An integrated in vitro and in silico test strategy for estimation of developmental neurotoxicity

Developmental neurotoxicity (DNT) studies of chemicals and pesticides are performed in animals according to established test guidelines.

Every DNT study requires about 700 individuals.The objective for this project is to develop a strategy for estimation of maternal external doses of chemicals that can be harmful for the fetal developing nervous system by using new approach methods (NAMs, i.e. cell and computer models).

To achieve this goal, in vitro data and mechanistic information on DNT will be compiled from ongoing and previous studies in our lab, from literature and from toxicity data bases. The mechanisms will be structured into key events with the aim to build adverse outcome pathways (AOPs) for DNT.

In vitro data for the test compounds on DNT (eg. benchmark concentrations (BMC) and lowest observed adverse effect concentrations (LOAEC)) derived from the cell models for the developing nervous system, will be extrapolated to in vivo doses for the pregnant woman at different time points in quantitative in vitro-in vivo extrapolation (QIVIVE).

To do this, physiologically-based toxicokinetic (PBTK) models will be developed by using literature data on adsorption, distribution, metabolism and excretion (ADME) for the pregnant woman and the fetus.

By structuring mechanisms into AOPs and by integrating in vitro DNT data (BMC or LOAEC) into the PBTK model, maternal doses can be estimated which can be used for risk assessment without any use of experimental animals.