Toxicokinetic and toxicodynamic (TK-TD) modeling to study oxidative stress-dependent toxicity of heavy metals in zebrafish.

Adverse outcome pathways (AOP) have been proposed as a new method to improve the ecological risk assessment of pollutants, but it requires quantitation linkage between exposure, biomarker response and toxicity of pollutants. A toxicokinetic and toxicodynamic (TK-TD) model was used to quantify AOP of the toxicity of Cd and Pb to zebrafish, including the quantitative relationship between Cd and Pb accumulation in gill and oxidative damage level based on ROS or MDA, and LC50 values at different times. Significant relationships were found between the oxidative damage level characterized by ROS and MDA content and Cd or Pb accumulation in gill (R2 > 0.60), and the TK model could better simulate the Pb accumulation in the gills (R2 > 0.60) than Cd. The increasing of Cd or Pb concentrations induced the generation of ROS and the formation of ROS initiated the fluctuation of MDA level in the cells as compared to controls (p < 0.05). For the individual level effect, the Damage Assessment Model (DAM) could successfully explain the change of LC50-ROS and LC50-MDA values at different times (R2 > 0.99). Our findings suggested that the TK-TD model based on ROS and MDA could be used as a quantitative AOP to predict toxicity of metals to zebrafish.