Basic concepts of mixture toxicity and relevance for risk evaluation and regulation

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Exposure to multiple substances is a challenge for risk evaluation. Currently, there is an ongoing debate if generic “mixture assessment/allocation factors” (MAF) should be introduced to increase public health protection. Here, we explore concepts of mixture toxicity and the potential influence of mixture regulation concepts for human health protection. Based on this analysis, we provide recommendations for research and risk assessment. One of the concepts of mixture toxicity is additivity. Substances may act additively by affecting the same molecular mechanism within a common target cell, for example, dioxin-like substances. In a second concept, an “enhancer substance” may act by increasing the target site concentration and aggravating the adverse effect of a “driver substance”. For both concepts, adequate risk management of individual substances can reliably prevent adverse effects to humans. Furthermore, we discuss the hypothesis that the large number of substances to which humans are exposed at very low and individually safe doses may interact to cause adverse effects. This commentary identifies knowledge gaps, such as the lack of a comprehensive overview of substances regulated under different silos, including food, environmentally and occupationally relevant substances, the absence of reliable human exposure data and the missing accessibility of ratios of current human exposure to threshold values, which are considered safe for individual substances. Moreover, a comprehensive overview of the molecular mechanisms and most susceptible target cells is required. We conclude that, currently, there is no scientific evidence supporting the need for a generic MAF. Rather, we recommend taking more specific measures, which focus on compounds with relatively small ratios between human exposure and doses, at which adverse effects can be expected.

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ISO 690BLOCH, Denise, Patrick DIEL, Bernd EPE, Michael HELLWIG, Alfonso LAMPEN, Angela MALLY, Doris MARKO, María A. VILLAR FERNÁNDEZ, Sabine GUTH, Marcel LEIST, 2023. Basic concepts of mixture toxicity and relevance for risk evaluation and regulation. In: Archives of Toxicology. Springer. 2023, 97, pp. 3005-3017. ISSN 0340-5761. eISSN 1432-0738. Available under: doi: 10.1007/s00204-023-03565-6
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@article{Bloch2023-08-24Basic-67741,
  year={2023},
  doi={10.1007/s00204-023-03565-6},
  title={Basic concepts of mixture toxicity and relevance for risk evaluation and regulation},
  volume={97},
  issn={0340-5761},
  journal={Archives of Toxicology},
  pages={3005--3017},
  author={Bloch, Denise and Diel, Patrick and Epe, Bernd and Hellwig, Michael and Lampen, Alfonso and Mally, Angela and Marko, Doris and Villar Fernández, María A. and Guth, Sabine and Leist, Marcel}
}
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