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Integr Environ Assess Manag. 2011 Jan;7(1):99-115. doi: 10.1002/ieam.106.
At the SETAC Pellston Workshop "The Tissue Residues Approach for Toxicity Assessment," held in June 2007, we discussed mixture toxicology in terms of the tissue residue approach (TRA). This article reviews the literature related to the TRA for mixtures of chemicals and recommends a practical, tiered approach that can be implemented in regulatory or risk assessment applications. As with the toxicity of individual chemicals, addressing mixture toxicity by means of the TRA has a number of significant advantages. Early work provided a theoretical basis and experimental data to support the use of TRA for mixtures; later work provided a field-based validation of the integration. However, subsequent development has been hindered by the lack of mixture toxicity data expressed in tissue or preferably target-site concentrations. We recommend a framework for addressing the toxicology of mixtures that integrates the TRA and mixture toxicology in a 3-tier approach. Tier I uses concentration addition (CA) to estimate the toxicity of mixtures regardless of the mechanism of action of the components. However, the common approach that uses a bioaccumulation factor (BAF) to predict TR from the exposure-water concentration for organics must be modified slightly for metals because, unlike organics, the BAF for a metal changes as 1) the aqueous exposure concentration changes, and 2) the concentration of other metals changes. In addition, total tissue residues of a metal are not a good predictor of toxicity, because some organisms store high concentrations of metals internally in detoxified forms. In tier I, if the combination of measured concentrations in the mixture exceeds that predicted to produce adverse effects or above-reference levels, it is necessary to proceed to tier II. Tier II is a mixed model that employs CA and independent action to estimate mixture toxicity. Tiers I and II estimate the toxicity of mixtures to individual species. In tier III, the TRA is integrated with the multisubstance potentially affected fraction (ms-PAF) method to derive TR levels that are protective of a selected percentage of species in aquatic communities (e.g., hazardous concentration for 5% of the species [HC5]).
在 2007 年 6 月举行的 SETAC 佩尔斯顿研讨会“毒性评估的组织残留方法”上，我们根据组织残留方法（TRA）讨论了混合物毒理学。本文回顾了与化学混合物 TRA 相关的文献，并推荐了一种实用的、分层的方法，可应用于监管或风险评估应用中。与单个化学物质的毒性一样，通过 TRA 解决混合物的毒性有许多显著的优势。早期的工作为使用 TRA 处理混合物提供了理论基础和实验数据；后来的工作提供了整合的现场验证。然而，随后的发展受到缺乏以组织或优选靶部位浓度表示的混合物毒性数据的阻碍。我们建议一种解决混合物毒理学的框架，该框架将 TRA 和混合物毒理学整合在一个三级方法中。第 I 级使用浓度加和（CA）来估计混合物的毒性，而不管成分的作用机制如何。然而，用于从暴露水浓度预测有机化合物 TRA 的常见方法，即生物蓄积因子（BAF），必须稍作修改，因为与有机物不同，金属的 BAF 会随着 1）水暴露浓度的变化，以及 2）其他金属浓度的变化而变化。此外，金属的总组织残留量不是毒性的良好预测指标，因为一些生物体以解毒形式在体内储存高浓度的金属。在第 I 级，如果混合物中测量浓度的组合超过预测产生不利影响或超过参考水平，则需要进入第 II 级。第 II 级是一种混合模型，它采用 CA 和独立作用来估计混合物的毒性。第 I 级和第 II 级估计混合物对单个物种的毒性。在第 III 级，TRA 与多物质受影响分数（ms-PAF）方法相结合，以得出对水生群落中选定百分比物种（例如，对 5%物种的危险浓度 [HC5]）具有保护作用的 TR 水平。
