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的一个复杂的，但可访问的数学模型，该模型密切模仿人体皮肤中化学物质的经皮渗透，组织浓度和清除。在前一支助期间制订的工作模式将通过新的实验加以校正，并扩大以包括更广泛的化学品。将初步开发用于皮肤去污的瞬态肿胀和收缩模型以及用于化学混合物相互作用的基于热力学的模型。皮肤去污模型将得到人体体内和体外避蚊胺研究的支持。单组分、多组分和肿胀模型将用于解释职业健康实践中发现的复杂皮肤吸收现象。模型软件将以电子表格格式打包，以便向职业健康和安全/工业卫生社区提供可访问性。皮肤吸收模型的关键技术特征包括：(1)依赖水化的、基于显微的角质层渗透性模型；(2)真皮血管模型，可以准确预测活皮层的渗透浓度和清除；(3)挥发性渗透物蒸发速率的定量估算；(4)结合对流流动和表面活性剂和有机溶剂的作用，用于皮肤去污；(5)表皮渗透运输的详细微观模型；(6)基于热力学活性的化学混合物接触皮肤的相互作用模型。职业性接触发生的主要途径是吸入和皮肤接触（皮肤接触）。要对接触危险化学品（溶剂、农药、清洗液等）的工人进行有效的皮肤风险评估，需要有准确的方法来估计化学品的暴露和吸收，以及对这一事件可能产生的生物反应。为了减轻皮肤风险而评估洗涤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计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.