Wenyuan Zhao

Electrophysiological Changes Induced by Different Doses of 1-Bromopropane and 2-Bromopropane

Electrophysiological Changes Induced by Different Doses of 1‐Bromopropane and 2‐Bromopropane: Wenyuan Zhao, et al. Department of Public Health and Hygiene, Oita Medical University—To ascertain the neurotoxicity of 2‐bromopropane and 1‐bromopropane, three doses of 2‐bromopropane (1.1, 3.7 and 11.0 mmol/kg), two doses of 1‐bromopropane (3.7 and 11.0 mmol/kg), and a dose of 2,5‐hexanedione (2,5‐HD) as a positive reference (2.6 mmol/kg) dissolved in olive oil were subcutaneously injected into rats once a day, 5 d/wk for 4 weeks. A control group were injected with olive oil alone. The maximum motor conduction velocity (MCV) and the motor latency (ML) in rat tail nerve, as indexes of the electrophysiological changes, were investigated for 4 weeks. From 2 weeks after the injections, the MCV in the 1‐bromopropane and 2‐bromopropane‐treated groups began to decrease in a dose‐dependent fashion. These dose‐related decreases continued, and the MCV in the groups injected with 1‐bromopropane (11.0 mmol/kg) and 2‐bromopropane (3.7 and 11.0 mmol/kg) decreased significantly compared with that in the control group. The ML in the 1‐bromopropane and 2‐bromopropane‐treated groups increased in reverse correlation with the MCV decreases. The changes in ML occurred earlier than the MCV changes in the 1‐bromopropane and 2‐bromopropane‐treated groups. The potency of the peripheral neurotoxic changes induced by 1‐bromopropane and 2‐bromopropane at the doses used in the present study was weaker than that observed in the positive reference 2,5‐HD (2.6 mmol/kg) group.

Different Administration Schedules of the Same Dose of 2,5- Hexanedione Influence the Development of Neuropathy and the Toxicokinetics

The same total dose (1.2 g/kg/week) of 2,5-hexanedione (2,5-HD) was administered subcutaneously at 100 mg/kg/12 hr, 200 mg/kg/24 hr, and 400 mg/kg/48 hr to three groups of Donryu rats. The peripheral neuropathy induced by 2,5-HD was confirmed by clinical observation every day, and neurophysiological measurements every 4 weeks. During the 15th week of this experiment, 2,5-HD concentrations in plasma 0.5 to 24 hours after injection were determined. It was found that the greater the dose of 2,5-HD per treatment injected, the earlier peripheral neuropathy developed. Toxicokinetic analysis showed that both the values of the area under the plasma concentration versus time curve and the half life of 2,5-HD were increased, but the excretion parameters (Ke) were decreased, in animals treated with 200 mg/kg/24 hr and 400 mg/kg/48 hr 2,5-HD.

Inhibition of vacuolation toxin activity of Helicobacter pylori by iodine, nitrite and potentiation by sodium chloride, sterigmatocystin and fluoride.

The toxin VacA produced by Helicobacter pylori is an important determinant of virulence. VacA causes vacuolation of cultured cells such as HeLa cells. Iodine, nitrite, sodium chloride, thiocyanate and fungus toxin sterigmatocystin are universally present in nature and could possibly be related to carcinogenesis of the stomach. The present study was designed to examine the effects of the above-mentioned compound on VacA-induced vacuolation of HeLa cells, which was quantitated using the neutral red uptake assay. VacA-induced vacuolation was inhibited by BafA1 and NPPB. Formation of large vacuoles was inhibited in the presence of iodine, nitrite, but enhanced by sodium chloride, thiocyanate, fluoride and sterigmatocystin. Our results indicate that VacA toxin may interact with other gastric cancer risk factors present naturally in the environment, and suggest that those compounds may modulate the development of gastric cancer induced by H. pylori.

Relationship Between 2,5-Hexanedione Concentrations in Nerve, Serum, and Urine Alone or Under Co-Treatment With Different Doses of Methyl Ethyl Ketone, Acetone, and Toluene

To ascertain the relationship among 2,5-hexanedione (2,5-HD) concentrations in nerve, serum and urine, rats were injected subcutaneously with 2.6 mmol/kg 2,5-HD alone, or together with 2.6 or 13.0 mmol/kg of methyl ethyl ketone, acetone and toluene. 2,5-HD concentrations in sciatic nerve (NC), serum (SC) and urine (UC) were determined, and the linear regression between each two of NC, SC, and UC were calculated. There was good correlation between NC and SC, SC and UC in the 2,5-HD alone group, and good correlation between NC and SC in the co-treated groups. Co-treatment solvent had little effect on the relationship between SC and NC. 13.0 mmol/kg co-treated solvent tended to decrease the regression coefficients compared with 2.6 mmol/kg co-treated solvent. These results show that SC can be used in estimating NC in the 2,5-HD alone or co-treated groups, and UC can be used in estimating SC in the 2,5-HD alone group.

Changes in 2,5-Hexanedione Concentration in the Sciatic Nerve, Serum and Urine of Rats Induced by Combined Administration of 2,5-Hexanedione with Acetone or Methyl Ethyl Ketone.

Changes in 2,5‐Hexanedione Concentration in the Sciatic Nerve, Serum and Urine of Rats Induced by Combined Administration of 2,5‐ Hexanedione or Methyl Ethyl Ketone: Kazuo Aoki, et al. Department of Public Health and Hygiene, Oita Medical University—To clarify whether there is a difference in the toxicokinetic changes in 2,5‐ hexanedione (2,5‐HD) on coadministration with acetone or methyl ethyl ketone (MEK), 108 rats were treated subcutaneously with 2,5‐HD at a dose of 2.6 mmol/kg alone (HD group), with 2,5‐HD and acetone both at 2.6 mmol/kg (HD + AC group), or with 2,5 ‐HD and MEK both at 2.6 mmol/kg (HD + MEK group). At 0.5, 1, 2, 4, 8, and 16 hours after injection, 2,5‐HD concentrations in serum, the sciatic nerve and urine (16 hours only) were determined and some toxicokinetic parameters were then estimated. The 2,5‐HD concentrations in serum and the sciatic nerve were significantly higher in both the coadministered groups at 16 hours, and the AUC (area under the serum or nerve concentration versus time curve) in serum and the sciatic nerve of both the coadministered groups increased significantly during 8 to 1 6 hours compared with the 2,5‐HD alone group. The differences in urinary 2,5‐HD concentrations among the three groups were at the marginal level for significance by ANOVA (p = 0.053), but the values for the total amount of urinary 2,5‐HD within 16 hours were not significantly different (p = 0.55) among the three groups. There were good correlations between 2,5‐HD concentrations in the sciatic nerve and those in serum in the three groups (r = 0.91, r = 0.91 and r = 0.85 for HD, HD + AC and HD + MEK groups, respectively). The ratios of 2,5‐HD concentration in the sciatic nerve/2,5‐HD concentration in serum were not significantly different among the three groups (0.17, 0.19 and 0.20 for HD, HD + AC and HD + MEK groups, respectively). The estimated biological halflife t1/2 in the HD + AC group was prolonged significantly as was that in the HD + MEK group when compared with that in the HD alone group. The retarded elimination of 2,5‐HD from serum seemed not to be directly related to urinary excretion in the coadministered groups. The present study revealed that the coadministration of 2,5‐HD with acetone produced similar toxicokinetic changes in serum and in the sciatic nerve as that with MEK. It was suggested that the retardation of disappearance of 2,5‐HD from serum and the sciatic nerve on administration of a combination of 2,5‐HD with acetone was not related to urinary excretion but to the overloading of the metabolic capacity of 2,5‐HD in the liver.

Neurophysiological Changes in Rats Subchronically Treated with Styrene or Its Metabolites.

Neurophysiological Changes in Rats Subchronically Treated with Styrene or Its Metabolites: Junichi Misumi, et al. Department of Public Health and Hygiene, Oita Medical University—The purpose of this study was to clarify the causative agent(s) in the peripheral neuropathy induced by styrene. Styrene 600 or 300, and its metabolites; hippuric acid 600 or 300; mandelic acid 300; styrene oxide 100; mg/kg were subcutaneously injected into rats for 10 to 12 wk. The changes in maximum sensory conduction velocity (SCV), maximum motor conduction velocity (MCV), and motor distal latency (DL) in the rats tail nerve were tested. Compared with the control group, decreases in MCV, SCV, and an increase in DL were observed in the rats injected with styrene 600, styrene oxide 100 and mandelic acid 300 mg/kg. No significant changes were found in the rats treated with hippuric acid 300 or 600 mg/kg. The MCV and SCV values in the styrene oxide 100 and mandelic acid 300 mg/kg groups were significantly lower, and DL values were significantly longer than those in the styrene 600 mg/kg group. It is presumed that the neuropathy caused by styrene is related to the neurotoxicity of its intermediate metabolites, namely mandelic acid and styrene oxide. It appears that the neurotoxicity of mandelic acid needs to be further evaluated in styrene‐produced neuropathy.

Electrophysiological and Biochemical Effects of Exposure to 2,5-Hexanedione on Peripheral Nerve in Experimental Diabetic Rats.

Electrophysiological and Biochemical Effects of Exposure to 2,5‐Hexanedione on Peripheral Nerve in Experimental Diabetic Rats: Takashi Kimura, et al. Department of Public Health and Hygiene, Oita Medical University—Both 2,5‐ hexanedione (2,5‐HD) and diabetes mellitus (DM) cause peripheral neuropathy. Workers with asymptomatic DM could possibly be exposed to n‐ hexane converted to 2,5‐HD in liver. To clarify 2,5‐HD influences on peripheral nerves in DM, electrophysiological and biochemical changes in DM rats were compared in 2,5‐HD treated and untreated groups. Four groups of rats were studied: the Control group consisted of non‐diabetic rats treated with a placebo: the HD group, of non‐diabetic rats treated with 2.5‐HD; the DM group, of diabetic rats treated with a placebo: the DM+HD group, of diabetic rats treated with 2.5‐HD. 2,5‐HD was administered at 100 mg/kg/day, five days a week for 8 weeks. The motor nerve conduction velocity (MCV) and motor distal latency (DL) in the rat s tails and glucose, fructose, sorbitol and myo‐ inositol levels in the sciatic nerves were measured. The MCV in the DM+HD group was significantly reduced from the 4th week compared with those in the other groups. 2,5‐HD had no influence on the levels of glucose, fructose, sorbitol and myo‐inositol in either the diabetic or non‐diabetic group. These results indicated that exposure to 2,5‐HD hastened the onset of peripheral neuropathy in experimental diabetic rats. This study indicates that 2,5‐HD in combination with DM enhances the neurotoxicity. But the mechanisms of the neurotoxic interactions between 2,5‐HD and DM are still unknown. It can be hypothesized that workers with hyperglycemia can suffer from neuropathy due to exposure to n‐hexane earlier than those without hyperglycemia.

Does the Exposure to 2, 5-Hexanedione Hasten the Onset of Peripheral Neuropathy in Streptozotocin-Induced Diabetic Rats?

g (mean ± SD), were randomly allocated to diabetic and normal (non-diabetic) groups (12 in each group). The rats allocated to the diabetic group were injected intraperitoneally with streptozotocin at a dose of 60 mg/kg to induce diabetes. Two weeks after the injection, 11 rats whose nonfasting serum glucose concentrations were higher than 250 mg/dl were assigned to the diabetic group. Five diabetic rats were subcutaneously injected in the back with 2,5-HD (100 mg/ kg/day) dissolved in 0.2 ml of 0.9% NaCl solution, five days a week, for 6 weeks (group DM + HD). The remaining 6 diabetic rats were injected with 0.2 ml of 0.9% NaCI solution alone and allocated as diabetic controls (group DM). The 12 normal non-diabetic rats were also subdivided into two groups, one group of 6 rats were treated with 2,5-HD (100 mg/kg/ day) in the same manner as the DM + HD group rats (group HD), and the remaining 6 rats were injected with 0.2 ml of 0.9% NaCI solution alone and allocated to the control group. The rats were fed CE-2 rat chow (Clea Company Japan) and water ad libitum. Electrophysiological examinations The measurements of motor nerve conduction velocity