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研究生: 葉慧容
Yeh, Hui-Jung
論文名稱: 二異氰酸甲苯之暴露與生物指標關係之探討
Investigation of the relationship between the exposure to toluene diisocyanate (TDI) and biomarker
指導教授: 張火炎
Chang, Ho-Yuan
學位類別: 博士
Doctor
系所名稱: 醫學院 - 基礎醫學研究所
Institute of Basic Medical Sciences
論文出版年: 2007
畢業學年度: 95
語文別: 中文
論文頁數: 131
中文關鍵詞: 二胺基甲苯生物偵測暴露評估二異氰酸甲苯皮膚吸收動力學微波輔助加熱半衰期
外文關鍵詞: toluene diamine, biological monitoring, exposure assessment, Toluene diisocyante, kinetic, half-life, dermal absorption
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  • 二異氰酸甲苯 (toluene diisocyanate,TDI) 在工業上主要作為製造聚氨基甲酸乙酯 (polyurethane, PU) 等產品製造。文獻上TDI可以引起職業性氣喘及過敏性肺炎等。針對TDI相關工廠之職業衛生研究目前有三項待研究改進:(1)代表TDI相關工廠勞工暴露實態 (exposure profile);(2)TDI經皮吸收;(3)改善TDI生物偵測分析效率。
    本研究以實際職場研究為起點,系統性調查全國TDI相關工廠作業勞工TDI暴露實態、除呼吸外之皮膚暴露及其與製程之關係,並進一步以動物模式探討TDI皮膚暴露後是否經由皮膚吸收,並以尿中代謝物二胺基甲苯 (toluene diamine, TDA) 作為TDI內在暴露評估指標,建立TDI皮膚暴露劑量與效應關係。另又因在分析尿中TDA前,尿液樣本需在強酸、100℃下經16小時以上加熱水解,非常費時,在經濟、儀器可近性及節省時間考量下,以微波輔助加熱 (microwave assisted heating, MAH) 方式進行尿液樣本水解之可行性研究。
    職場研究結果發現TDI濃度隨產品別有顯著差異,其中以泡綿業濃度最高,再者2,4-與2,6-TDI濃度比例不同於原料中兩種異構物之比例且非為定值。空氣中2,4-TDI濃度約有1/3樣本數超過法令容許濃度標準,我國在2003年以前只規定2,4-TDI作業環境空氣容許濃度標準,而2,6-TDI亦對人體有健康危害,對於2,6-TDI未有規範,故有增訂其容許濃度之必要,且由製程發現液態TDI在混料、注入或發泡時而污染勞工皮膚,勞工可能因皮膚暴露而增加健康風險。以大鼠動物模式進行TDI液體皮膚暴露發現,能在尿中檢測出TDA,顯示TDI的確可經皮吸收,且TDI暴露與TDA內在劑量呈正比關係。而尿中2,6-與2,4-TDA為first-order kinetic排除方式,半衰期約為20小時,惟在高劑量組似乎排除速率較慢。為節省上述TDA分析時間,使用MAH進行尿液樣本前處理水解,傳統加熱 (16小時) 與微波加熱之2,4-及2,6-TDA釋出量、回收率並無顯著差異,但MAH時間只需20分鐘即可達CH之效率,運用MAH進行TDI暴露之尿中TDA生物偵測樣品前處理方法是可行的。

    Toluene diisocyanates (TDIs) are widely used in the production of polyurethane (PU). TDIs have been documented to cause occupational asthma. Up to the present time, three issues, however, are still waiting for further investigation with respect to TDI-related occupational health: (1) to determine the general exposure scenario among various TDI-related industries; (2) to develop a method accelerating the urine analysis in biological monitoring of TDIs exposure; and (3) to affirm skin absorption of TDIs.
    In summary, the objectives of this study were to determine the nationwide 2,4- and 2,6-TDIs exposure profile on an industry-specific basis by a systematic survey. The results showed a significant difference in TDIs concentrations among three industries and PU foam with the highest TDIs concentration. Moreover, the TDIs could easily expose workers to TDIs via skin contact during the manufacturing processes e.g. charging and foaming. The findings hypothesized that TDIs skin exposure could results in skin absorption, but warrant a more thorough study to affirm. A rat model was used to evaluate the skin absorption to explore the dose-response pattern and determine the kinetic characteristics of U-TDAs during skin exposure. We confirmed that skin absorption of TDIs through skin contact and there is a clear dose-response fashion. U-TDAs concentrations via skin exposure reveal the first-order elimination kinetics and the apparent half-lives are about 20 hr. An attempt is made to apply microwave-assisted heating (MAH) to reduce the duration in analysis. The hydrolysis efficiency obtained from MAH procedure is significantly greater than that from conventional one. Hydrolysis by MAH required only 20 minutes, 48 times faster than with conventional heating. The use of the MAH method in hydrolysis was demonstrated to be a reproducible, timesaving and efficient technique in measuring the concentration of urinary TDAs. This method could be applied for analysis of U-TDAs in occupational health.

    目錄 中文摘要………………………………………………………………………1 英文摘要………………………………………………………………2 致 謝…………………………………………………………………3 縮寫表…………………………………………………………………8 第一章 研究緣起……………………………………………………10 第二章 背景資料……………………………………………………14 第一節 TDI物化特性及使用…………………………………………14 第二節 動物實驗 (毒理資料)…………………………………….19 第三節 TDI之職業暴露途徑與健康危害……………………………20 第四節 TDI在生物體內代謝…………………………………………23 第五節 TDI之作業環境測定…………………………………………24 第六節 職場空氣中TDI之容許暴露標準……………………………25 第七節 TDI暴露之生物偵測…………………………………………26 第八節 TDI皮膚暴露…………………………………………………29 第九節 目前TDI相關暴露與生物偵測之缺點………………………34 第三章 本研究之意義與顯著性……………………………….……35 第四章 研究假說與目的……………………………………………38 第五章 研究對象、材料、方法與步驟………………………………40 第六章 研究結果………………………………………………………49 第七章 討論……………………………………………………………57 第八章 結論……………………………………………………………65 未來之研究方向………………………………………………………67 第九章 參考文獻……………………………………………………70 表目錄 表 1.異氰酸鹽類相關工廠勞工空氣暴露於異氰酸鹽型態…………77 表 2.ACGIH、OSHA 及UK-HSE 針對異氰酸的暴露基準……………78 表 3.本研究之TDI相關工廠基本資料………………………………79 表 4.以個人採樣方式測定三類TDI相關工廠空氣中2,4-及2,6-TDI濃度、無法檢測比率及超過容許濃度比率之結果……………………80 表 5.以區域採樣方式測定三類TDI相關工廠空氣中2,4-及2,6-TDI濃度、無法檢測比率及超過容許濃度比率之結果……………………81 表 6.依據產品別,個人及區域採樣空氣中2,4-/2,6-TDI濃度比例之比較……82 表 7.以短時間(≦15分鐘)與全程工作日時量(>15分鐘)採樣測定空氣中TDI濃度比較…………………………………………………83 表 8.TDI皮膚暴露後之尿中代謝物TDA排出動力學參數……………84 表 9.六種微波加熱最佳條件測試之程式……………………………85 表10.以傳統加熱(CH)及微波加熱(MAH)酸水解方式進行空白尿液添加不同濃度free-form TDA之回收率測試…………………………87 表11.以傳統加熱(CH)及微波加熱(MAH)方式進行酸水解效率測試……88 圖目錄 圖1.TDI化學結構………………………………………………………89 圖2.新型三層濾紙系統(Triple filter system)…………………90 圖3.大鼠經口服或呼吸2,4-TDI暴露之代謝物種類…………………91 圖4.TDI皮膚暴露動物試驗(a)暴露部位;(b)敷料密封包紮完成圖92 圖5.200 ng/mL標準溶液的2,4-與2,6-TDA衍生物之GC/ECD層析圖…93 圖6.採樣方式與空氣中2,4-及2,6-TDI濃度之關係…………………94 圖7.以產品別分析空氣中2,4-及2,6-TDI濃度之關係………………95 圖8.三類TDI相關行業之空氣中2,4-與2,6-TDI濃度之比值…………96 圖9.TDI相關工廠現場調查……………………………………………97 圖10.終止TDI皮膚暴露後尿中代謝物TDA連續六天的濃度變化……98 圖11.尿中代謝物TDA濃度對數值與時間關係…………………………99 圖12.TDI皮膚暴露劑量與U-TDA之關係………………………………100 圖13.以六種MAH加熱程式進行水解之2,6- and 2,4-TDA濃度比較101 圖14.分別以CH與MAH加熱進行三種尿液稀釋倍數與U-TDA線性關係比較………………………………………………………………………102 圖15.傳統加熱與微波加熱之比較……………………………………103 附件目錄 附件一 動物實驗申請書………………………………………………104 附件二 已發表之相關論文……………………………………………108

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