皮膚暴露危害評估模式中皮膚滲透性及系統吸收閾值劑量之預測

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Title:	皮膚暴露危害評估模式中皮膚滲透性及系統吸收閾值劑量之預測 The Estimation of Skin Permeability and Threshold Dose of Systemic Uptake in Skin Exposure Hazard Modeling
Authors:	張晏青;Yen-Ching Chang
Contributors:	職業安全與衛生學系碩士班
Keywords:	皮膚暴露危害;數學預測模式;皮膚滲透係數;量化結構－活性關係;立即危害生命健康濃度;呼吸半致死濃度;Skin exposure hazard;predictive model;skin permeability;quantitative structure-activity relationship;Immediately Dangerous to Life or Health concentration;inhalational lethal concentration 50%
Date:	2013-07-25
Issue Date:	2013-10-02 11:24:05 (UTC+8)
Publisher:	中國醫藥大學
Abstract:	隨著作業環境化學品使用與日俱增，勞工或緊急應變人員面臨化學性危害因子暴露之問題益形嚴重，亦使面臨意外發生時所需緊急應變之處理需求愈趨嚴峻，因此化學毒物之暴露危害評估成為工業衛生以及法規毒理學之重要課題。針對工業化學毒物之皮膚暴露風險評估，預測性數學模式之發展已逐漸成為傳統生物毒害效應測試結果缺乏時之替代性評估工具，並獲接受於作業環境皮膚暴露危害管制以及緊急應變暴露標準制定時應用。本研究針對工業化學毒物危害風險評估之資訊需求建構不同類別之預測性數學模式，包含適用於皮膚滲透係數(Kp)推論之量化結構−活性關係(QSAR)、以美國國家職業安全衛生研究所(NIOSH)運用於皮膚註記制定之危害預測模式(NIOSH模式)為基礎所擴充之高濃度、短期皮膚暴露危害預測模式、以及適用於立即危害生命健康濃度(IDLH)暴露標準預測之QSAR。其中NIOSH模式之功能擴充乃透過利用IDLH以及急性毒害效應閾值呼吸半致死濃度及最低呼吸致死濃度作為參考空氣濃度達成。本研究重要發現如下：針對預測Kp所建立之QSAR與早期Kp QSAR相較能較精確描述與化學物皮膚滲透性相關之分子特徵，同時透過分子描述符之演繹可重行界定化學物分子量影響皮膚滲透行為之次領域。NIOSH模式經擴充後已具備分別以緊急暴露管制標準以及急性毒害效應為人體累積劑量計算基礎、適用緊急應變作業評估之子模式；評估高濃度、短期暴露之子模式間替換性高。本研究同時針對各模式界定皮膚暴露危害辨識閾值。針對防範急性毒害效應以及防範嚴重呼吸道/皮膚刺激發炎之二IDLH QSARs中，以刺激發炎為防範標的之模式預測效能高，可作為針對重度刺激IDLH或類似緊急應變標準制定時之參考。本研究所發展之數學模式及適用條件分析，當可提供作為預測性數學模式在職業暴露限制標準發展所需之參考健康風險評估工具。 With an increasing and diversified use of chemical in the workplace, the exposure of workers or emergency responders to chemical hazard has become a critical issue in industrial health and regulatory toxicology. Correspondingly, attention has been focused on developing instruments of health hazard assessment for regulatory application. For industrial chemical of potential skin exposure hazard, predictive modeling has been applied as an alterative to conventional biological testing in meeting the demand of data needs and in the development of regulatory standards for prevention of occupational skin exposure and for operation in emergency response. This study developed various types of state-of-the-art predictive algorhtms for estimating health risks associated with exposure to industrial toxic chemicals. These algorithms included: a molecular descriptor-based quantitative structure-activity relationship (QSAR) that described the skin permeability of chemical (Kp); skin exposure hazard-predicting models for evaluating hazard potential of chemical under scenarios of short-term, high-concentration exposure based on an algorithm adopted by the US National Institute for Occupational Safety and Health (NIOSH) for assignment of NIOSH skin notations (the NIOSH model); and two QSARs fitted to characterize the moelecular properties that might be essential in the development of Immediately Dangerous to Life and Health concentrations (IDLHs). In the expanded NIOSH model, the IDLH and two acute toxicity thresholds, inhalational lethal concentration 50% and lowest observed lethal concentration, were used as reference airborne concentration in the estimation of acceptable uptake of target chemical through systemic circulation. The followings were a summary of key findings: The Kp QSAR developed and validated in this study compared to those constructed in the last decades was capable of describing molecular characteristics significantly involved in the epidermal transport behaviors of compounds and interpreting a sub-domain that quantitatively defined the molecular weight as a property of influence to skin permeability of chemical. The revised NIOSH models were able to estimate the acceptable uptake and accumulation of chemical in the body upon contingency exposure using either an emergency response standard or lethal concentration data, thus qualified for use as a preliminary tool of hazard evaluation in emergency response operation. These models were compatible in their power of predictability, and thresholds of hazard identification were defined in each model. Between the two QSARs developed to predict the acute toxicity-based and severe respiratory/dermal irriation-based IDLH, the model describing the acute irritation-based IDLH was of a superior predictability and sufficient reliability to serve as a referece if development of acute irritation-based IDLHs or comparable standards was attempted. Overall, the predictive models that this study developed and the conclusions/recommendations made herein for their application could serve as a supplementary instrument in the health risk assessment applied in the development of occupational exposure limits.
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