镍的生理毒代动力学模型

Physiologically based toxicokinetic model for nickel

目的构建氯化镍腹腔注射染毒大鼠的生理毒代动力学(physiologically based toxicokinetic,PBTK)模型,估计氯化镍染毒后不同脏器的组织分配系数,外推构建职业人群呼吸道一次性镍暴露的PBTK模型,预测镍暴露后其在人体内的分布特征。方法通过构建大鼠氯化镍染毒PBTK模型并结合大鼠镍染毒后的矢量数据,应用Acslx软件对镍染毒后大鼠不同组织器官的分配系数进行拟合,外推建立职业人群呼吸道暴露镍的PBTK模型。结果构建了大鼠氯化镍腹腔注射染毒的PBTK模型,估计出镍在大鼠不同脏器的组织分配系数,分别是肾/血分配系数最高为0.668,肺/血分配系数为0.102,脾/血分配系数为0.037,肝/血分配系数为0.028,心/血分配系数为0.022,脑/血分配系数最低为0.006。外推构建了职业人群呼吸道暴露0.1 mg/m^3镍8 h的PBTK模型,结果显示肾脏中镍含量最高,8 h高达3.328μg/kg,其次是脾脏(0.185μg/kg)、肝脏(0.140μg/kg)和心脏(0.110μg/kg),脑中含量最低为0.030μg/kg,肾脏为镍离子主要的代谢器官。结论 PBTK模型能够较好地预测镍在职业人群体内的分布特征,阐明镍分布的时间-内剂量关系。

Objective To estimate the metabolic parameters in different tissues and organs,build the physiologically based pharmacokinetic（ PBPK） model of rat and occupational population,and predict the toxic dynamic characteristics exposure to nickel.Methods The partition coefficients in different tissues and organs were estimated using vector datas of nickel by the optimization and statistics files of acslx software. The PBTK model of occupational population exposure to nickel was built according to the metabolic parameters by acslx software. Results The evaluated partition coefficient of nickel were kidney blood（ 0. 668）, lung blood（ 0. 102）, spleen blood（ 0. 037）, liver blood（ 0. 028）,heart blood（ 0. 022）,and brain blood（ 0. 006）. The constructed successful PBPK model of occupational population exposed to 0. 1 mg/m^3 nickel for 8 hours showed that the nickel concentration is higher in kidney reached at 3. 328 μg/kg,followed by the spleen（ 0. 185 μg/kg）,liver（ 0. 140 μg/kg） and heart（ 0. 110 μg/kg）. The content of nickel is lower in the brain（ 0. 030 μg/kg）. The kidneys is the major metabolic organs for nickel. Conclusion The PBPK model can be used to convert the nickel levels from external exposure to internal exposure for each organ and to evaluate the time-dose relationship exposure to nickel in both rat and occupational population studies.