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The central nervous system (CNS) coordinates responses to the fluctuating metabolic requirements of the body and modulates behavior, memory, and higher levels of thinking. These functions require a diversity of cells: astrocytes, neurons, ependymal cells, and vascular endothelial cells. Disruption or death of any one cell type can cause critical changes in the function or viability of another. This cellular interdependence, along with the high metabolic demands of the CNS, make neurons especially vulnerable to injury from both endogenous neurotoxins and xenobiotics. Endogenous neurotoxins like the metals iron, copper, and manganese, are substances that may be critical to CNS function, but are harmful when their penetration into the CNS is poorly controlled.

The understanding of the normal chemical and molecular functions of the CNS is limited at best. Interestingly, cellular mechanisms have sometimes been revealed by investigating xenobiotic-induced neuronal injuries.38,66 For example, the pathophysiology of Parkinson disease, which affects movement and motor tone, was elucidated by the inadvertent exposure of individuals to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The mechanisms of axonal transport were elucidated by investigations of the effects of acrylamide exposures in human and animal models.57 The neurodegenerative changes of amyotrophic lateral sclerosis have a promising xenobiotic model in β-methylamino-L-alanine (BMAA), a neurotoxin found in the cyanobacteria associated with cycad plants ingested by the Chamorro people of Guam.67

There are few minimally invasive methods available to investigate xenobiotic-induced CNS injury. Biomarkers are usually nonspecific and not readily available. Xenobiotic concentrations of blood and urine rarely reflect tissue concentrations of the CNS.58Cerebrospinal fluid may be useful in excluding CNS injury from infection, hemorrhage and inflammatory processes, but is, with few exceptions, poorly reflective of the mechanisms of neuronal injuries.88 Similarly, electroencephalograms and electromyelograms are useful in only a few types of xenobiotic exposures, and neuroimaging, while progressively evolving,54 is a poor substitute for neuroanatomical evaluations which are usually only available on autopsy. Much of the current study to elucidate the mechanisms of CNS injury uses animal models, cultured astrocytes, and other tissue, or postmortem investigations. Less commonly, occupational evaluations, such as the enzyme activity of cholinesterases in pesticide workers, are employed.

This chapter reviews some basic anatomic and physiological principles of the nervous system and the common mechanisms by which xenobiotics exploit the functional and protective components of the CNS with a few relevant examples. The multiple factors determining the clinical expression of neurotoxicity are reviewed.


Neurons are the major route of cellular communication in the CNS. Having one of the highest metabolic rates in the body, these cells are especially sensitive to changes in the microenvironment and are dependent on astrocytes, choroidal epithelium, and capillary endothelium to confer protection and deliver glucose and other sources of energy.

While each neuron is capable of receiving information through different neurotransmitters and receptor subtypes at the dendrite, neurons typically ...

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