Izumi Harabuchi

Neurobehavioural effects and pharmacokinetics of toluene in rats and their relevance to man.

The present study was designed to determine the critical concentrations in blood and brain associated with specific behavioural changes during and after exposure to toluene. The effects of a single four hour exposure to toluene on signalled bar press shock avoidance in rats were tested. Rats exposed to 125, 250, and 500 ppm toluene showed a decline in conditioned avoidance responses at 20 minutes exposure compared with the pre-exposure baseline, although they recovered to almost the same level of performance as that before exposure. Exposure to 1000 ppm toluene for about four hours and 2000 ppm for two hours produced a concentration related increase in incorrect responses, acceleration of the reaction time, and decreases in the effective avoidance response rate. Beginning at 4000 ppm toluene exposure, the response rate increased; thereafter, it gradually decreased and finally slight ataxia was observed. After 4000 ppm exposure, all rats showed signs of excitation such as a pronounced increase in response rate. From analysis of the temporal courses of the blood and brain toluene concentrations during and after each exposure, excitative performance decrements were noticed in rats with blood and brain concentrations about 27 micrograms/ml blood and 32 micrograms/g respectively. Anaesthetic performance decrements were seen when the blood toluene concentration increased to 120 micrograms/ml and that of the brain reached about 160 micrograms/g. According to our results, the effects on the central nervous system are considered to be a function of both the exposure concentration and its duration, which are closely related to the increase of brain and blood toluene concentration.

Impaired colour discrimination among workers exposed to styrene : relevance of a urinary metabolite

OBJECTIVES--To survey the loss of colour vision among Japanese workers who have been exposed to styrene concentrations currently considered low (about 20 ppm). Also to assess the effects of styrene by examination of the nature of the relation between disorder of colour vision and age, alcohol consumption, and other variables. METHODS--Colour discrimination was examined in 64 male workers exposed to styrene (mean age; 38.0, mean exposed years; 7.0) and in 69 controls (mean age; 38.0). A standardised questionnaire was adopted to collect work history, occupational or non-occupational solvent exposure, alcohol consumption, and drug use. Colour vision was evaluated by the Lanthony desaturated panel D-15 test. The results of the test were expressed as the colour confusion index (CCI). RESULTS--The mean atmospheric styrene concentration was about 20 ppm. The mean urinary concentration of mandelic acid was 0.22 g/l. There was a significant difference in CCI between exposed workers and age matched controls. Colour vision of workers whose concentration of urinary mandelic acid was > or = 0.42 g/l was significantly impaired when compared with workers whose concentration was < 0.42 g/l. Multiple linear regression analysis that controlled confounding variables such as age, alcohol consumption, smoking, and educational attainment showed that the CCI was significantly related to the concentration of urinary mandelic acid. In both exposed workers and controls, the types of defects were mostly blue-yellow loss, although a few subjects showed complex loss. No one showed only red-green loss. CONCLUSIONS--These findings suggest that exposure to moderate styrene concentrations can lead to impairment of colour vision, and that there is a significant correlation with the urinary metabolite of styrene.

Exposure monitoring and health effect studies of workers occupationally exposed to cyclohexane vapor.

SummaryA survey was conducted in the second half of a working week on 33 women who either applied glue (with cyclohexane as an almost exclusive solvent component) or worked in the vicinity of glue application. Carbon cloth-equipped diffusive samplers were used for personal measurement of time-weighted average intensity of exposure to the solvent. The geometric mean and the highest cyclohexane concentration observed in air were 27 ppm and 274 ppm, respectively. Concentrations of cyclohexanol in urine samples and cyclohexane in whole blood and serum collected at the end of a shift showed significant correlations with the solvent exposure levels. Urinary cyclohexanone also correlated, but with a smaller correlation coefficient. The observation suggests that cyclohexanol in urine and cyclohexane in blood or serum collected at the end of a shift are useful indicators of occupational exposure to cyclohexane vapor. Quantitative estimation of balance at the end of the shift suggested that only a minute portion (< 1%) of cyclohexane absorbed is excreted in the urine as cyclohexanol, almost exclusively as a glucuronide. A survey of subjective symptoms revealed an increase in the prevalence of “dimmed vision” and “unusual smell”, but hematology and serum biochemistry testing did not indicate any specific signs.

Study of urinary mandelic acid concentration and peripheral nerve conduction among styrene workers

The relationship between exposure to styrene and nerve conduction velocities was investigated in 32 workers occupationally exposed to styrene. There was a dose-dependent relationship between urinary mandelic acid and ulnar and peroneal motor distal latencies (MDLs). The ulnar and peroneal MDLs of subgroup B (urinary mandelic acid > or = 250 mg/l) were significantly longer than those of subgroup A (urinary mandelic acid < 250 mg/l)(p < 0.05), and the referent group (p < 0.03). After adjusting confounding factors, urinary mandelic acid had a significant positive relationship with ulnar and peroneal MDL. Our study suggests that a low level of styrene, below the 50 ppm exposure limit of the American Conference of Governmental Industrial Hygienists (ACGIH), involves the risk of inducing adverse effects on the peripheral nervous system. The study also indicated that motor distal latency is a sensitive parameter of toxic peripheral neuropathy.

Acute effects of trichloroethylene on blood concentrations and performance decrements in rats and their relevance to humans.

This study was designed to clarify the nature of effects of trichloroethylene (TCE) on the central nervous system, and to determine the critical concentrations in blood associated with specific behavioural changes. This was achieved by a follow up of the whole time course of TCE intoxication during and after exposure. The effects of a single four hour exposure to TCE on signalled bar press shock avoidance in rats were tested by methods previously applied to investigate the acute neurobehavioural effects of exposure to toluene. Even low exposure to TCE induced shock avoidance performance decrements in rats. Rats exposed to 250 ppm TCE showed a significant decrease both in the total number of lever presses and in avoidance responses at 140 minutes of exposure compared with controls. The rats did not recover their pre-exposure performance until 140 minutes after the exhaustion of TCE vapour. Exposures in the range 250 ppm to 2000 ppm TCE for four hours produced concentration related decreases in the avoidance response rate. No apparent acceleration of the reaction time was seen during exposure to 1000 or 2000 ppm TCE. The latency to a light signal was somewhat prolonged during the exposure to 2000 to 4000 ppm TCE. It is estimated that there was depression of the central nervous system with slight performance decrements and the corresponding blood concentration was 40 micrograms/ml during exposure. Depression of the central nervous system with anaesthetic performance decrements was produced by a blood TCE concentration of about 100 micrograms/ml. These results showed effects of TCE on the central nervous system that were considered to be a function of both the exposure concentration and the duration of exposure, which are closely related to the TCE concentration in blood.

Symptoms among workers with long-term exposure to methyl bromide.

Symptoms as an important sign of the effects of methyl bromide were studied in 56 male workers (37 currently exposed and 19 previously exposed) in a methyl bromide factory. The workers were 18 to 62 yr of age (mean age: 41) and were exposed from 1 to 25 yr (mean: 7 yr). They were compared to 56 age-matched referents with a standardized questionnaire. The results of pairwise comparison of the symptoms of the age-matched pairs of exposed and referent subjects showed that the occurrence of dizziness, numbness, paresthesia and weakness of extremities, nightmares, fatigue and dry and scaly skin was statistically significantly higher among the workers than among the referents. When the symptoms during the work shift (acute symptoms) were compared, irritation symptoms such as itching, bullae or reddish swollen hands and runny noses with nasal irritation were reported significantly more often in the exposed groups. The correlation of the symptoms among the exposed workers suggested that chronic symptoms are closely related to acute irritation symptoms and exposure duration. The results suggest that symptom inquiry is useful for detecting the possible effects of exposure to methyl bromide.

Effects of trichloroethylene exposure on hearing

SummaryFour groups of guinea pigs with normal Preyers reflex were exposed to trichloroethylene (TCE). Each group consisted of nine to 10 naive male albino Hartley guinea pigs of 9 weeks of age with a body weight of approximately 400 g.To test the suggestion that TCE causes damage to the cochlear system, a study was conducted involving four experiments.The results were as follows: No significant difference was observed between the intensity functions of the CM (4 kHz) and AP (7 kHz) potentials of the control groups and those of the TCE-exposed groups by analysis of variance. It was considered that there was no difference in the cochlear reaction to high frequency sound between guinea pig and man. It therefore might be suggested that acute exposure to TCE of a high concentration does not always induce dysfunction of the organ of Corti and the 8th nerve in man.

Investigation on neurotoxicity of occupational exposure to cyclohexane: a neurophysiological study

OBJECTIVES: To examine the effect of occupational exposure to cyclohexane on the peripheral nervous system. METHODS: A nerve conduction study was performed on 18 workers exposed to cyclohexane in a luggage factory and on age and sex matched occupationally unexposed controls. 12 workers had been exposed to n-hexane (median 2.8 years) before the start of exposure to cyclohexane. To confirm the effect of exposure, a follow up study was performed on nine workers one year after the first study. The mean exposure to cyclohexane was 1.2 years in the first study. A symptom survey was performed. The exposure was measured by air sampling of the breathing zone of each worker. The urinary metabolite cyclohexanol was also monitored. RESULTS: The concentration of airborne cyclohexane ranged from 5 to 211 ppm. The urinary concentration of cyclohexanol ranged from 0.12 to 1.51 mg/l. There was a strong correlation between the cyclohexane exposure in personal air and urinary cyclohexanol. No differences were found in nerve conduction velocities (NCV) between workers exposed to cyclohexane and age and sex matched controls. The results of the follow up study showed significant improvements in peroneal motor NCV (P < 0.01) and sural sensory NCV (P < 0.05) and in ulnar motor distal latency (MDL, P < 0.05) and peroneal MDL (P < 0.05) compared with the first study. Although the past n-hexane exposure affected the first neurophysiological study, the effect had disappeared in the second study, one year later. CONCLUSION: Occupational exposure to the concentrations of cyclohexane experienced in this study had no adverse effects on the peripheral nervous system.

Effect of Infrasound and Low Frequency Sound Exposure at Intensities below 100 dB(SPL) on the Rota-Rod Treadmill Performance of Guinea Pigs

A preliminary study to investigate whether or not long-term exposure to very low frequency sound at a moderate intensity below 100 dB(SPL) affects the vestibular function and/or motor coordination in guinea pigs was carried out. At first, optimal conditions of Rota-Rod Treadmill performance for guinea pigs were determined. Then, 20 and 40 Hz-low frequency sound at 80–90 dB(SPL) exposure was used for 150 minutes and measurement of the endurance time on the Rota-Rod Treadmill was carried out at rotation speeds of 8 rpm or 10 rpm. At 10 rpm rotation speed, and 20 Hz, 90 dB(SPL) stimulus, the endurance time was significantly reduced at 150 minutes, compared with that of the control, whereas no significant reduction in endurance time was obtained at 85 dB(SPL).

Effects of 8 hour exposure to 40 Hz and 80 Hz low frequency sound at intensities below 100 dB (SPL) on the Rota-Rod Treadmill performance of guinea pigs

Taking fieldwork reports into consideration, an experiment was designed to evaluate the effects of low frequency sound exposure on the vestibular and/or motor coordination of guinea pigs. For 8 hour exposure, 40 Hz at 80 dB(SPL) and 80 Hz at 80 dB(SPL) stimuli, caused significant reductions of the endurance time of the poor performing group on the Rota-Rod Treadmill from 240th to 360th minute and to the 240th minute, respectively. When the intensities were stronger, the changes in the endurance times showed similar patterns to that in the control. In addition, the endurance times at the 480th minute recovered almost to the pre-exposure levels in all conditions of exposure tested.