Abstract

In the real world, metals are generally present as mixtures, but evaluating their mixture toxicity is still a daunting challenge. The classic conceptual models of concentration addition (CA) and independent action (IA) have been widely used by simply adding doses and responses to predict mixture effects assuming there is non-interaction. In cases where interactions do occur in a mixture, both CA and IA are no longer applicable for quantifying the toxicity, because interpretation of the observed joint effects is often limited to overall antagonism or synergism. In metal mixtures, interactive effects may occur at various levels, such as the exposure level, the uptake level, and the target level. A comprehensive understanding of the mechanisms of joint toxicity is therefore needed to incorporate the interactive effects of mixture components in predicting mixture toxicity. With this in mind, numerous bioavailability-based methods may be considered, with diverse mechanistic perspectives, such as the biotic ligand model (BLM), the electrostatic toxicity model (ETM), the WHAM-F _tox approach, a toxicokinetic-toxicodynamic (TK-TD) and an omics-based approach. This review therefore timely summarizes the representative predictive tools and their underlying mechanisms and highlights the importance of integrating mixture interactions and bioavailability in assessing the toxicity and risks of metal mixtures.

摘要

在现实世界中，金属通常以混合物形式存在，但是评估其混合物毒性仍然是一项艰巨的挑战。假设没有相互作用，简单地增加剂量和响应以预测混合物的作用，就已经广泛使用了浓度增加（CA）和独立作用（IA）的经典概念模型。在混合物中确实发生相互作用的情况下，CA和IA都不再适用于定量毒性，因为对观察到的关节作用的解释通常仅限于总体拮抗作用或协同作用。在金属混合物中，相互作用的影响可能发生在不同的水平，例如暴露水平，吸收水平和目标水平。因此，需要对关节毒性的机理有一个全面的了解，以便在预测混合物毒性时纳入混合物成分的相互作用。考虑到这一点，可以考虑采用多种基于生物利用度的方法，并具有不同的机理，例如生物配体模型（BLM），静电毒性模型（ETM），WHAM-˚F _TOX方法中，毒代动力学-toxicodynamic（TK-TD）和组学为基础的方法。因此，本综述及时总结了代表性的预测工具及其潜在机理，并强调了在评估金属混合物的毒性和风险时整合混合物相互作用和生物利用度的重要性。