Improved Methods for Dermal Exposure Estimation

描述(由申请人提供)：调查人员建议制定一项 复杂而又易于访问的数学模型，可紧密模拟 人体皮肤的透皮吸收、组织浓度和清除 活着。这一发展将极大地促进对机械论的理解 过敏性和刺激性皮炎与皮肤暴露的机制 评估。这一目标将通过建设和 基于生理和物理特性的模型的实验验证 用于经皮吸收，结合了 目前用于估计皮肤暴露的数学模型。成功 该建议的具体目标的完成将导致以下几个方面：(1) 一种经实验验证的人类地层运输的微观模型 角质层和皮肤附件(毛囊、汗腺)；(2)真皮 血管模型，允许准确预测预想浓度和 (3)可存活皮肤层的瞬时扩散模型。 计算低至中等剂量暴露后的皮肤吸收 潜在挥发性化合物；(4)皮肤保湿模型 以上是目前使用的稳态渗透率模型；以及(5)一个 易于使用的电子表格，用于皮肤暴露计算，纳入了 来自调查的重要特征。 研究方法包括： 模拟非均质输运的复杂数值技术 结构和这些结果的高级图形表示。 角质层超微结构和微运输的详细检查 利用激光扫描共聚焦显微镜、荧光等性能 光漂白等光学显微技术。 选定渗透剂的扩散系数和分配系数的测定 角质层、表皮、真皮和皮下组织中蛋白质的作用 对这些值具有约束力。

DESCRIPTION (provided by applicant): The investigators propose to develop a sophisticated, yet accessible mathematical model that closely mimics percutaneous penetration, tissue concentrations and clearance in human skin in vivo. This development will significantly advance the mechanistic understanding of allergic and irritant dermatitis and the mechanics of dermal exposure assessment. This objective will be accomplished through the construction and experimental verification of physiological and physical properties-based models for percutaneous absorption incorporating features not found in the mathematical models presently used to estimate dermal exposure. Successful completion of the specific aims of the proposal will lead to the following: (1) an experimentally verified, microscopic model of transport in human stratum corneum and skin appendages (hair follicles, sweat glands); (2) a dermal vascular model that allows accurate predictions of permeant concentrations and clearance in the viable skin layers; (3) a transient diffusion model for calculating dermal absorption subsequent to low-to-moderate exposures to potentially volatile compounds; (4) a skin hydration model for linking the above with steady-state permeability models presently in use; and (5) an easy-to-use spreadsheet for dermal exposure calculations incorporating the most important features from the investigation. The research methods include: Sophisticated numerical techniques for modeling transport in heterogeneous structures and advanced graphical representation of these results. Detailed examination of stratum corneum ultra structure and microtransport properties using laser scanning confocal microscopy, fluorescence photobleaching,and other light microscopic techniques. Determination of diffusivities and partition coefficients of selected permeants in stratum corneum, epidermis, dermis, and hypodermis and the role of protein binding on these values.