Development and testing of a new approach methodology for the prediction of human risk following exposure to mixtures of toxic chemicals

Human population is continuously exposed to a multitude of chemical compounds, among which perand polyfluoroalkyl substances (PFASs), organophosphate esters (OPEs) and polybrominated
diphenyl ethers (PBDEs). Sustained exposure to these chemical compounds poses safety concerns to
human health, including hepatotoxicity, partly due to their persistent and bioaccumulative nature.
The combined toxicological impact of these compounds may exceed individual effects, as mixtures
can alter the overall toxicity through additive or synergistic mechanisms. This doctoral thesis project
will develop a new approach methodology (NAM) to investigate the combined adverse effects of
PFASs, OPEs and PBDEs on the liver. For this purpose, 3D spheroid cultures of primary human
hepatocytes and 2D monolayer cultures of human hepatoma cells will be used. Relative potency
factors will be determined for PFASs, OPEs and PBDEs related to steatosis and cholestasis.
Subsequently, equipotent mixtures of PFASs, OPEs and PBDEs will be tested at the transcriptional,
translational and functional level benchmarked against established adverse outcome pathway
constructs. Physiologically based kinetic (PBK) modelling will allow extrapolation to human relevant
dosages. This doctoral thesis project will not only shed more light onto the mechanistic basis of the
hepatotoxic effects of PFASs, OPEs and PBDEs, but, first and foremost, will introduce a NAM for risk
assessment of chemical mixtures.