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研究生:吳錦煌
論文名稱:運用生理暨藥理動力學模式推估苯乙烯於生物體內之傳輸與流佈
指導教授:林伯雄林伯雄引用關係
指導教授(外文):Po-hsiung Lin
學位類別:碩士
校院名稱:國立中興大學
系所名稱:環境工程學系
學門:工程學門
學類:環境工程學類
論文種類:學術論文
論文出版年:2001
畢業學年度:89
語文別:中文
論文頁數:162
中文關鍵詞:苯乙烯苯乙烯環氧化物藥理動力學蛋白質蛋白質胼何物
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苯乙烯(STYRENE)為工業中廣泛使用之化學物質,由於STYRENE及其具活性之代謝產物亦即苯乙烯環氧化物(STYRENE-OXIDE)會引起致基因毒性及致癌等方面之毒性,因此了解STYRENE及其代謝物於人體及其他動物體內之傳輸與流佈(disposition)之差異,以及推估其活性代謝產物STYRENE-OXIDE於標的器官所累積之組織劑量(tissue dose),由於健康風險評估之風險與毒性物質之組織劑量有正相關性,因此推估組織劑量的多寡及其於生物體間之差異,有助於了解STYRENE及其代謝物的對人體之健康風險評估,對STYRENE之人體健康風險之推估,將能提供重要的資訊。本研究之主旨即在於建立及發展以生理為基礎之藥理動力學(Fortran-Based Physiologically-Based Pharmacokinetics, PBPK)模式,透過Fortran應用程式語言,以及動物體與人體之生化參數、生理參數、及組織器官間傳輸及質量平衡的觀念,來推估STYRENE及其代謝產物STYRENE-OXIDE於人體及大鼠體內之傳輸與流佈,並結合苯乙烯環氧化物與血液中紅血球蛋白質(hemoglobin)、血清白蛋白質(serum albumin)產生蛋白質併合物(protein-adduct)之特性,將此一蛋白質併合物作為生物性指標(biomarkers),並運用其動力學模式,透過PBPK模式描述出STYRENE-OXIDE之蛋白質併合物在體內隨時間之變化情況,進而推估STYRENE-OXIDE於標的器官(target organ)之組織劑量。研究之結果顯示,本研究建立之Fortran-Based PBPK模式,經由比對已知之文獻,驗證本模式可成功地精確預測STYRENE及其代謝物在組織器官的濃度隨時間之變化趨勢。同時透過比對已知之文獻中有關STYRENE-OXIDE與血液中蛋白質所生成蛋白質併合物實驗測量值發現,質量平衡模式中苯乙烯環氧化物在血液與肝臟中會同時發生代謝移除,且其與血清中白蛋白質胼合物之生成處所應僅在血液中生成的狀況,進一步確認STYRENE-OXIDE可經由血液之傳輸進而流佈至其它重要組織及器官。此一Fortran-Based PBPK模式將能進一步提供作為其它毒性物質,於活體動物中推估其傳輸與流佈之有效工具。

摘要--------------------------I
目錄--------------------------III
圖 目 錄---------------------VI
表 目 錄---------------------XVI
第一章 前言----------------1
一、研究動機--------------1
二、研究目的---------------3
第二章 文獻回顧------------4
2-1 苯乙烯(STYRENE)--------4
2-1-1 苯乙烯單體(STYRENE monomer)物理及化學特性------5
2-1-2 作業環境中STYRENE的來源及其影響因素-----------6
2-1-3藥理動力學---------------------7
2-1-4 STYRENE之毒性效應(Health Effects)-------10
2-2 生理為基礎之藥理動力學(Physiologically-Based-Pharmaco-Kinetics,PBPK)-----13
2-2-1 STYRENE之藥理動力學模式-----19
2-2-2 STYRENE與STYRENE-OXIDE之血液與組織器官間之分配係數及代謝速率常數---------21
2-2-3 STYRENE-OXIDE於胃臟之水解作用-------22
2-3應用蛋白質胼合物 (protein adducts)作為生物性偵測性指標 (biomarker)---------24
2-4蛋白質胼合物(protein adducts)的動力學模式------26
2-5劑量計算--------28
2-5-1估算活性親電子物質的劑量-----------28
2-5-2利用protein-adducts濃度估算暴露劑量---------29
2-5-3 估算工作場所中重複暴露劑量-----------30
第三章 Fortran-Based STYRENE-PBPK模式理論推導與模式建立------32
3-1 理論基礎------32
3-1-1 基本架構考量----------32
3-1-2模式之基本假設--------33
3-2 模式建立--------------35
3-2-1 統御方程式----------35
3-2-2 初始條件-----------46
3-2-3 模式求解與參數求取-----------47
第四章 材料與方法-------49
4-1 材料---------------49
4-1-1 模式驗證----------49
4-1-2 其他周邊設備----------50
4-2 STYRENE-PBPK模式之模擬方法---------52
4-2-1 驗證模式可行性-------------52
4-2-2蛋白質併合物消失速率的探討----------52
4-2-3組織劑量推估----------------53
4-2-4長期暴露下,蛋白質併合物的評估--------53
第五章 結果與討論-----------55
5-1模式之驗證--------------55
5-2長期暴露於苯乙烯、苯乙烯環氧化物下,蛋白質胼合物濃度隨時間之變化------------------125
5-3 組織劑量推估--------133
第六章 結論與建議------138
6-1 結論--------138
6-2 建議--------139
參考文獻--------140
附錄一 電腦程式--------148

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