Yourdasmine Ali Daoud

Title: Predicting adverse effects of environmental contaminants in human biomonitoring studies: contribution of the coupling of physiology-based toxicokinetic models (PBTK) and effect models (AOP)

Health risk assessment (HRA) of substances is essential for the protection of the human population. It consists of identify the hazard, characterise it, determine the exposure and characterise the risk. However, the relationship between external exposure and internal dose is not easy to demonstrate with the classical HRA studies. The use of mechanistic models such as pharmacokinetic or toxicokinetic models is an alternative way of linking external exposure and dose in organ or tissue. These models can be coupled with pharmacodynamic or toxicodynamic models to link external exposure, internal dose and adverse effects on an organ or tissue.

Physiologically based toxicokinetic modelling (PBTK) is a mechanistic approach used to describe and quantify absorption, distribution, metabolism and elimination (ADME) processes that are based on physiological, anatomical, biochemical mechanisms and the physicochemical properties of the molecule. Their use in toxicology allows the results of exposure studies in animals to be extrapolated to predict the internal dose in humans. An Adverse Outcome Pathway (AOP) is a conceptualized framework that describes a sequence of events leading to an adverse effect. AOPs are one of these new tools that make it possible to link the internal dose received by a target organ or tissue to an adverse effect. There are different types of AOPs: qualitative AOPs, which are purely descriptive, and semi-quantitative or quantitative AOPs (qAOPs), which make it possible to estimate the exposure dose corresponding to the appearance of the adverse effect.

The aim of thesis project is to develop a predictive tool for predicting the effects of chemical substances in humans, by coupling a PBTK model to predict the internal exposure of individuals and AOP to predict the effects related to this exposure. Lead was chosen as the study substance. It is a ubiquitous molecule and its effects on the general population are known and well documented. Lead affects the development of the nervous system in children and several epidemiological studies have shown a positive correlation between the lead concentrations in blood and a decline of the intelligence quotient (IQ). We will develop a PBTK model to describe the disposition of lead in the prenatal period and in early childhood coupled with a qAOP to predict effects on brain development.