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研究生(外文):Szu-Yi Yu
論文名稱(外文):The Study of a Hemoglobin Adduct of Acrylonitrile in Exposed Workers
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丙烯腈(Acrylonitrile, CAS no. 107-13-1)c為一工業上常用之化學原料或聚合單體原料,主要作為製造ABS 樹酯的原料,另外也用來製造人造纖維、塑膠、橡膠、SAN 樹酯、丙烯醯胺;台灣去年(民國99年)進口丙烯腈原料約11萬公噸,約有3萬名勞工暴露在丙烯腈之下。
根據International Agency for Research on Cancer (IARC)丙烯腈被歸類為Group 2B,疑似人類致癌物。其親電性質在動物實驗上已證實會導致癌症風險增加,但是在流行病學研究上對丙烯腈人類的致癌危害並無具體的結論。
丙烯腈在進入人體內後會與蛋白質上的胺基酸形成共價鍵結,其中與血紅素(Hemoglobin) N端之纈胺酸(Valine)鍵結形成N-2-Cyanoethyl-valine(CEV),此CEV即丙烯腈之血紅素共價鍵結物(Hemoglobin adduct),動物實驗也證實在低濃度暴露時CEV會與暴露濃度呈線性相關。因此利用修正之艾德蒙降解(modified Edman degradation)切下CEV可做為丙烯腈暴露的血液生物指標。
本研究目的在於利用修正的艾德蒙降解,處理血液當中之血紅素並以液相層析串質譜儀(LC-MS/MS)作定量分析,分析並探討以CEV作為職場勞工長期丙烯腈暴露指標。實驗的結果發現AN暴露組CEV濃度範圍為ND~45655 pmol/g globin,平均值為5138.5 pmol/g globin,而非暴露組之濃度範圍為ND~1900.2 pmol/g globin,平均值為1212.9 pmol/g globin,暴露組有顯著高於非暴露組,對照其個人空氣採樣結果後發現,即使個人空氣採樣丙烯腈濃度低於偵測極限(0.002 ppm)仍可在其體內分析得到CEV。目前丙烯腈為動物致癌物,為保護國人健康安全,未來也可以分析體內CEV作AN生物指標作為職場勞工AN暴露參考值,以改善職場環境保護職場勞工。

Acrylonitrile(AN, CAS no. 107-13-1) is a common chemical used in industrial and a monomer used extensively in the production of plastics, synthetic fibers, and rubber. Last year(2010), there were about 114,000 tones of AN imported in Taiwan and there were about 30,000 wokers potentially expose to AN.
AN is classified in Group 2B by IARC due to its carcinogenicity to experimental animals. In vivo genotoxicity studies shown AN a weak mutagen, particularly in the presence of metabolic activation enzymes. However, it is still not conclusive in AN carcinogenity to human.
Once AN absorbed, it could bind covalently with amino acid, such as cysteine and valine of proteins. AN binds with N-terminal valine of hemoglobin to form N-2-Cyanoethyl-valine (CEV). A linear relationship between CEV and AN exposures. CEV could be digested from hemoglobin with the modified Edman degradation and further analyzed with LC-MS/MS. Sixty three workers exposed to AN at workplaces and 8 staff worker serving as control were recruited for this study. The concentrations of CEV in the AN-exposed workers are ND~45655 pmol/g globin, and the concentrations of CEV in the non-exposed are ND~1900.2 pmol/g globin. The CEV level is significantly higher in AN-exposed group than those in the non-exposed group. Compared with the air sampling data less than the regulation of occupational hygiene( 2 ppm) and mainly undetectable, the CEV are still detectable.
Results from this study demonstrate that an LC-MS/MS method was successfully developed to analyze CEV after hemoglobin was processed with the modified Edman degradation and CEV can serve as a biomarker for long-term AN exposures.

致謝 i
摘 要 iii
Abstract iv
目錄 v
圖目錄 vii
表目錄 ix
第一章 前言 1
1.1 丙烯腈基本資訊 1
1.2 人類流行病學研究與急性毒理 3
1.3 動物實驗研究 5
1.4 代謝機制 7
1.5 生物指標 8
1.6 蛋白質共價鍵結物 10
1.7 修正之艾德蒙降解方法(Modified Edman Degardation) 14
第二章 材料與方法 16
2.1 個案收集 16
2.2 分析方法 16
2.3 血液分析 21
2.4 統計方法 22
第三章 結果與討論 23
3.1. 標準品合成 23
3.2. 血液樣本分析 26
3.3. 暴露資料 29
3.4. 統計結果 31
3.5. 討論 33
3.6. 丙烯腈長期暴露生物指標之探討 40
3.7. 研究限制 42
第四章 結論與建議 43
參考文獻 45
附錄 49

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