NEURODEVELOPMENTAL TOXICITY IN-VITRO - PRIMARY-CELL CULTURE MODELS FOR SCREENING AND RISK ASSESSMENT

Robust models for the evaluation of developmental toxicity are briefly reviewed with emphasis on embryonic brain and retina cells in vitro. Organ slice and aggregate cultures under constant gyratory movement as well as high cell density monolayer (''micromass'') cultures are cons idered as robust models. An in vitro model using high cell density mon olayer and re-aggregated cells isolated from embryonic chick brain (ED 6) is presented. Cell development and differentiation of the astrocyt es and nerve cells are monitored by marker proteins and cytotoxicity w as quantified by neutral red uptake and protein content. Four human te ratogens, six possible human teratogens and six unlikely human teratog ens were tested in brain and retina cells for their cytotoxic and morp hologic effect. All 16 substances were classified correctly except the neurotoxicants MPTP and MPP+, both of which are strong dopaminergic t oxicants in vitro as well as in humans and are therefore proposed to b e classified as human neuroteratogens. Preliminary data on the lowest effect levels of four potential neurotoxicants (cadmium chloride, Ara- C, Phenytoin, MPTP) in chick brain aggregate cultures correlate surpri singly well with known toxic human plasma levels. Further validation h as to be undertaken to confirm these promising results. A battery of s uch robust in vitro models is proposed that could cover neurodevelopme ntal toxicity of drugs and chemicals for screening and risk assessment purposes.