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Historically the rst indication of neurotoxic potential by a chemical has often followed accidental human exposure in the workplace. Case reports of incidents involving individuals, or clusters of individuals, are useful for documentation but generally provide a limited amount of information about the speci c details of an exposure. Procedures included in most case reports include a patient medical history and clinical neurological exam, sometimes supplemented with psychiatric or neurophysiological tests, and/or neuroimaging. Although the speci c tests involved vary depending on the clinician, most basic clinical neurological exams rely heavily on evaluation of mental status (level of consciousness, orientation, mood, etc.) and sensorimotor function (gait, coordination, muscle tone, sensitivity to touch, re exes). Human epidemiological studies generally represent a deeper investigation into the causal relationship between an exposure and neurotoxicological effects. Some of the methods used to identify neurotoxic effects in epidemiological studies include behavioral assessments, neurophysiological evaluations, and neuroimaging techniques. Neurobehavioral assessments examine a variety of psychological and cognitive functions such as mood, attention, memory, perceptual and visuospatial ability, and psychomotor performance. In an effort to standardize neurotoxicological testing of human behavioral effects, particularly for studies involving worksite exposure, the World Health Organization (WHO) and the US National Institute for Occupational Safety and Health (NIOSH) devised a the Neurobehavioral Core Test Battery (NCBT). The NCBT (Table 16.1) consists of seven tests that were shown previously to be sensitive indicators of neurotoxicant exposure. The battery is designed to be administered one on one by an examiner. Although this battery has a relatively narrow
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TOXICOLOGY OF THE NERVOUS SYSTEM
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Table 16.1 The WHO Neurobehavioral Core Test Battery (NBCT) Domain Psychomotor performance Analysis Motor speed, motor steadiness Test Pursuit aiming Task Follow a pattern of small circles, placing a dot in each circle around a pattern; subject s score is number of taps in circle within one minute. Perform skillful movements with hands and arms. Each number in a list is associated with a simple symbol. On a list of random digits with blank spaces below them, write the correct symbols in blank spaces as fast as possible. Test reactions of hands or feet from visual and auditory signals. Recall and reproduce gures. Recall digits in series forwards and backwards immediately after hearing them. Evaluate, by questionnaire, anger, tension, confusion, depression, etc.
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Manual dexterity, hand eye coordination Perceptual coding and perceptual motor speed
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Santa Ana Dexterity Test Wechsler Digit Symbol Test
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Attention and short-term memory
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Attention and response speed Visual perception and memory Auditory memory
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Simple reaction time Benton Visual Retention Test Wechsler Digit Span Test
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focus, primarily on the effects most commonly seen in CNS toxicity, it also provides suggestions for the selection of further testing depending on the exposure setting. The NCBT has been widely used because of its ease of administration, relatively low cost, and its large base of control data. A broader battery of cognitive and psychomotor tests that is often used is the Neurobehavioral Evaluation System (NES). The NES consists of a combination of automated (computerized) and hand-administered tests. The sensitivity of the NES to effects caused by neurotoxicants in industrial settings has been validated internationally. Neurobehavioral examinations are useful for identifying neurotoxicant-mediated de cits, but it is often dif cult to localize the site of toxic action from such tests. For example, sensorimotor tests of reaction time, manual dexterity, hand-eye coordination, and nger tapping can indicate either neuromuscular or psychomotor damage.
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NEUROTOXICITY TESTING
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The results of these tests thus should be interpreted in the context of other experiments. For example, electrophysiological techniques can help to focus an investigation to the site of the lesion, and characterize electrical dysfunction within the damaged nerves. Electrophysiological nerve conduction studies can distinguish between proximal and distal axonal lesions in peripheral nerves and can be performed noninvasively (i.e., with skin surface electrodes). Characteristic changes in the velocity, duration, amplitude, waveform, or refractory period of peripheral nerves may be detected, depending on the agent. Evoked potentials represent another useful electrophysiological endpoint. These procedures measure the function of an entire system, such as the visual, auditory, or motor systems. The speci c pathway is stimulated by an evoking stimulus, such as a ash of light or electrical nerve stimulation. The evoked potentials are read as changes in ongoing electroencephalograms (EEGs) in response to the stimulation. Thus the activity of the entire neural circuit is evaluated in the brain after peripheral stimulation. Evoked potentials can be very sensitive indicators of changes in neural activity when performed in a carefully controlled environment, and when interpreted in light of behavioral or other physiological ndings. An increasingly popular method of documenting brain pathology is the use of neuroimaging methods. Computerized axial tomography (CAT) and magnetic resonance imaging (MRI) can produce images of the brain that can show structural changes in the volume or density of a speci c region or ventricle. Other techniques, such as positron emission tomography (PET) and single photon emission computerized tomography (SPECT), use radioactive tracer molecules to determine functional biochemical changes in processes like glucose utilization or receptor binding. The number of cases so far analyzed with neuroimaging techniques is still relatively small, and thus speci c toxicant-mediated effects are not well characterized. Nevertheless, this growing eld promises to contribute signi cantly to neurotoxicity studies in the future.
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