PRINCIPLES OF TOXICOLOGY

an effect seen with some neurotoxicants described later, will result in the inappropriate and continuous
stimulation of the postsynaptic cell by the accumulated ACh molecules.
Other neurotransmitters are known and include γ-aminobutyric acid (GABA—a component of the
central nervous system), amines (epinephrine, norepinephrine, dopamine, serotonin), amino acids
(glycine, glutamate), and peptides (enkephalins, endorphins). Their actions on the postsynaptic cell
may be either excitatory or inhibitory, and may be directed toward another neuron, a muscle fiber, or
a glandular cell.
7.2 AGENTS THAT ACT ON THE NEURON
7.2 AGENTS THAT ACT ON THE NEURON 149
Membrane Disruption
Effective transmission of neuronal signal depends on intact membranes, both along the length of the
axon and at the terminus where neurotransmitter is released. In addition, the axons of many neurons
are typically wrapped with myelin, which aids in the propagation of the action potential by minimizing
any loss of potential across the membrane to the outside of the cell. Chemicals that disrupt the integrity
of this membrane system can seriously impair nervous system function.
Many commonly used industrial solvents, such as methanol, trichloroethylene, and tetrachloroethylene,
are excellent cleaning agents and degreasers because of their lipophilicity. However, this
same property also makes them destructive to the lipids in cell membranes. Coupled with the potential
for substantial inhalation exposure resulting from their volatility, these membrane disrupters may pose
a serious threat to the nervous system.
Some metals are disruptive of the myelin sheath that surrounds neurons of the central nervous
system and some of the peripheral nervous system. In an industrial setting, some of these metal
compounds, such as lead, thallium, and triethyltin, may be readily inhaled in the course of smelting or
soldering operations. They may then directly attack the myelin sheath, or disrupt the functioning of
the accessory cells that myelinate neurons, namely, the Schwann cells and oligodendrocytes. The
results of such damage may vary from the vision loss commonly seen with thallium poisoning to the
impaired cognition associated with lead exposure.
Many insecticides impair membrane function by interfering with the ion channels responsible for
maintaining the proper balance of sodium and potassium ions across the membrane. An example is
the organochlorine insecticide DDT (dichlorodiphenyltrichloroethane), which blocks ion channels and
inhibits active transport, thus impeding the repolarization of the membrane after propagation of the
action potential. The resulting symptoms, which include tremors, seizures, and increased sensitivity
to stimuli, are seen in both the poisoned target insect and the accidentally exposed human. The use of
DDT has been banned in the United States (though more because of its environmental persistence than
its neurotoxicity), but many organochlorine insecticides, as well as some similarly acting pyrethroid
esters, remain in use worldwide and are thus a potential hazard for workers involved in both their
manufacture and application.
Peripheral Sensory and Motor Nerves
Effects on peripheral sensorimotor nerves are manifested as abnormal sensation and impaired motor
control in the distal regions of the body, primarily hands and feet. Peripheral nerves often have the
capacity to regenerate if damage is limited to the axonal region, so that quick action to limit exposure
to the toxicant may result in complete reversal of the toxic effects. This is a fortunate contrast to CNS
neuropathy, which usually results in permanent and irreversible damage.
Some peripheral neurotoxicants, such as the solvents methyl n-butyl ketone and n-hexane, are
thought to exert their effects mainly through the formation of toxic metabolites formed in the liver.
The observed pathology is distal axonal swelling in both motor and sensory neurons, and is
thought to be caused mainly by the metabolite 2, 5-hexanedione. A similar effect is seen as a result