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| Toluene (), also known as toluol (), is a substituted aromatic hydrocarbon with the chemical formula C6H5CH3, often abbreviated as PhCH3, where Ph stands for the phenyl group. It is a colorless, water-insoluble liquid with the odor associated with paint thinners. It is a mono-substituted benzene derivative, consisting of a methyl group (CH3) attached to a phenyl group by a single bond. As such, its systematic IUPAC name is methylbenzene. Toluene is predominantly used as an industrial feedstock and a solvent.
As the solvent in some types of paint thinner, permanent markers, contact cement and certain types of glue, toluene is sometimes used as a recreational inhalant and has the potential of causing severe neurological harm. |
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Read full article at Wikipedia
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| InChI=1S/C7H8/c1-7-5-3-2-4-6-7/h2-6H,1H3 |
| YXFVVABEGXRONW-UHFFFAOYSA-N |
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non-polar solvent
fuel additive
Any additive that enhances the efficiency of fuel.
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cholinergic antagonist
Any drug that binds to but does not activate cholinergic receptors, thereby blocking the actions of acetylcholine or cholinergic agonists.
neurotoxin
A poison that interferes with the functions of the nervous system.
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non-polar solvent
cholinergic antagonist
Any drug that binds to but does not activate cholinergic receptors, thereby blocking the actions of acetylcholine or cholinergic agonists.
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View more via ChEBI Ontology
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methylbenzene
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PDBeChem
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phenylmethane
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ChemIDplus
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Toluen
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NIST Chemistry WebBook
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Toluene
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KEGG COMPOUND
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TOLUENE
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PDBeChem
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toluene
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UniProt
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toluène
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ChEBI
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Toluol
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NIST Chemistry WebBook
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c0114
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UM-BBD
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C01455
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KEGG COMPOUND
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DB01900
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DrugBank
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MBN
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PDBeChem
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Toluene
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Wikipedia
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| View more database links |
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108-88-3
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CAS Registry Number
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KEGG COMPOUND
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108-88-3
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CAS Registry Number
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ChemIDplus
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108-88-3
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CAS Registry Number
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NIST Chemistry WebBook
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2456
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Gmelin Registry Number
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Gmelin
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635760
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Reaxys Registry Number
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Reaxys
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Alfaro-Rodríguez A, Bueno-Nava A, González-Piña R, Arch-Tirado E, Vargas-Sánchez J, Avila-Luna A (2011)
Chronic exposure to toluene changes the sleep-wake pattern and brain monoamine content in rats.
Acta neurobiologiae experimentalis 71, 183-192 [PubMed:21731073]
[show Abstract]
Toluene, found in glues and cleaners, is among the inhalants most commonly abused by workers and young drug addicts. In this study, we examined the changes in sleep patterns and monoamine content induced by chronic toluene exposure. Rats were chronically exposed to toluene vapors beginning at 30 days of age for a duration of 30 days. Experiment I was performed in a control group (n=10) and a chronic toluene exposure group (n=10). Rats were implanted with bipolar stainless steel electrodes for electroencephalographic recording (EEG). In experiment II, conducted in two other groups (control and exposed to toluene, n=10 each), animals were sacrificed by decapitation prior to chromatographic analysis. We found that chronic toluene administration affected the organization of sleep patterns and monoamine content. Dopamine (DA) and noradrenaline (NA) increased in the midbrain and striatum. 3,4-dihydroxyphenylacetic acid (DOPAC) increased only in the striatum. Midbrain levels of serotonin (5-HT) increased in the pons and decreased in the hypothalamus and striatum. 5-hydroxyindoleacetic acid (5-HIAA) increased in the pons, midbrain and striatum and decreased in the hypothalamus. Chronic toluene exposure induced changes in the serotonergic and dopaminergic systems and increased SWS and PS deficits. We conclude that toluene exposure disrupts the sleep-wake cycle by affecting the monoaminergic response in cerebral areas related to sleep. | Yan S, Zhou Q (2011)
Toxic effects of Hydrilla verticillata exposed to toluene, ethylbenzene and xylene and safety assessment for protecting aquatic macrophytes.
Chemosphere 85, 1088-1094 [PubMed:21840036]
[show Abstract]
Little information is available about the toxicity of toluene, ethylbenzene and xylene acting on macrophytes, and their toxicity data are rarely used in regulation and criteria decisions. The results extended the knowledge on toxic effects of toluene, ethylbenzene and xylene on aquatic plants. The responses of Hydrilla verticillata to these pollutants were investigated. Chlorophyll levels, lipid peroxidation, and antioxidant enzymes (superoxide dismutase and guaiacol peroxidase) showed diverse responses at different concentrations of toluene, ethylbenzene and xylene. The linear regression analyses were performed respectively, suggesting the concentrations of toluene, ethylbenzene and xylene expected to protect aquatic macrophytes were 7.30 mg L⁻¹, 1.15 mg L⁻¹ and 2.36 mg L⁻¹, respectively. This study emphasized that aquatic plants are also sensitive to organic pollutants as fishes and zooplanktons, indicating that macrophytes could be helpful in predicting the toxicity of these pollutants and should be considered in regulation and criteria decisions for aquatic environment protection. | Pascual R, Pilar Zamora-León S, Pérez N, Rojas T, Rojo A, José Salinas M, Reyes A, Bustamante C (2011)
Melatonin ameliorates neocortical neuronal dendritic impairment induced by toluene inhalation in the rat.
Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie 63, 467-471 [PubMed:20347282]
[show Abstract]
The present study investigated the effects of toluene inhalation and the restorative effects of melatonin on branching and basal dendritic outgrowth of superficial pyramidal neurons in rat's frontal, parietal, and occipital cortices. At postnatal day 21 (P21), Sprague-Dawley male rats were randomly assigned to either an air-only group or a toluene group. From P22 to P32 the animals were exposed to either clean air or toluene vapors (5000-6000 ppm) for 10 min/day. This strategy simulated common toluene abuse in humans, which consists of 15-20 rapid inhalations of highly concentrated solvent. Once the inhalation period was over (P32), toluene exposed animals were randomly reassigned to one of following experimental groups: (i) air-control/saline; (ii) toluene/saline; (iii) toluene/melatonin 0.5mg/kg; (iv) toluene/melatonin 1.0mg/kg; (v) toluene/melatonin 5.0mg/kg; and (vi) toluene/melatonin 10mg/kg. Seven days after the last inhalation (P39), all the animals were sacrificed under deep anesthesia; brains were dissected out and stained according to the Golgi-Cox-Sholl procedure. Layer II/III pyramidal neurons were morphologically analyzed by measuring their basilar dendritic length and the number of branches. The results obtained revealed that (i) toluene inhalation significantly reduced dendritic outgrowth and branching in all cortical areas studied, and (ii) intraperitoneal administration of melatonin (0.5-10mg/kg) was able to restore the dendritic impairment induced by toluene exposure. | Beckley JT, Woodward JJ (2011)
The abused inhalant toluene differentially modulates excitatory and inhibitory synaptic transmission in deep-layer neurons of the medial prefrontal cortex.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 36, 1531-1542 [PubMed:21430649]
[show Abstract]
Volatile organic solvents such as toluene are voluntarily inhaled for their intoxicating effects. Solvent use is especially prevalent among adolescents, and is associated with deficits in a wide range of cognitive tasks including attention, behavioral control, and risk assessment. Despite these findings, little is known about the effects of toluene on brain areas mediating these behaviors. In this study, whole-cell patch-clamp recordings were used to determine the effect toluene on neurons within the medial PFC, a region critically involved in cognitive function. Toluene had no effect on measures of intrinsic excitability, but enhanced stimulus-evoked γ-amino butyric acid A-mediated inhibitory postsynaptic currents (IPSCs). In the presence of tetrodotoxin (TTX) to block action potentials, toluene increased the frequency and amplitude of miniature IPSCs. In contrast, toluene induced a delayed but persistent decrease in evoked or spontaneous AMPA-mediated excitatory postsynaptic currents (EPSCs). This effect was prevented by an intracellular calcium chelator or by the ryanodine receptor and SERCA inhibitors, dantrolene or thapsigargin, respectively, suggesting that toluene may mobilize intracellular calcium pools. The toluene-induced reduction in AMPA EPSCs was also prevented by a cannabinoid receptor (CB1R) antagonist, and was occluded by the CB1 agonist WIN 55,212-2 that itself induced a profound decrease in AMPA-mediated EPSCs. Toluene had no effect on the frequency or amplitude of miniature EPSCs recorded in the presence of TTX. Finally, toluene dose-dependently inhibited N-methyl-D-aspartate (NMDA)-mediated EPSCs and the magnitude and reversibility of this effect was CB1R sensitive indicating both direct and indirect actions of toluene on NMDA-mediated responses. Together, these results suggest that the effect of toluene on cognitive behaviors may result from its action on inhibitory and excitatory synaptic transmission of PFC neurons. | Win-Shwe TT, Kunugita N, Yoshida Y, Fujimaki H (2011)
Role of hippocampal TLR4 in neurotoxicity in mice following toluene exposure.
Neurotoxicology and teratology 33, 598-602 [PubMed:21802510]
[show Abstract]
The present study was designed to investigate the possible involvement of TLR4 pathway in the mouse hippocampus following toluene exposure. Male C3H/HeN and C3H/HeJ (TLR4 defective) mice were exposed to 0, 5, 50 or 500 ppm of toluene for 6 weeks. The expressions of TLR4-related signal transduction pathway mRNAs in the hippocampi were examined using real-time RT-PCR and an immunohistochemical analysis. In C3H/HeN mice, the relative mRNA expression levels of TLR4 and NF-κB activating protein were significantly up-regulated in the groups exposed to toluene, but not in the C3H/HeJ mice. Heat shock protein 70, a possible endogenous ligand for TLR4, mRNA was increased in the C3H/HeN mice exposed to toluene. This is the first report to show that TLR4 may have a role in the neurotoxic effects in mice exposed to toluene. | Omar AS, Rahman MU, Abuhasna S (2011)
Reported survival with severe mixed acidosis and hyperlactemia after toluene poisoning.
Saudi journal of anaesthesia 5, 73-75 [PubMed:21655021]
[show Abstract]
Lactic acidosis is a recognized complication of the inhalant abuse such as toluene, especially in patients with renal insufficiency. We report a case of severe metabolic acidosis and hyperlactemia due to toluene sniffing. The favorable outcome, despite extremely poor clinical symptoms, signs, laboratory and radiological findings, was unexpected. Specific aspects of the clinical course are addressed. Toluene sniffing should be considered in evaluating sever metabolic acidosis. Favorable outcome could be achieved with early diagnosis and proper interventions. | Kanter M (2011)
Thymoquinone reestablishes spermatogenesis after testicular injury caused by chronic toluene exposure in rats.
Toxicology and industrial health 27, 155-166 [PubMed:20837561]
[show Abstract]
The aim of this study was designed to evaluate the possible protective effects of thymoquinone (TQ) on the spermatogenesis after testicular injury caused by chronic toluene exposure in rats. The rats were randomly allotted into one of three experimental groups: control, toluene-treated and toluene treated with TQ; each group contained 10 animals. Control group received 1 mL serum physiologic and toluene treatment was performed by inhalation of 3000 ppm toluene, in an 8-hour/day and 6-day/week order for 12 weeks. The rats in TQ-treated group was given TQ (50 mg/kg body weight) once a day orally for 12 weeks starting just after toluene exposure. Tissue samples were obtained for histopathological investigation. To date, no histopathological changes of testis in rats after chronic toluene exposure by TQ treatment have been reported. Spermatogenesis and mean seminiferous tubule diameter (MSTD) were significantly decreased in toluene treated groups when compared to the control group. Furthermore, the TQ-treated animals showed an improved histological appearance in toluene-treated group. Our data indicate a significant reduction in the activity of in situ identification of apoptosis using terminal dUTP nick end-labeling (TUNEL), endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS) and there was a rise in the expression of proliferating cell nuclear antigen (PCNA) in testis tissues of the toluene-treated group with TQ therapy. Electron microscopy of the testes of the rats demonstrated that pretreatment with TQ was particularly effective in preventing the mitochondrial degeneration, dilatation of smooth endoplasmic reticulum (SER) and enlarged intercellular spaces in both Sertoli and spermatid cells in the toluene-treated animals. We believe that further preclinical research into the utility of TQ may indicate its usefulness as a potential treatment on the spermatogenesis after testicular injury caused by chronic toluene exposure in rats. | Seo HS, Yang M, Song MS, Kim JS, Kim SH, Kim JC, Kim H, Shin T, Wang H, Moon C (2010)
Toluene inhibits hippocampal neurogenesis in adult mice.
Pharmacology, biochemistry, and behavior 94, 588-594 [PubMed:19969016]
[show Abstract]
Toluene, a representative industrial solvent and abused inhalant, decreases neuronal activity in vitro and causes mental depression and cognitive impairment in humans. However, the effects of toluene on brain function and the sites of its action are poorly understood. This study investigated the temporal changes of neurogenesis in the hippocampus of adult C57BL/6 mice after acute administration of toluene using two immunohistochemical markers for neurogenesis, Ki-67 and doublecortin (DCX). In addition, after toluene treatment, depression-like behaviors and learning and memory tasks were examined to assess hippocampal neurogenesis-related behavioral dysfunction. The number of Ki-67- and DCX-positive cells in the dentate gyrus of adult hippocampi declined acutely between 0 h and 24 h after toluene treatment (500 mg/kg, i.p.) and increased gradually from 2 to 8 days post-administration. The level of Ki-67 and DCX immunoreactivity decreased in a dose-dependent manner within the range of toluene administered (0-1000 mg/kg). In tail suspension and forced-swim tests performed at 1 and 4 days after toluene treatment (500 mg/kg), mice showed significant depression-like behaviors compared to the vehicle-treated controls. In the contextual fear conditioning and object recognition memory test, the mice trained at 1 and 4 days after toluene treatment showed significant memory defects compared to the vehicle-treated controls. This study suggests that acute exposure to toluene reduces the rate of adult hippocampal neurogenesis and can cause hippocampal dysfunction such as depression and cognitive impairment. | Hogie M, Guerbet M, Reber A (2009)
The toxic effects of toluene on the optokinetic nystagmus in pigmented rats.
Ecotoxicology and environmental safety 72, 872-878 [PubMed:18397809]
[show Abstract]
The effects of 375 mgm(-3) (100 ppm) toluene in air inhalation were evaluated on pigmented rats during either repeated exposures over five consecutive days 3h a day or during a single 4-h exposure. At the end of the inhalation period, the animals were returned to fresh air to evaluate their ability to recover optokinetic performance. The optokinetic responses were analyzed using a magnetic search coil technique previously described. After repeated toluene exposure, the eye position at rest of all the rats was unsteady. In response to visual stimulation, the eye velocity was slower and more irregular than in the control state. At the end of the stimulation, the environment of the animals became stationary, but the eye did not immediately return to a fixed stable position. A similar effect was observed after a single exposure. An increase of the optokinetic deficit was observed after single or repeated 375 mgm(-3) toluene exposures. No recovery was observed even after a single exposure. In view of the fact that toluene is a widely used solvent, these results show that inhalation of low concentrations, even for short single exposures, must be taken into account, because gaze destabilization could cause vertigo symptoms. | Capron B, Logan BK (2009)
Toluene-impaired drivers: behavioral observations, impairment assessment, and toxicological findings.
Journal of forensic sciences 54, 486-489 [PubMed:19261054]
[show Abstract]
Toluene is an aromatic hydrocarbon solvent frequently abused for its euphoric and intoxicating properties. This report describes a series of six cases involving drivers arrested for driving under the influence who subsequently tested positive for toluene. Case data including driving behavior, physiological signs and symptoms, evidence of impairment, and toxicology findings were reviewed. Blood toluene concentrations in the drivers ranged from 12 to 45 mg/L (median 23 mg/L, mean 25 mg/L, SD 12.1 mg/L). All drivers were determined to be intoxicated, and displayed symptoms including balance problems, confusion and disorientation, loss of coordination, and inability to follow instructions. They also displayed horizontal but not vertical nystagmus, elevated pulse and blood pressure, and lower body temperature. These findings are consistent with prior reports that subjects with blood toluene concentrations above 10 mg/L are invariably under the influence and their driving skills are affected. | Ghosh S, Gomathi A, Rao CN (2009)
Stable dispersions of metal oxide nanowires and nanoparticles in water, dimethylformamide and toluene.
Journal of nanoscience and nanotechnology 9, 5214-5222 [PubMed:19928203]
[show Abstract]
In view of the important need to generate well-dispersed inorganic nanostructures in various solvents, we have explored the dispersion of nanostructures of metal oxides such as TiO2, Fe3O4 and ZnO in solvents of differing polarity in the presence of several surfactants. The solvents used are water, dimethylformamide (DMF) and toluene. The surfactant-solvent combinations yielding the best dispersions are reported alongwith some of the characteristics of the nanostructures in the dispersions. The surfactants which dispersed TiO2 nanowires in water were polyethylene oxide (PEO), Triton X-100 (TX-100), polyvinyl alcohol (PVA) and sodium bis(2-ethylhexyl) sulphosuccinate (AOT). TiO, nanoparticles could also be dispersed with AOT and PEO in water, and with AOT in toluene. In DMF, PVA, PEO and TX-100 were found to be effective, while in toluene, only AOT gave good dispersions. Fe3O4 nanoparticles were held for long periods of time in water by PEO, AOT, PVA and polyethylene glycol (PEG), and by AOT in toluene. In the case of ZnO nanowires, the best surfactant-solvent combinations were found to be, PEO, sodium dodecyl sulphate (SDS) and AOT in water and AOT, PEG, PVA, PEO and TX-100 in DMF. In toluene, stable dispersions of ZnO nanowires were obtained with PEO. We have also been able to disperse oxide nanostructures in non-polar solvents by employing a hydrophobic silane coating on the surface. | Sari-Minodier I, Truchon G, Charest-Tardif G, Bérubé A, Tardif R (2009)
The effect of workload on biological monitoring of occupational exposure to toluene and n-Hexane: contribution of physiologically based toxicokinetic modeling.
Journal of occupational and environmental hygiene 6, 415-432 [PubMed:19384711]
[show Abstract]
A physiologically based toxicokinetic model was used to examine the impact of work load on the relationship between the airborne concentrations and exposure indicator levels of two industrial solvents, toluene and n-Hexane. The authors simulated occupational exposure (8 hr/day, 5 days/week) at different concentrations, notably 20 ppm and 50 ppm, which are the current threshold limit values recommended by ACGIH for toluene and n-hexane, respectively. Different levels of physical activity, namely, rest, 25 W, and 50 W (for 12 hr followed by 12 hr at rest) were simulated to assess the impact of work load on the recommended biological exposure indices: toluene in blood prior to the last shift of the workweek, urinary o-cresol (a metabolite of toluene) at the end of the shift, and free (nonhydrolyzed) 2,5-hexanedione (a metabolite of n-hexane) at the end of the shift at the end of the workweek. In addition, urinary excretion of unchanged toluene was simulated. The predicted biological concentrations were compared with the results of both experimental studies among human volunteers and field studies among workers. The highest predicted increase with physical exercise was noted for toluene in blood (39 microg/L at 50 W vs. 14 microg/L at rest for 20 ppm, i.e., a 2.8-fold increase). The end-of-shift urinary concentrations of o-cresol and toluene were two times higher at 50 W than at rest (for 20 ppm, 0.65 vs. 0.33 mg/L for o-cresol and 43 vs. 21 microg/L for toluene). Urinary 2,5-hexanedione predicted for 50 ppm was 1.07 mg/L at 50 W and 0.92 mg/L at rest (+16%). The simulations that best describe the concentrations among workers exposed to toluene are those corresponding to 25 W or less. In conclusion, toxicokinetic modeling confirms the significant impact of work load on toluene exposure indicators, whereas only a very slight effect is noted on n-hexane kinetics. These results highlight the necessity of taking work load into account in risk assessment relative to toluene exposure. | Bowen SE, McDonald P (2009)
Abuse pattern of toluene exposure alters mouse behavior in a waiting-for-reward operant task.
Neurotoxicology and teratology 31, 18-25 [PubMed:18832024]
[show Abstract]
Inhaling solvents for recreational purposes continues to be a world-wide public health concern. Toluene, a volatile solvent in many abused products, adversely affects the central nervous system. However, the long-term neurobehavioral effects of exposure to high-concentration, binge patterns typical of toluene abuse remain understudied. We studied the behavioral effects of repeated toluene exposure on cognitive function following binge toluene exposure on behavioral impulse control in Swiss Webster mice using a "wait-for-reward" operant task. Mice were trained on a fixed-ratio (FR) schedule using sweetened milk as a reward. Upon achieving FR15, a wait component was added which delivered free rewards in the absence of responses at increasing time intervals (2s, 4s, 6s, etc...). Mice continued to receive free rewards until they pressed a lever that reinstated the FR component (FR Reset). Once proficient in the FR-Wait task, mice were exposed to either 1000 ppm, 3600 ppm or 6000 ppm toluene, or 0ppm (air controls) for 30 min per day for 40 days. To avoid acute effects of toluene exposure, behavior was assessed approximately 22-23 h later. Repeated toluene exposure decreased response rates, the number of FR resets, and increased mean wait time, resulting in a higher response-to-reinforcer ratio than exhibited by controls. Mice receiving the higher exposure level (6000 ppm) showed a dramatic decrease in the number of rewards received, which was reversed when toluene exposure ceased. Mice receiving the lower exposure level (1000 ppm) showed little change in the number of rewards. These results indicate that repeated binge exposures to high concentrations of toluene can significantly interfere with performance as measured by a waiting-for-reward task, suggesting a significant impact on cognitive and/or psychomotor function. | Bowen SE, Irtenkauf S, Hannigan JH, Stefanski AL (2009)
Alterations in rat fetal morphology following abuse patterns of toluene exposure.
Reproductive toxicology (Elmsford, N.Y.) 27, 161-169 [PubMed:19429395]
[show Abstract]
Toluene is a commonly abused organic solvent. Inhalant abusers are increasingly women in their prime childbearing years. Children born to mothers who abused solvents during pregnancy may exhibit characteristics of a "fetal solvent syndrome" which may include dysmorphic features. This study examined the teratological effects of an abuse pattern of binge toluene exposure during gestation on skeletal and soft tissue abnormalities, body weight, and body size in fetal rats. Pregnant Sprague-Dawley rats were exposed for 30 min, twice daily, from gestational day (GD) 8 through GD20 to either air (0 ppm), 8000 ppm, 12,000 ppm, or 16,000 ppm toluene. Two-thirds of each litter was prepared for skeletal examination using Alizarin Red S staining while the remaining third of each litter was fixed in Bouin's solution for Wilson's soft tissue evaluation. Exposure to toluene at all levels significantly reduced growth, including decreases in placental weight, fetal weight, and crown-rump length. In addition, numerous gross morphological anomalies were observed such as short or missing digits and missing limbs. Skeletal examination revealed that ossification of the extremities was significantly reduced as a result of toluene exposure at all levels. Specific skeletal defects included misshapen scapula, missing and supernumerary vertebrae and ribs, and fused digits. Soft tissue anomalies were also observed at all toluene levels and there was a dose-dependent increase in the number of anomalies which included cryptorchidism, displaced abdominal organs, gastromegaly, distended/hypoplastic bladder, and delayed cardiac development, among others. These results indicate that animals exposed prenatally to levels and patterns of toluene typical of inhalant abuse are at increased risk for skeletal and soft tissue abnormalities. | Waniusiow D, Campo P, Venet T, Cossec B, Cosnier F, Beydon D, Rieger B, Burgart M, Ferrari L, Parietti-Winkler C (2009)
Toluene-induced hearing loss in the guinea pig.
Toxicological sciences : an official journal of the Society of Toxicology 111, 362-371 [PubMed:19635754]
[show Abstract]
Toluene is a high-production industrial solvent, which can disrupt the auditory system in rats. However, toluene-induced hearing loss is species dependent. For instance, despite long-lasting exposures to high concentrations of aromatic solvent, no study has yet succeeded in causing convincing hearing loss in the guinea pig. This latter species can be characterized by two metabolic particularities: a high amount of hepatic cytochrome P-450s (P-450s) and a high concentration of glutathione in the cochlea. It is therefore likely that the efficiency of both the hepatic and cochlear metabolisms plays a key role in the innocuousness of the hearing of guinea pigs to exposure to solvent. The present study was carried out to test the auditory resistance to toluene in glutathione-depleted guinea pigs whose the P-450 activity was partly inhibited. To this end, animals on a low-protein diet received a general P-450 inhibitor, namely SKF525-A. Meanwhile, they were exposed to 1750 ppm toluene for 4 weeks, 5 days/week, 6 h/day. Auditory function was tested by electrocochleography and completed by histological analyses. For the first time, a significant toluene-induced hearing loss was provoked in the P-450-inhibited guinea pigs. However, the ototoxic process caused by the solvent exposure was different from that observed in the rat. Only the stria vascularis and the spiral fibers were disrupted in the apical coil of the cochlea. The protective mechanisms developed by guinea pigs are discussed in the present publication. | Lo PS, Wu CY, Sue HZ, Chen HH (2009)
Acute neurobehavioral effects of toluene: involvement of dopamine and NMDA receptors.
Toxicology 265, 34-40 [PubMed:19765629]
[show Abstract]
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. | Karabulut I, Balkanci ZD, Pehlivanoglu B, Erdem A, Fadillioglu E (2009)
Effect of toluene on erythrocyte membrane stability under in vivo and in vitro conditions with assessment of oxidant/antioxidant status.
Toxicology and industrial health 25, 545-550 [PubMed:19825861]
[show Abstract]
Toluene, an organic solvent used widely in the industry, is highly lipophilic and accumulates in the cell membrane impeding transport through it. Its metabolites cause oxygen radical formation that react with unsaturated fatty acids and proteins in erythrocytes leading to lipid peroxidation and protein breakdown. In this study, we aimed to investigate the membrane stabilizing and the oxidative stress-inducing effects of toluene in human erythrocytes. Measurements of osmotic fragility, mean corpuscular volume (MCV), oxidative stress parameters and antioxidant enzyme activities were performed simultaneously both in individuals exposed to toluene professionally (in vivo) and human erythrocytes treated with toluene (in vitro). To measure osmotic fragility, erythrocytes were placed in NaCl solutions at various concentrations (0.1% [blank], 0.38%, 0.40%, 0.42%, 0.44%, 0.46%, 0.48% and 1% [stock]). Percentage of haemolysis in each solution was calculated with respect to the 100% haemolysis in the blank solution. The erythrocyte packs prepared at the day of the above-mentioned measurements were kept at -80 degrees C until the time for determination of malonyldialdehyde and protein carbonyl levels, and catalase (CAT) and glutathione peroxidase activities as indicators of oxidative stress. Toluene increased oxidative stress parameters significantly both in vivo and in vitro; it also caused a significant decrease in the activities of antioxidant enzymes. Osmotic fragility was altered only in the case of in vitro exposure. In conclusion, toluene exposure resulted in increased lipid peroxidation and protein damage both in vivo and in vitro. Although, it is natural to expect increased osmotic fragility due to oxidative properties of toluene, its membrane-stabilizing effect overcame the oxidative properties leading to decreased osmotic fragility or preventing its deterioration in vitro and in vivo toluene exposures, respectively, in the present study. | McNary JE, Jackson EM (2007)
Inhalation exposure to formaldehyde and toluene in the same occupational and consumer setting.
Inhalation toxicology 19, 573-576 [PubMed:17497535]
[show Abstract]
Formaldehyde, a natural component of all mammalian cells, is metabolized to carbon dioxide. It is a colorless gas used as a preservative and a reactant in chemical processes in a wide variety of commercial and consumer products. Toluene is an organic solvent also used in a wide variety of commercial and consumer products. There is a growing concern that chemical exposure from consumer products including cosmetics adds to the overall toxic exposure bioburden. This study was designed to quantify the actual amount of formaldehyde and toluene exposure to professional nail technicians and their customers during the application of cosmetic nail products containing either formaldehyde or toluene. Formaldehyde concentrations were measured on workers and consumers using treated silica gel absorption tubes. Formaldehyde concentrations varied between 0.0012 and 0.0038 ppm. The results of this study clearly demonstrate that neither workers nor consumers are at any additional risk from exposure to formaldehyde or toluene in cosmetic nail products beyond daily exposure from commercial products in a work setting and in the home. | Park HM, Lee SH, Chung H, Kwon OH, Yoo KY, Kim HH, Heo SC, Park JS, Tae GS (2007)
Immunochromatographic analysis of hippuric acid in urine.
Journal of analytical toxicology 31, 347-353 [PubMed:17725881]
[show Abstract]
Toluene, a clear, colorless liquid with a distinctive smell, is the most commonly used industrial organic solvent. The adverse effects of chronic toluene exposure have been reported. The abuse of volatile substances is practiced mainly by adolescents and young adults. Chronic toluene abuse causes permanent changes in brain structure correlated with brain dysfunction; therefore, it is important to monitor the level of toluene exposure to prevent neurological damages. In this study, immunochromatographic analysis was performed to measure a level of the exposed toluene easily and accurately in urine. Inhaled toluene is metabolized to hippuric acid (HA) in the liver and secreted in urine. Therefore, the monoclonal antibodies against HA were generated and characterized by indirect competitive ELISA. The sensitivity was then monitored in order to adjust the cutoff concentration to 2 mg of HA/mL of urine. Using these monoclonal antibodies as raw materials, the immunochromatographic device was manufactured with the lateral flow system. The clinical studies were performed with suspected users' urine samples, and the results were confirmed by high-performance liquid chromatography. | Oshiro WM, Krantz QT, Bushnell PJ (2007)
Repeated inhalation of toluene by rats performing a signal detection task leads to behavioral tolerance on some performance measures.
Neurotoxicology and teratology 29, 247-254 [PubMed:17175136]
[show Abstract]
Previous work showed that trichloroethylene (TCE) impairs sustained attention as evidenced by a reduction in accuracy and elevation of response latencies in rats trained to perform a visual signal detection task (SDT). This work also showed that these effects abate during repeated exposures if rats inhale TCE while performing the SDT. The present experiment sought to determine whether toluene, another commonly-used solvent, would induce tolerance similarly if inhaled repeatedly during SDT testing. Sixteen male, Long-Evans rats were trained to perform the SDT. Upon completion of training, rats were divided into 2 groups. In Phase I, concentration-effect functions were determined for toluene (0, 1200, 1600, 2000, 2400 ppm) in both groups. Toluene reduced the proportion of correct responses [P(correct)], and increased response time (RT) and response failures. In Phase II, Group-Tol inhaled 1600 ppm toluene while Group-Air inhaled clean air during 11 daily SDT sessions. In Group-Tol the effect of toluene on P(correct) abated after 3 days, while RT remained elevated for the duration of the repeated exposures. In Phase III, toluene concentration-effect functions were re-determined for both groups. Group-Air remained impaired on all test measures, whereas for Group-Tol, toluene did not reduce P(correct), but continued to increase RT. These data confirm our previous hypothesis that animals can develop tolerance to chemical exposures that impair appetitively-motivated behaviors if that impairment leads to loss of reinforcement. | Win-Shwe TT, Mitsushima D, Nakajima D, Ahmed S, Yamamoto S, Tsukahara S, Kakeyama M, Goto S, Fujimaki H (2007)
Toluene induces rapid and reversible rise of hippocampal glutamate and taurine neurotransmitter levels in mice.
Toxicology letters 168, 75-82 [PubMed:17145141]
[show Abstract]
Toluene, a widely used aromatic organic solvent, has been well characterized as a neurotoxic chemical. Although the neurobehavioral effects of toluene have been studied substantially, the mechanisms involved are not clearly understood. Hippocampus, which is one of the limbic areas of brain associated with neuronal plasticity, and learning and memory functions, may be a principal target of toluene. In the present study, to establish a mouse model for investigating the effects of acute toluene exposure on the amino acid neurotransmitter levels in the hippocampus, in vivo microdialysis study was performed in freely moving mice after a single intraperitoneal administration of toluene (150 and 300 mg/kg). Amino acid neurotransmitters in microdialysates were measured by a high performance liquid chromatography system. The extracellular levels of glutamate and taurine were rapidly and reversibly increased within 30 min after the toluene administration in a dose-dependent manner and returned to the basal level by 1h. Conversely, the extracellular level of glycine and GABA were stable, and no significant change was observed after the toluene administration. To further investigate the brain toluene level in the hippocampus of toluene-administered mice, we used a solid-phase microextraction (SPME) method and examined the time course changes of toluene in the hippocampus of living mice. The brain toluene level reached the peak at 30 min after injection and returned to the basal level after 2h. In the present study, we observed the relationship between brain toluene levels and amino acid neurotransmitter glutamate and taurine levels in the hippocampus. Therefore, we suggest that toluene may mediate its action through the glutamatergic and taurinergic neurotransmission in the hippocampus of freely moving mice. | Bowen SE (2006)
Increases in amphetamine-like discriminative stimulus effects of the abused inhalant toluene in mice.
Psychopharmacology 186, 517-524 [PubMed:16601996]
[show Abstract]
RationaleToluene, an abused solvent, shares behavioral and pharmacological effects with abused depressant drugs. These effects include ethanol- and pentobarbital-like discriminative stimulus effects. There is also emerging evidence that this abused inhalant may share stimulus effects with abused central nervous system (CNS) stimulants.ObjectiveTo further explore the discriminative stimulus effects of one abused inhalant, this experiment evaluated the amphetamine-like discriminative stimulus effects of toluene.Materials and methodsMice were trained to discriminate between d-amphetamine (1.0 mg/kg) and saline in a two-lever drug discrimination procedure in which responding was under the control of a fixed-ratio 15 schedule. Mice were tested after 10-min inhalation exposures to air or toluene (500-6,000 ppm) and stimulus generalization was examined at 0, 15, 30, 45, 60, and 75 min post-exposure.ResultsConcentration-related increases in amphetamine-lever responding were observed for amphetamine doses >0.56 mg/kg with full substitution occurring immediately after testing for 1.0 and 1.78 mg/kg. Partial amphetamine-lever responding was observed for all concentrations of toluene across the 75-min post-exposure test trials. Response rates that had decreased immediately after all toluene exposures recovered within 15-min post exposure.ConclusionThis partial substitution of toluene for amphetamine suggests that studies of the effects of abused solvents on brain dopaminergic systems need to be included in the study of possible CNS mechanisms. | Gauthereau MY, Salinas-Stefanon EM, Cruz SL (2005)
A mutation in the local anaesthetic binding site abolishes toluene effects in sodium channels.
European journal of pharmacology 528, 17-26 [PubMed:16316648]
[show Abstract]
Toluene is a solvent of abuse that inhibits cardiac sodium channels in a manner that resembles the action of local anaesthetics. The purpose of this work was to analyze toluene effects on skeletal muscle sodium channels with and without beta1 subunit (Nav1.4+beta1 and Nav1.4-beta1, respectively) expressed in Xenopus laevis oocytes and to compare them with those produced in the F1579A mutant channel lacking a local anaesthetic binding site. Toluene inhibited Nav1.4 sodium currents (IC50=2.7 mM in Nav1.4+beta1 and 2.2 mM in Nav1.4-beta1 in a concentration dependent way. Toluene (3 mM) blocked sodium currents in Nav1.4 channels proportionally throughout the entire current-voltage relationship producing inactivation at more negative potentials. Minimal inhibition was produced by 3 mM toluene in F1579A mutant channels. Recovery from inactivation was slower both in Nav1.4 and F1579A channels in the presence of 3 mM toluene. The solvent blocked sodium currents in a use-dependent and frequency-dependent manner in Nav1.4 channels. A single mutation in the local anaesthetic binding site of Nav1.4 channels almost abolished toluene effects. These results suggest that this site is important for toluene action. | Williams JM, Stafford D, Steketee JD (2005)
Effects of repeated inhalation of toluene on ionotropic GABA A and glutamate receptor subunit levels in rat brain.
Neurochemistry international 46, 1-10 [PubMed:15567510]
[show Abstract]
Toluene is a commonly abused solvent found in many industrial and commercial products. The neurobiological effects of toluene remain unclear, but many of them, like those of ethanol, may be mediated by gamma-aminobutyric acid (GABA) and glutamate receptors. Chronic ethanol administration has been shown to alter levels of specific subunits for GABA type A (GABA(A)), N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. However, little is known about the effects of toluene on subunit levels of these receptors. To examine this, rats were exposed to toluene vapors (8000 ppm) or air for 10 days (30 min/day), and afterwards GABA(A) alpha1, NR1 and NR2B (NMDA) and GluR1 and GluR2/3 (AMPA) receptor subunit levels were determined in discrete brain regions of these animals by Western blotting. Toluene increased GABA(A) alpha1, NR1, NR2B and GluR2/3 subunits in the medial prefrontal cortex and decreased GABA(A) alpha1 and NR1 subunits in the substantia nigra compacta. Toluene inhalation produced modest increases in GABA(A) alpha1 subunits in the striatum, as well as slight decreases in this subunit in the ventral tegmental area. NR2B subunit levels were also slightly increased within the nucleus accumbens by toluene. These studies show that toluene differentially alters the levels of specific GABAergic and glutamatergic receptor subunits in a regionally selective manner. | Lee YF, Lo PS, Wang YJ, Hu A, Chen HH (2005)
Neonatal toluene exposure alters N-methyl-D-aspartate receptor subunit expression in the hippocampus and cerebellum in juvenile rats.
Neuropharmacology 48, 195-203 [PubMed:15695158]
[show Abstract]
Recent evidence indicates that toluene is a non-competitive inhibitor of N-methyl-d-aspartate (NMDA) receptor-mediated synaptic currents. The NMDA receptor plays a major role in neuronal development and differentiation. The present study characterized the long-term effects of toluene exposure during synaptogenesis on the expression of NMDA receptor subunits (NR1, NR2A and NR2B). Neonatal rats were administered toluene (500 mg/kg, ip) daily over postnatal days (PN) 4-9. The expression of NMDA receptor subunits in rat brain was measured on PN 30. Western blot analysis demonstrated that toluene exposure significantly increased NR2A expression in the hippocampus and cerebellum. Immunohistochemical results indicated that the increased NR2A expression is mainly in hippocampal CA1-stratum oriens, CA1-stratum radiatum, CA1-lacunosm molecular, CA2- stratum oriens, and dentate gyrus-molecular layer and the cerebellar Purkinje cell layer, respectively. In contrast, the levels of NR2B in the toluene-exposed rats were decreased in the molecular layer. These results suggest that the region-specific changes in the expression of NMDA receptor subunits may be related to the neurobehavioral dysfunction following toluene exposure during synaptogenesis. | Funada M, Sato M, Zhou X, Kanai H, Wada K (2005)
[Neuroadaptive mechanisms form development of psychological dependence on volatile organic solvents].
Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology 25, 1-9 [PubMed:15796064]
[show Abstract]
Abuse of volatile organic solvents among youth remains a major social problem. Organic solvents are cheap and relatively easy to obtain, so they carry the risk of becoming a so-called "gateway drug" for users. Most research regarding organic solvents has until now focused on their neurotoxicity, specifically examining the mechanism of neuron death in terms of the involvement of substances such as nerve growth factor. However, systems to assess psychological dependence on volatile organic solvents that take into account the mechanism involved in the development of this dependence have not been established due to the difficulty of creating animal models. The conditioned place preference procedure, which can easily assess whether psychological dependence has been formed, has been phased in in recent years, and dependence assessment systems have been established for drug inhalation. There have also been new research developments regarding dependence on volatile organic solvents. The importance of mesolimbic dopamine neurons has been indicated in the expression of CNS stimulant action and the development of psychological dependence on drugs such as stimulants, cocaine, and heroin, which are typical abused drugs. It has recently become apparent that the increase in dopamine release in the nucleus accumbens accompanying activation of mesolimbic dopamine neurons, as has conventionally been proposed, is important to the expression of CNS stimulant action and the formation of psychological dependence in response to inhalation of toluene, a volatile organic solvent. Furthermore, research with regard to organic solvents' site of action is also proceeding based on studies using molecular biological techniques. Research regarding toluene is progressing, and the importance of receptors that gate ion channels such as N-methyl-D-aspartate (NMDA) and y-aminobutyric acid (GABA)A receptors as candidates for toluene's site of action has been indicated. Clarification of organic solvents' mechanism for the development of psychological dependence is expected to progress, thanks to analysis focusing on such new sites of action. | Riegel AC, Ali SF, Torinese S, French ED (2004)
Repeated exposure to the abused inhalant toluene alters levels of neurotransmitters and generates peroxynitrite in nigrostriatal and mesolimbic nuclei in rat.
Annals of the New York Academy of Sciences 1025, 543-551 [PubMed:15542760]
[show Abstract]
Toluene, a volatile hydrocarbon found in a variety of chemical compounds, is misused and abused by inhalation for its euphorigenic effects. Toluene's reinforcing properties may share a common characteristic with other drugs of abuse, namely, activation of the mesolimbic dopamine system. Prior studies in our laboratory found that acutely inhaled toluene activated midbrain dopamine neurons in the rat. Moreover, single systemic injections of toluene in rats produced a dose-dependent increase in locomotor activity which was blocked by depletion of nucleus accumbens dopamine or by pretreatment with a D2 dopamine receptor antagonist. Here we examined the effects of seven daily intraperitoneal injections of 600 mg/kg toluene on the content of serotonin and dopamine in the caudate nucleus (CN) and nucleus accumbens (NAC), substantia nigra, and ventral tegmental area at 2, 4, and 24 h after the last injection. Also, the roles of nitric oxide, peroxynitrite, and the production of 3-nitrosotyrosine (3-NT), in the CN and NAC were assessed at the same time points. Toluene treatments increased dopamine levels in the CN and NAC, and serotonin levels in CN, NAC, and ventral tegmental area. Measurements of the dopamine metabolite dihydroxyphenylacetic acid (DOPAC) further suggested a change in transmitter utilization in CN and NAC. Lastly, 3-NT levels also showed a differential change between CN and NAC, but at different time points post-toluene injection. These results point out the complexity of action of toluene on neurotransmitter function following a course of chronic exposure. Changes in the production of 3-NT also suggest that toluene-induced neurotoxicity may mediate via generation of peroxynitrite. | Woodward JJ, Nowak M, Davies DL (2004)
Effects of the abused solvent toluene on recombinant P2X receptors expressed in HEK293 cells.
Brain research. Molecular brain research 125, 86-95 [PubMed:15193425]
[show Abstract]
ATP acts as a neurotransmitter in both the peripheral and central nervous systems by activating receptors in the P2Y and P2X families. P2Y receptors are coupled to intracellular signaling pathways, while P2X receptors contain an integral membrane-spanning pore and act as ion channels. Previous studies have established that certain abused drugs such as alcohol inhibit P2X receptors. In this study, we have examined the sensitivity of both homomeric and heteromeric P2X receptors to toluene, a commercial solvent widely used as a drug of abuse. P2X receptors were transiently expressed in HEK293 cells, and agonist-gated currents were measured using whole-cell patch clamp electrophysiology. Toluene potentiated currents in cells expressing homomeric P2X2 or P2X4 subunits when ATP concentrations were near or below the EC50 concentration. This potentiation was rapid in onset, voltage independent and was readily reversed upon washout of the toluene-containing solution. The toluene-induced potentiation of P2X2 currents was not altered by lowering the pH of the recording media to 5.5 or by including the heavy-metal chelator EDTA in the recording solution. At maximal ATP concentrations, toluene did not affect ATP-gated currents in cells expressing P2X2 or P2X4 receptors. ATP-gated currents were also markedly potentiated by toluene in cells transfected with both P2X4 and P2X6 subunits. In contrast, P2X3 receptor currents were inhibited by toluene at both low and high ATP concentrations. HEK293 cells transfected with both P2X2 and P2X3 subunits showed non-desensitizing currents when stimulated with alpha, beta-methylene ATP. In these cells, toluene potentiated currents only at sub-maximal concentrations of alpha, beta-methylene ATP. The results of this study suggest that the abused solvent toluene affects the function of P2X receptors in a subunit-dependent and agonist-dependent fashion. | Akbaş E, Derici E, Söylemez F, Kanik A, Polat F (2004)
An investigation of effects of toluene and cigarette smoking on some blood parameters and lymphocyte life span.
Cell biology and toxicology 20, 33-40 [PubMed:15119846]
[show Abstract]
As toluene is an organic solvent, its cytotoxic effect on the cell is known. Similarly, it has been demonstrated that many of the chemical agents that enter the body through smoking have cytotoxic and genotoxic effects on the cells. In this study, the effects of these two toxic agents, both separately and in combination, on leukocyte counts, lymphocyte counts and mitotic index values were investigated. The study was carried out on blood samples of 100 males, divided into four groups: 25 non-smokers and 25 smokers, 25 toluene-exposed non-smokers and 25 no toluene-exposed smokers. The blood cell values of the blood samples were determined automatically on the hemogram apparatus. In addition slides of the blood samples were prepared according to the chromosome analysis procedure and the mitotic index values were determined through microscopy. The possible effects of smoking and toluene on lymphocyte life span was considered by correlating mitotic index values with lymphocyte counts in the same way for each of the subgroups. Results revealed that leukocyte counts and mitotic index values were higher in the smokers than the non-smokers whether or not they had been exposed to toluene. In addition the results indicate that lymphocyte life span may be shortened due to cigarette smoking and toluene exposure. | Bråtveit M, Hollund BE, Moen BE (2004)
Reduced exposure to organic solvents by use of water-based paint systems in car repair shops.
International archives of occupational and environmental health 77, 31-38 [PubMed:14605898]
[show Abstract]
ObjectiveThe objective of this study was to determine to what extent the substitution of solvent-based paint by water-based paint has reduced potential exposure to organic solvents for spray painters in car repair shops.MethodsFull-shift personal air sampling (n=79) was carried out over 3 consecutive days in eight car repair shops. Blood samples on the Monday morning (n=26) and at the end of the shift on the Wednesday (n=26), were analysed for organic solvents by headspace techniques.ResultsToluene was the organic solvent detected at the highest geometric mean concentration in air samples when solvent-based paint systems were used (0.8 ppm), whereas xylene was found at the highest level when water-based systems were used (0.25 ppm). Toluene, isopropanol, acetone and butyl acetate were detected at higher concentrations when solvent-based paint was used than when water-based paint was employed. The additive factor, based on Norwegian limit values, was three-times higher for the painters using solvent-based paint (0.15) than for those using water-based paint (0.05). On Wednesday after shift the geometric mean of toluene in blood was significantly higher for the painters using solvent-based paint (0.044 microg/ml) than for the painters using water-based paint (0.007 microg/ml). There was a significant correlation between toluene in personal air samples and toluene in blood samples taken at the end of the shift on the same day.ConclusionsWhen solvent-based paint systems were used the additive factor for organic solvent exposure was three-times higher than when water-based systems were employed. The exposure levels of the organic solvents were well below the Norwegian limit values. The significant correlation between the toluene concentration in air and blood samples indicated that the uptake of organic solvents was correspondingly reduced. At the levels of organic solvents presently described the risk of acute and chronic health effects caused by organic solvents is low. | Morón L, Pascual J, Portillo MP, Casis L, Macarulla MT, Abecia LC, Echevarría E (2004)
Toluene alters appetite, NPY, and galanin immunostaining in the rat hypothalamus.
Neurotoxicology and teratology 26, 195-200 [PubMed:15019953]
[show Abstract]
Toluene is a neurotoxic organic solvent widely used in industry and extensively inhaled by solvent abusers. Toluene, diluted 1:1 in olive oil, was administered intraperitoneally at a dose of 1.3 ml/kg/day for 4 days. Controls received the vehicle in the same dose and duration. Food intake and body weight were measured daily. A regional hypothalamic NPY and galanin immunocytochemical study was also performed. Acute toluene administration in rats generated a reduction in food intake and body weight gain. A significant decrease in NPY immunostaining in the paraventricular nucleus and an increase in arcuate nucleus without changes in other hypothalamic regions were observed. Also, acute toluene administration increased galanin immunostaining in paraventricular and arcuate nuclei. These results suggest that the hypothalamic NPY arcuate-paraventricular projection is involved in the anorectic effect of acute high-dose toluene administration. Changes in regional hypothalamic galanin expression could represent a compensatory mechanism against toluene-induced anorexia. | Burry M, Guizzetti M, Oberdoerster J, Costa LG (2003)
Developmental neurotoxicity of toluene: in vivo and in vitro effects on astroglial cells.
Developmental neuroscience 25, 14-19 [PubMed:12876426]
[show Abstract]
Toluene, an inexpensive and available industrial solvent, has become increasingly popular as a drug of abuse. Inhaling toluene leads to a feeling of euphoria and several reports have shown that children born to women who had abused toluene during pregnancy present a syndrome (toluene embryopathy or fetal solvent syndrome) that is characterized by CNS effects (e.g. microencephaly), growth retardation and facial dysmorphologies. The characteristics of the fetal solvent syndrome are very similar to those observed in the fetal alcohol syndrome. As exposure of rats to ethanol during the brain growth spurt has been shown to cause microencephaly and to affect glial cell proliferation and maturation, the present study examines the effects of toluene administration (250, 500 and 750 mg/kg) in neonatal rats from postnatal day 4 to 10. This treatment resulted in a significant decrease in both brain and body weights, and in a significant reduction of levels of glial fibrillary acidic protein, but not of neuron-specific enolase in rat brain. In vitro experiments demonstrate that pharmacologically relevant concentrations of toluene (250-1,000 microM) significantly inhibit proliferation of rat cortical astrocytes without causing overt cytotoxicity. These results indicate that toluene does not cause selective microencephaly; however, it affects brain weight, and appears to target developing astrocytes, possibly by inhibiting their proliferation. | Gerasimov MR, Collier L, Ferrieri A, Alexoff D, Lee D, Gifford AN, Balster RL (2003)
Toluene inhalation produces a conditioned place preference in rats.
European journal of pharmacology 477, 45-52 [PubMed:14512097]
[show Abstract]
Toluene is a widely abused solvent with demonstrated addictive potential in humans. Here we explore if conditioned place preference can be used to study the abuse-related effects of inhaled toluene in rats. Animals were confined to a distinctive compartment of a three-compartment chamber while exposed to toluene vapor and later tested for preference for that compartment compared to appropriate control subjects. In this study, a flame ionization detector was used for on-line monitoring of toluene vapor concentrations inside the conditioning apparatus coupled with computerized recording of the time spent by the animals on the test day in each of the chambers. Sprague-Dawley rats were exposed to 810, 1895 or 4950 ppm of toluene vapors in either the black or white compartment during 30-min pairing sessions given every other day alternating with air exposure for the total of six pairings for each treatment. Rats that received air in both sides (control group) did not show any preference for either side with approximately equal time spent in each compartment on the test day (241 +/- 33 and 234 +/- 34 s, for white and black box, respectively). However, the 1895- and 4950-ppm test groups, but not the 810-ppm group, demonstrated a significant preference for the side paired with toluene exposure. When a subsequent test session was performed during toluene exposures, no conditioned place preference was observed. Thus, toluene produced a clear conditioned place preference that appears to be most evident when animals are not intoxicated. This procedure should be useful for further studies of the abuse-related effects of abused inhalants. | Chen HF, Chen SW, Chen P, Su MC, See TT, Lee HY (2003)
Chronic glue sniffing with transient central hypothyroidism and hypergonadotropism.
Journal of the Chinese Medical Association : JCMA 66, 747-751 [PubMed:15015825]
[show Abstract]
Neuropsychiatric, gastrointestinal and muscular disorders associated with glue sniffing have been widely reported, but endocrinologic abnormalities of glue exposure are rarely mentioned in the literature. We report a 26-year old male patient, a chronic glue sniffer, who presented with weakness of both lower limbs. On physical examination, he had reduced muscle strength of his 4 limbs, especially in his lower limbs. Laboratory examination revealed hypokalemia with hyperchloremic metabolic acidosis. His thyroid function showed low TSH, T4, T3, free T4 and reverse T3 level. Other pituitary functions were normal apart from high FSH and LH level. TSH response to TRH stimulation was normal, but there was impaired T3 response to TRH. MRI of pituitary showed no significant changes. He continued glue sniffing after discharge. He repeatedly came to our hospital for recurrent hypokalemic paralysis. His serum T4 and free T4 level were low when he had certain amount of glue sniffing and it returned to normal after he stopped sniffing or sniffed less amount of glue. His serum T3 concentrations were normal most of the times thereafter. His FSH and LH level were persistently elevated, even after he did not sniff glue for 2 weeks. Low free T4, TSH and reverse T3 level associated with glue sniffing in our patient were compatible with central hypothyroidism. Toluene, a neurotoxic organic solvent, is present in glues. Being highly lipophilic, it can easily enter and is retained within the lipid-rich nervous system after being inhaled. Like other organic solvents, toluene has been shown to affect dopaminergic and adrenergic turnover within various parts of the brain. The effects on these neurotransmitters could lead to abnormal secretion of pituitary hormones resulting in transient central hypothyroidism and abnormal gonadotropin levels. Long-term harmful effect of central hypothyroidism and chronic influence of abnormal gonadotropins to reproduction function needs further observation. | Aydin K, Sencer S, Ogel K, Genchellac H, Demir T, Minareci O (2003)
Single-voxel proton MR spectroscopy in toluene abuse.
Magnetic resonance imaging 21, 777-785 [PubMed:14559343]
[show Abstract]
Inhalation of toluene, which is an organic solvent, causes toxic encephalopathy characterized by cognitive impairment, cerebellar and extra-pyramidal symptoms. We studied cranial MR images and single-voxel MR spectroscopy of 22 toluene abusers and age-matched control subjects. The mean age of the abusers and mean duration of abuse were 18,1 years and 47 months, respectively. We got three MR spectra from the centrum semiovale, cerebellum and thalamus by using STEAM sequence with a TE value of 30 ms. N-acetyl aspartate (NAA)/Creatine (Cr), Choline (Cho)/Cr, myo-inositol (mI)/Cr peak integral ratios were calculated. NAA/Cr in the cerebellum and centrum semiovale of the abusers were significantly lower than those of the control subjects. mI/Cr in centrum semiovale and cerebellum were higher in toluene abusers. No significant difference was found in the metabolite ratios of the thalami. The association of NAA/Cr and mI/Cr ratios in cerebellum and centrum semiovale with the duration of abuse was significant. Normal level of NAA in thalamus, which was a neuron rich gray matter structure, might imply that toluene inhalation did not cause direct neuronal injury. Selective reduction of NAA and increased level of mI in white matter supported the theory of that axonopathy and gliosis were the main mechanisms of pathophysiology in chronic toluene encepholopathy. Insignificance of elevation of Cho/Cr ratios demonstrated that toluene inhalation did not cause active demyelination. | Riegel AC, Ali SF, French ED (2003)
Toluene-induced locomotor activity is blocked by 6-hydroxydopamine lesions of the nucleus accumbens and the mGluR2/3 agonist LY379268.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 28, 1440-1447 [PubMed:12784113]
[show Abstract]
The abuse of volatile inhalants remains a prominent, yet poorly understood, form of substance abuse among youth. Nevertheless, the identification of a mechanism underlying the reinforcing properties of inhalants has been hampered by the lack of a clearly identifiable neural substrate upon which these chemicals act. One ingredient that is common to many abused inhalants is toluene, an organic solvent that is self-administered by nonhuman primates and rodents. Most drugs of abuse have been found to elicit forward locomotion in rats, an effect owing to the activation of mesoaccumbal dopamine (DA) pathways. Thus, the present study was undertaken using two different approaches to determine whether toluene-induced locomotor hyperactivity is also ultimately dependent upon DA neurotransmission in the mesolimbic nucleus accumbens (NAC). Here we report on the effects of 6-hydroxydopamine (6-OHDA) lesions of the NAC or pretreatment with the metabotropic mGlu2/3 receptor agonist LY379268 on toluene-induced locomotor activity. Both procedures, which are known to alter neurotransmission within the NAC, significantly attenuated toluene's locomotor stimulatory effects. These results provide strong support for a central mechanism of action of inhalants, which in the past has been more typically attributed to general nonspecific mechanisms throughout the brain. Moreover, as with other drugs of abuse, the NAC may be the final common pathway subserving toluene's abuse liability. | Bale AS, Smothers CT, Woodward JJ (2002)
Inhibition of neuronal nicotinic acetylcholine receptors by the abused solvent, toluene.
British journal of pharmacology 137, 375-383 [PubMed:12237258]
[show Abstract]
1 Toluene is a representative example of a class of industrial solvents that are voluntarily inhaled as drugs of abuse. Previous data from this lab and others has shown that toluene modulates the function of N-methyl-D-aspartate (NMDA), gamma-aminobutyric acid (GABA) and glycine receptors at concentrations that do not affect non-NMDA receptors. 2 We utilized two-electrode voltage-clamp and whole cell patch-clamp techniques to assess the effects of toluene on neuronal nicotinic acetylcholine receptors expressed in oocytes and cultured hippocampal neurons. Toluene (50 micro M to 10 mM) produced a reversible, concentration-dependent inhibition of acetylcholine-induced current in Xenopus oocytes expressing various nicotinic receptor subtypes. The alpha4beta2 and alpha3beta2 subunit combinations were significantly more sensitive to toluene inhibition than the alpha4beta4, alpha3beta4 and alpha7 receptors. 3 Receptors composed of alpha4 and beta2(V253F) subunits showed alpha4beta4-like toluene sensitivity while those containing alpha4 and beta4(F255V) subunits showed alpha4beta2-like sensitivity. 4 In hippocampal neurons, toluene (50 micro M to 10 mM) dose-dependently inhibited ACh-mediated responses with an IC(50) of 1.1 mM. 5 Taken together, these results suggest that nicotinic receptors, like NMDA receptors, show a subunit-dependent sensitivity to toluene and may represent an important site of action for some of the neurobehavioural effects of toluene. | Davis RR, Murphy WJ, Snawder JE, Striley CA, Henderson D, Khan A, Krieg EF (2002)
Susceptibility to the ototoxic properties of toluene is species specific.
Hearing research 166, 24-32 [PubMed:12062755]
[show Abstract]
Toluene is the most widely used industrial solvent. It has been shown to be ototoxic in mice and rats, and to increase permanent threshold shift in conjunction with exposure to noise. Chinchillas are widely used for studying noise effects on the cochlea. The present study was initiated to study toluene and noise interaction in chinchillas. Thirty-three chinchillas were exposed to a 95 dBA 500 Hz octave band noise plus 2000 ppm toluene, 8 or 12 h per day for 10 days. Auditory function was estimated using the auditory brainstem response (ABR) to tones between 500 Hz and 16 kHz. There was no effect on the ABR of toluene alone. Noise alone produced a threshold shift. There was no interaction of noise and toluene on the ear. The present study suggests that chinchillas are markedly less susceptible to the ototoxic effect of toluene than mice and rats. A working hypothesis as to the species differences was that chinchilla liver was able to detoxify the toluene. Hepatic microsomes from chinchillas, rats and humans were tested for their ability to convert toluene to the more water-soluble compound - benzyl alcohol. Chinchilla livers were found to contain more of the P450 enzymes CYP2E1 and CYP2B than rats or humans. In addition, the data show that the P450 enzymes are more active in chinchillas than in rats and humans. In conclusion, the results suggest that rats and mice are a more appropriate model for human toluene ototoxicity. However, chinchillas may provide a valuable model for investigating how ototoxic agents can be detoxified to less damaging compounds. | Berek D (2002)
Evaluation of high-performance liquid chromatography column retentivity using macromolecular probes I.
Journal of chromatography. A 950, 75-80 [PubMed:11991009]
[show Abstract]
The application of macromolecular probes is proposed for evaluation of HPLC column retentivity. The idea is tested with a set of different commercial silica C18 reversed-phases. For comparison, porous glass C18 and polystyrene/divinylbenzene column packings are also included. Polar, mainly silanophilic interactions are evaluated. The retention volumes of a series of narrow molar mass distribution polystyrenes (PS) and poly(methyl methacrylate)s (PMMA) in toluene eluent are compared. Toluene is a weak mobile phase concerning silica gel surface and it promotes adsorption of PMMA on silanols, while PS is not adsorbed from toluene. Simultaneously, toluene is a thermodynamically good solvent for both polymers so that extensive partition in favour of stationary phase is not probable. Differences in retention behaviour of PS and PMMA indicate presence of abundant free silanols on the surface of some reversed-phases. These silanols are accessible even for large macromolecules of PMMA. Pore diameter and pore volume of the column packing can be semiquantitatively evaluated from the elution data of PS in toluene in the course of retentivity tests. | Lefkowitz D, Zambrowski M, Uchrin C (2002)
Development of a method for extraction of methyl tert-butyl (MTBE) from soil samples.
Journal of environmental science and health. Part A, Toxic/hazardous substances & environmental engineering 37, 17-27 [PubMed:11846266]
[show Abstract]
Methyl tert-Butyl Ether (MTBE) is ubiquitous in both ground and surface waters in the United States, and it can also be found in many unsaturated soil systems. Until recently, MTBE was not thought to adsorb appreciably to soil solids. MTBE, however, will adsorb to some soil types, and additionally, can be found in both soil water and soil gas. Since sorbed MTBE can serve as a long term, low level, source to water systems, a practical method for quantifying soil concentrations is needed to fully understand the environmental impact of MTBE. In this paper, we examine the analytical parameters critical to MTBE extraction methods, including extraction solvent and gas chromatograph characteristics. As the result, we have discovered toluene to be an effective solvent (exhibiting adequate recovery and excellent separation from MTBE) using a GC/FID with Suppelcowax column. | Chen HH, Lee YF (2002)
Neonatal toluene exposure selectively alters sensitivity to different chemoconvulsant drugs in juvenile rats.
Pharmacology, biochemistry, and behavior 73, 921-927 [PubMed:12213539]
[show Abstract]
Toluene is an abused solvent widely used in several commercial products. Recent evidence indicates that this solvent is a noncompetitive inhibitor of N-methyl-D-aspartate (NMDA) receptors and enhances gamma-aminobutyric acid(A) (GABA(A)) receptor-mediated synaptic currents. Since NMDA and GABA(A) receptors have been implicated in seizures, this study investigated whether toluene exposure during synaptogenesis period alters the NMDA and GABA(A) receptor-mediated seizure susceptibility in juvenile rats. Neonatal rats were administered toluene (1 g/kg ip) daily over postnatal days (PN) 4-9. Rats were administered NMDA (10 mg/ml), picrotoxin (2 mg/ml), pentylenetetrazol, (5 mg/ml) and 4-aminopyridine (4-AP; 2 mg/ml) via timed tail vein infusion on PN 34-36. Toluene exposure increased sensitivity to NMDA, picrotoxin and pentylenetetrazol, but did not affect 4-aminoyridine-induced seizures in both male and female rats. These results suggest that toluene may possess a risk to the developing brain by inducing a long-term alteration in the function of NMDA and GABA(A) receptors. | Cruz SL, Páez-Martínez N, Pellicer F, Salazar LA, López-Rubalcava C (2001)
Toluene increases acute thermonociception in mice.
Behavioural brain research 120, 213-220 [PubMed:11182169]
[show Abstract]
Toluene is an abused solvent widely used in several commercial products. Recent evidence indicates that this solvent is a non-competitive inhibitor of NMDA receptors. Since NMDA receptors have been implicated in pain, this paper describes studies of the effects of increasing concentrations of inhaled toluene on nociception. Swiss Webster mice were exposed to toluene (500-8000 ppm) in static exposure chambers for 30 min. After completing the exposure period, animals were tested for nociception using the hot plate test. Toluene dose-dependently increased nociception as reflected by shorter latencies for the reflex, paw-lick and escape responses in toluene-treated mice with respect to their controls (animals exposed to air). In order to determine the possible role of opioids in this response, morphine (1-10 mg/kg) was injected before toluene inhalation. Toluene was not able to block morphine-induced antinocieption, however, it produced a shift of the morphine dose-response curve to lower effects, suggesting a physiological antagonism. No potentiation was seen when toluene was administered in combination with naloxone. Present results suggest that toluene increases nociception via neurotransmitter systems others than the glutamatergic. | Beyer CE, Stafford D, LeSage MG, Glowa JR, Steketee JD (2001)
Repeated exposure to inhaled toluene induces behavioral and neurochemical cross-sensitization to cocaine in rats.
Psychopharmacology 154, 198-204 [PubMed:11314682]
[show Abstract]
RationaleToluene is a solvent found in many commercial products and is frequently abused by inhalation. Whether previous exposure to toluene alters subsequent responses to other drugs of abuse is not known.ObjectivesThis study determined the effects of repeated toluene exposure on the acute motor-stimulant response to cocaine and on cocaine-induced dopamine (DA) concentrations in the nucleus accumbens (NAc).MethodsOne week following bilateral cannulae implantation over the NAc, 27 adult, male Wistar rats began a daily 30-min exposure regimen to either toluene (8,000 ppm) or air for ten sessions. Approximately 24 h or 96 h after their last exposure, animals were injected with either saline or cocaine (15 mg/kg, i.p.) and locomotor activity and DA concentrations in the NAc were measured.ResultsExposure to toluene rendered the rats immobile, and the time required for recovery of normal posture decreased across the ten sessions. In all animals tested, systemic cocaine administration enhanced both locomotor activity and DA concentrations in the NAc. These increases, however, were significantly greater in rats previously exposed to toluene.ConclusionsOverall, these findings show that repeated toluene exposure enhances behavioral and neurochemical responses to subsequent cocaine administration. | Lovley DR, Lonergan DJ (1990)
Anaerobic Oxidation of Toluene, Phenol, and p-Cresol by the Dissimilatory Iron-Reducing Organism, GS-15.
Applied and environmental microbiology 56, 1858-1864 [PubMed:16348226]
[show Abstract]
The dissimilatory Fe(III) reducer, GS-15, is the first microorganism known to couple the oxidation of aromatic compounds to the reduction of Fe(III) and the first example of a pure culture of any kind known to anaerobically oxidize an aromatic hydrocarbon, toluene. In this study, the metabolism of toluene, phenol, and p-cresol by GS-15 was investigated in more detail. GS-15 grew in an anaerobic medium with toluene as the sole electron donor and Fe(III) oxide as the electron acceptor. Growth coincided with Fe(III) reduction. [ring-C]toluene was oxidized to CO(2), and the stoichiometry of CO(2) production and Fe(III) reduction indicated that GS-15 completely oxidized toluene to carbon dioxide with Fe(III) as the electron acceptor. Magnetite was the primary iron end product during toluene oxidation. Phenol and p-cresol were also completely oxidized to carbon dioxide with Fe(III) as the sole electron acceptor, and GS-15 could obtain energy to support growth by oxidizing either of these compounds as the sole electron donor. p-Hydroxybenzoate was a transitory extracellular intermediate of phenol and p-cresol metabolism but not of toluene metabolism. GS-15 oxidized potential aromatic intermediates in the oxidation of toluene (benzylalcohol and benzaldehyde) and p-cresol (p-hydroxybenzylalcohol and p-hydroxybenzaldehyde). The metabolism described here provides a model for how aromatic hydrocarbons and phenols may be oxidized with the reduction of Fe(III) in contaminated aquifers and petroleum-containing sediments. |
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