[Occupational neurotoxicology due to heavy metals-especially manganese poisoning].

The most hazardous manganese exposures occur in mining and smelting of ore. Recently, the poisoning has been frequently reported to be associated with welding. In occupational exposure, manganese is absorbed mainly by inhalation. Manganese preferentially accumulates in tissues rich in mitochondria. It also penetrates the blood brain barrior and accumulate in the basal ganglia, especially the globus pallidus, but also the striatum. Manganese poisoning is clinically characterized by the central nervous system involvement including psychiatric symptomes, extrapyramidal signs, and less frequently other neurological manifestations, Psychiatric symptomes are well described in the manganese miners and incrude sleep disturbance, disorientation, emotional lability, compulsive acts, hallucinations, illusions, and delusions. The main characteristic manifestations usually begin shortly after the appearance of these psychiatric symptomes. The latter neurological signs are progressive bradykinesia, dystonia, and disturbance of gait. Bradykinesia is one of the most important findings. There is a remarkable slowing of both active and passive movements of the extremities. Micrographia is frequently observed and a characteristic finding. The patients may show some symmetrical tremor, which usually not so marked. The dystonic posture of the limbs is often accompanied by painfull cramps. This attitudal hypertonia has a tenndency to decrease or disappear in the supine position and to increase in orthostation. Cog-wheel rigidity is also elisited on the passive movement of all extremities. Gait disturbance is also characteristic in this poisoning. In the severe cases, cook gait has been reported. The patient uses small steps, but has a tendency to elevate the heels and to rotate them outward. He progress without pressing on the flat of his feet, but only upon the metatarsophalangeal articulations, mainly of the fourth and fifth toes. Increased signal in T1-weighted image in the basal ganglia has been reported in patients with the poisoning. Thus, increasd signal intensities as a target site dose can be a more useful biomakers of the manganese than other biological indicies such as ambient manganese concentration or blood manganese concentration on individual basis. Manganese poisoning ultimately becomes chronic. However, if the disease is diagnosed while still at the early stages and the patient is removed from exposure, the course may be reversed. Once well established, it becomes progressive and irreversible, even when exposure is terminated. Levodopa therapy is not effective for the management of manganese poisoning. Levodopa unresponsiveness may be usefull to distinguish manganese-induced parkinsonism from Parkinson disease.

High-performance liquid chromatographic-mass spectrometric determination of methamphetamine and amphetamine enantiomers, desmethylselegiline and selegiline, in hair samples of long-term methamphetamine abusers or selegiline users.

We devised a highly sensitive method for simultaneously determining methamphetamine (MA) and amphetamine (AP) enantiomers, desmethylselegiline (DMSG) and selegiline (SG), in human hair using a derivatization technique and high-performance liquid chromatography-electrospray ionization-mass spectrometry (HPLC-ESI-MS). MA and AP enantiomers and DMSG were effectively converted to trifluoroacetic acid (TFA) derivatives, and the sensitivity of MA and DMSG increased five times over compared with that of free bases. The TFA derivatives of each compound were stable within one week in a stock solution of methanol or for 24 h in the HPLC mobile phase (mixture of methanol and ammonium formate buffer). Each compound was well separated, and calibration curves were linear in the concentration range 0.04-40 ng/mg for MA enantiomers, SG and DMSG, and 0.2-40 ng/mg for AP enantiomers. The accuracy and precision of the method were evaluated, and relative standard deviations were within 7%. Our method was successfully applied to hair samples obtained from long-term MA abusers and SG users. (+)-MA and (+)-AP were detected from three MA abusers at concentrations of 0.79-20.85 and 0.04-3.30 ng/mg, respectively. On the other hand, (-)-MA, (-)-AP, DMSG, and SG were detected in three SG users at concentrations of 2.48-9.05, 0.72-3.10, 0.12-0.59, and 0-0.04 ng/mg, respectively. Based on our obtained data, discrimination of MA abusers from SG users was considered to be possible by comparing optical isomers of MA and AP, the existence of DMSG and/or SG, and the concentration ratio of AP to MA in hair samples.

Distribution of tributyltin, dibutyltin and monobutyltin in the liver, brain and fat of rats: two-generation toxicity study of tributyltin chloride.

The distribution of tributyltin (TBT) and its metabolites, dibutyltin (DBT) and monobutyltin (MBT), was examined in the liver, brain and fat tissues in a two-generation reproductive toxicity study of tributyltin chloride (TBTCl) in rats using dietary supplementation at concentrations of 5, 25 and 125 ppm. In the liver, irrespective of TBTCl dietary concentration, gender or generation, the highest concentration of metabolite was consistently MBT, followed by DBT, and then TBT. In contrast, TBT was consistently present at the highest concentration in the brain, nearly always followed by DBT and MBT. In fat tissues, the concentrations of the three butyltin compounds showed similar relationships to those observed in the brain, although the concentrations were much lower. In the liver, the concentration of TBT was higher in females, and those of DBT and MBT were higher in males. Factorial ANOVA also suggested the effect of gender on the concentrations of the three butyltin compounds in the liver. The results of this study suggest tissue-dependent distribution of TBT, DBT and MBT and gender-dependent distribution of the three metabolites in the liver of rats.

Systemic effects of orally administered p, p'-DDE on immature male Wistar rats during pubertal period.

Systemic effects of p, p'-DDE (1, 1-dichloro-2, 2 bis (p-chlorophenyl) ethylene; DDE) on immature male rats were investigated in pubertal Wistar rats after oral administration of DDE. Special rat chow containing 125 ppm DDE (approximately 10 mg/kg DDE) had been administered daily for 42 d since 6 wk of age and its effects had been observed until 12 wk of age. The administration of DDE did not produce any overt signs of toxicity. Neither physical development nor sexual maturation was affected, and serum biochemistry was not impaired at the dose used in this experiment. Moreover, the male reproductive organs and epididymal sperm count were not affected by the administration of DDE during the pubertal period. Our results showed that even immature male rats were resistant to DDE exposure at the daily dose of ca. 10 mg/kg, but metabolic and immunological changes still remained uncertain. Further investigation should be conducted to reveal all the effects of DDE on immature male rats.

Systemic toxicity of p,p'-DDE in aged male Wistar rats following oral administration.

Systemic toxicity of p,p'-DDE (DDE) in aged male rats was investigated in Wistar rats by oral administration of DDE. About 10 mg/kg DDE had been daily administered for 28 days from 48 weeks to 52 weeks of age and its effects were observed subsequently. The administration of DDE did not give rise to any overt signs of toxicity. Male reproductive organs were not affected and serum biochemistry was not impaired at the dose of this experiment. Organ weights of the liver and spleen slightly increased and the thymus weight reduced with DDE administration. Serum total cholesterol and free T4 levels slightly decreased with DDE administration, albeit statistically insignificant. Our results indicated that even aged male rats were resistant to DDE exposure at the daily dose of ca. 10 mg/kg. However, metabolic and immunological changes still remained uncertain. Further investigation should be performed to reveal the entire effects of DDE on aged male rats.

[Neurological effects of chemical and biological weapons].

Neurological manifestations of chemical and biological weapons are reviewed. Nerve agents in current use, storage, or production include tabun, sarin, soman and VX. The initial effects of exposure to a nerve agent depend on the dose and on the route of exposure. Sarin, the agent studied most thoroughly in man in Matumoto and Tokyo attacked by Aum shinrikyo will cause miosis, rhinorrehea and shortness of breath are initial complaints immediately after inhalation exposure of the vapor. The severe cases showed loss of consciousness and convulsions. Respiratory arrest may occur. The most toxic of the nerve agents is VX. It is thought to be 100 times as toxic as sarin for humans by the percutaneous rout. The similar findings to sarin exposure are also observed in cases exposured to VX. Atropin and PAM will be effective in the early stage. BZ (benzilate) is a delayed onset incapacitation agent. It causes severe hallucination. The cyanide compounds are among the most rapidly acting of war gases, resulting in death. Anthrax has been the most attractive biological weapon for a long time. Anthrax is an acute bacterial infection of the skin and lungs in man and animals. Meningoencephalitis has been reported in the terminal stage in anthrax infection. In autopsy, it is really confirmed in the characteristic findings of the meningeal abnormality. The potential weaponization of variola virus continues to pose a military threat because the aerosol infectivity of the virus and the development of susceptible populations. A high rate of lethality, a staunch resistance to treatments and a rapid onset of severe generalised muscle weakness make botulinum toxin a suitable agent for biological warfare particularly by oral administration.

[A patient with Parkinson's disease complicated by hypothyroidism who developed malignant syndrome after discontinuation of etizolam].

A 59-year-old man, who was diagnosed as having Parkinson's disease and depression seven years ago and was on oral antiparkinsonian agents, antianxiety agents, and antidepressants, developed a high fever, disturbed consciousness, and marked muscle rigidity after discontinuation of etizolam and amitriptyline. He was admitted to a nearby hospital. Hypothyroidism had been noted two months before admission. Marked muscle rigidity and increased serum CK were observed. Since discontinuation of benzodiazepine has been known to rarely trigger a neuroleptic malignant syndrome (NMS), he was diagnosed as having NMS. After receiving dantrolene and bromocriptine, these symptoms temporarily improved but he again developed consciousness disturbance, and convulsive seizures associated with an elevated serum CK. He was transferred to our hospital. On admission, the CK level was normal at 168 IU/l, while free T4 was 0.6 ng/dl (normal range, 0.9-2.3) and TSH was 108.7 mU/ml (normal range, 0.2-4.2) in serum, indicating the presence of primary hypothyroidism. As an increase in thyroid hormone dosage improved the thyroid function to normal level, his disturbed consciousness and muscle rigidity gradually improved. Convulsive seizure and recurrence of NMS in a short interval are unusual in neuroleptic malignant syndrome. In this patient, hypothyroidism may have contributed to the development of malignant syndrome through metabolic changes of the central dopaminergic system, and discontinuation of etizolam, a kind of benzodiazepine, may have triggered NMS, since there has not been reported that discontinuation of antidepressants including amitriptyline triggers NMS.

Mutagenic activity in roadside soils.

Mutagenicity of soils sampled at median strips, roadsides and a park neighboring arterial roads in Kurume City was determined by Ames test. Organic extracts of soils were mutagenic in strains TA98, TA100, YG1041 and YG1042 with and without S9mix. No sample showed mutagenic responses in strains YG3003 or YG7108. Extracts from soils of median strips and beside intersections showed higher mutagenicity and concentrations of PAHs and heavy metals than others, and mutagenic activity of soils correlated significantly with concentrations of PAHs and heavy metals. However, PAHs accounted for less than 12% of total mutagenicity in strains TA98 and TA100 of soil extracts. These extracts showed much higher mutagenicity in YG strains than in TA strains. The results indicate that these soils may be polluted with nitroarenes and aromatic amines.

Toxicological analysis of chlorhexidine in human serum using HPLC on a polymer-coated ODS column.

A simple and reliable high-performance liquid chromatographic (HPLC) method for analyzing chlorhexidine in human serum was developed. After the addition of an internal standard, levomepromazine, 0.2 mL serum was deproteinized with 10% perchloric acid. The acidic supernatant was neutralized with 1M potassium carbonate solution, and the insoluble salt was removed by centrifugation. An aliquot of the supernatant was applied to HPLC with UV detection (260 nm). HPLC separation was achieved on a polymer-coated ODS column equilibrated with acetonitrile/water containing 0.05% trifluoroacetic acid, 0.05% heptafluorobutyric acid, and 0.1% triethylamine (40:60, v/v). The calibration curve was linear in the concentration range from 0.05 to 50.0 microg/mL, and the lower limit of detection was 0.05 microg/mL. The accuracy and precision of the method were evaluated at concentrations of 0.5 microg/mL and 5.0 microg/mL. The coefficients of variation ranged from 4.0 to 4.5%. The concentration of chlorhexidine in the serum of a patient who died after a suspected intravenous injection of chlorhexidine gluconate was determined.

Testicular toxicity evaluation of two antimony compounds, antimony trioxide and antimony potassium tartrate, in rats and mice.

OBJECTIVES: Testicular toxicities of antimony compounds were evaluated in rats and mice. The slightly water-soluble antimony compound antimony trioxide (ATO) and the highly water-soluble antimony compound antimony potassium tartrate (APT) were examined. METHODS: Daily doses of the compounds were 27.4, 12.0 and 1,200 mg/kg body weight in the APT group, low-ATO group and high-ATO group, respectively. The corresponding daily doses of antimony were 10, 10 and 1,000 mg/kg body weight, in the APT group, low-ATO group and high-ATO group, respectively. Both compounds were administered by gavage: rats, 3 days per week for 4 weeks; mice, 5 days per week for 4 weeks. RESULTS: Neither compound reduced the weights of reproductive organs or accessory sex organs nor affected sperm parameters. Few marked histopathologic changes were found in the testes of the treated animals. Even at 1,200 mg/kg body weight, which is greater than the LD(50) of APT, ATO produced no effects. CONCLUSIONS: In this study, it was found that ATO and APT are not toxic to testes in rodents.