Bookout R L, McDaniel C R, Quinn D W, McDougal J N
Air Force Institute of Technology, Wright-Patterson AFB, OH 45433, USA.
SAR QSAR Environ Res. 1996;5(3):133-50. doi: 10.1080/10629369608032985.
Dermal penetration of chemicals and drugs is of concern to both toxicologists and pharmacologists. Environmental professionals try to limit exposure to chemicals using protective clothing and gloves or barrier creams to trap chemicals. Drug developers try to enhance penetration of chemicals through the skin for medical purposes. Both can use predictive biologically-based mathematical models to assist in understanding the processes involved. These models are especially useful when they are based on physiological and biochemical parameters which can be measured in the laboratory. Appropriately validated models based on conservation of mass, diffusion and chemical transport by flow can be predictive of human exposures. In this paper we develop two new physiologically-based pharmacokinetic (PBPK) skin models to predict blood concentrations of dibromomethane in rats after skin-only vapor exposures. These new models improve the predictions of the blood concentrations especially at the beginning of the exposures. Sensitivity analysis shows that the permeability constants followed by partition coefficients have the most impact on blood concentration predictions. With proper validation the new models could be used to improve species, dose, and duration extrapolations of chemical or drug penetration. They could also be used to investigate and predict concentrations of drugs or chemicals in the skin.
化学物质和药物的皮肤渗透是毒理学家和药理学家都关注的问题。环境专业人员试图通过使用防护服、手套或阻隔霜来限制对化学物质的接触，以捕获化学物质。药物研发人员试图为了医学目的提高化学物质透过皮肤的渗透率。两者都可以使用基于生物学的预测性数学模型来辅助理解其中涉及的过程。当这些模型基于可在实验室测量的生理和生化参数时，它们特别有用。基于质量守恒、扩散和流动化学传输的经过适当验证的模型可以预测人体接触情况。在本文中，我们开发了两个新的基于生理学的药代动力学（PBPK）皮肤模型，以预测仅经皮肤蒸汽暴露后大鼠体内二溴甲烷的血药浓度。这些新模型尤其在暴露开始时改善了对血药浓度的预测。敏感性分析表明，渗透常数其次是分配系数对血药浓度预测的影响最大。经过适当验证后，新模型可用于改进化学物质或药物渗透的物种、剂量和持续时间外推。它们还可用于研究和预测皮肤中药物或化学物质的浓度。
