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: n euroblastoma cell lines, primary cultures of rat and chick midbrain, a nd organotypic whole brain reaggregate cultures. A tiered system has b een proposed involving hierarchical testing through three layers of di fferent neural complexities. This scheme is currently undergoing valid ation under the auspices of FRAME/EC using 40 test chemicals. To deter mine the performance and suitability of these culture models studies o n selected neurotoxins have been performed: ethylcholine mustard aziri dinium, vincristine, aluminium, glutamate, 1-methyl-4-phenyl-1,2,3,6-t etrahydropyridine and T-3-deprivation, Aspects of this work are descri bed, including mechanistic investigations in rat brain reaggregate cul tures. In vitro exposure of xenobiotics through a tiered testing syste m (ranging from simple cell-based assays measuring cytotoxicological p arameters to more complex markers in organotypic cultures) may permit detection of central nervous system neurotoxicity in the contexts of b oth 'screening' and mechanistics. The degree of simplicity, automatici ty and transportability of the tests requires consideration as will th e possibility of endpoints for specific classes of chemicals, for exam ple cholinesterase for organophosphorus insecticides. Factors such as extrapolation from the central nervous system to the peripheral nervou s system, metabolic activation, the blood-brain barrier, degree of neu ral cell activation, repair mechanisms, and developing versus adult ne rvous systems are considered.