Richard Tham

Otoneurological Findings in Psycho-organic Syndrome Caused by Industrial Solvent Exposure

Nine subjects with long-term (8-30 years) occupational exposure to industrial solvents and a confirmed diagnosis of psycho-organic syndrome (POS) have been studied with audiological and otoneurological test batteries. The results were compared to a matched control group of nine industrial workers not exposed to solvents and to normal data from healthy volunteers. In the clinical examination, the Romberg test identified 5/9 workers as pathologic and concurrently the stabilometry showed significantly larger sway areas in the POS-group. In the audiological test battery, the significantly pathologic tests were discrimination of interrupted speech and evoked cortical responses to frequency glides (CRA-delta-f). The saccade test disclosed abnormal findings in 5/9 workers. In the smooth pursuit test, abnormality was found at some test frequencies using pseudorandomized stimulus. The VOR-suppression test was significantly abnormal at all test frequencies. The test battery used strongly indicates CNS lesions due to industrial solvents.

Effects of toluene, styrene, trichloroethylene, and trichloroethane on the vestibulo- and opto-oculo motor system in rats

The acute effects of inhalation of four solvents on the central vestibular system of rats were analyzed by recording eye movements upon different stimuli. The dose-response relationship was investigated. Optokinetic stimulation was obtained by placing the animals in front of a surrounding visual pattern, moving at different velocities. The slow-phase eye velocity (SPV) of nystagmus was calculated and divided by the stimulus velocity, giving the gain. All the solvents caused a decrease of the gain. Vestibular stimulation was performed on a turntable by an angular acceleration/deceleration in darkness. The SPV and the duration of the post-stimulatory nystagmus were calculated. The shape of the SPV dose-response curves differed among the four solvents. Toluene, styrene, and trichloroethylene prolonged the duration of nystagmus while trichloroethane did not. A conflicting vestibular and optokinetic stimulation was performed by an angular acceleration/deceleration with a surrounding visual pattern moving with the turntable. All solvents decreased the ability to cancel nystagmus, elicited by vestibular stimulation in conflict with a visual input. Quick movements of the eyes, saccades, were elicited by tactile stimulation. Toluene, styrene, and trichloroethylene changed the generation of the saccades while trichloroethane did not. Most of the findings indicate a common site of action in the central vestibular system, viz, the cerebellar-vestibular circuit. However, within this domain, there are evident differences in the effects among the solvents. This findings, together with previous results obtained in other experimental models of the central nervous system (CNS), suggest that different solvents should be considered as individual compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Early compensation of vestibulo-oculomotor symptoms after unilateral vestibular loss in rats is related to GABAB receptor function

The horizontal vestibulo-oculomotor reflex was studied in pigmented rats during the first 5 days after a unilateral chemical or surgical vestibular deafferentation. Spontaneous eye movements in darkness and slow phase velocity gain of compensatory eye movements during horizontal sinusoidal rotation were evaluated. The most evident vestibulo-oculomotor symptom immediately after a unilateral vestibular loss was a spontaneous nystagmus, which gradually abated during the following days. Further, an asymmetry between ipsi- and contra-lesional gains was evident during sinusoidal vestibular stimulation. Single systemic doses of the GABA(B) receptor antagonist [3-[1-(S)-[[3-(cyclohexylmethyl)-hydroxyphosphinoyl]-2-(S)-hydroxypropyl]amino]ethyl]-benzoic acid (CGP 56433A), the agonist baclofen, or the GABA(A) receptor agonist (4,5,6,7-tetrahydroisoxazolo-[5,4-c]-pyridin-3-ol (THIP) were given at different intervals after unilateral vestibular deafferentation. CGP 56433A highly aggravated the vestibulo-oculomotor symptoms, observed as an increase in spontaneous nystagmus and slow phase velocity gain asymmetry. This effect was most pronounced during the first 2 days after unilateral vestibular loss, when CGP 56433A even decompensated the vestibular system to the extent that all vestibular responses were abolished. Baclofen caused no effect during the first days after unilateral vestibular loss, but in parallel with the abatement of spontaneous nystagmus, the drug equilibrated or even reversed the remaining spontaneous nystagmus with corresponding effects on the slow-phase velocity gain asymmetry. The effects of baclofen were very similar after both chemical and surgical deafferentation. THIP caused a slight depression of all vestibular responses. All single dose effects of the drugs were transient. Altogether these results reveal that endogenous stimulation of GABA(B) receptors in GABA-ergic vestibulo-oculomotor circuits are important for reducing the vestibular asymmetry during the early period after unilateral vestibular deafferentation. A possible role for GABA(B) receptors in the reciprocal inhibitory commissural pathways in the vestibular nuclei is suggested.

Audiological Disturbances Caused by Long-term Exposure to Industrial Solvents. Relation to the Diagnosis of Toxic Encephalopathy

Sixty workers, consecutively admitted due to suspicion of solvent-induced chronic toxic encephalopathy (CTE), were investigated with pure-tone audiometry, determination of speech recognition of monosyllabic words and distorted speech and cortical response audiometry (CRA). Eighteen workers not exposed to occupational solvents and noise were also investigated. The scores in the distorted speech test were significantly lower and the CRA latencies were significantly longer in the solvent group than in the control group. There was no difference between the groups in the pure-tone and monosyllabic speech recognition tests. In the solvent group, 19 subjects had one or several pathological audiological test results (values exceeding the mean result of the control group by 2 SD). Independently of the audiological examination all the workers in the solvent group underwent the traditional clinical assessment of CTE, which is based on symptoms, history of exposure, clinical neurological examination and a neuropsychological investigation. They were classified in three groups--CTE, incipient CTE and non-CTE. There was no correlation between these groups and the audiological test results. A previous report on vestibular pathology in the same group of subjects and the present investigation on hearing deficits suggest that long-term exposure to solvents causes disturbances of the central pathways in the otovestibular system. Hitherto, no attention has been paid to these disturbances in the definition of the CTE syndrome.

Impairment of Visuo-Vestibular Interaction in Humans Exposed to Toluene

15 healthy volunteers were investigated in a vestibulo-oculomotor test battery during toluene exposure. The concentration was comparable to the threshold limit value. The results were compared to an identical air experiment. The intoxication caused an impaired visual suppression during a pseudo-random oscillatory swing test and also an increased saccade speed. Other vestibular-oculomotor parameters were normal. The findings are in accordance with our earlier study on styrene in humans, showing that the visual suppression test and the saccade test are sensitive parameters assessing neurotoxic influences by organic solvents.

Effects of the GABA agonists baclofen and THIP on long-term compensation in hemilabyrinthectomised rats.

Horizontal eye movements, elicited by sinusoidal rotation in darkness, were recorded with a magnetic search coil technique in pigmented rats, hemilabyrinthectomised 8-12 weeks before the investigation. Separate gains during rotation towards the lesioned side (LS) and the intact side (IS) were calculated by a computer program, demonstrating an asymmetry. Systemic single administration of the GABAB agonist baclofen caused a dose-related temporary rebalancing of the compensatory eye movements to the LS and the IS. At an optimal dose of 14 micromol/kg b.wt symmetry was achieved by excitation of eye movements during rotation to the LS and depression during rotation to the IS. Administration of the GABAA agonist THIP did not obviously reduce the asymmetry. It is suggested that stimulation of GABAB receptors modifies the tonic imbalance between the bilateral vestibular nuclei and/or the central processing of the input from the peripheral sensory organs.

Vestibulo-oculomotor disturbances caused by industrial solvents.

Animal experiments show that intoxication with hydrocarbon solvents influences the vestibulo-oculomotor reflex arc and indicate that the solvents block the inhibition of the vestibulo-oculomotor reflex presumably exerted by the cerebellum. The blood concentrations necessary to elicit oculomotor disturbances in animals were smaller than those that disturbed the vestibular function. Accordingly, in human experiments styrene and toluene exposure did not elicit any positional nystagmus but caused an increased saccade speed and a diminished visual suppression of vestibular nystagmus. Some cerebellar clinical pathologic process in patients who suffer from a psycho-organic syndrome caused by solvents leads us to believe that the cerebellum might be the most vulnerable part of the brain. Some patients had a positional nystagmus, but the most prominent pathologic signs were elicited by the visual suppression test. Our findings compare well with the increased saccade speed and diminished visual suppression in patients with cerebellar tumors and infarctions.

Vestibulo-oculomotor disturbances in humans exposed to styrene.

Several reports indicate that disturbances of the vestibulo-oculomotor ability are a manifestation of the toxic action on the central nervous system exerted by some industrial solvents. The aim of the present investigation was to examine the vestibulo-oculomotor system during exposure to styrene, which is extensively used in the production of plastics. Healthy volunteers were exposed to styrene for one hour. Rotatory and optokinetic nystagmus, visual suppression as well as speed, latency and accuracy of saccades were tested before, during, and one hour after the exposure. The pulmonary uptake and the blood level of the solvent were continuously analysed by gas chromatography. The styrene blood concentration was equivalent to that which may well be reached after serveral hours of hard work in an industrial environment with a concentration of styrene within permitted limits. No spontaneous nystagmus appeared. The rotatory and optokinetic nystagmus was not influenced by styrene. However, the speed of the saccade was significantly enhanced. The visual suppression was disturbed, shown by an increased gain after styrene exposure. The experiments thus indicate that styrene given to healthy test persons induced disturbances, thus consistent with the theory that some organic solvents block the cerebellar inhibition of the vestibulo-oculomotor system.

Xylene Exposure Electronystagmographic and Gaschromatographic Studies in Rabbits

Complaints of vertigo from people who are exposed to industrial solvents have focused interest on their toxic effect on the nervous system. In order to evaluate the influence of an organic solvent, xylene, on the mammalian vestibular system, a series of rabbit experiments were performed. To achieve a constant concentration, the xylene was infused as a lipid emulsion. Blood concentrations were estimated by gas chromatography. Elec-tronystagmography in darkness revealed that at blood xylene concentrations of 30 ppm all rabbits had a positional nystagmus. The beat direction was the opposite of positional alcohol nystagmus. Another difference between the alcohol and the xylene reaction was that rotatory nystagmus responses were exaggerated. The relations between the present findings and the reactions and blood concentrations in people exposed to industrial solvents are discussed.

Effects of toluene on tonic firing and membrane properties of rat medial vestibular nucleus neurones in vitro

The effects of toluene on discharge rate and membrane properties of tonically active medial vestibular nucleus (MVN) neurones were investigated in an in vitro slice preparation of the dorsal brainstem of the rat. The majority of the cells (50/56) were inhibited in a dose-dependent manner by toluene. The inhibitory effects of toluene persisted after blockade of synaptic transmission. Complementary patch-clamp recordings showed that toluene caused a hyperpolarisation of 2-5 mV associated with an increase in membrane conductance. These findings indicate that toluene might interfere with specific ion channels or the receptors regulating them along the cell membrane. The effective toluene concentrations used in this experiment are comparable to the concentrations producing vestibulo-ocular disturbances in vivo.