结合体质量生长函数的幼年大鼠毒死蜱经口暴露PBTK/TD模型的研究  

A physiologically based toxicokinetic/toxicodynamic model with growth function of the Juvenile rat following the oral exposure to chlorpyrifos

作　　者：姚欣雅[1] 赵敏娴[1] 曹正颖 王灿楠[1] 

机构地区：[1]东南大学公共卫生学院环境医学工程教育部重点实验室,东南大学公共卫生学院营养与食品卫生系,江苏南京210009

出　　处：《癌变．畸变．突变》2015年第4期249-259,共11页Carcinogenesis,Teratogenesis & Mutagenesis

基　　金：国家自然科学基金(81273080;81072304)

摘　　要：目的:结合体质量生长函数,构建幼年大鼠毒死蜱(CPF)经口暴露生理基础毒代动力学及毒效应学(PBTK/TD)模型,并进行验证。方法:首先进行模型构建与验证,包括划分模型房室,确定所需参数;拟合大鼠体质量生长函数方程;编写微分方程和软件程序;利用动物实验数据优化参数,进行参数灵敏度分析和模型验证。然后进行动物实验,21日龄雌性SD大鼠按体质量随机分成对照组和12.5、25.0、50.0 mg/kg剂量组,一次性经口灌胃毒死蜱,在给药后1、3、6、12和24 h收集大鼠血清和大脑皮质,并测定各个时间点的血清毒死蜱(CPF)和3,5,6-三氯-2-吡啶(TCP)浓度,血清和大脑皮质乙酰胆碱酯酶(AChE)活力。结果:实验数据显示血清CPF和TCP浓度随时间先上升后下降,在3 h到达峰值,血清和皮质ACh E活力随时间先下降后上升,血清ACh E在6 h达最低值,皮质AChE在12 h达最低值。模型曲线与实验结果的变化趋势一致,模型的拟合预测情况较好;外推时会出现高估或低估的情况。结论:本模型结构和参数设计合理,且具备一定的外推能力,适用于个体平均水平的预测,但模型仍需要进一步改进。OBJECTIVE： Build and validate PBTK/TD with growth function of the Juvenile rat following the oral exposure to chlorpyrifos（CPF）. METHODS： Model construction and validation： to determine the model structure and parameters; establish the growth function of body weight for rats, and write the differential equations as well as the program. Using experimental data to optimize the model parameters, make Sensitivity Analysis and model validation. Animal experiment： 21 days-old female SD rats were randomly divided into 1 control group and 3 treated groups （12.5, 25.0 and 50.0 mg/kg） according to the weight. Serum and cerebral cortex were collected after single garage at lh, 3 h, 6 h, 12 h and 24 h, then to determine the concentration of CPF and 3, 5, 6-trichloropyridinol（TCP） in serum, the activity of acetylcholinesterase （ACHE） in cerebral cortex. RESULTS： Experimental data showed that the concentrations of serum CPF and TCP increased to the peak level at the 3rd hour, then the concentrations decreased. With time, the activity of AChE in serum and cerebral cortex decreased first and then rose slowly. The minimum activity of serum AChE and cortex AChE was observed at 6th hour and 12th hour, respectively. The model predictions is consistent with the experimental results, while there were an overvalued or undervalued problem when using the model to make extrapolation. CONCLUSION： The model has reasonable structure and parameters, and can be used for extrapolation, especially in prediction of the individual average level, but the model still need further improvement.

关 键 词：毒死蜱 PBTK/TD模型 生长函数 经口暴露 年龄相关性 

分 类 号：R394.6[医药卫生—医学遗传学]