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研究生:蔡家雄
論文名稱:運用生理暨藥理動力學模式評估苯於生物體內之傳輸與流佈
論文名稱(外文):Disposition of benzene in mice, rats, and human by PBPK model
指導教授:林伯雄林伯雄引用關係
指導教授(外文):Lin Po-Hsiung
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:2002
畢業學年度:90
語文別:中文
論文頁數:98
中文關鍵詞:
外文關鍵詞:benzenepbpkbenzene oxide
相關次數:
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苯已被科學研究證實為人體致癌物,除了職業性暴露為主要對象外,一般人於日常生活中亦會接觸到低劑量的苯。同時研究證據顯示,長時間暴露於低劑量下的苯對人體也會造成相當的健康危害。目前大部分的研究都一致認為苯的活性代謝物為致癌的主要原因,而這些活性代謝物都具有半衰期短及偵測不易等特性,因此運用生物指標(biomarker)研究苯的活性代謝物體內組織劑量即有其是必要性。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(Physiologically-Based Pharmacokinetics, PBPK)模式,透過Visual Basic 6.0應用程式語言,以及動物與人體之生化參數、生理參數、及組織器官間傳輸及質量平衡的觀念,針對苯、苯之活性代謝產物、及蛋白質胼合物生物指標,探討苯與其活性代謝產物benzene oxide (BO)於動物與人體之傳輸與流佈,同時進一步推估苯於生物體內累積之劑量。
本研究所建立之苯之PBPK模式模擬結果顯示,苯於小鼠、大鼠、及人體之濃度隨時間之變化曲線,經與其他文獻相較,結果一致,驗證模式架構無誤。若參考以體外測試所得之小鼠之BO一次移除速率常數Ke,及BO與蛋白質間生成胼合物之二次反應速率常數Kr,經模式推估,所得之BO及BO-Hb胼合物濃度與實際實測值相當吻合。若藉由數值趨近推估方式所得之大鼠Ke及Kr來進行模擬推估BO及BO-Hb胼合物濃度約為實驗值相當接近,但BO-Alb胼合物實驗值約為模擬值的3倍。若進一步以BO-Hb胼合物推估血液中BO的組織劑量,當口服劑量為200 mg苯/kg body weight時小鼠之BO的組織劑量推估值為5.27×103 nM-h,所得結果與實驗值4.31×103 nM-h,大致吻合﹔大鼠之BO組織劑量推估值濃為11.5×103 nM-h,所得結果與實驗值9.61×103 nM-h大致吻合。同時本研究中亦運用monte carlo simulation來評估小鼠Ke和Kr兩參數於模式中所造成的變動範圍,所得最大值和最小值之結果與平均值之間的落差最大約為6%。

摘要 I
ABSTRACT III
縮寫對照表 V
目錄 VI
圖目錄 VIII
表目錄 IX
第一章、前言 1
1-1 研究動機 1
1-2 研究目的 2
第二章、文獻回顧 3
2-1苯(Benzene) 3
2-1-1苯物理及化學特性 3
2-1-2環境中苯的來源及其影響因素 4
2-1-3苯之基本藥理動力學資訊 4
2-1-4苯對人體健康之危害 7
2-1-5苯對動物的影響 8
2-2 生理為基礎之藥理動力學(Physiologically-Based-Pharmaco-Kinetics,PBPK) 9
2-2-1 苯的藥理動力學模式 14
2-3應用蛋白質胼合物 (protein-adducts)作為生物性偵測性指標 (biomarker) 15
2-4蛋白質胼合物(protein adducts)的動力學模式 16
2-5劑量計算 18
2-6 Monte Carlo Simulation 19
第三章、苯-PBPK模式理論推導與模式建立 20
3-1 理論基礎 20
3-1-1 基本架構考量 20
3-1-2 模式之基本假設 20
3-2 模式建立 22
3-2-1 統御方程式 22
3-2-2 初始條件 32
3-2-3 模式求解與參數求取 33
3-2-4 Monte Carlo Simulation 33
第四章、研究方法 37
4-1 材料 37
4-1-1 模式驗證 37
4-1-2 其他周邊設備 38
4-2 苯-PBPK模式之模擬方法 39
4-2-1 驗證模式可行性 39
4-2-2蛋白質胼合物消失速率的探討 39
4-2-3長期暴露下,蛋白質胼合物的評估 39
第五章、結果與討論 41
5-1模式之驗證 41
5-2 長期暴露於苯環境之模擬(simulation) 56
5-3 BO於組織劑量之推估 63
5-4敏感度分析(sensitivity analysis) 65
5-5 Monte Carlo Simulation 68
第六章、結論與建議 73
6-1 結論 73
6-2 建議 74
參考文獻 75
附錄一 電腦程式 79

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