A review of DEB theory in assessing toxic effects of mixtures.

In this manuscript we review the use of mechanistic models to interpret effects of mixtures of compounds within the framework of the Dynamic Energy Budget (DEB) theory. Within this approach the effect of a mixture is built up from the effects of the individual components making up the mixture. Understanding effects of mixtures is essential as it is impossible to assess effects of all possible mixtures experimentally. In contrast to the more classical way of interpreting effects of mixtures with concentration addition or effect addition models, DEB theory offers a single consistent framework to understand effects of mixtures on growth, reproduction and survival in an integrated, way. It systematically incorporates exposure time and biology of the organisms, including the natural links between the processes of feeding, maintenance, growth, development and reproduction. We also give directions for an experimental setup to interpret the results within the DEB framework. The DEB framework was successfully applied to assess effects of complex mixtures on survival and binary mixtures on sub-lethal endpoints. It gives the possibility to explain observed interactions by the underlying biological mechanisms or pinpoint interactions. We expect this approach to help in identifying key mechanisms and enable to focus further research in cooperation with modelers and experimentalists to improve our understanding of the mechanisms underlying mixture toxicity.