Severe dopaminergic pathways damage in a case of chronic toluene abuse

Introduction

Toluene toxicity primarily affects central nervous system white matter, causing a characteristic brain MRI pattern.

Case report

A toluene addicted man, after an abstinence period and a treatment with neuroleptics, presented with severe worsening of preexisting generalized tremor, opsoclonus, dysarthria, gait inability, jerky tendon reflexes and behaviour disorders. Magnetic resonance imaging showed mild leukoencephalopathy and hypointensities in deep gray matter nuclei. The DaT-scan revealed a decrease in presynaptic dopamine reuptake.

Conclusion

Clinical and neuroradiological findings and the possible sensitivity to neuroleptics indicate dopaminergic impairment. Our case suggests that chronic toluene abuse causes presynaptic dopaminergic depletion.     

Acute neurobehavioral effects of toluene: Involvement of dopamine and NMDA receptors

Toluene, a widely used and commonly abused organic solvent, causes a variety of behavioral disturbances in both humans and animals. In this study, the effects of toluene on locomotor activity, motor coordination, and passive avoidance learning, along with the possible mechanism underlying these toluene-induced behavioral manifestations, were investigated. Sprague–Dawley rats were tested in the open field test, rotarod test, and step-through avoidance learning task after receiving toluene (250–750 mg/kg, i.p.). Toluene dose-dependently produced locomotor hyperactivity, motor incoordination, and memory impairment. In order to determine the possible roles of dopamine and NMDA receptors in these behavioral responses to toluene, dopamine D1 receptor antagonist SCH23390, D2 receptor antagonist raclopride, D3 receptor antagonist nafadotride, or d-serine, a co-agonist at the glycine binding site of NMDA receptors, were given prior to toluene administration. SCH23390, raclopride, and nafadotride attenuated locomotor hyperactivity, but not motor incoordination and memory impairment in response to toluene, whereas d-serine reduced all the toluene-induced behavioral alterations. These findings suggest that blockade of NMDA receptors may play a critical role in acute toluene-induced locomotor hyperactivity, motor incoordination, and memory impairment, and that dopamine neurotransmission may be specifically involved in locomotor hyperactivity.     

低浓度甲苯对果蝇寿命的影响

目的：为观察甲苯对果蝇寿命的影响。方法：采用黑腹果蝇Ｏｒｅｐｏｎ／Ｃ品系，分别在培养管中以０ｍｇ／ｍ３，１００ｍｇ／ｍ３，３７５ｍｇ／ｍ３和１０００ｍｇ／ｍ３浓度甲苯染毒，观察果蝇生存情况。结果：随染毒浓度增大，雌雄两性果蝇均表现为平均生存时间（平均寿命）显著缩短。三个浓度组中，雄性果蝇分别减寿１２．９％，１５．４％和２２．７％；雌性果蝇分别减寿７．５％，１３．７和２６．６％，有明显的浓度－反应关系。从果蝇的生存曲线来看，随着观察时间的推移，可以观察到雌雄果蝇生存总数均逐渐下降，且随浓度增加，下降速度加快，生存曲线终止时间（最长寿命）提前。结论：可以认为在这些浓度下，甲苯可以缩短果蝇寿命，加速果蝇老龄化的速度。     

苯系物对工人健康的影响

本文报道９７名长期接触苯系物的工人其神经衰弱综合征、出血倾向、心电图ＳＴ－Ｔ改变发生率显著高于对照组；白细胞数、中性粒细胞效和淋巴细胞数的均值分别低于对照组；Ｎ—ＬＡＰ活性水平及其升高的发生率显著高于对照组；ＨＤＬ—ｃ、Ｔｃ、ＬＤＬ—ｃ和水平皆显著区别于对照组；ＴＣ．ＬＤＬ—ｃ与比值增高的检出率分别高于对照组。上述结果提示苯系物影响工人神经系统、血液和心血管机能，并高度提示苯系作业工人患冠心病的危险增高。     

Studies on the prenatal toxicity of toluene in rabbits following inhalation exposure and proposal of a pregnancy guidance value

Prenatal toxicity of toluene was determined in two separate studies by inhalation exposure of Himalayan rabbits. In the first study 15 artificially inseminated females per group were exposed to 30, 100, or 300 ppm and in the second study 20 artificially inseminated females per group inhaled 100 or 500 ppm. In each case the rabbits were exposed for 6 hours per day from day 6 post-insemination (p. i.) to day 18 p. i. The respective controls inhaled conditioned clean air under the same exposure conditions. No signs of maternal toxicity were observed. All data obtained on gestational parameters were found to be within the variation range reported for this rabbit strain. The fetal external, soft tissue and skeletal findings were seen in toluene exposed fetuses in a frequency similar to the corresponding and/or historical controls. Differences observed between the groups were not concentration dependent and were considered incidental rather than compound related. Therefore, toluene was not embryotoxic, fetotoxic, or teratogenic for rabbits exposed during the period of organogenesis. The highest concentration tested under these conditions (500 ppm) was found to be a no-observable-adverse-effect level (NOAEL) for both the adult and the fetal Himalayan rabbit. Based on these and previous results of animal studies of prenatal toxicity, a safety or uncertainty factor approach is considered for setting limits of exposure for women at workplaces. A pregnancy guidance value of 20 ppm is proposed.The present studies were sponsored by the Berufsgenossenschaft der Chemischen Industrie, W-6900 Heidelberg, FRG     

Regional brain distribution of toluene in rats and in a human autopsy

Toluene concentrations in 9 brain regions of acutely exposed rats and that in 11 brain regions of a human case who inhaled toluene prior to death are described. After exposure to toluene by inhalation (2000 or 10000 ppm) for 0.5 h or by oral dosing (400 mg/kg), rats were killed by decapitation 0.5 and 4 h after onset of inhalation and 2 and 10 h after oral ingestion. After each experimental condition the highest range of brain region/blood toluene concentration ratio (BBCR) was in the brain stem regions (2.85–3.22) such as the pons and medulla oblongata, the middle range (1.77–2.12) in the midbrain, thalamus, caudate-putamen, hypothalamus and cerebellum, and the lowest range (1.22–1.64) in the hippocampus and cerebral cortex. These distribution patterns were quite constant. Toluene concentration in various brain regions were unevenly distributed and directly related blood levels. In a human case who had inhaled toluene vapor, the distribution among brain regions was relatively similar to that in rats, the highest concentration ratios being in the corpus callosum (BBCR: 2.66) and the lowest in the hippocampus (BBCR: 1.47)     

Detection and measurement of S-benzyl-N-acetylcysteine in urine of toluene sniffers using capillary gas chromatography

We examined the urinary excretion of S-benzyl-N-acetylcysteine (SBAC) of toluene sniffers using capillary gas chromatography. SBAC was extracted from 10 ml urine with chloroform and backextracted into 1 M sodium bicarbonate solution. After acidification, the aqueous solution was reextracted with ethyl acetate, and then derivatized to its methyl ester (ME). The peak appearing in the gas chromatogram was identified as SBAC-ME by mass spectrometry. The calibration curve was constructed by plotting the peak height ratio of SBAC-ME and internal standard (S-phenethyl-N-acetylcysteine)-ME against analyte concentration using 10 ml toluene unexposed urine. It showed good linearity over the range of 0.05–3.0 mg/l (r = 0.99). We have applied this technique to urine samples from toluene sniffers. SBAC was detected in all urinary samples of sniffers (n = 30, 0.11–47.13 mg/l), but not at all in the urine of toluene unexposed subjects (n = 60). These results prove that SBAC is also formed from toluene by human metabolism, and detection of SBAC is considered a useful marker for inhalation of toluene.Some of these results were presented at the 30th International Meeting of the International Association of Forensic Toxicologists (Fukuoka) in 1992.     

MRI in chronic toluene abuse: low signal in the cerebral cortex on T2-weighted images

Abstract MRI may be helpful in showing brain toxicity associated with chronic toluene inhalation. We report clinical and MRI findings over 3 years in a man with gradual neurologic decline secondary to toluene abuse. Cerebral atrophy most prominently involved the corpus callosum and cerebellar vermis. On T2-weighted images, loss of gray-white matter contrast, diffuse supratentorial white matter high-signal lesions, and low signal in the basal ganglia and midbrain were seen. In addition, MRI showed abnormal labor cortical low signal on T2-weighted images, most prominent in the primary motor and visual cortex. This cortical T2 shortening, not previously described in this condition, may reflect iron deposition. Received: 14 October 1997 Accepted: 18 December 1997