el-Masri H A, Reardon K F, Yang R S
Department of Environmental Health, Colorado State University, Fort Collins 80523, USA.
Crit Rev Toxicol. 1997 Mar;27(2):175-97. doi: 10.3109/10408449709021618.
Although an overwhelmingly large portion of the resources in toxicologic research is devoted to single chemical studies, the toxicology of chemical mixtures, not single chemicals, is the real issue regarding health effects of environmental and/or occupational exposure to chemicals. The relative lack of activities in the area of toxicology of chemical mixtures does not suggest ignorance of the importance of the issue by the toxicology community. Instead, it is a reflection of the difficulty, complexity, and controversy surrounding this area of research. Until recently, much of the literature on the toxicology of chemical mixtures has been either very focused on certain specific interaction studies or slanted toward broad-based, relatively vague theoretical deliberation. The typical interaction study involved binary mixtures at relatively high dose levels with acute toxicities as endpoints. Although the theoretical papers have been valuable contributions, little is available on actual, practical experimental approaches toward a systematic solution of this immensely complex area of research. We present here a broad discussion on the important issues of the toxicology of chemical mixtures. First, we provide some background information with respect to the problem and significance of toxicology of chemical mixtures in relation to some of the real life issues. Second, we review and compare the existing experimental approaches relevant to toxicologic interactions of chemical mixtures. Third, we propose three integrated approaches that involve the combination of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling with: (1) Monte Carlo simulation, (2) median effect principle (MEP), and (3) response surface methodology (RSM). These modeling approaches, coupled with very focused mechanistically based toxicology studies, could be the basis for solving the problems of toxicology and risk assessment of chemical mixtures.
尽管毒理学研究中绝大部分资源都用于单一化学物质的研究，但化学混合物而非单一化学物质的毒理学才是环境和/或职业接触化学物质对健康影响的真正问题。化学混合物毒理学领域相对缺乏研究活动，并不意味着毒理学界忽视了这个问题的重要性。相反，这反映了围绕该研究领域的困难、复杂性和争议性。直到最近，关于化学混合物毒理学的许多文献要么非常专注于某些特定的相互作用研究，要么倾向于广泛的、相对模糊的理论探讨。典型的相互作用研究涉及以急性毒性为终点的相对高剂量水平的二元混合物。虽然理论论文有宝贵的贡献，但对于系统解决这个极其复杂的研究领域的实际、实用实验方法却很少。我们在此对化学混合物毒理学的重要问题进行广泛讨论。首先，我们提供一些关于化学混合物毒理学问题及其与一些现实生活问题相关性的背景信息。其次，我们回顾并比较与化学混合物毒理学相互作用相关的现有实验方法。第三，我们提出三种综合方法，这些方法涉及将基于生理学的药代动力学/药效学（PBPK/PD）模型与：（1）蒙特卡罗模拟，（2）中位效应原理（MEP），以及（3）响应面方法（RSM）相结合。这些建模方法，再加上非常专注的基于机制的毒理学研究，可能是解决化学混合物毒理学和风险评估问题的基础。
