Nong A, McCarver D G, Hines R N, Krishnan K
Occupational and Environmental Health, Université de Montréal, Montreal, QC, Canada.
Toxicol Appl Pharmacol. 2006 Jul 1;214(1):78-87. doi: 10.1016/j.taap.2005.12.001. Epub 2006 Feb 7.
The objective of the present study was to evaluate the magnitude of interindividual variability in the internal dose of toluene in children of various age groups, on the basis of subject-specific hepatic CYP2E1 content and physiology. The methodology involved the use of a previously validated physiologically based pharmacokinetic (PBPK) model, in which the intrinsic clearance for hepatic metabolism (CL(int)) was expressed in terms of the CYP2E1 content. The adult toluene PBPK model, with enzyme content-normalized CL(int), facilitated the calculation of child-specific CL(int) based on knowledge of hepatic CYP2E1 protein levels. The child-specific physiological parameters, except liver volume, were computed with knowledge of age and body weight, whereas physicochemical parameters for toluene were kept age-invariant based on available data. The actual individual-specific liver volume (autopsy data) was also included in the model. The resulting model was used to simulate the blood concentration profiles in children exposed by inhalation, to 1 ppm toluene for 24 h. For this exposure scenario, the area under the venous blood concentration vs. time curve (AUC) ranged from 0.30 to 1.01 microg/ml x h in neonates with low CYP2E1 concentration (<3.69 pmol/mg protein). The simulations indicated that neonates with higher levels of CYP2E1 (4.33 to 55.93 pmol/mg protein) as well as older children would have lower AUC (0.16 to 0.43 microg/ml x h). The latter values were closer to those simulated for adults. Similar results were also obtained for 7 h exposure to 17 ppm toluene, a scenario previously evaluated in human volunteers. The interindividual variability factor for each subgroup of children and adults, calculated as the ratio of the 95th and 50th percentile values of AUC, was within a factor of 2. The 95th percentile value of the low metabolizing neonate group, however, was greater than the mean adult AUC by a factor of 3.9. This study demonstrates the feasibility of incorporating subject-specific data on hepatic CYP2E1 content and physiology within PBPK models for evaluating the age, interchild and population variability of internal dose for use in risk assessment of inhaled volatile organics.
本研究的目的是基于个体特异性肝脏CYP2E1含量和生理学，评估不同年龄组儿童体内甲苯内剂量的个体间变异性大小。该方法涉及使用先前验证的基于生理学的药代动力学（PBPK）模型，其中肝脏代谢的内在清除率（CL(int)）根据CYP2E1含量表示。具有酶含量标准化CL(int)的成人甲苯PBPK模型，基于肝脏CYP2E1蛋白水平的知识，便于计算儿童特异性CL(int)。除肝脏体积外，儿童特异性生理参数根据年龄和体重计算得出，而甲苯的物理化学参数根据现有数据保持与年龄无关。模型中还纳入了实际个体特异性肝脏体积（尸检数据）。所得模型用于模拟吸入1 ppm甲苯24小时的儿童的血药浓度曲线。对于这种暴露情况，CYP2E1浓度低（<3.69 pmol/mg蛋白）的新生儿静脉血药浓度与时间曲线下面积（AUC）范围为0.30至1.01 microg/ml·h。模拟表明，CYP2E1水平较高（4.33至55.93 pmol/mg蛋白）的新生儿以及年龄较大的儿童AUC较低（0.16至0.43 microg/ml·h）。后者的值更接近成人模拟值。对于暴露于17 ppm甲苯7小时的情况，也获得了类似结果，这是先前在人类志愿者中评估过的情况。儿童和成人各亚组的个体间变异系数，计算为AUC的第95百分位数与第50百分位数之比，在2倍以内。然而，低代谢新生儿组的第95百分位数比成人AUC平均值大3.9倍。本研究证明了将肝脏CYP2E1含量和生理学的个体特异性数据纳入PBPK模型以评估吸入挥发性有机物风险评估中内剂量的年龄、儿童间和人群变异性的可行性。
