Fisher H L, Hall L L, Sumler M R, Shah P V
Environmental Toxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711.
J Toxicol Environ Health. 1992 Jul;36(3):251-71. doi: 10.1080/15287399209531636.
Age dependence in dermal absorption has been a major concern in risk assessment. Captan, a chloroalkyl thio heterocyclic fungicide, was selected for study of age dependence as representative of this class of pesticides. Dermal penetration of [14C]captan applied at 0.286 mumol/cm2 was determined in young (33-d-old) and adult (82-d-old) female Fischer 344 rats in vivo and by two in vitro methods. Dermal penetration in vivo at 72 h was about 9% of the recovered dose in both young and adult rats. The percentage penetration was found to increase as dosage (0.1, 0.5, 2.7 mumol/cm2) decreased. Two in vitro methods gave variable dermal penetration values compared with in vivo results. A static system yielded twofold higher dermal penetration values compared with in vivo results for both young and adult rats. A flow system yielded higher dermal penetration values in young rats and lower penetration values in adults compared with in vivo results. Concentration in body, kidney, and liver was less in young than in adult rats given the same absorbed dosage. A physiological pharmacokinetic model was developed having a dual compartment for the treated skin and appeared to describe dermal absorption and disposition well. From this model, tissue/blood ratios of captan-derived radioactivity for organs were found to range from 0.35 to 3.4, indicating no large uptake or binding preferences by any organ. This preliminary pharmacokinetic model summarizes the experimental findings and could provide impetus for more complex and realistic models.
皮肤吸收的年龄依赖性一直是风险评估中的一个主要问题。克菌丹，一种氯代烷基硫代杂环类杀菌剂，被选作这类农药中年龄依赖性研究的代表。通过两种体外方法和在体实验，测定了[14C]克菌丹在0.286 μmol/cm2剂量下对年轻（33日龄）和成年（82日龄）雌性Fischer 344大鼠的皮肤渗透情况。在体实验中，72小时时年轻和成年大鼠皮肤对克菌丹的渗透率均约为回收剂量的9%。发现渗透率百分比随剂量（0.1、0.5、2.7 μmol/cm2）降低而增加。与在体实验结果相比，两种体外方法得到的皮肤渗透率值各不相同。静态系统得到的年轻和成年大鼠皮肤渗透率值比在体实验结果高两倍。流动系统得到的年轻大鼠皮肤渗透率值比在体实验结果高，成年大鼠则低。给予相同吸收剂量时，年轻大鼠体内、肾脏和肝脏中的浓度低于成年大鼠。建立了一个生理药代动力学模型，该模型对处理过的皮肤有一个双室结构，似乎能很好地描述皮肤吸收和处置情况。从这个模型中发现，克菌丹衍生放射性在各器官中的组织/血液比率在0.35至3.4之间，表明没有任何器官有大量摄取或结合偏好。这个初步的药代动力学模型总结了实验结果，并可能为更复杂和现实的模型提供动力。
