New Insights to Compare and Choose TKTD Models for Survival Based on an Interlaboratory Study for Lymnaea stagnalis Exposed to Cd

Abstract

Toxicokinetic-toxicodynamic (TKTD) models, as the General Unified Threshold model of Survival (GUTS), provide a consistent process-based framework compared to classical dose-response models to analyze both time and concentration-dependent data sets. However, the extent to which GUTS models (Stochastic Death (SD) and Individual Tolerance (IT)) lead to a better fitting than classical dose-response model at a given target time (TT) has poorly been investigated. Our paper highlights that GUTS estimates are generally more conservative and have a reduced uncertainty through smaller credible intervals for the studied data sets than classical TT approaches. Also, GUTS models enable estimating any x% lethal concentration at any time (LC), and provide biological information on the internal processes occurring during the experiments. While both GUTS-SD and GUTS-IT models outcompete classical TT approaches, choosing one preferentially to the other is still challenging. Indeed, the estimates of survival rate over time and LC are very close between both models, but our study also points out that the joint posterior distributions of SD model parameters are sometimes bimodal, while two parameters of the IT model seems strongly correlated. Therefore, the selection between these two models has to be supported by the experimental design and the biological objectives, and this paper provides some insights to drive this choice.

Comparison of the General Threshold Model of Survival and Dose–Response Models in Simulating the Acute Toxicity of Metals to Danio rerio

“…The goodness-of-fit of the GUTS models was slightly smaller than that of the dose-response model. This difference was possibly due to the deviation between the observed and fitted values, which was mainly caused by the dominant parameters of the GUTS model (K d , Z, or α) that had been correlated for laboratories and had an influence on the survival rate over time (Baudrot et al 2018 FIGURE 4: Comparison of the observed and fitted values by using different general unified threshold (GUTS) models with different levels of cadmium (Cd) and lead (Pb). (A) GUTS-stochastic death (SD) exposed to Cd.…”

“…The GUTS models had a greater ability than the dose-response model to predict toxicity. Moreover, the dose-response model is empirical, with no information on mechanisms of toxic action, whereas the GUTS model incorporates some mechanistic understanding (Brock et al 2010;Baudrot et al 2018). The current paradigm of GUTS for most metals is spillover, in which metals are bound by metal-binding proteins to a threshold, above which free metals spill over into the cell and cause toxicity (Morcillo et al 2016).…”

“…The deaths of the organisms were assumed to be independent of one another, and the average survival rate at a target time was expressed as a function of the contaminant concentration (c). The specific model equation followed that of Baudrot et al (2018), with a slight modification of the log-logistic equation for the 3 parameters described as follows:…”

“…The model equation and parameter estimations of GUTS-stochastic death and GUTS-IT have been described by Virgile Baudrot (2018).…”

Recommendations to address uncertainties in environmental risk assessment using toxicokinetics-toxicodynamics models

“…In contrast, the GUTS-RED-IT model is based on the critical body residue (CBR) approach, which assumes that individuals differ in their thresholds, following a probability distribution, and die as soon as the internal concentration reaches the individualspecific threshold [29]. The robustness of GUTS models in calibration and prediction has been widely demonstrated, with little difference between GUTS-RED-SD and GUTS-RED-IT models [7,10,30]. Sensitivity analysis of toxicity endpoints derived from GUTS models, such as LC(x, t) and M F (x, t), has also been investigated [7,10], but the question of how uncertainties are propagated is still under-studied.…”