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Thursday, 17 February 2011 23:31

Measuring Neurotoxic Deficits

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Neuro-functional Test Batteries

Sub-clinical neurologic signs and symptoms have long been noted among active workers exposed to neurotoxins; however, it is only since the mid-1960s that research efforts have focused on the development of sensitive test batteries capable of detecting subtle, mild changes that are present in the early stages of intoxication, in perceptual, psychomotor, cognitive, sensory and motor functions, and affect.

The first neurobehavioural test battery for use in worksite studies was developed by Helena Hänninen, a pioneer in the field of neurobehavioural deficits associated with toxic exposure (Hänninen Test Battery) (Hänninen and Lindstrom 1979). Since then, there have been worldwide efforts to develop, refine and, in some cases, computerize neurobehavioural test batteries. Anger (1990) describes five worksite neurobehavioural test batteries from Australia, Sweden, Britain, Finland and the United States, as well as two neurotoxic screening batteries from the United States, that have been used in studies of neurotoxin-exposed workers. In addition, the computerized Neurobehavioral Evaluation System (NES) and the Swedish Performance Evaluation System (SPES) have been extensively used around the world. There are also test batteries designed to assess sensory functions, including measures of vision, vibrotactile perception threshold, smell, hearing and sway (Mergler 1995). Studies of various neurotoxic agents using one or another of these batteries have greatly contributed to our knowledge of early neurotoxic impairment; however, cross-study comparisons have been difficult since different tests are used and tests with similar names may be administered using a different protocol.

In an attempt to standardize information from studies on neurotoxic substances, the notion of a “core” battery was put forward by a working committee of the World Health Organization (WHO) (Johnson 1987). Based on knowledge at the time of the meeting (1985), a series of tests were selected to make up the Neurobehavioral Core Test Battery (NCTB), a relatively inexpensive, hand-administered battery, which has been successfully used in many countries (Anger et al. 1993). The tests that make up this battery were chosen to cover specific nervous system domains, which had been previously shown to be sensitive to neurotoxic damage. A more recent core battery, which comprises both hand-administered and computerized tests, has been proposed by a workgroup of the United States Agency for Toxic Substances and Disease Registry (Hutchison et al. 1992). Both batteries are presented in Table 1.

Table 1. Examples of "core" batteries for assessment of early neurotoxic effects

Neurobehavioural Core Test Battery (NCTB)+

Test order

Agency for Toxic Substances and Disease Registry Adult Environmental Neurobehavioural Test Battery (AENTB)+

Functional domain



Functional domain


Motor steadiness

Aiming (Pursuit Aiming II)



Visual acuity, near contrast sensitivity

Attention/response speed

Simple Reaction Time



Colour vision (Lanthony D-15 desaturated test)

Perceptual motor speed

Digit Symbol (WAIS-R)



Vibrotactile perception threshold

Manual dexterity

Santa Ana (Helsinki Version)


Motor strength

Dynamometer (including fatigue assessment)

Visual perception/memory

Benton Visual Retention


Motor coordination

Santa Ana

Auditory memory

Digit Span (WAIS-R, WMS)


Higher intellectual function

Raven Progressive Matrices (Revised)


POMS (Profile of Mood States)


Motor coordination

Fingertapping Test (one hand)1



Sustained attention (cognitive), speed (motor)

Simple Reaction Time (SRT) (extended)1



Cognitive coding

Symbol-digit with delayed recall1



Learning and memory

Serial Digit Learning1



Index of educational level





Mood Scale1

1 Available in computerized version; WAIS = Wechsler Adult Intelligence Scale; WMS = Wechsler Memory Scale.


The authors of both core batteries stress that, although the batteries are useful to standardize results, they by no means provide complete assessment of nervous system functions. Additional tests should be used depending upon the type of exposure; for example, a test battery to assess nervous system dysfunction among manganese-exposed workers would include more tests of motor functions, particularly those that require rapid alternating movements, while one for methylmercury-exposed workers would include visual field testing. The choice of tests for any particular workplace should be made on the basis of current knowledge on the action of the particular toxin or toxins to which the persons are exposed.

More sophisticated test batteries, administered and interpreted by trained psychologists, are an important part of the clinical assessment for neurotoxic poisoning (Hart 1988). It includes tests of intellectual ability, attention, concentration and orientation, memory, visuo-perceptive, constructive and motor skills, language, conceptual and executive functions, and psychological well-being, as well as an assessment of possible malingering. The profile of the patient’s performance is examined in the light of past and present medical and psychological history, as well as exposure history. The final diagnosis is based on a constellation of deficits interpreted in relation to the type of exposure.

Measures of Emotional State and Personality

Studies of the effects of neurotoxic substances usually include measures of affective or personality disturbance, in the form of symptoms questionnaires, mood scales or personality indices. The NCTB, described above, includes the Profile of Mood States (POMS), a quantitative measure of mood. Using 65 qualifying adjectives of mood states over the past 8 days, the degrees of tension, depression, hostility, vigour, fatigue and confusion are derived. Most comparative workplace studies of neurotoxic exposure indicate differences between exposed and non-exposed. A recent study of styrene-exposed workers shows dose-response relations between post-shift urinary mandelic acid level, a biological indicator of styrene, and scale scores of tension, hostility, fatigue and confusion (Sassine et al. 1996).

Lengthier and more sophisticated tests of affect and personality, such as the Minnesota Multiphasic Personality Index (MMPI), which reflect both emotional states and personality traits, have been used primarily for clinical evaluation, but also in workplace studies. The MMPI likewise provides an assessment of symptom exaggeration and inconsistent responses. In a study of microelectronics workers with a history of exposure to neurotoxic substances, results from the MMPI indicated clinically significant levels of depression, anxiety, somatic concerns and disturbances of thinking (Bowler et al. 1991).

Electrophysiological Measures

Electrical activity generated by the transmission of information along nerve fibres and from one cell to another, can be recorded and used in the determination of what is happening in the nervous system of persons with toxic exposures. Interference with neuronal activity can slow down transmission or modify the electrical pattern. Electrophysiological recordings require precise instruments and are most frequently carried out in a laboratory or hospital setting. There have, however, been efforts to develop more portable equipment for use in workplace studies.

Electrophysiological measures record a global response of a large number of nerve fibres and/or fibres, and a fair amount of damage must exist before it can be adequately recorded. Thus, for most neurotoxic substances, symptoms, as well as sensory, motor and cognitive changes, usually can be detected in groups of exposed workers before electrophysiological differences are observed. For clinical examination of persons with suspected neurotoxic disorders, electrophysiological methods provide information concerning the type and extent of nervous system damage. A review of electrophysiological techniques used in the detection of early neurotoxicity in humans is provided by Seppalaïnen (1988).

The nerve conduction velocity of sensory nerves (going towards the brain) and motor nerves (going away from the brain) are measured by electroneurography (ENG). By stimulating at different anatomical positions and recording at another, the conduction velocity can be calculated. This technique can provide information about the large myelinated fibres; slowing of conduction velocity occurs when demyelination is present. Reduced conduction velocities have frequently been observed among lead-exposed workers, in the absence of neurological symptoms (Maizlish and Feo 1994). Slow conduction velocities of peripheral nerves have also been associated with other neurotoxins, such as mercury, hexacarbons, carbon disulphide, styrene, methyl-n-butyl ketone, methyl ethyl ketone, and certain solvent mixtures. The trigeminal nerve (a facial nerve) is affected by trichloroethylene exposure. However, if the toxic substance acts primarily on thinly myelinated or unmyelinated fibres, conduction velocities usually remain normal.

Electromyography (EMG) is used for measuring the electrical activity in muscles. Electromyographic abnormalities have been observed among workers with exposure to such substances as n-hexane, carbon disulphide, methyl-n-butyl ketone, mercury and certain pesticides. These changes are often accompanied by changes in ENG and symptoms of peripheral neuropathy.

Changes in brainwaves are evidenced by electroencephalography (EEG). In patients with organic solvent poisoning, local and diffuse slow wave abnormalities have been observed. Some studies report evidence of dose-related EEG alterations among active workers, with exposure to organic solvent mixtures, styrene and carbon disulphide. Organochlorine pesticides can cause epileptic seizures, with EEG abnormalities. EEG changes have been reported with long-term exposure to organophosphorus and zinc phosphide pesticides.

Evoked potentials (EP) provides another means of examining nervous system activity in response to a sensory stimulus. Recording electrodes are placed on the specific area of the brain that responds to the particular stimuli, and the latency and amplitude of the event-related slow potential are recorded. Increased latency and/or reduced peak amplitudes have been observed in response to visual, auditory and somatosensory stimuli for a wide range of neurotoxic substances.

Electrocardiography (ECG or EKG) records changes in the electrical conduction of the heart. Although it is not often used in studies of neurotoxic substances, changes in ECG waves have been observed among persons with exposure to trichloroethylene. Electro-oculographic (EOG) recordings of eye movements have shown alterations among workers with exposure to lead.

Brain Imaging Techniques

In recent years, different techniques have been developed for brain imaging. Computed tomographic (CT) images reveal the anatomy of the brain and spinal cord. They have been used to study cerebral atrophy among solvent-exposed workers and patients; however, the results are not consistent. Magnetic resonance imaging (MRI) examines the nervous system using a powerful magnetic field. It is particularly useful clinically to rule out an alternative diagnosis, such as brain tumours. Positron Emission Tomography (PET), which yields images of biochemical processes, has been successfully used to study changes in the brain induced by manganese intoxication. Single photon emission computed tomography (SPECT) provides information about brain metabolism and may prove to be an important tool in understanding how neurotoxins act on the brain. These techniques are all very costly, and not readily available in most hospitals or laboratories throughout the world.



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