Haddad S, Krishnan K
Groupe de Recherche en Toxicologie Humaine, Faculté de Médecine, Université de Montréal, Canada.
Environ Health Perspect. 1998 Dec;106 Suppl 6(Suppl 6):1377-84. doi: 10.1289/ehp.98106s61377.
Most of the available data on chemical interactions have been obtained in animal studies conducted by administering high doses of chemicals by routes and scenarios different from anticipated human exposures. A mechanistic approach potentially useful for conducting dose, scenario, species, and route extrapolations of toxic interactions is physiological modeling. This approach involves the development of mathematical descriptions of the interrelationships among the critical determinants of toxicokinetics and toxicodynamics. The mechanistic basis of the physiological modeling approach not only enables the species, dose, route, and scenario extrapolations of the occurrence of toxicokinetic interactions but also allows the extrapolation of the occurrence of interactions from binary to multichemical mixtures. Examples are presented to show the feasibility of predicting changes in toxicokinetics of the components of complex chemical mixtures based on the incorporation of binary interaction data within physiologically based models. Interactions-based mixture risk assessment can be performed by simulating the change in the tissue dose of the toxic moiety of each mixture component during combined exposures and calculating the risk associated with each tissue dose estimate using a tissue dose versus response curve for all components. The use of such a mechanistic approach should facilitate the evaluation of the magnitude and relevance of chemical interactions in assessing the risks of low-level human exposures to complex chemical mixtures.
关于化学相互作用的现有数据大多来自动物研究，这些研究通过与预期人类接触途径和情况不同的方式给予高剂量化学物质。一种可能有助于进行毒性相互作用的剂量、情况、物种和途径外推的机制方法是生理建模。这种方法涉及对毒代动力学和毒效动力学关键决定因素之间相互关系的数学描述的开发。生理建模方法的机制基础不仅能够对毒代动力学相互作用发生的物种、剂量、途径和情况进行外推，还能将相互作用发生情况从二元混合物外推到多化学物质混合物。文中给出了示例，以展示基于在生理模型中纳入二元相互作用数据来预测复杂化学混合物成分毒代动力学变化的可行性。基于相互作用的混合物风险评估可以通过模拟联合暴露期间每种混合物成分毒性部分的组织剂量变化，并使用所有成分的组织剂量与反应曲线计算与每个组织剂量估计相关的风险来进行。使用这种机制方法应有助于在评估人类低水平接触复杂化学混合物的风险时评估化学相互作用的程度和相关性。
