NEW MODELS FOR THE IN-VITRO ASSESSMENT OF NEUROTOXICITY IN THE NERVOUS-SYSTEM AND THE PRELIMINARY VALIDATION STAGES OF A TIERED-TEST MODEL

Many cell culture models are available for the in vitro assessment of neurotoxicity. The use of three culture types has been investigated: neuroblastoma cell lines, primary cultures of rat and chick midbrain, and organotypic whole brain reaggregate cultures. A tiered system has been proposed involving hierarchical testing through three layers of different neural complexities. This scheme is currently undergoing validation under the auspices of FRAME/EC using 40 test chemicals. To determine the performance and suitability of these culture models studies on selected neurotoxins have been performed: ethylcholine mustard aziridinium, vincristine, aluminium, glutamate, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and T-3-deprivation, Aspects of this work are described, including mechanistic investigations in rat brain reaggregate cultures. In vitro exposure of xenobiotics through a tiered testing system (ranging from simple cell-based assays measuring cytotoxicological parameters to more complex markers in organotypic cultures) may permit detection of central nervous system neurotoxicity in the contexts of both 'screening' and mechanistics. The degree of simplicity, automaticity and transportability of the tests requires consideration as will the possibility of endpoints for specific classes of chemicals, for example cholinesterase for organophosphorus insecticides. Factors such as extrapolation from the central nervous system to the peripheral nervous system, metabolic activation, the blood-brain barrier, degree of neural cell activation, repair mechanisms, and developing versus adult nervous systems are considered.