MODELING OF THE TOXICOKINETICS OF POLYCHLORINATED DIBENZO-P-DIOXINS AND DIBENZOFURANS IN MAMMALIANS, INCLUDING HUMANS .1. NONLINEAR DISTRIBUTION OF PCDD/PCDF BODY BURDEN BETWEEN LIVER AND ADIPOSE TISSUES
MODELING OF THE TOXICOKINETICS OF POLYCHLORINATED DIBENZO-P-DIOXINS AND DIBENZOFURANS IN MAMMALIANS, INCLUDING HUMANS .1. NONLINEAR DISTRIBUTION OF PCDD/PCDF BODY BURDEN BETWEEN LIVER AND ADIPOSE TISSUES
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DOI：
10.1006/taap.1995.1068
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发表时间：
1995-04-01
影响因子：
3.8
通讯作者：
BRODEUR, J
中科院分区：
文献类型：
--
作者：
CARRIER, G;BRUNET, RC;BRODEUR, J
多氯二苯并对二恶英和二苯并呋喃的混合物，全球称为PCDXs，在环境中无处不在。它们在人体中积累，尤其是通过从食物中摄取。鉴于它们在体内停留时间长，对人类健康有潜在的不利影响，因此必须建立能够预测它们在人体组织中的分布的毒性动力学模型。在本研究中，提出了一个基于生理学的模型来描述PCDXs在各种哺乳动物物种中的分布动力学。这种方法既是理论的，也是实证的。首先，建立了一个合理的、通用的动力学模型，该模型考虑了细胞间扩散、pcdx受体和pcdx蛋白结合以及肝脏中pcdx依赖性酶的诱导。提出了简化公式来预测功能依赖性f(h)（C-b）和f(at)(C-b)，它们建立了肝脏和脂肪组织中PCDX总负荷的分数作为任意时刻整体浓度的函数。这些公式的自由参数较少，可以利用已有的数据确定各种物种的自由参数。模型模拟结果与已发表的pcdx在啮齿动物和猴子中的分布动力学数据以及人类的临床数据一致。在啮齿动物和猴子以及人类中，各自的关系f(h)（C-b）和f(at)f（C-b）遵循类似的非线性模式。这些不同的分布函数构成了在一篇相关文章（G. Carrier， R. C. Brunet, and J. Brodeur, 1995, Toxicol）中描述的吸收和处置的广义毒性动力学模型的基础。达成。药学杂志131,267-276)。(C) 1995学术出版社，Inc。
Mixtures of polychlorinated dibenzo-p-dioxins and dibenzofurans, globally called PCDXs, are ubiquitously present in the environment. They accumulate in the human organism, espe cially through uptake from food. In view of their long residence time in the body and their potential adverse health effects for humans, it is therefore important to develop toxicokinetic models capable of predicting their distribution in human tissues. In the present study a physiologically based model which describes the distribution kinetics of PCDXs in various mammalian species is proposed. The approach is both theoretical and empirical. First, a plausible and general dynamical model that takes into account intercellular diffusion, PCDX-receptor and PCDX-protein binding, and PCDX-dependent enzyme induction in the liver is developed. Simplified formulas are proposed to predict the functional dependencies f(h)(C-b) and f(at)(C-b), which establish the fractions of the total PCDX body burden contained in liver and adipose tissues as a function of overall body concentration at any one moment. These formulas have fewer free parameters that can be determined for various species with the use of already available data. Model simulations are in agreement with published data on the distribution kinetics of PCDXs in rodents and monkeys and clinical data in humans. In rodents and monkeys as well as in humans, the respective relations f(h)(C-b) and f(at)f(C-b) follow a similar nonlinear pattern. These varying distribution functions constitute the basis for a generalized toxicokinetic model of absorption and disposition described in a companion article (G. Carrier, R. C. Brunet, and J. Brodeur, 1995, Toxicol. Appl. Pharmacol 131, 267-276). (C) 1995 Academic Press, Inc.