||Association between blood dioxin level and health outcomes in an endemic area of exposure in southern Taiwan
||Institute of Environmental and Occupational Health
type 2 diabetes
Chronic kidney disease
研究目的：戴奧辛暴露已被證實可導致多種疾病，可經由活化AhR及抑制PPAR γ功能導致減少 GLUT4 轉化，最後導致胰島素阻抗及產生高血糖而形成糖尿病及代謝症候群。但過去對代謝疾病之相關研究仍然未有定論，而慢性腎臟疾病相關之流行病學報告闕如。過去的研究發現代謝症候群、糖尿病及慢性腎臟疾病與戴奧辛暴露濃度相關，本研究希望能探討高戴奧辛汙染區居民代謝症候群、糖尿病及慢性腎臟疾病及其相關危險因子與血中戴奧辛暴露濃度之相關性。
研究方法：本研究於2008-2010年選取戴奧辛血中濃度> 20 pg WHO98-TEQDF/g lipid之鹿耳、顯宮、四草里居民以及舊中石化台鹼安順廠員工為實驗組，另取< 20 pg WHO98-TEQDF/g lipid居民為對照組。個案需完成自願同意書及基本資料問卷，然後完成身體健康檢查及資料收集：包含性別、年齡、身高、體重、X光及生化血液檢查。代謝症侯群的定義為下列5項中符合3項: 空腹血糖 > 126 mg/dl，腰圍男性> 90 cm或女性> 80cm，三酸甘油脂>150 mg/dl，高密度膽固醇男性<40 mg/dl或女性< 50 mg/dl，及血壓> 130/85 mmHg。糖尿病的定義為空腹血糖> 126 mg/dl或已被醫師診斷為糖尿病者。慢性腎臟疾病的定義為腎絲球過濾率(e-GFR)< 60 mL/min/1.73m2或已被診斷為慢性腎臟疾病者。
1. 2898位參與研究個案中有156位為慢性腎臟疾病患者，戴奧辛暴露、年齡、性別、代謝症候群、糖尿病、高血壓、胰島素及尿酸與慢性腎臟疾病有關(all with p < 0.05)。調整相關危險暴露因子後，高戴奧辛暴露 (AOR = 1.76，95% CI: 1.04-2.99)，女性(AOR = 1.74，95% CI: 1.20-2.53)，高血壓(AOR = 1.68, 95% CI: 1.17-2.42) ，高胰島素阻抗(AOR = 2.14，95% CI: 1.26-3.61)，高尿酸(AOR = 4.25, 95% CI: 2.92-6.20)及年齡較高(AOR for 40-64 years old =4.66，95% CI: 1.87-11.62; AOR for ≥ 65 years old = 26.66，95% CI: 10.51-67.62)均為戴奧辛汙染區居民慢性腎臟疾病的獨立危險因子。
2. 2758位參與研究個案中有785位為代謝症候群患者，血中高戴奧辛濃度與代謝症候群有關(p < 0.05)。調整相關危險暴露因子後，高戴奧辛暴露(> 20 pg WHO98-TEQDF/g lipid) (adjusted odds ratio [AOR] = 1.38，95% confidence interval [CI]: 1.11-1.72)，男性(AOR = 1.22, 95% CI: 1.02-1.46)，年齡較高(AOR for 40-64 years old = 2.61，95% CI: 2.04-3.34; AOR for ≥ 65 years old =3.13，95% CI: 2.15-4.56) 及暴露年齡> 12歲(AOR=1.51，95% CI: 1.15-1.99)均為戴奧辛汙染區居民慢性腎臟疾病的獨立危險因子。進一步以性別分層分析，不論開始暴露年齡的早晚，高戴奧辛暴露在男性都是代謝症候群的獨立危險因子。
3. 2898位參與研究個案中有1427位為高戴奧辛暴露者、425位為糖尿病患者，戴奧辛暴露與糖尿病呈正向相關。調整相關危險暴露因子如年齡、BMI後，高戴奧辛暴露(AOR for 20-64 pg WHO98-TEQDF/g lipid =2.1，95% confidence interval [CI]: 1.5-2.9; AOR for > 64 pg WHO98-TEQDF/g lipid =3.2，95% CI: 2.1-4.8)為糖尿病的獨立危險因子，而且具劑量效應關係。
Background: Dioxin is an industrial pollutant related to various diseases. It can activate the AhR and then suppress the function of PPAR γ, which may progressively lower the translation of GLUT4 and then cause metabolic effect like insulin resistance and hyperglycemia. However, epidemiology studies on its effects on metabolic disease or kidney disease found inconsistent results. This study in an area in Taiwan where the residents were exposed to dioxin released from environmental pollution has three parts:
1. Studies on sex differences in metabolic disorders found inconsistent results from and did not evaluate the differences in effects according to the age at starting exposure. Therefore, we conducted a study to evaluate the associations between dioxin exposure and metabolic syndrome (MetS) and to determine whether the associations are different between men and women and whether the associations depend on the age at starting exposure.
2. Previous studies of diabetes mellitus (DM) did not have consistent findings on the effects of dioxin between the two sexes. Therefore, we conducted a study to assess the effects according to sex and years of residency and to identify related factors.
3. Regarding the association between dioxin and chronic kidney disease (CKD), there were only animal studies on mechanisms, and no epidemiology studies. Therefore, we conducted a study to evaluate the association between dioxin and CKD and identify the related factors.
We recruited participants from an area where residents were exposed to polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) released from a factory
1. We defined serum PCDD/Fs levels ≥ 20 pg WHO98-TEQDF/g lipid as high dioxin levels. MetS was defined as meeting three of the following: 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.
2. Using 20 and 64 pg WHO98-TEQDF/g lipid as the cut-offs, we categorized participants into three groups according to the level of PCDD/Fs in the serum. We defined DM as a fasting plasma glucose level > 126 mg/dl or an existing diagnosis.
3. We defined a “high dioxin level” as PCDD/Fs ≥ 20 pg WHO98-TEQDF/g lipid in the serum and defined CKD as having an estimated glomerular filtration rate (e-GFR) ≤ 60 mL/min/1.73m2 or a diagnosis of CKD by a physician. The renal function was assessed between 2005 and 2010, and we excluded those who had had kidney diseases before the study started. Comparisons between patients of CKD and those who did not have CKD were made to identify the risk factors for CKD.
1. Of the 2898 participants, 1427 had high dioxin levels, and 156 had CKD. In the univariate analyses, CKD was associated with high dioxin levels, age, gender, metabolic syndrome, diabetes mellitus, hypertension, and high insulin and uric acid levels. After adjusting for other factors, we found high dioxin levels (AOR = 1.76, 95% CI: 1.04-2.99), female gender (AOR = 1.74, 95%CI: 1.20-2.53), hypertension (AOR = 1.68, 95%CI: 1.17-2.42), high insulin levels (AOR = 2.14, 95% CI: 1.26-3.61), high uric acid levels (AOR = 4.25, 95% CI: 2.92-6.20), and older age (AOR = 4.66, 95% CI: 1.87-11.62 for 40-64 year and AOR = 26.66, 95% CI: 10.51-67.62 for age ≥ 65 year) were independent predictors of CKD.
2. Of the 2758 participants, 785 patients of 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 a high dioxin level was an independent predictor for MetS (AOR = 1.38, 95% CI: 1.11-1.72). Male (AOR = 1.22, 95% CI: 1.02-1.46), old age (AOR for 40-64 years old = 2.61, 95% CI: 2.04-3.34; AOR for ≥ 65 years old = 3.13, 95% CI: 2.15-4.56), and exposure age> 12 years (AOR = 1.51, 95% CI: 1.15-1.99) are independent predictor, too. When we stratified the participants by sex, we found that a high dioxin remained an independent predictor of MetS in men, but not in women, regardless of the age at starting exposure.
3. Of the 2898 participants, 425 patients of DM were identified, and we observed positive associations between dioxin and DM. After adjusting for age and BMI, we found a high serum dioxin level was an independent risk factor for DM (associated with 20-64 pg WHO98-TEQDF/g lipid AOR = 2.1, 95% CI: 1.5-2.9; AOR for > 64 pg WHO98-TEQDF/g lipid = 3.2, 95% CI: 2.1-4.8). The findings are compatible with those in previous studies of PCDD/Fs. When we stratified the participants by gender, the serum dioxin level remained an independent risk factor for DM in both men and women.
In conclusion, we found that exposure to dioxin is a risk factor for DM, independent of age and BMI, in both men and women. It is also a predictor of MetS in men, independent of age and age at starting exposure, but not in women. In our study but the gender differance still need further study to clarify. Our study also observed an association between high blood dioxin levels and CKD. Whereas the mechanisms by which dioxin causes renal toxicity are still unclear and need further research, results of this study suggested that there might be pathways other than the association between dioxin and hypertension or DM. As dioxin becomes an emerging environmental health hazard globally, the kidney function of exposed populations should be monitored, and screening programs for identifying DM and MetS in its early stage and intervention programs for prevention and control of DM and MetS should be considered in endemic areas of exposure.
Table List XI
Figure List XII
Chapter 1. Introduction 1
1.1. Background 1
1.2. Toxicity of dioxin 2
1.2.1. Liver toxicity 2
1.2.2. Immune toxicity 3
1.2.3. Neurological toxicity 3
1.2.4. Dermatological toxicity 3
1.2.6. Renal toxicity 3
1.2.7. Endocrinological toxicity 4
1.2.8. Metabolic toxicity 4
1.3. Animal mechanistic studies 6
1.3.1. Etiology of diabetes and metabolic syndromes 6
1.3.2. Etiology of chronic kidney disease 6
1.4. Human epidemiology studies 8
1.4.1. Epidemiology studies of chronic kidney disease 8
1.4.2. Epidemiology studies of metabolic syndrome 8
1.4.3. Epidemiology studies of diabetes 8
1.5. Objectives of this study 10
Chapter 2. Material and methods 11
2.1. Study flowchart 11
2.2. Study population 12
2.3. Association between blood dioxin level and chronic kidney disease 13
2.3.1. Assessment of health outcomes 13
2.3.2. Statistical analysis 13
2.3.3. Ethics statement 14
2.4. Association between dioxin and metabolic syndrome by age and sex 14
2.4.1. Assessment of health outcomes 14
2.4.2. Statistical analysis 15
2.5. Association between dioxin and diabetes mellitus by sex and the duration of residency 17
2.5.1. Assessment of health outcomes 17
2.5.2. Statistical analysis 17
Chapter 3. Results 19
3.1. Association between blood dioxin level and chronic kidney disease 19
3.1.1. Demographic data of the participants with and without a high level of dioxin 19
3.1.2. Demographic data of variables according to quartiles of PCDD/Fs. 19
3.1.3. Demographic data of participants with and without chronic kidney disease 19
3.1.4. Risk factors and associated odds ratios for chronic kidney disease among the participants 20
3.1.5. The risk factors of chronic kidney disease among participants stratified with or without diabetes mellitus 20
3.2. Association between dioxin and metabolic syndrome by age and sex 21
3.2.1. Distribution of age, metabolic syndrome, diabetes mellitus and hypertension in men and women 21
3.2.2. Comparisons between participants with and without metabolic syndrome 21
3.2.3. The predictors of metabolic syndrome 21
3.2.4. Predictors of metabolic syndrome stratified by sex 22
3.2.5. Predictors of metabolic syndrome stratified by the age at starting exposure 22
3.3. Association between dioxin and diabetes mellitus by sex and the duration of residency 24
3.3.1. Comparisons between patients of diabetes and the normal population 24
3.3.2. Risk factors for diabetes 24
3.3.3. Risk factors for diabetes stratified by sex 25
3.3.4. Risk factors for diabetes with the duration of residency 25
Chapter 4. Discussion 26
4.1 Association between blood dioxin level and chronic kidney disease 26
4.1.1. The mechanism of renal toxicity by dioxin 26
4.1.2. Comparison dioxin exposure with age to chronic kidney disease 27
4.1.3. Comparison dioxin exposure with diabetes mellitus to chronic kidney disease 27
4.1.4. Comparison dioxin exposure with hypertension to chronic kidney disease 28
4.1.5. Comparison dioxin exposure with hyperuricemia to chronic kidney disease 28
4.1.6. Limitation 29
4.1.7. Environmental PCDD/Fs exposure be an emerging health problem in world 30
4.2.1. The mechanism of dioxins related to metabolic syndrome 31
4.2.2. Comparison dioxin exposure with age to metabolic syndrome 31
4.2.3. Sex difference between dioxin and metabolic syndrome 32
4.2.4. Exposure age and dioxin level in metabolic syndrome 33
4.2.5. Co-exposure of dioxin and mercury in endemic area 33
4.2.6. Limitation 34
4.3. Association between dioxin and diabetes mellitus by sex and the duration of residency 35
4.3.1. The association of dioxin and diabetes mellitus 35
4.3.2. The mechanism of dioxin related to diabetes mellitus 36
4.3.3. Comparison dioxin exposure with age to diabetes mellitus 36
4.3.4. Comparison dioxin exposure with obesity to diabetes mellitus 37
4.3.5. Sex difference between dioxin and diabetes mellitus 37
4.3.6. Limitation 37
4.4. Sex difference between serum dioxin level and the metabolic health effect 39
Chapter 5. Conclusion 40
Chapter 6. Reference 41
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