PRINCIPLES OF TOXICOLOGY

146 NEUROTOXICITY: TOXIC RESPONSES OF THE NERVOUS SYSTEM
• Chemicals may disrupt the electrical impulse along the axon, either by harming the myelin
sheath or membrane integrity, or by impairing the synthesis or functioning of proteins
essential to axonal transport.
• Chemicals may also inhibit the neurotransmitters by blocking their synthesis, release, or
binding to receptors.
• General protein synthesis impairment may have an effect not only on neurotransmitter
production, but also the production of important enzymes which break down neurotransmitters
when they are no longer needed.
We will next consider the mechanisms of electrical and chemical signal transmission through the
nervous system in more detail. The reader should keep in mind that proper nervous system function
depends on all steps in signal transmission working properly, and a disruption in any step may result
in what would be described as a neurotoxic effect.
7.1 MECHANISMS OF NEURONAL TRANSMISSION
In one sense, the nervous system is little more than an enormous network of interconnected nerve cells,
or neurons, supported by various other auxilliary cell types. However, this description is deceptive in
its simplicity. Neurons come in many shapes, sizes, and functions, but may be generically described
as having dendrites, a cell body, and an axon. The dendrites receive chemical signals from an adjacent
neuron. These signals then trigger electrical impulses along the axon and in turn stimulate the release
of more chemical signals at the terminal boutons. In this way, a stimulus may travel the entire length
of the human body. The electrical impulse is often maintained along the length of the neuron with the
aid of the myelin sheath, which acts as an insulator surrounding the axon. Successive neurons meet at
a gap called the synapse, and it is across this gap that the chemical signals, or neurotransmitters, diffuse
from one neuron to the dendrites of the next. Alternatively, neurons may terminate at muscles or glands,
releasing neurotransmitters to specialized receptors at these sites.
It has been found that these basic features of the nervous system are similar throughout a wide
taxonomic range. Most multicellular organisms possess some form of nervous system which includes
neurons, neurotransmitters, and electrical signal conduction. This similarity provides us with substantial
confidence in using neurotoxicity test results in animals to predict neurotoxic effects in humans.
The Action Potential
Electrical signals are initiated and propagated along the axon by what is called an action potential.
The source of this potential is a charge difference across the nerve membrane, created by the movement
of sodium (Na + ), potassium (K + ), and chloride (Cl – ) ions. This charge difference is determined by the
selective permeability of the membrane, as well as concentration and potential gradients, and active
transport. When the membrane is at rest, the concentration of K + ions is greater inside the cell than
outside, while the concentrations of Na + and Cl – are greater outside the cell. The concentrations of K +
and Cl – ions counterbalance each other, and this balance is maintained against their concentration
gradients by the resulting potential gradient. Thus, in this equilibrium state, the tendency of either ion
to diffuse across the membrane and down its concentration gradient is controlled by the imbalance
caused by the potential gradient. Meanwhile, the membrane is relatively impermeable to Na + , and
therefore a net positive charge exists on the outside of the cell relative to the inside (Figure 7.1a).
When the cell is stimulated and an action potential is created, the membrane becomes locally
permeable to sodium, and an influx of positive charge occurs. The result is a depolarization of the
membrane that is propagated down the axon as current flows ahead of the action potential, depolarizing
the membrane further (Figure 7.1b). Behind the action potential, the membrane permeability again
shifts to favor K + movement and to decrease Na + movement. The resulting repolarization from the K +