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系統識別號 U0026-1408201502162000
論文名稱(中文) PVC作業勞工DEHP暴露解析及其對生殖荷爾蒙干擾之研究
論文名稱(英文) The Study on DEHP Exposure Analysis and Reproductive Hormones Disruption for PVC Workers
校院名稱 成功大學
系所名稱(中) 環境醫學研究所
系所名稱(英) Institute of Environmental and Occupational Health
學年度 103
學期 2
出版年 104
研究生(中文) 方澤沛
研究生(英文) Jer-Pei Fong
學號 s78951043
學位類別 博士
語文別 英文
論文頁數 73頁
口試委員 指導教授-李俊璋
召集委員-蔡瑞真
口試委員-石東生
口試委員-王文忻
口試委員-張志欽
口試委員-許昺奇
口試委員-陳秀玲
中文關鍵字 鄰苯二甲酸2-乙基己基酯  塑膠  職業暴露  生殖荷爾蒙  雌二醇 
英文關鍵字 Di(2-ethylhexyl) phthalate (DEHP)  Polyvinyl chloride (PVC), Occupational Exposure  Reproductive Hormone  Estradiol. 
學科別分類
中文摘要 已有相關研究指出,PVC塑膠產品作業勞工在職業環境中所暴露到的鄰苯二甲酸2-乙基己基酯 (Di (2-ethylhexyl) phthalate, DEHP),在尿液樣本可測得相當高的DEHP代謝物濃度,且可能與生殖健康效應之相關危害有關,此外,職場環境中各式暴露途徑對人體吸收之貢獻量,目前仍無切確之研究結果。DEHP 可在人體內快速代謝為水解代謝產物:monoester (mono(2-ethylhexyl) phthalate, MEHP,以及氧化代謝產物 mono (2-ethyl-5-hydroxyhexyl) phthalate, MEHHP、mono (2-ethyl-5-oxohexyl) phthalate, MEOHP,這些代謝物均與生殖荷爾蒙干擾、睪丸組織毒害有關。部份研究亦發現,職業暴露勞工尿中DEHP代謝物濃度顯著高於一般民眾,但對於職業族群的暴露評估與生殖荷爾蒙干擾等相關研究,仍缺少深入之探討與分析。本研究共分為兩部份,第一部份題目為:使用個人空氣採樣與DEHP尿中代謝物量測結果,推估PVC產品作業勞工之呼吸暴露貢獻量;第二部份題目為:PVC產品作業勞工DEHP尿中代謝物濃度與生殖荷爾蒙之相關性。
第一部份研究,分別採用個人空氣暴露採樣與生物偵測技術,並搭配DEHP內劑量藥物動力學參數,以推估在職業暴露環境中,呼吸暴露佔整體DEHP吸收之貢獻量。該項研究以89位男性PVC產品作業勞工為研究對象(現場製程勞工為高暴露組,共66位;行政辦公人員為低暴露組,共23位),並採集當日上班前與下班後的尿液樣本,尿中代謝物之分析包括:MEHP、MEOHP、MEHHP。研究結果顯示,低暴露組個人空氣暴露濃度為5.3 μg/m3,高暴露組個人空氣暴露濃度為32.7 μg/m3,達統計上顯著差異 (p < 0.01)。相關性分析結果亦發現,高暴露組下班後尿中DEHP代謝物濃度與個人空氣採樣結果,達統計上顯著相關。以尿中DEHP代謝物濃度推估個人每日吸收劑量,低暴露組為9.2 μg/kg/day,高暴露組為15.5 μg/kg/day,達統計上顯著差異 (p < 0.01)。進一步再以四分位數值趨勢分析,探討呼吸暴露是否為職業族群的重要暴露途徑,其分析結果仍顯示,隨著呼吸暴露濃度之增加,DEHP尿中代謝物濃度亦隨之升高,且達顯著上升趨勢。在最高的四分位組別中,呼吸暴露對整體DEHP之吸收,約佔46.7%。該項研究證明,對PVC產品之職業暴露族群而言,呼吸暴露是重要的DEHP吸收途徑,與一般民眾大多由食入途徑有所不同。此為第一篇同時以採用環境監測與生物偵測技術,針對PVC產品職業暴露族群進行完整的暴露評估研究,並證明呼吸暴露途徑對該項暴露情境及其作業勞工之重要性。
第二部份研究,篩選該廠工作年資滿一年以上之男性勞工,共82人。分別量測個人生殖荷爾蒙與尿中DEHP代謝物濃度。進一步再以多變量回歸統計分析與四分位數值趨勢分析,探討DEHP對生殖荷爾蒙之相關性與可能的健康影響。該項研究結果發現,下班後尿中DEHP代謝物濃度以幾何平均值表示,分別為:23.9 μg/g-Cre (MEHP), 66.9 μg/g-Cre (MEOHP), 以及 84.6 μg/g-Cre (MEHHP)。多變量回歸統計分析發現,尿中DEHP代謝物濃度與血液中雌二醇濃度達統計上顯著正相關(p < 0.01),同時亦對雌二醇/睪固酮之比值達統計上顯著正相關(p < 0.05);四分位數值趨勢分析發現,尿中DEHP代謝物濃度與血液中雌二醇濃度達統計上顯著上升趨勢(ptrend = 0.024),同時亦對雌二醇/睪固酮之比值達統計上顯著上升趨勢(ptrend = 0.031)。該項研究結果證實,PVC產品之職業暴露族群,較一般民眾暴露更多的DEHP,且對男性體內之生殖荷爾蒙(雌二醇、雌二醇/睪固酮比值)造成顯著上升趨勢,此項發現可推論為男性體內的芳香轉化酶蛋白(aromatase)活性增強,進一步與其它動物試驗之研究結果比較,高劑量DEHP的確會造成aromatase活性增強,導致雄性大鼠體內的雌二醇、雌二醇/睪固酮比值上升。本項研究之發現與過去的動物試驗結果一致。
本研究建議,PVC職業暴露族群應採用個人呼吸防護具,並針對生產機台裝設局部排氣裝置,以降低DEHP之暴露;本研究亦觀察到DEHP對男性生殖荷爾蒙具有調控干擾之情形,此項可能的健康危害亦適用於一般民眾,因含有DEHP的民生消費性產品仍大量出現在日常生活中,一般民眾仍有相當高的機會,暴露到過量的 DEHP。
英文摘要 The published studies had showed the troubling reports of high urinary metabolite levels and adverse reproductive health effects in workers exposed to di(2-ethylhexyl)phthalate (DEHP) in occupational settings, and the contributions of different routes of exposure to DEHP are unclear. After exposure, most of the DEHP is rapidly metabolized to hydrolytic monoester (mono(2-ethylhexyl) phthalate: [MEHP]), and oxidative metabolites (mono (2-ethyl-5-hydroxyhexyl) phthalate: [MEHHP], mono (2-ethyl-5-oxohexyl) phthalate: [MEOHP]), which are associated with reproductive hormone interruption and testicular toxicity. Some studies report that urinary concentrations of phthalate metabolites for plastics workers are significantly higher than for the general population. However, little is known about the disruption of reproductive hormones for workers exposed to DEHP. There are two parts in this research: Part_I, Estimating the Contribution of Inhalation Exposure to Di-2-ethylhexyl Phthalate (DEHP) for PVC Production Workers, Using Personal Air Sampling and Urinary Metabolite Monitoring; Part_II: Relationship between urinary concentrations of di(2-ethylhexyl) phthalate (DEHP) metabolites and reproductive hormones in polyvinyl chloride production workers.
In part_I study, we used personal air sampling and bio-monitoring to determine the contribution of inhalation exposure to the body burden of DEHP in the workplace. Eighty-nine workers (high-exposure group: 66 raw-materials workers; low-exposure group: 23 administrative workers) were recruited from three polyvinyl chloride (PVC) factories. Urinary levels of MEHP, MEOHP, and MEHHP were measured in pre-shift and post-shift samples. The geometric means of airborne concentrations of DEHP were 5.3 μg/m3 (low-exposure group) and 32.7 μg/m3 (high-exposure group) (p < 0.01). Correlation analysis showed a consistently significant association between airborne DEHP concentration and urinary DEHP metabolite levels in the high-exposure group. Calculating daily DEHP intake based on total urinary metabolite levels showed that the geometric means of total daily urinary metabolite levels of DEHP were 9.2 μg/kg/day (low-exposure group) and 15.5 μg/kg/day (high-exposure group) (p < 0.01). A quartile analysis of all workers showed a significant trend toward an association between the individual contribution of inhalation exposure to DEHP and urinary DEHP metabolite levels, for which the mean inhalation contribution was 46.7% in the highest quartile. We conclude that inhalation-absorbed airborne DEHP significantly increased the total body burden of DEHP in these occupationally exposed workers.
In part_II study, the cross-sectional study of 82 male workers (seniority in current job > 1year) measured the biomarkers for their reproductive hormones and their exposure to DEHP. Relationships between urinary concentrations of DEHP metabolites were estimated using multivariate linear regression and quartile analysis models. The geometric means (GMs) of urinary creatinine-adjusted (μg/g-Cre) concentrations of MEHP, MEOHP, and MEHHP metabolites during the post-shift period were 23.9, 66.9, and 84.6, respectively. In multiple regression models adjusted for potential confounders, there were significant positive associations between urinary concentrations of DEHP metabolites and estradiol (E2) (p < 0.01), and in the ratio of E2 to testosterone (p < 0.05). Moreover, quartile analysis showed significant positive relationships between the total urinary concentration of DEHP metabolites and E2 (ptrend = 0.024), and in the ratio of E2 to testosterone (ptrend = 0.031). Relationships between reproductive hormones and the total urinary concentration of DEHP metabolites in male PVC production workers were significantly positive. This indicated that aromatase activity had increased in male workers exposed to DEHP, which is consistent with animal studies.
We suggest that workers with high urinary DEHP metabolite levels use personal protection equipment and be assigned to work areas well ventilated by local exhaust systems. The potential harm these flexible PVC products pose to male workers could be considerable because of their wide use in myriad consumer products.
論文目次 中文摘要.......................I
Abstract.......................III
Acknowledgments.......................V
Table of contents.......................VI
List of tables.......................VIII
List of figures.......................IX
Abbreviations.......................X
1. About this thesis.......................1
2. Introduction.......................2
2.1 Di(2-ethylhexyl) phthalate (DEHP).......................2
2.2 Exposure pathway of DEHP.......................6
2.3 Health Effect and Reproductive Hormones Disruption.......................9
2.4 Pharmacokinetic data of DEHP in human.......................12
2.5 Exposure assessment in general population and DEHP exposed workers.......................15
3. Estimating the Contribution of Inhalation Exposure to Di-2-ethylhexyl Phthalate (DEHP) for PVC Production Workers, Using Personal Air Sampling and Urinary Metabolite Monitoring.......................19
3.1 Material and methods.......................19
3.1.1 Study population recruitment.......................19
3.1.2 Collecting samples.......................19
3.1.3 Environmental monitoring of airborne exposure to DEHP.......................20
3.1.4 Biological monitoring strategies and urine analysis .......................22
3.1.5 Daily intake estimates.......................23
3.1.6 Statistical analysis.......................24
3.2 Results & Discussions.......................26
3.2.1 Demographic characteristics of participants.......................26
3.2.2 Urinary DEHP metabolite levels.......................29
3.2.3 Correlation between concentrations of urinary DEHP metabolites and airborne DEHP 32
3.2.4 Using biomonitoring data to calculate the intake of phthalates.......................33
3.2.5 Contribution of DEHP inhalation exposure to the total body burden of DEHP.......................34
4. Relationship between urinary concentrations of di(2-ethylhexyl) phthalate (DEHP) metabolites and reproductive hormones in polyvinyl chloride production workers.......................38
4.1 Material and methods.......................38
4.1.1 Recruiting participants and collecting samples.......................38
4.1.2 Serum hormone analysis.......................39
4.1.3 Urinary phthalate metabolite measures.......................40
4.1.4 Statistical analysis.......................40
4.2 Results & Discussions.......................42
4.2.1 Participants’ characteristics.......................42
4.2.2 Urinary DEHP metabolites and serum reproductive hormone levels.......................44
4.2.3 Association between urinary DEHP metabolites and reproductive hormones.......................48
4.2.4 Quartile analysis of creatinine-adjusted concentrations of DEHP metabolites and reproductive hormones.......................53
5. Conclusion.......................59
6. References.......................61
7. List of publications.......................73
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