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G. Jean Harry,¹ Melvin Billingsley,² Arend Bruinink,³ Iain L. Campbell,⁴ Werner Classen,⁵ David C. Dorman,⁶ Corrado Galli,⁷ David Ray,⁸ Robert A. Smith,⁹ and Hugh A. Tilson¹⁰

Abstract

Risk assessment is a process often divided into the following steps: a) hazard identification, b) dose-response assessment, c) exposure assessment, and d) risk characterization. Regulatory toxicity studies usually are aimed at providing data for the first two steps. Human case reports, environmental research, and in vitro studies may also be used to identify or to further characterize a toxic hazard. In this report the strengths and limitations of in vitro techniques are discussed in light of their usefulness to identify neurotoxic hazards, as well as for the subsequent dose-response assessment. Because of the complexity of the nervous system, multiple functions of individual cells, and our limited knowledge of biochemical processes involved in neurotoxicity, it is not known how well any in vitro system would recapitulate the in vivo system. Thus, it would be difficult to design an in vitro test battery to replace in vivo test systems. In vitro systems are well suited to the study of biological processes in a more isolated context and have been most successfully used to elucidate mechanisms of toxicity, identify target cells of neurotoxicity, and delineate the development and intricate cellular changes induced by neurotoxicants. Both biochemical and morphological end points can be used, but many of the end points used can be altered by pharmacological actions as well as toxicity. Therefore, for many of these end points it is difficult or impossible to set a criterion that allows one to differentiate between a pharmacological and a neurotoxic effect. For the process of risk assessment such a discrimination is central. Therefore, end points used to determine potential neurotoxicity of a compound have to be carefully selected and evaluated with respect to their potential to discriminate between an adverse neurotoxic effect and a pharmacologic effect. It is obvious that for in vitro neurotoxicity studies the primary end points that can be used are those affected through specific mechanisms of neurotoxicity. For example, in vitro systems may be useful for certain structurally defined compounds and mechanisms of toxicity, such as organophosphorus compounds and delayed neuropathy, for which target cells and the biochemical processes involved in the neurotoxicity are well known. For other compounds and the different types of neurotoxicity, a mechanism of toxicity needs to be identified first. Once identified, by either in vivo or in vitro methods, a system can be developed to detect and to evaluate predictive ability for the type of in vivo neurotoxicity produced. Therefore, in vitro tests have their greatest potential in providing information on basic mechanistic processes in order to refine specific experimental questions to be addressed in the whole animal. -- Environ Health Perspect 106(Suppl 1) :131-158 (1998) . http://ehpnet1.niehs.nih.gov/docs/1998/Suppl-1/131-158harry/abstract.html

Key words: primary cell cultures, cell lines, central nervous system, peripheral nervous system, neuron, astrocyte, glia, oligodendroglia, astrocytomas, glutamate, neuropathy target esterase, organophosphate, reaggregate cell culture, organ culture, tissue slice, glioma cell line, neuroblastoma cell line, PC-12 cells, cytotoxicity, myelin, axonal transport, blood-brain barrier, neurotransmitter, calcium