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Calibration and validation of toxicokinetic-toxicodynamic models for three neonicotinoids and some aquatic macroinvertebrates.

ABSTRACT: Exposure patterns in ecotoxicological experiments often do not match the exposure profiles for which a risk assessment needs to be performed. This limitation can be overcome by using toxicokinetic-toxicodynamic (TKTD) models for the prediction of effects under time-variable exposure. For the use of TKTD models in the environmental risk assessment of chemicals, it is required to calibrate and validate the model for specific compound-species combinations. In this study, the survival of macroinvertebrates after exposure to the neonicotinoid insecticide was modelled using TKTD models from the General Unified Threshold models of Survival (GUTS) framework. The models were calibrated on existing survival data from acute or chronic tests under static exposure regime. Validation experiments were performed for two sets of species-compound combinations: one set focussed on multiple species sensitivity to a single compound: imidacloprid, and the other set on the effects of multiple compounds for a single species, i.e., the three neonicotinoid compounds imidacloprid, thiacloprid and thiamethoxam, on the survival of the mayfly Cloeon dipterum. The calibrated models were used to predict survival over time, including uncertainty ranges, for the different time-variable exposure profiles used in the validation experiments. From the comparison between observed and predicted survival, it appeared that the accuracy of the model predictions was acceptable for four of five tested species in the multiple species data set. For compounds such as neonicotinoids, which are known to have the potential to show increased toxicity under prolonged exposure, the calibration and validation of TKTD models for survival needs to be performed ideally by considering calibration data from both acute and chronic tests.

SUBMITTER: Focks A

PROVIDER: S-EPMC6132984 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Providing reliable environmental quality standards (EQSs) is a challenging issue in environmental risk assessment (ERA). These EQSs are derived from toxicity endpoints estimated from dose-response models to identify and characterize the environmental hazard of chemical compounds released by human activities. These toxicity endpoints include the classical x% effect/lethal concentrations at a specific time t (EC/LC(x, t)) and the new multiplication factors applied to environmental exposure profiles leading to x% effect reduction at a specific time t (MF(x, t), or denoted LP(x, t) by the EFSA). However, classical dose-response models used to estimate toxicity endpoints have some weaknesses, such as their dependency on observation time points, which are likely to differ between species (e.g., experiment duration). Furthermore, real-world exposure profiles are rarely constant over time, which makes the use of classical dose-response models difficult and may prevent the derivation of MF(x, t). When dealing with survival or immobility toxicity test data, these issues can be overcome with the use of the general unified threshold model of survival (GUTS), a toxicokinetic-toxicodynamic (TKTD) model that provides an explicit framework to analyse both time- and concentration-dependent data sets as well as obtain a mechanistic derivation of EC/LC(x, t) and MF(x, t) regardless of x and at any time t of interest. In ERA, the assessment of a risk is inherently built upon probability distributions, such that the next critical step is to characterize the uncertainties of toxicity endpoints and, consequently, those of EQSs. With this perspective, we investigated the use of a Bayesian framework to obtain the uncertainties from the calibration process and to propagate them to model predictions, including LC(x, t) and MF(x, t) derivations. We also explored the mathematical properties of LC(x, t) and MF(x, t) as well as the impact of different experimental designs to provide some recommendations for a robust derivation of toxicity endpoints leading to reliable EQSs: avoid computing LC(x, t) and MF(x, t) for extreme x values (0 or 100%), where uncertainty is maximal; compute MF(x, t) after a long period of time to take depuration time into account and test survival under pulses with different periods of time between them.

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Calibration and validation of toxicokinetic-toxicodynamic models for three neonicotinoids and some aquatic macroinvertebrates.

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