有机磷农药膳食暴露风险评估生物学机制模型研究

Dietary exposure is the main route for the population of chronic low dose exposure to organophosphorus pesticides, and its risk assessment is the focus of food safety at home and abroad. For a long time, troubled by the major problem of dietary exposure risk assessment to organophosphorus pesticides is the disjunction of dietary intake (external exposure), vivo toxicant concentration (internal exposure) and toxic effect on the quantitative assessment. The recently developed model for biological mechanism research integrates external exposure, internal exposure and toxic effect into one model through relevant biological mechanism, which has become one of the hot issues for the United States, European Union and other developed countries to carry out the study of food safety risk assessment. This project aims at international development frontier and the goal is to build biological mechanism model for dietary exposure of organophosphorus pesticides to conform to actual condition of our country. The deep and systematic studies are done from model construction, parameters obtaining, model calibration, model validation, model applications, and so on. Research is expected to add new methods to food safety risk assessment of our country and provides new technologies for the use of multi-disciplinary information to develop dietary exposure assessment, and offers scientific basis for risk management of organophosphorus pesticides. The research contents are initiatively developed in China, and the features are comprehensive and profound, compared with foreign counterparts. This project is the depth and expansion of our previous studies for many years, and contains a solid foundation for the work and good research conditions.

膳食暴露是人群长期低剂量接触有机磷农药的主要途径，其风险评估是国内外食品安全关注的重点问题。长期以来，困扰有机磷农药膳食暴露风险评估的主要问题是：膳食摄入量与内暴露剂量及毒效应之间在定量评估上的脱节。新近出现的生物学机制模型可将外暴露剂量、内暴露剂量和毒效应通过生物学机制结合为一整体，现已成为美国、欧盟等发达国家开展食品安全风险评估研究的热点问题之一。本课题瞄准国际科学前沿，以建立符合我国实际的有机磷农药膳食暴露生物学机制模型为目标，从模型构建、参数获取、模型校准、模型验证和模型应用诸方面进行深入系统的研究，以期为我国食品安全风险评估增添新方法，为利用多学科信息开展膳食暴露风险评估提供新技术，为我国有机磷农药风险管理提供科学依据。本研究内容属国内首创，与国外同类研究比较，具有全面、深入的特点。本项目是我们既往多年研究的深入和拓展，具有扎实的工作基础和良好的研究条件。

目前我国食品安全风险评估缺乏把暴露评估、危害特征描述、风险特征描述结合为一体的评估方法。生物学机制模型将外暴露、内暴露和毒效应通过相关的生物学机制结合于一个模型内，被视为定量风险评估中的理想方法。为提升我国食品安全风险评估水平，缩短与发达国家差距，本课题组瞄准国际科学前沿，以有机磷农药毒死蜱为研究对象分别构建了经口暴露、经皮暴露及两种途径联合暴露的生物学机制模型，探讨将外暴露剂量、内暴露剂量和毒效应相结合评估暴露风险。我们首先构建了大鼠经口暴露毒死蜱PBPK模型，在此基础上，改变相关模型参数，进行人群PBPK模型的外推探索，模型模拟结果显示，我国成年人单剂量经口暴露372.952 ug/kg CPF（P99.9）后，血清CPF、TCP和CPF-oxon以及肝脏CPF和CPF-oxon在0~24小时内随时间变化先上升后下降，模型能够预测内暴露剂量以及代谢产物在体内浓度变化情况，说明构建的PBPK模型对有机磷农药内暴露剂量以及代谢产物含量的评估和预测是可行的。我们又将大鼠参数的年龄相关函数编写入PBTK/TD模型程序，构建了能够反映年龄差异的幼年大鼠毒死蜱经口暴露的PBTK/TD模型，并对所构建的模型，通过两种方法（即利用模型计算参考剂量和预测人群暴露情况），对模型的功能进行初步探索和应用。所构建的经皮暴露毒死蜱的PBTK/TD模型，通过对模型预测结果和实验结果的相关性分析，证明我们所构建大鼠经皮暴露毒死蜱的PBTK/TD模型的模拟能力较好。所构建的经口、经皮联合暴露CPF的PBTK/TD模型，模型验证结果显示，模型能够较好地预测毒死蜱的毒动学和毒效学变化，对模型拟合结果与实验值进行相关性分析，二者的相关性在0.850-0.997之间（p<0.05）。我们的研究结果提示，运用PBTK/TD模型可模拟和预测染毒后毒死蜱在体内吸收、分布、代谢和排泄情况，评估毒死蜱多途径暴露对大鼠乙酰胆碱酯酶活性影响的剂量-效应关系。