Messerer P. Morbidity follow up study of BASF employees exposed to 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) after a 1953 chemical reactor incident. Occup Environ Med. 1994;51: 479–486. 2. Henriksen GL, Ketchum NS, Michalek JE, Swaby JA. Serum dioxin and diabetes mellitus in veterans of Operation Ranch Hand. Epidemiology. 1997;8:252–258. 3.Bertazzi PA, Bernucci I, Brambilla G, Consonni D, Pesatori AC. The Seveso studies on early and long-term effects of dioxin exposure: a review. Environ Health Perspect. 1998;106(suppl 2):625–633. 4. Chang JW, Chen HL, Su HJ, Liao PC, Guo HR, Lee CC. Dioxin exposure and insulin resistance in Taiwanese living near a highly contaminated area. Epidemiology. 2010;21:56–61. 5. Warner M, Mocarelli P, Brambilla P, et al. Diabetes, metabolic syndrome, and obesity in relation to serum dioxin concentrations: the Seveso women’s health study. Environ Health Perspect. 2013;121:906–911. © 2017 Wolters Kluwer Health, Inc. All rights reserved. Dioxin and Metabolic Syndrome 6.Wang SL, Tsai PC, Yang CY, Guo YL. Increased risk of diabetes and polychlorinated biphenyls and dioxins: a 24-year follow-up study of the Yucheng cohort. Diabetes Care. 2008;31:1574–1579. 7. Chen HL, Su HJ, Liao PC, Chen CH, Lee CC. Serum PCDD/F concentration distribution in residents living in the vicinity of an incinerator and its association with predicted ambient dioxin exposure. Chemosphere. 2004;54:1421–1429. 8. Lee CC, Lin WT, Liao PC, Su HJ, Chen HL. High average daily intake of PCDD/Fs and serum levels in residents living near a deserted factory producing pentachlorophenol (PCP) in Taiwan: influence of contaminated fish consumption. Environ Pollut. 2006;141:381–386. 9.Lee CC, Guo YL, Kuei CH, et al. Human PCDD/PCDF levels near a pentachlorophenol contamination site in Tainan, Taiwan. Chemosphere. 2006;65:436–448. 10. Chen HL, Liao PC, Su HJ, Guo YL, Chen CH, Lee CC. Profile of PCDD/F levels in serum of general Taiwanese between different gender, age and smoking status. Sci Total Environ. 2005;337:31–43. 11.Alberti KG, Eckel RH, Grundy SM, et al; International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120:1640–1645. 12. Bureau for Health Promotion. Manual for Metabolic Syndrome. 2007. Avail able at: http://www.hpa.gov.tw/Pages/Detail.aspx?nodeid=1176&pid=6664. Accessed 25 June 2017. 13.Grumbach MM, Styne DM. Puberty: ontogeny, neuroendocrinology, physiology, and disorders. In: Larsen PR, Kronenberg HM, Melmed S, et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia, PA: WB Saunders Company; 2003:1115–1239. 14.Lee DH, Lee IK, Porta M, Steffes M, Jacobs DR Jr. Relationship between serum concentrations of persistent organic pollutants and the prevalence of metabolic syndrome among non-diabetic adults: results from the National Health and Nutrition Examination Survey 1999-2002. Diabetologia. 2007;50:1841–1851. 15. Chang JW, Ou HY, Chen HL, Guo HR, Liao PC, Lee CC. Interrelationship between exposure to PCDD/Fs and hypertension in metabolic syndrome in Taiwanese living near a highly contaminated area. Chemosphere. 2010;81:1027–1032. 16.Uemura H, Arisawa K, Hiyoshi M, et al. Prevalence of metabolic syndrome associated with body burden levels of dioxin and related compounds among Japan’s general population. Environ Health Perspect. 2009;117:568–573. 17. Nebert DW, Dalton TP, Okey AB, Gonzalez FJ. Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer. J Biol Chem. 2004;279:23847–23850. 18.Alexander DL, Ganem LG, Fernandez-Salguero P, Gonzalez F, Jefcoate CR. Aryl-hydrocarbon receptor is an inhibitory regulator of lipid synthesis and of commitment to adipogenesis. J Cell Sci. 1998;111(pt 22):3311–3322. 19.Remillard RB, Bunce NJ. Linking dioxins to diabetes: epidemiology and biologic plausibility. Environ Health Perspect. 2002;110:853– 858. 20.Shimaya A, Kurosaki E, Shioduka K, Nakano R, Shibasaki M, Shikama H. YM268 increases the glucose uptake, cell differentiation, and mRNA expression of glucose transporter in 3T3-L1 adipocytes. Horm Metab Res. 1998;30:543–548. 21.Park WH, Jun DW, Kim JT, et al. Novel cell-based assay reveals associations of circulating serum AhR-ligands with metabolic syndrome and mitochondrial dysfunction. Biofactors. 2013;39:494–504. 22.Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002;287:356–359. 23.Cheung BM, Ong KL, Man YB, Wong LY, Lau CP, Lam KS. Prevalence of the metabolic syndrome in the United States National Health and Nutrition Examination Survey 1999-2002 according to different defining criteria. J Clin Hypertens (Greenwich). 2006;8:562–570. www.epidem.com | S87 Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Epidemiology • Volume 28, Suppl 1, October 2017 Huang et al. 24. Gina Dellios. Epidemiology of metabolic syndrome in Europe. Available at: http://www.medicalnewstoday.com/releases/30241.php. Accessed 25 June 2017. 25. Xu S, Gao B, Xing Y, et al. Gender differences in the prevalence and development of metabolic syndrome in Chinese population with abdominal obesity. PLoS One. 2013;8:e78270. 26.Yeh CJ, Chang HY, Pan WH. Time trend of obesity, the metabolic syndrome and related dietary pattern in Taiwan: from NAHSIT 19931996 to NAHSIT 2005-2008. Asia Pac J Clin Nutr. 2011;20:292– 300. 27. Hwang LC, Bai CH, Chen CJ, Chien KL. Gender difference on the development of metabolic syndrome: a population-based study in Taiwan. Eur J Epidemiol. 2007;22:899–906. S88 | www.epidem.com 28.Sweeney MH, Calvert GA, Egeland GM, Fingerhut MA, Halperin WE, Piacitelli LA. Review and update on the results of the NIOSH medical study of workers exposed to chemicals contaminated with 2,3,7,8-tetrachlorodibenzodioxin. Teratog Carcinog Mutagen. 1997–1998;17:241–247. 29. Paustenbach DJ, Kerger BD. The University of Michigan Dioxin Exposure Study: estimating residential soil and house dust exposures to young children. Chemosphere. 2013;91:200–204. 30.Kerger BD, Scott PK, Pavuk M, Gough M, Paustenbach DJ. Re-analysis of Ranch Hand study supports reverse causation hypothesis between dioxin and diabetes. Crit Rev Toxicol. 2012;42:669–687. 31.Michalek JE, Pavuk M. Diabetes and cancer in veterans of Operation Ranch Hand after adjustment for calendar period, days of spraying, and time spent in Southeast Asia. J Occup Environ Med. 2008;50:330–340. © 2017 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.