PRINCIPLES OF TOXICOLOGY - Biology East Borneo

7.2 AGENTS THAT ACT ON THE NEURON 149an effect seen with some neurotoxicants described later, will result in the inappropriate and continuousstimulation of the postsynaptic cell by the accumulated ACh molecules.Other neurotransmitters are known and include γ-aminobutyric acid (GABA—a component of thecentral nervous system), amines (epinephrine, norepinephrine, dopamine, serotonin), amino acids(glycine, glutamate), and peptides (enkephalins, endorphins). Their actions on the postsynaptic cellmay be either excitatory or inhibitory, and may be directed toward another neuron, a muscle fiber, ora glandular cell.7.2 AGENTS THAT ACT ON THE NEURONMembrane DisruptionEffective transmission of neuronal signal depends on intact membranes, both along the length of theaxon and at the terminus where neurotransmitter is released. In addition, the axons of many neuronsare typically wrapped with myelin, which aids in the propagation of the action potential by minimizingany loss of potential across the membrane to the outside of the cell. Chemicals that disrupt the integrityof 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, thissame property also makes them destructive to the lipids in cell membranes. Coupled with the potentialfor substantial inhalation exposure resulting from their volatility, these membrane disrupters may posea serious threat to the nervous system.Some metals are disruptive of the myelin sheath that surrounds neurons of the central nervoussystem and some of the peripheral nervous system. In an industrial setting, some of these metalcompounds, such as lead, thallium, and triethyltin, may be readily inhaled in the course of smelting orsoldering operations. They may then directly attack the myelin sheath, or disrupt the functioning ofthe accessory cells that myelinate neurons, namely, the Schwann cells and oligodendrocytes. Theresults of such damage may vary from the vision loss commonly seen with thallium poisoning to theimpaired cognition associated with lead exposure.Many insecticides impair membrane function by interfering with the ion channels responsible formaintaining the proper balance of sodium and potassium ions across the membrane. An example isthe organochlorine insecticide DDT (dichlorodiphenyltrichloroethane), which blocks ion channels andinhibits active transport, thus impeding the repolarization of the membrane after propagation of theaction potential. The resulting symptoms, which include tremors, seizures, and increased sensitivityto stimuli, are seen in both the poisoned target insect and the accidentally exposed human. The use ofDDT has been banned in the United States (though more because of its environmental persistence thanits neurotoxicity), but many organochlorine insecticides, as well as some similarly acting pyrethroidesters, remain in use worldwide and are thus a potential hazard for workers involved in both theirmanufacture and application.Peripheral Sensory and Motor NervesEffects on peripheral sensorimotor nerves are manifested as abnormal sensation and impaired motorcontrol in the distal regions of the body, primarily hands and feet. Peripheral nerves often have thecapacity to regenerate if damage is limited to the axonal region, so that quick action to limit exposureto the toxicant may result in complete reversal of the toxic effects. This is a fortunate contrast to CNSneuropathy, which usually results in permanent and irreversible damage.Some peripheral neurotoxicants, such as the solvents methyl n-butyl ketone and n-hexane, arethought 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 isthought to be caused mainly by the metabolite 2, 5-hexanedione. A similar effect is seen as a result