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Évaluation de l’exposition fœtale aux substances chimiques grâce à la modélisation pharmacocinétique basée sur la physiologie (PBPK) et son application aux données d’imprégnation des populations.

Abstract : Numerous biomonitoring studies have shown the exposure of pregnant women to synthetic substances. In parallel, several epidemiological studies have highlighted associations between maternal blood concentrations measured during pregnancy or cord blood concentrations measured at birth and adverse effects in the offspring at birth or later in life. However, this type of measurements does not guarantee being representative of in utero exposures throughout pregnancy. Furthermore, it is not possible to measure longitudinally fetal concentrations due to obvious ethical reasons. Pregnancy physiologically-based pharmacokinetic (pPBPK) models allow the simulation of xenobiotic internal exposures in different maternal and fetal organs during gestation. Therefore, they offer an opportunity to better estimate the relationship between the dose and the risk of a toxic effect by considering tissue dosimetry. Although pPBPK models often incorporate physiological changes associated with pregnancy, some processes are still poorly known such as placental transfer (PT). The aim of the thesis is to improve the integration of PT in pPBPK modelling in order to predict fetal internal exposures from biomonitoring data.First, a scientific literature review of the published pPBPK models was conducted with a focus on the various model structures used to describe PT. It allowed the identification of 12 structures among 50 original models which corresponded to 4 types of kinetic profiles according to the number of transfer constants. Animal in vivo data were identified as the main source to support their parameterization although they cannot be directly extrapolated to humans and imply the killing of numerous animals. From this basis, we developed a pPBPK model which integrated four transfer models calibrated using non-animal methods so as to assess their performance to predict the fetal dosimetry on a set of ten substances. Our results show that the performance varied among models and substances, preventing the identification of a reference predictive model. Monte-Carlo simulations showed that one of the transfer models differed from the others in terms of fetal exposure variation across trimesters. Finally, a global sensitivity analysis shed light on a great extent of influence of the transfer constants as well as the metabolic clearance and fraction unbound, to a lesser extent, on simulated fetal exposure. The last part of the thesis consisted in applying the developed pPBPK model to estimate the internal fetal concentrations of two PCB and two PBDE substances from observed maternal plasma concentrations taken from the French ELFE cohort. To that end, we selected a specific PT model for each compound based on the prediction of fetal to maternal concentrations ratio at term. The ranking of chemicals based on the simulated exposure indicators varied between mother and fetus at term, as between the first and the other two trimesters in fetal plasma.In conclusion, this work highlights the potential of pPBPK modelling in the prenatal exposures assessment. It demonstrates the ability of a model to simulate adequate internal exposure indicators from a mechanistic and temporal points of view, notably from biomonitoring data. Furthermore, in light of strong ethical and regulatory constraints, this work indicates the role of alternative methods in the parameterization of key processes of the internal fetal dose such as the transplacental passage. This work could be used for the assessment of the prenatal exposome as well as in the developmental toxicity risk assessment of a substance.
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Marc Codaccioni. Évaluation de l’exposition fœtale aux substances chimiques grâce à la modélisation pharmacocinétique basée sur la physiologie (PBPK) et son application aux données d’imprégnation des populations.. Médecine humaine et pathologie. Institut agronomique, vétérinaire et forestier de France, 2020. Français. ⟨NNT : 2020IAVF0019⟩. ⟨tel-03191616⟩

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