Dr. Audrey Grech

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PhD Project

Développement et application de modèles toxicocinétiques génériques chez le poisson : étude des facteurs de variabilité

The goal of environmental risk assessment (ERA) is to protect the ecosystem from adverse effects resulting from exposure to chemicals. Exposure assessment aims to quantify the external dose as the amount of chemical agent that reaches an organism. Over the last two decades, many research efforts have aimed at improving quantification of dose-response relationships through the integration of the “internal dose”, directly responsible for toxicity. However, biotic factors such as physiological changes during growth and abiotic factors such as temperature are often not considered in ERA although they may have an effect on the internal dose of chemicals. Among the animal species relevant to ERA, fish are considered as sentinel species of the aquatic environment. Thus, fish toxicokinetic (TK) models have been developed to estimate internal doses from external doses in a time-dependent manner, as well as to extrapolate between laboratory and environmental conditions or between species.

The aim of this PhD project was to develop a generic physiologically-based TK model (PBTK) for four teleost fishes (rainbow trout, zebrafish, fathead minnow, and three-spined stickleback) to predict internal doses according to different scenarios of environmental exposure. The model represents the main physiological characteristics of fishes to model absorption, distribution, metabolism, and excretion processes during their development and at any water temperature and oxygen concentration. Extensive literature searches were performed to collect physiological and TK parameters for each fish species to parameterize the PBTK model. Tools such as allometric scaling and quantitative structure-activity relationship (QSAR) models were used to fill the gaps in physiological and TK parameters. As a first step, PBTK model predictions were evaluated with nine case studies including lipophilic and hydrophilic compounds. In a second step, the model was used to identify and quantify the relative weight of biotic and abiotic factors on the TK variations of chemicals in fish exposed in natural conditions. Interindividual and interspecies variabilities were compared with variability induced by temperature and growth variation. A hierarchy of the impact of these variability sources on TK has been realized. Of the four sources of variability studied, inter-species variability seems to affect the TK most.

The experimental data gap is the major limit for the development and evaluation of the PBTK model. Some physiological data is still lacking regarding model parameterization and to reduce sources of uncertainty. For example, organ blood flows in small fish (e.g., zebrafish) are currently unavailable in the literature. Similarly, the PBTK model evaluation is hindered by the lack of experimentally measured internal doses of chemicals in various fish organs.

To conclude, this PhD work has highlighted that using PBTK models in ERA requires species-specific physiological values because the species has a strong influence on TK predictions. The work has also highlighted the need to perform ERA on several different fish species. Default uncertainty factors used in risk assessment have proven to be safe enough for compounds tested. However, not taking into account the effect of temperature on TK of ectotherm species is a gap for ERA. New uncertainty factors including temperature should be used for these species.