Predicting Mixture Effects over Time with Toxicokinetic–Toxicodynamic Models (GUTS): Assumptions, Experimental Testing, and Predictive Power

Current methods to assess the impact of chemical mixtures on organisms ignore temporal dimension. The General Unified Threshold model for Survival (GUTS) provides a framework deriving toxicokinetic–toxicodynamic (TKTD) models, which account effects toxicant exposure survival in time. Starting from classic assumptions independent action and concentration addition, we derive equations GUTS reduced (GUTS-RED) corresponding these mixture toxicity concepts go demonstrate their application. Using experimental binary studies with Enchytraeus crypticus previously published data Daphnia magna Apis mellifera, assessed predictive power extended GUTS-RED assessment. models accurately predicted effect. parameters single data, calibration, analyses offer novel diagnostic tools inform mode action, specifically whether similar or dissimilar form damage is caused by components. Finally, observed deviations predictions can identify interactions, e.g., synergism antagonism, between chemicals mixture, are not accounted models. TKTD such as GUTS-RED, thus implement new mechanistic knowledge hazard assessments.