应用PBTK/TD模型研究毒死蜱经口重复染毒幼年大鼠的毒代动力学及毒效应学

doi:10.3969/j.issn.1004-616x.2015.05.013

癌变·畸变·突变 ›› 2015, Vol. 27 ›› Issue (5): 386-393.doi: 10.3969/j.issn.1004-616x.2015.05.013

应用PBTK/TD模型研究毒死蜱经口重复染毒幼年大鼠的毒代动力学及毒效应学

姚欣雅, 赵敏娴, 曹正颖, 王灿楠

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

收稿日期:2015-04-16 修回日期:2015-06-26 出版日期:2015-09-30 发布日期:2015-09-30
通讯作者: 王灿楠,E-mail:wcnseu@126.com E-mail:wcnseu@126.com
作者简介:姚欣雅,E-mail:yaoxinya@foxmail.com。
基金资助:
国家自然科学基金(81273080,81072304)

Toxicokinetics and toxicodynamics in juvenile rats following repeated oral exposure to chlorpyifos by using PBTK/TD model

YAO Xinya, ZHAO Minxian, CAO Zhengying, WANG Cannan

The Key Laboratory of Medical Engineering Environment, Nutrition and Food Hygiene Department, School of Public Health, Southeast University, Nanjing 210009, Jiangsu, China

Received:2015-04-16 Revised:2015-06-26 Online:2015-09-30 Published:2015-09-30

摘要/Abstract

摘要：

目的:应用PBTK/TD模型研究幼年大鼠经口重复暴露毒死蜱(CPF)的毒代动力学及毒效应学。方法:21日龄雌性SD大鼠按体质量随机分成对照组、1.0、2.5、5.0、10.0和15.0 mg/kg毒死蜱剂量组,每天1次,连续灌胃10 d,在第3、6、10和11天收集血清和大脑皮质,测定血清CPF和3,5,6-三氯-2-吡啶(TCP)浓度、血清和皮质的乙酰胆碱酯酶活力(AChE)活力;收集第3、6和11天的尿液,测定尿液TCP累积量。在幼年大鼠毒死蜱经口暴露PBTK/TD模型中输入暴露条件,模拟各个指标的时量变化曲线。结果:以24 h为1个周期,每次染毒后血清CPF和TCP浓度随时间的增加先上升后下降,与对照组间的差异具有统计学意义(P<0.05)。血清和皮质AChE活力随时间亦呈周期性变化,均随着染毒剂量的增加而减小,具有统计学意义(P<0.05);而在停止染毒后第1天,血清AChE活力显著恢复,具有统计学意义(P<0.05)。结论:毒死蜱在重复染毒时,毒代谢动力学与毒效应学指标均呈周期性变化,其持续暴露会使血清和大脑皮质AChE维持在一定的抑制水平,停止暴露后可显著恢复。

关键词: 毒死蜱, PBTK/TD模型, 重复经口暴露, 毒代动力学, 毒效应学

Abstract:

OBJECTIVE: To describe the characteristics of toxicokinetics and toxicodynamics of chlorpyifos (CPF) in juvenile rats after repeated oral gavage of chlorpyrifos by using PBTK/TD model. METHODS:21 days-old female SD rats were given daily gavage doses of CPF at doses of 0, 1.0, 2.5, 5.0, 10.0 and 15.0 mg/kg/d for 10 days. Serum and cerebral cortex were collected on days 3, 6, 10 and 11, to determine the concentration of CPF and 3, 5, 6- trichloropyridinol (TCP) in serum and the activity of acetylcholinesterase (AChE) in cerebral cortex. Urine samples were collected on days 3, 6 and 11, to determine the cumulative amount of TCP in urine. PBTK/TD model was used to predict the time-concentration curve of the indexes. RESULTS:The concentrations of serum CPF and TCP first increased and then decreased with time every 24 h during the period of administration, significantly different with the control group (P<0.05). The activities of AChE in serum and cerebral cortex also showed cyclical changes over time. The activities of AChE in cortex and serum both decreased as the CPF dose increased (P<0.05). The first day after exposure stopped, the activity of AChE in serum had a remarkable recovery (P<0.05). CONCLUSION:In repeated exposure, toxicokinetic and toxicodynamic indexes showed periodic variation. Continuous exposure to chlorpyrifos resulted in AChE in cortex and serum to be maintained at a certain level of inhibition, which only recovered when until significantly exposure stopped.

Key words: chlorpyrifos, PBTK/TD model, repeated oral exposure, toxicokinetics, toxicodynamics

中图分类号:

R394.6

姚欣雅, 赵敏娴, 曹正颖, 王灿楠. 应用PBTK/TD模型研究毒死蜱经口重复染毒幼年大鼠的毒代动力学及毒效应学[J]. 癌变·畸变·突变, 2015, 27(5): 386-393.

YAO Xinya, ZHAO Minxian, CAO Zhengying, WANG Cannan. Toxicokinetics and toxicodynamics in juvenile rats following repeated oral exposure to chlorpyifos by using PBTK/TD model[J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2015, 27(5): 386-393.

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应用PBTK/TD模型研究毒死蜱经口重复染毒幼年大鼠的毒代动力学及毒效应学

Toxicokinetics and toxicodynamics in juvenile rats following repeated oral exposure to chlorpyifos by using PBTK/TD model

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