Predictive models for neurotoxicity assessment

INTRODUCTION The human nervous system is one of the most complex organ systems in terms of both structure and function. It contains billions of neurons, each forming thousands of synapses leading to a very large number of connections. It also contains perhaps ten times more glial cells (astrocytes, oligodendrocytes, microglia) than neurons, which play important roles in the overall development and functioning of the nervous system. Anatomically, the nervous system is composed of a central (CNS) and a peripheral (PNS) component, whose basic functions are to detect and relay sensory information inside and outside the body, to direct motor functions, and to integrate thought processes, learning, and memory. Such functions and their complexity, together with some intrinsic characteristics (e.g., mature neurons do not divide, they are highly dependent upon oxygen and glucose) make the nervous system particularly vulnerable to toxic insults. Neurotoxicity can be defined as any adverse effect on the chemistry, structure, or function of the nervous system, during development or at maturity, induced by chemical or physical influences. A first issue is what constitutes an adverse effect. A proposed definition of an adverse effect is “any treatment related change which interferes with normal function and compromises adaptation to the environment.” Thus, most morphological changes such as neuronopathy (a loss of neurons), axonopathy (a degeneration of the neuronal axon), or myelinopathy (a loss of the glial cells surrounding the axon), or other gliopathies, would be considered adverse, even if structural and/or functional changes were mild or transitory.