Environmental contamination with metals generally occurs as mixtures of different metals. Toxicity of metal mixtures is known to show all potential outcomes, i.e. metals act additive, more than additive or less than additive on organisms. There is a need to understand and quantify these interactions for a better assessment of environmental risks of metals. Here, we will analyze the mixture effects on metal uptake and toxicity by accounting for the factors that control the metal bioavailability in natural waters or soils. We postulate that a large variation of potential metal interactions are related to metal speciation in the external medium, transport to the receptor and competitions at the receptor site. Practically we will test if unidirectional fluxes of metals in biota, as measured with a cocktail of stable isotopes (HR-IPC-MS), are predictive for the net interactions during net uptake and toxicity. In turn, these fluxes are related back to the metals bound to the biotic ligands, calculated with existing or improved biotic ligand models or, when mass transfer limitations prevail, with the total concentrations of kinetically labile metals in solution. Plants (barley) will be exposed to mixtures of metals (Cu, Ni, Zn) in chelex resin buffered synthetic solutions or in soils. These data will serve as proof of concept of a novel mechanistic model for metal interactions in mixtures.