Mattie D R, Grabau J H, McDougal J N
Toxicology Division, Armstrong Laboratory, Wright-Patterson Air Force Base, Ohio 45433-7400.
Risk Anal. 1994 Jun;14(3):277-84. doi: 10.1111/j.1539-6924.1994.tb00242.x.
The skin is a route of exposure that needs to be considered when conducting a risk assessment. It is necessary to identify the potential for dermal penetration by a chemical as well as to determine the overall importance of the dermal route of exposure as compared with inhalation or oral routes of exposure. The physical state of the chemical, vapor or liquid, the concentration, neat or dilute, and the vehicle, lipid or aqueous, is also important. Dermal risk is related to the product of the amounts of penetration and toxicity. Toxicity involves local effects on the skin itself and the potential for systemic effects. Dermal penetration is described in large part by the permeability constant. When permeability constants are not known, partition coefficients can be used to estimate a chemical's potential to permeate the skin. With these concepts in mind, a tiered approach is proposed for dermal risk assessment. A key first step is the determination of a skin-to-air or skin-to-medium partition coefficient to estimate a potential for dermal absorption. Building a physiologically-based pharmacokinetic (PBPK) model is another step in the tiered approach and is useful prior to classical in vivo toxicity tests. A PBPK model can be used to determine a permeability constant for a chemical as well as to show the distribution of the chemical systemically. A detailed understanding of species differences in the structure and function of the skin and how they relate to differences in penetration rates is necessary in order to extrapolate animal data from PBPK models to the human. A study is in progress to examine anatomical differences for four species.
在进行风险评估时，皮肤是一个需要考虑的暴露途径。有必要确定化学品经皮渗透的可能性，并确定与吸入或口服暴露途径相比，经皮暴露途径的总体重要性。化学品的物理状态（气态或液态）、浓度（纯品或稀释品）以及载体（脂质或水性）也很重要。经皮风险与渗透量和毒性的乘积有关。毒性涉及对皮肤本身的局部影响以及产生全身影响的可能性。经皮渗透在很大程度上由渗透常数来描述。当渗透常数未知时，可以使用分配系数来估计化学品渗透皮肤的可能性。基于这些概念，提出了一种分层的经皮风险评估方法。关键的第一步是确定皮肤与空气或皮肤与介质的分配系数，以估计经皮吸收的可能性。构建基于生理学的药代动力学（PBPK）模型是分层方法的另一步骤，并且在经典的体内毒性试验之前很有用。PBPK模型可用于确定化学品的渗透常数，并显示化学品在全身的分布。为了将PBPK模型中的动物数据外推至人类，有必要详细了解不同物种皮肤结构和功能的差异以及它们与渗透率差异的关系。正在进行一项研究以检查四个物种的解剖学差异。
