Gentry P Robinan, Covington Tammie R, Clewell Harvey J
ENVIRON International Corp., 602 East Georgia Avenue, Ruston, LA 71270, USA.
Regul Toxicol Pharmacol. 2003 Aug;38(1):1-16. doi: 10.1016/s0273-2300(03)00047-3.
In recent years efforts have increased to develop a framework for assessing differences, both pharmacokinetic and pharmacodynamic, between children and adults for purposes of assessing risk of adverse effects following chemical exposure. The specific goal of this study was to demonstrate an approach for using PBPK modeling to compare maternal and fetal/neonatal blood and tissue dose metrics during pregnancy and lactation. Six chemical classes were targeted to provide a variety of physicochemical properties (volatility, lipophilicity, water solubility), and surrogate chemicals were selected to represent each class (isopropanol, vinyl chloride, methylene chloride, perchloroethylene, nicotine, and TCDD), based on the availability of pharmacokinetic information. These chemicals were also selected to provide different pharmacokinetic characteristics, including metabolic production of stable or reactive intermediates in the liver and competing pathways for metabolism. Changes in dosimetry during pregnancy predicted by the modeling were mainly attributable to the development of enzymatic pathways in the fetus or to changes in tissue composition in the mother and fetus during pregnancy. In general, blood concentrations were lower in the neonate during the lactation period than in the fetus during gestation. This postnatal decrease varied from only a slight change (for TCDD) to approximately four orders of magnitude (for vinyl chloride). As compared to maternal exposure, fetal/neonatal exposures ranged from approximately twice as great (for TCDD) to several orders of magnitude lower (for isopropanol). The results of this study are in general agreement with the analyses of data on pharmaceutical chemicals, which have suggested that the largest difference in pharmacokinetics observed between children and adults is for the perinatal period. The most important factor appears to be the potential for decreased clearance of toxic chemicals in the perinatal period due to immature metabolic enzyme systems, although this same factor can also reduce the risk from reactive metabolites during the same period.
近年来，人们加大了力度来制定一个框架，用于评估儿童和成人在药代动力学和药效学方面的差异，以便评估化学物质暴露后不良反应的风险。本研究的具体目标是展示一种使用生理药代动力学（PBPK）模型来比较孕期和哺乳期母体与胎儿/新生儿血液及组织剂量指标的方法。选定了六类化学物质以提供各种物理化学性质（挥发性、亲脂性、水溶性），并根据药代动力学信息的可获得性选择替代化学物质来代表每一类（异丙醇、氯乙烯、二氯甲烷、全氯乙烯、尼古丁和四氯二苯并二恶英）。选择这些化学物质还为了提供不同的药代动力学特征，包括肝脏中稳定或活性中间体的代谢产生以及代谢的竞争途径。模型预测的孕期剂量学变化主要归因于胎儿酶途径的发育或孕期母体和胎儿组织组成的变化。一般来说，哺乳期新生儿的血液浓度低于孕期胎儿的血液浓度。这种出生后的降低幅度从轻微变化（四氯二苯并二恶英）到大约四个数量级（氯乙烯）不等。与母体暴露相比，胎儿/新生儿暴露范围从大约两倍（四氯二苯并二恶英）到几个数量级更低（异丙醇）。本研究结果与药物化学物质数据的分析总体一致，这些分析表明儿童和成人之间观察到的药代动力学最大差异出现在围产期。最重要的因素似乎是围产期由于代谢酶系统不成熟导致有毒化学物质清除率降低的可能性，尽管同一因素在同一时期也可以降低来自活性代谢物的风险。
