Developmental Neurotoxicity Testing Using In vitro Approaches

There is a main concern about children¿s health as the developing brain in foetuses and children is much more vulnerable to injury caused by different classes of chemicals than the adult brain. This vulnerability is partly due to the fact that the adult brain is well protected against chemicals by the blood brain barrier (BBB) and children have increased absorption rates and diminished ability to detoxify many exogenous compounds, in comparison to that of adults. Moreover, the development of the central nervous system (CNS) is a very complex process involving several different important events, e.g. proliferation, migration and differentiation of cells. These events are occurring within a strictly controlled time frame and therefore create different windows of vulnerability. Furthermore, the brain is consisting of numerous of different cell types (neuronal, glial and endothelial cells) that have specific functions. The development of each cell type is at a special time window and is therefore susceptible to environmental disturbances at different time periods. Evidence indicates that exposure to industrial chemicals, pesticides or drugs, is contributing to the increasing incidence of neurodevelopment disorders. However, due to lack of studies only a few industrial chemicals have been identified as developmental neurotoxicants so far. The current developmental neurotoxicity (DNT) guidelines (OECD TG 426 and US EPA 712-C-98-239) are based entirely on in vivo studies that are both time consuming, complex, costly and not suitable for testing of a high number of chemicals. Applying alternative approaches such as in silico, in vitro and non-mammalian models as a part of an integrated test strategy, could speed up the process of DNT evaluation and finely reduce and refine animal usage. Both in vitro and non-mammalian test systems offer the possibility of providing an early screen for a large number of chemicals, and could be particularly useful in characterising the compoundinduced mechanism of toxicity of various developmental processes. This thesis has characterised two primary neuronal cultures (cerebellar granule cells (CGCs) and cortical neuronal cultures) and recognized them as relevant models for DNT testing as the key processes of brain development such cell proliferation, migration and neuronal/glial differentiation are present. Furthermore, two emerging technologies (gene expression and electrical activity) have been evaluated and were identified as promising tools for in vitro DNT assessment. In a combination with other assays they could be included into a DNT intelligent testing strategy to speed up the process of DNT evaluation mainly by initial prioritization of chemicals with DNT potential for further testing.

HOGBERG Helena; 

2009-11-23

University Press

JRC54486

https://publications.jrc.ec.europa.eu/repository/handle/JRC54486,