Interindividual differences in 2H8-toluene toxicokinetics assessed by semiempirical physiologically based model.
Interindividual differences in 2H8-toluene toxicokinetics assessed by semiempirical physiologically based model.
复制标题
通过半经验生理学模型评估 2H8-甲苯毒代动力学的个体差异。
DOI：
10.1006/taap.1996.0142
复制
发表时间：
1996
影响因子：
3.8
通讯作者：
Kalman,DA
中科院分区：
文献类型：
--
作者：
Pierce,CH;Dills,RL;Morgan,MS;Nothstein,GL;Shen,DD;Kalman,DA
基于生理学的毒代动力学 (PBTK) 模型的最新应用已使用动物与人类的比例、假设的普通人和蒙特卡罗技术来估计人类接触有毒物质的情况。我们的研究建立了适合个体剂量测定的 PBTK 模型。对暴露于 50 ppm 2H8-甲苯和 50 ppm 甲苯静息 2 小时的 26 名男性受试者进行年龄、通气率、血液/空气分配系数、体重和脂肪组织分数的单独测量，并在暴露后 120 小时收集静脉血样。拟合的肺代谢是 PBTK 模型的一个新特征，用于解释 2H8-甲苯的全身清除率超过肝血流量。发现静脉浓度存在 10 倍的个体差异。特定主题模型解释了 91% 的观察到的数据变异性，而使用模型参数的文献值只能解释 53%。体重、脂肪组织分数和血液/空气分配系数与终末半衰期、稳态分布容积和终末分布容积相关。肺代谢与全身清除率和终末半衰期相关。肺代谢的个体间差异导致 2H8-甲苯在 2 小时和 100 小时时体内的预测分数不同。暴露后 8 小时内，脂肪分数的增加导致血液浓度降低，模拟显示，在 98 小时时，体内脂肪组织含有 97-99% 的 2H8-甲苯。使用特定于受试者的模型参数极大地改善了模型拟合并证明了毒代动力学的个体间差异。
Recent applications of physiologically based toxicokinetic (PBTK) models have used animal to human scaling, the hypothetical average man, and Monte Carlo techniques to estimate human exposure to toxicants. Our study built a PBTK model suitable for person-specific dosimetry. Individual measurements of age, ventilation rate, blood/air partition coefficient, body weight, and adipose tissue fraction were made on 26 male subjects exposed to 50 ppm2H8-toluene and 50 ppm toluene for 2 hr at rest, with collection of venous blood samples for 120 hr postexposure. Fitted lung metabolism was a novel feature of the PBTK model, used to explain a systemic clearance of2H8-toluene well in excess of hepatic blood flow. A 10-fold interindividual range in venous concentrations was found. Subject-specific modeling explained 91% of the observed data variability, compared to 53% using literature values for model parameters. Body weight, adipose tissue fraction, and blood/air partition coefficient were correlated with terminal half-life, steady-state volume of distribution, and terminal volume of distribution. Lung metabolism was correlated with systemic clearance and terminal half-life. Interindividual differences in lung metabolism resulted in divergent predicted fractions of2H8-toluene in the body at 2 and 100 hr. An increased adipose fraction led to lower blood concentrations up to 8 hr postexposure, and simulations showed that at 98 hr, adipose tissue contained 97–99% of2H8-toluene in the body. Use of subject-specific model parameters greatly improved model fit and demonstrated interindividual differences in toxicokinetics.