Mechanistically-Based In Silico Estimation of Dermal Absorption in the Workplace

描述（由申请人提供）：研究人员建议进一步开发并应用于职业风险评估，该模型复杂且易于使用，可密切模拟体内经皮渗透、组织浓度和人体皮肤中化学品的清除。将通过新的实验对上一个支助期间开发的工作模型进行校准，并将其扩展到包括更广泛的化学品。初步发展的一个短暂的肿胀和收缩模型的皮肤去污和化学混合物相互作用的化学为基础的模型将进行。皮肤去污模型将得到DEET人体体内和体外研究的支持。单组分模型、多组分模型和溶胀模型可用于解释职业卫生实践中发现的复杂皮肤吸收现象。示范软件将以电子表格的形式打包，以便职业健康和安全/工业卫生界能够使用。皮肤吸收模型中的关键技术特征包括：（1）角质层渗透性的水化依赖的、基于显微镜的模型;（2）真皮血管模型，其允许准确预测活性皮肤层中的渗透物浓度和清除率;（3）挥发性渗透物的蒸发速率的定量估计;（4）结合对流、表面活性剂和有机溶剂对皮肤去污的影响;（5）表皮渗透物运输的详细微观模型;以及（6）用于接触皮肤的化学混合物中的相互作用的基于热力学活性的模型。职业接触的主要途径是吸入和皮肤接触（皮肤接触）。对涉及危险化学品（溶剂、杀虫剂、清洁液等）的工人进行有效的皮肤风险评估需要准确的方法来估计化学品的接触和吸收情况，以及对这一事件可能产生的生物反应。评估清洗对减轻皮肤风险的潜在有效性是这一过程的重要组成部分。拟议项目的完成将大大改进目前用于估算工作场所皮肤接触后化学品吸收情况的方法。

DESCRIPTION (provided by applicant): The investigators propose to further develop and apply to occupational risk assessment a sophisticated, yet accessible mathematical model that closely mimics percutaneous penetration, tissue concentrations and clearance of chemicals in human skin in vivo. The working model, developed during the previous period of support, will be calibrated by means of new experiments and extended to include a wider range of chemicals. Initial development of a transient swelling and shrinkage model for skin decontamination and a thermodynamically-based model for interacting chemical mixtures will be undertaken. The skin decontamination model will be supported by human in vivo and in vitro studies with DEET. Single component, multicomponent and swelling models wll be used to interpret complex skin absorption phenomena found in occupational health practice. Model software will be packaged in a spreadsheet format to provide accessibility to the occupational health and safety/industrial hygiene communities. Key technical features in the skin absorption model include: (1) a hydration-dependent, microscopically-based model for stratum corneum permeability; (2) a dermal vascular model that allows accurate prediction of permeant concentrations and clearance in the viable skin layers; (3) quantitative estimation of the evaporation rates of volatile permeants; (4) incorporation of convective flow and surfactant and organic solvent effects for skin decontamination; (5) a detailed microscopic model for permeant transport in the epidermis; and (6) a thermodynamic activity-based model for interactions in chemical mixtures contacting the skin. The primary routes by which occupatational exposures occur are inhalation and dermal exposure (skin contact). Effective dermal risk assessment for workers involved with hazardous chemicals (solvents, pesticides, cleaning fluids, etc.) requires accurate methods for estimating exposure to and absorption of the chemical, and the probable biological response to this event. Evaluation of the potential effectiveness of washing for purposes of mitigating dermal risk is an essential part of this process. Completion of the proposed project will provide a significant improvement to current methods for estimating absorption of chemicals subsequent to dermal exposures in the workplace.