Carrier G, Brunet R C, Brodeur J
Département de Médecine du travail et d'Hygiène du milieu, Faculté de médecine, Université de Montréal, Québec, Canada.
Toxicol Appl Pharmacol. 1995 Apr;131(2):267-76. doi: 10.1006/taap.1995.1069.
In the present study, a physiologically based model which describes the absorption and disposition kinetics of PCDDs/PCDFs (globally called PCDXs) in mammalian species, including humans, is developed. The model integrates the distribution model developed in the first article of this series, which described the fractional distribution of total PCDXs between liver and adipose tissues as a function of overall body concentration (G. Carrier, R. C. Brunet, and J. Brodeur, 1995, Toxicol. Appl. Pharmacol. 131, 253-266). In particular it is shown that the liver fraction of the total body burden decreases as overall body concentration decreases. Since elimination is principally through the liver, this leads to lower global elimination rates and longer half-lives of PCDXs. Absorption and disposition kinetics of PCDXs are captured using nonlinear differential equations with anatomically and biochemically relevant input parameters which are readily available. These are solved to predict the fate of PCDXs in liver, adipose tissues, and the body as a whole, as a function of time. Model simulations are in agreement with published data on absorption and disposition kinetics of these substances in rats and in humans. The kinetic profiles are similar for rats and humans, but the varying half-lives differ considerably in both species: weeks with rats, years with humans. For a given body burden, the adipose tissue concentrations vary in an inversely proportional manner to the mass of the adipose tissues; this observation has considerable relevance for interpretation of clinical data for humans. The interest of the proposed model rests upon the fact that it is generalized and broadly applicable: it allows the study of the kinetics of PCDXs for any pattern of exposure from background to highly toxic levels, taking into account variations in time of anatomical and biochemical parameters.
在本研究中，开发了一种基于生理学的模型，该模型描述了包括人类在内的哺乳动物体内多氯二苯并对二噁英/多氯二苯并呋喃（统称为多氯二苯并对二噁英/呋喃）的吸收和处置动力学。该模型整合了本系列第一篇文章中开发的分布模型，该模型描述了肝脏和脂肪组织中总多氯二苯并对二噁英/呋喃的分数分布与全身浓度的函数关系（G. Carrier、R. C. Brunet和J. Brodeur，1995年，《毒理学与应用药理学》131卷，253 - 266页）。特别值得注意的是，随着全身浓度的降低，全身负荷中肝脏部分的比例也会下降。由于消除主要通过肝脏进行，这导致多氯二苯并对二噁英/呋喃的整体消除率降低，半衰期延长。多氯二苯并对二噁英/呋喃的吸收和处置动力学通过具有解剖学和生物化学相关输入参数的非线性微分方程来描述，这些参数易于获取。通过求解这些方程，可以预测多氯二苯并对二噁英/呋喃在肝脏、脂肪组织以及整个身体中的命运随时间的变化。模型模拟结果与已发表的关于这些物质在大鼠和人类体内吸收和处置动力学的数据一致。大鼠和人类的动力学特征相似，但不同物种的半衰期差异很大：大鼠为几周，人类为几年。对于给定的身体负荷，脂肪组织中的浓度与脂肪组织的质量成反比；这一观察结果对于解释人类临床数据具有重要意义。所提出模型的价值在于它具有通用性且广泛适用：它允许研究多氯二苯并对二噁英/呋喃在从背景暴露到高毒性水平的任何暴露模式下的动力学，同时考虑解剖学和生物化学参数随时间的变化。
