Investigating the interaction between melamine and cyanuric acid using a Physiologically-Based Toxicokinetic model in rainbow trout

Following outbreaks of feed and food adulterations with a melamine and cyanuric acid mixture in 2007 and melamine in 2008 respectively, the kinetics and toxicodynamics of the mixture have been investigated particularly in sensitive species such as the rainbow trout. Tissue concentrations and intensity of the adverse effect, melamine-cyanurate crystal formation in kidney, were reported in similar experimental conditions. Here, a recent PBTK model for rainbow trout has been applied to model the kinetics of both single compounds based on residue levels in tissues. Both PBTK models for the single compounds were combined and a model of crystal formation for the mixture melamine-cyanuric acid was also added to predict the intensity of crystal formation under the assumptions that crystals formed either in urine or in kidney tissue. Modelling the kinetics of melamine and cyanuric acid provided a better understanding and prediction of intensity of crystal formation in case of sequential exposures with varying intensity or co-exposure. This study demonstrates, for the first time, how fish PBTK models can play a key role in the understanding and prediction of toxicokinetics and toxicodynamics of mixtures. This study also illustrates how adverse effects may potentially occur even when the compounds are not administered together as a mixture.