Drinking Water and Health, Volume 6 (1986) / Chapter Skim
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4. Neurotoxic Effects
4. Neurotoxic Effects
Pages 105-138
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From page 105... ...
Although there are no reliable estimates of the number of persons who develop neurotoxic disorders in adult life, or of the impact of overexposure to chemical agents on the developing or aging nervous system, more than 850 chemicals are known to produce neurobehavioral disorders in humans or in animals (Anger and Johnson, 19851. The National Institute for Occupational Safety and Health (NIOSH)
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From page 106... ...
Neurotoxicology is concerned not only with the actions of chemical agents but also with biological and certain physical (e.g., radiation) agents that produce adverse effects on the developing, mature, and aging nervous system (including special sense organs as well as neuroendocrine and neuromuscular systems)
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From page 107... ...
, which conduct information to muscles and between muscles, glands, sense organs, and the spinal cord or brain. PNS axons are ensheathed by Schwann cells to form nerve fibers, which run together in bundles in peripheral and cranial nerves (I and III-XII)
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From page 108... ...
The spinal cord receives information via afferent fibers from PNS sensory receptors in the skin, voluntary muscles, tendons, blood vessels, and glands. It transmits signals for motor function through efferent fibers and communicates information via specific pathways, which include coordination centers within the brain.
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From page 109... ...
The motor area is generally divided into the pyramidal and extrapyramidal systems. The pyramidal tracts descend from the frontal cortex to the spinal cord, where they regulate the activity of nerve cells controlling the skeletal muscles.
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From page 110... ...
Speech becomes fixed at an earlier age in boys, who are therefore more likely to suffer more severe and enduring language deficits after cortical injury in childhood. Cellular Structure and Function The fundamental neurocellular components are neurons and glial cells, which are associated with blood vessels and other specialized epithelial and connective tissue cells (Jacobson, 19784.
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From page 111... ...
By contrast, chemical agents that induce loss of CNS neurons produce irreversible damage. Degeneration of CNS axons, initiated by blockade of axonal transport or by other methods, is also commonly irreversible, except for small-diameter unmyelinated monoaminergic axons that regenerate and elongate after injury.
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From page 112... ...
, which circulates between the ventricular system of the brain and spinal cord and spaces beneath the arachnoid and aural connective tissues that encase and protect the CNS. Interruption of the normal flow of CSF during development or adult life leads to hydrocephalus, a condition resulting from the accumulation of fluid in enlarged brain ventricles or between the brain and the overlying aura (Weller et al., 19831.
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From page 113... ...
alter the integrity or cause degeneration of sensory neurons in dorsal root ganglia (Cho et al., 1980~. The CNS and much of the PNS are also protected from exogenous agents by connective tissue sheaths, but the terminal regions of efferent PNS axons in muscle and glands may be directly exposed to noxious agents present in tissue fluid.
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From page 114... ...
Basal plates on the ventral sides of the neural tube form motor neurons, notably anterior horn cells, while the dorsal, alar plates form sensory association areas. These receive the central axon processes of sensory neurons in dorsal root ganglia, which develop from neural-crest cells that
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From page 115... ...
Preganglionic neurons of the parasympathetic system, located in the midbrain, medulla oblongata, and sacral spinal cord, also use acetylcholine as a neurotransmitter, as do their postganglionic counterparts located close to their effecter sites in the organs listed above. Functionally, the two divisions of the autonomic nervous system tend to counteract each other (Mayer, 19801: the sympathoadrenal system, which can discharge as a unit during rage or fright, accelerates heart rate; increases blood pressure and glucose concentration; shifts blood from the spleen, skin, and gut to the skeletal muscles; and dilates the pupils and bronchioles.
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From page 116... ...
50-541. However, some tissues, such as the cerebrum and cerebellum, continue active differentiation and thus remain susceptible to the action of certain chemical agents until term or even into the postnatal period.
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From page 117... ...
Other experimental factors positively correlated with fetal susceptibility to the teratogenic effects of chemical substances include maternal weight and, probably, age, litter size, implantation site, route of administration, and season. Ionizing radiation, hypoxia, and certain infections supplement the long list of factors associated with neuroteratogenesis in humans and animals.
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From page 118... ...
Evidence suggests that most direct-acting neurotoxicants induce structural or functional changes, as a result of either reversible or irreversible binding of toxic substances to receptors or other vital macromolecules in nervous tissue. There appears to be no good reason why neurotoxicity will not follow normal sigmoidal dose-response relationships.
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From page 119... ...
constitute approximately 90% of the Japanese population (Price Evans, 19781. The potency of other neurotoxic agents may be altered by concurrent exposure to another compound lacking the property.
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From page 120... ...
Astrocytes Ependymal cells Special sense organs Olfactory/gustatory Optical Otic Vestibular Muscles Striated muscles Cardiac muscles Neural vasculature Neuroendocrine system Hypothalamus/hypophysis Immune system, with secondary effects on nervous system or musculature Various cell types Malignant transformation, with primary or secondary growths affecting nervous system Doxorubicin, mercury, trimethyltin Acrylamide, n-hexane, methyl n-butyl ketone Glutamate excitotoxins Isoniazid, triethyltin Lead, diphtheria toxin 6 - Amino nic otin amide Amoscoline Penicillamine, thiouracil Methanol, chloroquine Noise, toluene Hydroquinone Anticholinesterases, dimethyl sulfoxide Diphtheria toxin Cadmium Chlordecone Gold thiourea Alkyl nitrosoureas based on chemical structure and target site in the nervous system—not on the source of the agent, type of usage, or, for most elements, position in the periodic table. A more appropriate classification of chemical neurotoxicants is based on apparent target sites within the nervous system (Table 4-1)
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From page 121... ...
Most of the disorders are not known to be associated with detectable structural changes in the nervous system or elsewhere, and a large majority of them are rapidly reversible. Some, such as the tardive dyskinetic states associated with chronic use of phenothiazines and certain other neuroactive drugs, are usually attributed to increased sensitivity of receptor sites on synaptic membranes and are irreversible, or slowly reversible after cessation of exposure.
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From page 122... ...
Delayed and then progressive deterioration of brain structure and function may occur in persons who recover from acute carbon monoxide intoxication (Ginsberg, 1980~. Loss of neurons may also be observed in dorsal root ganglia after exposure to mercury or doxorubicin, whereas adjacent motor neurons protected by the bloodnerve regulatory interface in the spinal cord are usually spared.
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From page 123... ...
Changes in muscle induced by chemical agents (mostly drugs) are well known.
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From page 124... ...
However, systematic studies of the effects of chemical neurotoxicants on laboratory animals of varying age have yet to be undertaken. The most intensively studied and best documented aspects of normal human aging are changes in intellect and memory.
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From page 125... ...
Morphological changes in the PNS include a probable reduction of sensory neurons, an increase in the normal incidence of demyelination in spinal roots and peripheral nerves, increased amounts of connective tissue, and a mild loss of myelinated fibers. The central processes of dorsal root ganglion cells typically undergo distal dystrophic and degenerative changes (Spencer and Ochoa, 19811.
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From page 126... ...
These include, for example, senile dementia of the Alzheimer type, a syndrome of progressive mental deterioration, loss of memory, and impaired cognitive function associated with primary degeneration of neurons predominantly in the cerebral cortex and hippocampus; parkinsonism and disorders of motor function associated with striatal degeneration of the substantia nigra and characterized by flexed posture, rigidity, tremor, and mental and autonomic deficits; and amyotrophic lateral sclerosis, a disorder predominantly affecting motor neurons in the motor cortex and spinal cord. Axonal syndromes, such as mild polyneuropathy, are also common among the elderly.
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From page 127... ...
Therefore, it is likely that aging populations with compromised neural structure and function, as well as reduced capacity for liver metabolism and renal clearance, are more susceptible to certain neurotoxic substances than are their younger adult counterparts. Other groups that may be especially susceptible to neurotoxic agents include those occupationally exposed to chemicals with neurotoxic properties, persons with renal dysfunction, and those with skin conditions that increase dermal absorption of chemical agents.
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From page 128... ...
urea Urination Dimethylaminopropionitrile Sexual function ,B-Chloroprene Immune system Myositis, vasculitis, fibrosis Guillain Barre syndrome Spanish toxic oil Gold salts aAdapted from Lane and Routledge, 1983. bData not conclusive.
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From page 129... ...
The occurrence of subclinical neurological and behavioral disorders associated with chemical substances is unknown but is believed by some to be widespread. Examples include the unre~.olved controversies about childhood cognitive impairment from environmental lead contamination and the neurobehavioral effects attributed to prolonged occupational exposure to a variety of industrial solvents.
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From page 130... ...
650-7071. Epidemiological Studies There have been several epidemiological studies of outbreaks of human neurobehavioral disorders in which chemical compounds have been implicated and subsequently proved to be neurotoxic in animal studies.
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From page 131... ...
STUDIES IN ANIMALS Many methods have been used to assess neurotoxicity in animals, and many types of data have been produced. Experimental studies of the adverse actions of chemical agents on the nervous system include systematic observation and measurement of behavior, neural function, structure, and biochemistry in various laboratory animals.
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From page 132... ...
Armed with these techniques and a knowledge of neurobiological principles, one can define different patterns of neurotoxic response to chemical agents and explain how these result in human diseases that vary in expression and prognosis. With the exception of certain developmental disorders associated with chemical overexposure, there is usually an excellent correlation between the neurotoxic disorders of mammals and human beings.
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From page 133... ...
, where one is operating in a portion of the dose-response curve that is likely to be less steep than the region in which most experimental studies have been performed. These rules do not apply to neurotoxic disorders of the developing animal, in which response rate and type of teratogenicity are often variable.
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From page 134... ...
Epidemiological dose-response information is extremely limited, and that which does exist may not be applicable to the general population. Although some animal models are particularly accurate for assessing neurological disorders in humans, the large number of potential toxic end points greatly complicates assessment since there may not be a single threshold dose for all end points.
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From page 135... ...
1979. Test Methods for Definition of Effects of Toxic Substances on Behavior and Neuromotor Function.
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From page 136... ...
1982. Possible Long-Term Health Effects of ShortTerm Exposure to Chemical Agents.
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From page 137... ...
1984. An expanded classification of neurotoxic responses based on cellular targets of chemical agents.
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From page 138... ...
1984. Microscopic anatomy of peripheral nerve fibers.
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