Dynamic interaction processes of rare earth metal mixtures in terrestrial organisms interpreted by toxicokinetic and toxicodynamic model

Despite the progress in explanation of mixture toxicity of rare earth elements (REEs), a large knowledge gap still exists in interpreting their mixed effects from a dynamic perspective. Here, we investigated the effects of La-Ce mixtures in Enchytraeus crypticus at different exposure times. The single and mixture toxicity of La and Ce increased with time, as reflected by the reduced LC50/MT50 values. With concentration addition as the reference model, the interactions between La and Ce were quantified by MIXTOX modelling tool, showing a time-dependent pattern with antagonistic effect after 1 and 2 d but additive effects afterwards. The dynamic accumulation and toxicity of La/Ce in organisms exposed to REE mixtures was fitted using a process-based toxicokinetic and toxicodynamic (TK-TD) model to unravel how the elements interacted. Generally, the estimated uptake, elimination, and damage rate constants of La/Ce declined with increasing level of each other, suggesting inhibited uptake and subsequently reduced toxicity of La/Ce due to competition effect. The interplay of La and Ce in TK and TD processes seemed responsible for the observed antagonism. Our study showed that mixture toxicity and interaction of REEs are time-dependent processes and application of TK-TD model may provide more insight into this dynamic effect.