CELLULAR METHODS FOR IDENTIFICATION OF NEUROTOXIC CHEMICALS AND ESTIMATION OF NEUROTOXICOLOGICAL RISK

This review critically addresses key aspects of neurotoxicity that can be assessed by using in vitro test procedures and batteries. Such test schemes must most probably be hierarchical and multi-optional in order to be able to cope with the large number of possible mechanisms of neurotoxicity. Although the regenerative capacity of the nervous system is low, lesions can be compensated for by a number of cellular dynamic functions (e.g. intracellular calcium sequestration, membrane-bound ion transport systems and increases in the rates of energy metabolism and protein synthesis). Therefore, cellular tests included in primary screens of a multiple system should be based on determinations of cell physiological parameters rather than on measurements of single biochemical reactions. A general neurotoxicity test system for the determination of critical neurotoxic concentrations is suggested to include, as a first step, the assessment of basal cytotoxicity in a human neuroblastoma cell line. In a second step, differential cytotoxicity is assayed in highly developed primary cultures of neuronal and non-neuronal cells. In order to find out whether the compound is likely to produce axonopathy, a test procedure in mouse neuroblastoma cells is carried out. Toxicokinetic information is obtained from hepatocyte/target cell and endothelial cell/astrocyte co-cultures. To disclose alterations in cell physiology, studies of cell respiration, protein synthesis, membrane permeability and calcium homoeostasis are suggested. When information from these test steps is evaluated together with available data on in vivo toxicity, toxicokinetics and physical/chemical parameters, it may be necessary to proceed to mom neuronal specific determinations or mechanistically oriented studies. If a consistent pattern of effects or non-critical and critical concentrations is found, the toxicokinetic distribution over the blood-brain barrier must be considered in relation to actual in vivo blood concentrations if estimates of neurotoxic risk am to be made.