以生理學為基礎之藥物動力學模式於職業衛生上應用與發展之探討

Application and Development of Physiologically-- Based Pharmacokinetic (PBPK) Modeling in Occupational Hygiene: a Review

生物偵測係直接測定生物體組織濃度，可評估體內危害物總負荷量。但一般生 物檢體樣本與危害標的器官之濃度變化並非一致，且因標的器官之生物樣本取得困難，環境暴露與生物體組織分佈之濃度在時序上之複雜性，與個體差異等因素，對於確立健康危害之劑量－效應關係仍有其困難性。本研究目的為利用以生理學為基礎之藥物動力學模式，探討因職業暴露之體內各器官劑量－效應與時序性關係。建立以生理學為基礎之藥物動力學模式分為五個步驟（1）選定組織區隔之組成架構；（2）列舉相關數學式；（3）確立模式之參數值；（4）計算各組織區隔時間－濃度關係；（5）模式確認。以生理學為基礎之藥物動力學於職業衛生上可應用之領域分別為（1）推估由不同暴露途徑之暴露量：（2）訂定符合劑量－效應關係之環境暴露標準；（3）從環境暴露值預測對應之生物暴露量；（4）評估取樣困難之標的器官暴露濃度；（5）改良生物偵測之採樣策略：（6）評估混合物暴露之劑量－效應關係；（7）鑑別職業與非職業之暴露量；（8）評估個體間劑量－效應之差異性；暨（9）評估防護具之功效等。但由於以生理學為基礎之藥物動力學模式組織區隔架構難有客觀之認定標準，所需參數值甚難取得個體實際值，暨真實作業環境中暴露瞬間變化難定等因素，以生理學為基礎之藥物動力學於職業衛生之應用仍有待進一步研究。

Several uncertainties hinder the application of biological monitoring in developing the exposure-response relationship: concentration of the biological samples and that of target tissue of the hazard are not always proportional, infeasibility of the target tissue sample, and the complexity of temporal association between the environmental exposure level and concentration of the biological sample. The purpose of this study is to use physiologically-based pharmacokinetic (PBPK) model to establish the temporal dose-response pattern in occupational exposure. There are five steps to set up a PBPK model: (1) selecting appropriate tissue compartments, (2) formulating the mathematical relationship, (3) determining model parameter values,(4) determining the timed concentration in each compartment, and (5) validating and reformulating model. PBPK can be applied in the following areas of occupational hygiene; (1) identifying the individual proportion from mixed exposure routes, (2) setting dose-response-based exposure criteria, (3) determining the value of biological exposure index based on the result of environmental monitoring, (4) estimating the hazard concentration for those target tissues infeasible to collect, (5) advancing the technique in biological monitoring, (6) evaluating metabolic interactions in chemical mixtures, (7) distinguishing the occupational exposure from the non-occtipational, (8) evaluating the interindividual variability using dose-response relationship, and (9) assessing the performance of personal protective equipment. However, due to the lack of a universally accepted compartmental structure, difficulty in approximating the empirical values of various parameters, and the uncertainty and fluctuation of the hazard concentration in actual occupational settings, the application of PBPK still requires more study to reach meaningful conclusion in occupational hygiene.