Robust Fit of Toxicokinetic–Toxicodynamic Models Using Prior Knowledge Contained in the Design of Survival Toxicity Tests

Abstract

Toxicokinetics-toxicodynamic (TKTD) models have emerged as a powerful means to describe survival as a function of time and concentration in ecotoxicology. They are especially powerful to extrapolate survival observed under constant exposure conditions to survival predicted under realistic fluctuating exposure conditions. But despite their obvious benefits, these models have not yet been adopted as a standard to analyze data of survival toxicity tests. Instead simple dose-response models are still often used although they only exploit data observed at the end of the experiment. We believe a reason precluding a wider adoption of TKTD models is that available software still requires strong expertise in model fitting. In this work, we propose a fully automated fitting procedure that extracts prior knowledge on parameters of the model from the design of the toxicity test (tested concentrations and observation times). We evaluated our procedure on three experimental and 300 simulated data sets and showed that it provides robust fits of the model, both in the frequentist and the Bayesian framework, with a better robustness of the Bayesian approach for the sparsest data sets.