PRINCIPLES OF TOXICOLOGY

150 NEUROTOXICITY: TOXIC RESPONSES OF THE NERVOUS SYSTEM
of exposure to carbon disulfide, another common industrial solvent, although the role of its
metabolites is less clear.
Other chemicals may be transformed outside of the body into products that remain closely
associated with the parent compound, leading to confusion about what is actually causing the observed
effect. An interesting example is the effect on the cranial nerves that has long been seen with
trichloroethylene inhalation. Trichloroethylene is known to target the central nervous system, while
the cranial nerves are part of the peripheral nervous system controlling sensory and motor functions
in the face and head. Recent studies suggest that the cranial neuropathy previously attributed to
trichloroethylene inhalation may be caused by dichloroacetylene, an abiologically formed breakdown
product of trichloroethylene that may occur in some industrial settings. Dichloroacetylene has clearly
been shown to target the cranial nerves, whereas this has not yet been demonstrated with pure
trichloroethylene.
Permanent Brain Lesions
Damage to the neurons of the brain may produce varying results, depending on the affected area.
Sensory, cognitive, or motor skills may be impaired, and the degree of effect may range from slightly
debilitating to severe or even fatal. As with other CNS effects, those resulting from lesions in the brain
are likely to be irreversible.
Due to the high metabolic rate of neuronal tissue, the brain is by necessity highly perfused with
blood vessels, and this presents a problem when a neurotoxic chemical finds its way into the
bloodstream. Humans have evolved an important protection against potential brain toxicants known
as the blood–brain barrier. This consists of several anatomical adaptations, such as tightly joined cells
with few transport vesicles, which serve to decrease the permeability of membranes to many bloodborne
chemicals. While it is quite effective at minimizing brain exposure to most large or hydrophilic
molecules, the blood–brain barrier may still be traversed by some highly lipophilic molecules, as
discussed below.
The classic example is the neurotoxic metal mercury. When it exists in its ionized form or as an
inorganic salt, mercury is water-soluble and, although it may circulate in the bloodstream of an exposed
individual, it is not likely to cross the blood–brain barrier and cause damage to the brain. The neurotoxic
symptoms of mercury poisoning, which may include tremors, mood disorders, psychosis, and possibly
death, are manifested when the lipophilic elemental mercury or an organic mercury species is formed.
The transformation of inorganic mercury to organic mercury is commonly performed by bacteria in
the environment, but may also occur as a result of bacterial activity within the human gut. Since
elemental mercury and organic mercury can cross membranes more easily than the ionized form, the
blood–brain barrier presents a less formidable obstacle. Once inside the brain, elemental or organic
form of mercury may be transformed into the ionized mercury, and thus remain there for a long time,
producing severe brain lesions.
Anoxia
In addition to those mentioned above, the nervous system depends on other important physiological
functions that, if impaired by toxic agents, may result in symptoms of neurotoxicity. Of particular
importance is the relationship between the nervous system and the respiratory system.
The high metabolic rate of neurons requires that they be well supplied with oxygen and a rapid
waste transport system. Compounds like carbon monoxide, which compete with oxygen for hemoglobin
binding sites, may severely reduce the oxygen supply to neurons and eventually cause their deaths
by anoxia. The most serious case would be destruction of neurons in the brain, leading to functional
damage or death of the individual. Other compounds may produce the same result but through a
different mechanism, as in the case of cyanide or hydrogen sulfide, which irreversibly bind to
cytochrome oxidase, an essential component of the respiratory electron transfer chain.