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Effects of toluene exposure on the spontaneous cortical activity in rats
Abstract
Effects of toluene on the electroencephalogram (EEG) and its power spectra were measured during a 2-hr exposure in a dynamic inhalational chamber in rats. Rats were exposed to one of six graded concentrations (110.6, 162.5, 432, 676, 1558, 2730 ppm) of toluene on different days. It was found that the duration of waking (W) was increased with a decrease in duration of rapid eye movement (REM) sleep even at 110.6 ppm. Duration of nonrapid eye movement (NREM) sleep was decreased with an increase of W and a decrease of REM sleep at 162.5 ppm. Dose-related effects were noted in higher concentrations. The power of delta frequency band was increased with a decrease of theta frequency band power at hr 1 of exposure to 676 ppm during REM sleep recorded from the visual cortex. The power of theta frequency band was also decreased at hr 2 of exposure at 432 ppm. During W and NREM sleep power spectra were not changed significantly. Results indicate that the changes of EEG are a sensitive measure of the effects of toluene on the central nervous system (CNS).
... A 22 gauge guide cannula (C 313-G, Roancke, Virginia, USA) was implanted at 1.00 mm anterior to bregma on the midline and 3.00 mm below the skull surface and was fixed on the skull with dental acrylic. For EEG recording two stainless steel screw electrodes (0.8 9 1/8 inch) were implanted over the visual cortex (6.0 mm posterior to bregma and 3.5 mm lateral to the midline on both side) and one stainless steel screw electrode placed 11.0 mm anterior to bregma on the midline served as ground following the method of Ghosh et al. (1989). For Electromyogram (EMG) recording, pairs of insulated wire electrodes were inserted into dorsal neck muscles. ...
... The sleep-wake stages were classified as wake, slow wave sleeps (SWS) and rapid eye movement sleep (REM) according to criteria described by Ghosh et al. (1989). Each stage was characterized as follows: wake, low amplitude EEG and high amplitude EMG; SWS, high amplitude EEG and low amplitude EMG; REM, low amplitude EEG with continuous theta wave in EEG and low amplitude of EMG. ...
Brain stem arousal systems transmit their effects to the cerebral cortex partly through basal forebrain including medial septum (MS). Cholinergic neurones of basal forebrain are inhibited by norepinephrine and acetylcholine. Glutamatergic neurones in MS may be an excitatory link between brain stem projecting systems and cholinergic system of MS. The present study has been designed to investigate the role of glutamate receptors present in MS on the duration of sleep-wake and electroencephalogram (EEG) power spectra in conscious rats. The duration of wake was increased and duration of slow wave sleep (SWS) was decreased after infusion of glutamate into MS. The durations of wake and SWS remained unaltered after infusion of glutamate receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) in MS of rats. The power of delta waves of EEG was decreased in both wake and SWS after infusion of glutamate in MS. There was a generalized increase of power of alpha, beta, theta and delta waves of EEG after infusion of DNQX in MS. Results of this study indicate that glutamate receptors in MS may modulate the cortical arousal mechanism.
... Besides marsiline MQ methanol extract contains various classes of saponins, alkaloids and polyphenols (Bhadra et al., 2012). The electroencephalogram (EEG) and its power spectral analysis have been widely used to identify the nature of pharmacological action of drugs on brain (Ghosh et al., 1989; Barbanoj et al., 2006; Dimpfel, 2009). Different psychotropic drugs appear to have their own EEG fingerprint (Dimpfel, 2003 ). ...
... The animals were anesthetized with sodium pentobarbital (40 mg/kg i.p; Thiopentone, Neon Laboratories Ltd., India) and then placed in a stereotaxic apparatus (ST141, Inco Ambala, India). For EEG recording, two stainless steel screw electrodes were implanted over the visual cortex (6.0 mm posterior to the bregma and 3.5 mm lateral to the midline on both sides) and one stainless steel screw electrode was placed 11 mm anterior to the bregma on the midline served as ground (Ghosh et al., 1989). The electrodes were soldered to a miniature socket and the whole assembly was fixed to the skull with dental acrylic. ...
Marsilea quadrifolia Linn (MQ) extract has been used traditionally as sedative and antiepileptic drug in India.
To investigate the anticonvulsive potential of MQ extracts by using behavior and electroencephalographic (EEG) analysis on pentylenetetrazole (PTZ) induced seizure model in rats.
For anticonvulsant effect, 60minutes after administration of MQ, behavior and EEG were analyzed during PTZ (60mg/kg) induced seizures. Changes of EEG power, latency of onset of seizure, seizure severity score, and duration of epileptic seizure were determined.
Both the water and ethanol extract of MQ increased the latency of seizure but also decreased duration of epileptic seizure and seizure severity score. This reduction of seizure severity was also observed in EEG recording and EEG power analysis. The effectiveness of MQ ethanol extract is better than MQ water extract.
Both water and ethanol extract of MQ were effective in reducing the severity of behavioral and EEG seizures induced by PTZ in rats. This study justifies the traditional use of this plant in epilepsy.
... 28 At present, the EEG method has been widely utilized to better understand cognitive activity, which proved to be a sensitive measure of assessing the impact of air pollutant on human brain. [29][30][31] Attention is the precondition of advanced cognitive functions composed of three functionally and anatomically distinct subsystems known as alerting network, orienting network, and executive network (EC). 32,33 The attention network test (ANT) designed by Fan et al. was used to evaluate the efficiency of three components of attention network, 34 and distinct brain oscillation pattern of the attention network has been found in previous research. ...
Despite accumulative literature reporting negative impacts of high‐concentration toluene, cognitive effects of toluene at low concentration are still unclear. Twenty‐two healthy college students were exposed in a closed environmental chamber to investigate the influence of indoor toluene on cognitive performance and brain activity. During each toluene exposure condition (0 ppb, 17.5 ppb, 35 ppb, and 70 ppb), attention network test and electroencephalogram (EEG) recording were synchronously performed after 4‐hour toluene exposure. Characteristic neural oscillation patterns in three attention networks were compared between four groups. The statistical analyses indicated that short‐term exposure to toluene had no significant impact on behavioral performance of attention network. However, there was a significant increase in the power of theta and alpha band of executive network and orienting network in the whole brain, especially in frontal region when exposed to toluene. Besides, no significant difference was observed in alerting network. The alternations in neural oscillation demonstrated that more effort was required to accomplish the same tasks when exposed to toluene. The present study revealed that short‐term exposure to toluene affected brain activity of attention network even at low concentration, which provided a theoretical basis for the development of safer evaluation methods and standards in the future.
... The EEG and its spectral power analyses are widely used to investigate brain dysfunctions and the nature of pharmacological action of drugs on the CNS (Ghosh et al., 1989;Barbanoj et al., 2006). A few EEG spectral power studies have been used as a screening measurement to identify the effects of different plant extracts in humans (Schulz et al., 1998;Vonderheid-Guth et al., 2000) and animals (Dimpfel, 2013;González-Trujano et al., 2016). ...
Ethnopharmacological relevance
Ruta chalepensis L. (Rutaceae) is used in traditional medicine to treat a wide variety of disorders such as rheumatism, fever, mental disorders, dropsy, neuralgia, menstrual problems, anxiety, and epilepsy.
Aim of the study
To evaluate and compare the anticonvulsant properties of an aqueous extract and ethyl acetate (AcOEt) fraction of R. chalepensis on pentylenetetrazole (PTZ)-induced seizures and maximal electroshock (MES) test in mice, by analyzing behavior and electroencephalogram (EEG), as well as GABAA receptors involvement.
Methods
The effect of an acute administration of different dosage of the aqueous extract (300 or 500 mg/kg) or AcOEt fraction (100, 300, 500 or 1000 mg/kg) of R. chalepensis was explored on two different models of acute seizure induction in mice, the PTZ and maximal electroshock (MES) tests. Behavioral and electrographic effects were quantified. Additionally, the possible involvement of the GABAA receptors was explored in the presence of picrotoxin (a non-competitive antagonist of the GABAA receptor).
Results
AcOEt fraction of R. chalepensis was more efficient than aqueous extract to reduce the incidence of tonic-clonic seizures and mortality in a significant and dose-dependent manner in both the PTZ and MES tests. This anticonvulsant effect was not abolished in the presence of picrotoxin. The EEG spectral power analysis revealed that aqueous extract decreased alpha and beta power, while AcOEt fraction decreased alpha and gamma power confirming previous findings of its depressant effect in the central nervous system. It is important to mention that the highest dosage of the AcOEt (1000 mg/kg) produced a severe suppression or isoelectric EEG activity (EEG flattening), recognized as a comatose state, suggesting a neurotoxic effect at this dosage.
Conclusion
Our data reinforce that depressant and anticonvulsant effects of R. chalepensis depend in part on the presence of constituents from medium polarity. We also found that anticonvulsant effect is not mediated by GABAA receptors. In addition, cautious is emphasized when high doses of this natural product are used in traditional medicine since it might produce neurotoxic effects.
Chemical intolerance is a phenomenon observed in multiple chemical sensitivity (MCS) syndrome, an ill-defined disorder in humans attributed to exposure to volatile organic compounds. Amplification of symptoms in individuals with MCS resembles the phenomenon of psychostimulant- and stress-induced sensitization in rodents. We have recently tested in rats the hypothesis that repeated chemical exposure produces sensitization of central nervous system (CNS) circuitry. A rat model of MCS in our laboratory has employed several endpoints of CNS function after repeated formaldehyde (Form) exposure (1 h/day × 5 days/week × 4 weeks). Repeated Form exposure produced behavioral sensitization to later cocaine injection, suggesting altered dopaminergic sensitivity in mesolimbic pathways. Rats given repeated Form also demonstrated increased fear conditioning to odor paired with footshock, implicating amplification of neural circuitry guiding fear responding to a conditioned odor cue. Recent studies examining the effects of repeated Form on locomotor activity during each daily exposure showed a decrease in rearing activity after 12-15 days of Form exposure compared to air-exposed controls. EEG recordings taken 1 week after withdrawal from daily Form revealed altered sleep architecture. Some of the differences in sleep disappeared after subsequent brief (15 min) challenge with Form the next day. Overall, the findings indicate that repeated low-level chemical exposure produces behavioral changes that may be akin to those observed in individuals with MCS, such as greater sensitivity to chemicals manifest as increased anxiety upon chemical exposure and altered sleep and/or fatigue. Study of the underlying CNS changes will provide a basis for mechanistically based animal models for MCS.
The nervous system differs from many other body organs by its central control of vital functions and its low regeneration capacity. Organic solvents have, as a group, been suspected to have neurotoxic effects. Because of their similar physical properties and the fact that in industrial uses, they are often present in various mixtures, organic solvents have also been regarded, unfortunately, to induce common neurotoxic effects. However, it is evident from experimental studies using specified exposure conditions that different organic solvents have very diverse neurotoxic effects and also that the toxic mechanism may differ between acute and chronic exposure. No specific method used to describe a neurotoxic effect or single toxic response can be used for the overall occupational risk assessment of all organic solvents. Each solvent has to be considered as having its own unique toxic effects.
Effects of ethanol on duration of stages of sleep-wake cycle and EEG power spectra were measured during a 2-h exposure in a dynamic inhalational chamber in rats. Rats were exposed to one of four graded concentrations (approx. 100, 400, 800 and 1600 ppm) of ethanol on different days. Ethanol was found to increase the duration of waking (W) with a decrease in duration of rapid eye movement (REM) sleep at 100 and 400 ppm. No effect was observed at 800 and 1600 ppm on the stages of sleep-wake cycle or at 100-1600 ppm on EEG power spectra from the somatosensory or visual cortices. Results indicate that ethanol administered by inhalation could produce arousal action at low doses, but did not have any effect on EEG power spectrum at the concentrations used.
Effects of toluene on the electroencephalogram (EEG) and its power spectra were measured during a 2-hr exposure in a dynamic inhalational chamber in young rats (30-53 days old) and compared to those in adult rats (63-77 days old). Rats were exposed to one of the three concentrations [low (108-111 ppm), medium (160-163 ppm), and high (407-432 ppm)] of toluene on different days. In tests on sleep-wake cycle, in the young animals the duration of the wake stage (W) was increased with decreases of rapid eye movement (REM) and non-REM (NREM) sleep during hr 1 and hr 2 of exposure to the low concentration. These effects were marked at the medium and the high concentrations. In adult rats, at the low concentration the increase of W and the decrease of REM were observed only at hr 1; however, at medium and high concentrations these changes of W and REM sleep were marked along with a decrease of NREM. Comparison of the changes of duration of different states in rats of two age groups showed that there was a significant difference in the increase of W and the decrease of NREM sleep in young rats at hr 2 of exposure to low concentrations only compared to those in adult rats. Tested on power spectrum in young rats during REM sleep recorded from the visual cortex, the power of delta waves increased at the medium and high concentrations and that of theta wave decreased at the high concentration during hr 2 of exposure compared to the controls.(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of toluene on synaptic transmission and neuronal morphology were investigated using guinea pig hippocampal slices. Population spikes (PS) were elicited in granule cell layer by stimulation of the perforant path and antidromic potentials (AP) were evoked in the same locii by stimulation of mossy fibers. Toluene at a concentration of 1000 micrograms/ml completely depressed post-synaptic responses within 15 min but increased the AP to 140% of its original value. The PS recovered completely when washout was begun 10 and 20 min after onset of depression, but exhibited only partial recovery following a 40 min depression. There were no evident changes in staining of axons or cell bodies after toluene treatment. These results indicate that toluene at high concentrations (1000 micrograms/ml) inhibits synaptic transmission selectively and with longer exposures causes lasting physiological effects unaccompanied by gross morphological changes.
To investigate the effect of toluene and its derivatives on neural activity, postsynaptic field potential (population spike, PS) of granule cells as well as antidromic potential (AP) and presynaptic fiber potential (FP) (perforant path) were recorded in the guinea pig hippocampal slices. Toluene at the concentration of 0.2 ng/ml to 20 micrograms/ml in the perfusion medium increased the amplitude of PS to 109-150%. Toluene also increased the amplitude of FP and AP, although the most remarkable enhancement was observed in the PS. However, toluene at the concentrations over 1000 micrograms/ml completely depressed the PS, whereas it increased the amplitude of AP to 130% of the original level. These results indicate that toluene has excitatory and inhibitory biphasic effects on neurotransmission in the hippocampal slices according to concentration applied.
Since the Chernobyl accident, the most significant problem for the population living in the contaminated areas is chronic exposure by ingestion of radionuclides, notably (137)Cs, a radioactive isotope of cesium. It can be found in the whole body, including the central nervous system. The present study aimed to assess the effect of (137)Cs on the central nervous system and notably on open-field activity and the electroencephalographic pattern. Rats were exposed up to 90 days to drinking water contaminated with (137)Cs at a dosage of 400 Bq kg(-1), which is similar to that ingested by the population living in contaminated territories. At this level of exposure, no significant effect was observed on open-field activity. On the other hand, at 30 days exposure, (137)Cs decreased the number of episodes of wakefulness and slow wave sleep and increased the mean duration of these stages. At 90 days exposure, the power of 0.5-4 Hz band of (137)Cs-exposed rats was increased in comparison with controls. These electrophysiological changes may be due to a regional (137)Cs accumulation in the brain stem. In conclusion, the neurocognitive effects of (137)Cs need further evaluation and central disorders of population living in contaminated territories must be considered.
Workers exposed to toluene develop many central and autonomic nervous symptoms. It has been suggested that the effects of toluene on the central nervous system may be detectable by EEG. In the present experiments, changes in EEG and behaviour of rats exposed to toluene were monitored in an attempt to clarify the relationship between exposure to toluene and central nervous system reaction. Chronically implanted electrodes were used in Wistar albino male rats to record EEG in cortex and hippocampus, cervical EEG and pulse rate. The rats were exposed to 4000 ppm, 2000 ppm and 1000 ppm toluene vapour for four hours. The sleep cycle was divided into five phases (wakeful, spindle, slow-wave, preparadoxical and paradoxical) judged by the cortical and hippocampal EEGs, the cervical EMG, and behaviour. This classification should be useful in assessment of the effects of toluene on the central nervous system. In our experiments, the changes in the sleep cycle suggest that 4000 ppm and 2000 ppm of toluene vapour disturb the sleep, and 1000 ppm of toluene vapour prevents sleep entering the slow-wave phase but facilitates its entry into the paradoxical phase. The changes of EEG components were peculiar to each concentration. The results suggest, in effect, that analysis of the changes in the EEG components would be helpful as an index to the reaction of the central nervous system to toluene vapour.
The discovery of electrical potentials of the brain is thought to have been made by Caton (1875), who presented the results of his research with rabbits and monkeys to the British Medical Association in Edinburgh. Half a century later in Jena, Austria, Hans Berger (1929) discovered human brain waves and, hence, Berger is recognized as the father of electroencephalography, the recording of oscillations in the potential differences between two points in the brain (Berger, 1937).
Large amount of organic solvents is used in the processing industries and most of these industries are medium or small enterprises. Therefore, health of workers working there is liable to be disturbed by organic solvents. And as the workers exposed to organic solvents usually complain of indefinite oilments, recently health of workers exposed to organic solvents became to be studied endocrinologically and neurologically.Two workers exposed to organic solvents in a paints industry consulted us and complained of dizziness, headache, tinnitus, insomnia, slight fever, disturbance of appetite, decrease of body weight, cramp of lower extremities, etc. And in our clinical examination, hypofunction of diencephalon-hypohysis-adrenal cortex system, hypesthesia on one side, continuous slight fever, slight orthostatism, abnormal EEG etc. were found and diagnosed as diencephalon syndrome.Working conditions were investigated. This paints industry is medium enterprise but the work room where the two patients were working was small and ventilated not sufficiently. And it was found that the two worker were being exposed to toluene vapor of which concentration ranged from several hundred ppm to one thausand and several hundred ppm and to smaller concentration of other organic solvents. Therefore, it was thought that the disorders of these two patients were caused chiefly by exposure to toluene vapor.The two patients were detached from the work place and treated in our hospital, but disorders of them were not rapidly improved.In view of these serious health disorders of the two workers, we think it is very important that the toxicity of organic solvents should be still more studied especially concerning the effect to the endocrine and nervous systems, and that the working conditions in work place using organic solvents should be still more improved for prevention of organic solvent poisoning.
The effect of toluene inhalation was studied on an operant behavior maintained by a fixed-ratio (FR-24) schedule of liquid reinforcement in rats. A dynamic (flow-through) inhalational behavioral chamber was used to expose rats to toluene vapor. Rats were exposed successively to three graded concentrations (105, 214, 382 ppm) of toluene vapor each for 2 hr in range-finding experiments during 6 1/4-hr sessions. The reinforcement rate was not altered at hours 1 and 2 but was decreased at hours 3 and 5 of exposure. However, at hours 4 and 6 the reinforcement rate showed recovery from depression. In 2-hr exposure experiments with four different concentrations of toluene on separate days, the reinforcement rate was decreased at hour 1 during exposure to 142, 211, and 496 ppm, but exposure to 121 ppm had no effect. There was also no effect when rats were exposed to 115 ppm of toluene during a 5-hr session. The experiment with 2-hr daily exposures to 212 ppm of toluene for 5 consecutive days indicated the development of tolerance to the decreased reinforcement rate during 4th and 5th days of exposure. This study thus shows a minimum effective concentration of 142 ppm of toluene, which would produce no effect on FR liquid-reinforced behavior, and indicates that tolerance develops to the behavioral effect of toluene.
Toluene is used extensively as a solvent in the lacquer industry, and in the explosives industry it plays an important role as a starting material for trinitrotoluene. At present it is generally assumed that the maximal permissible concentration of toluene is about 200 parts per million parts of air. It appears, however, that there is little evidence to sustain the validity of this concentration as the maximal permissible limit. For this reason the following study was undertaken with the hope of establishing more definite data on which maximal permissible concentrations could be based.Cole and Armstrong1 established, by spectrophotometric determination, that the toluene used for this investigation was of a high degree of purity, containing not more than 0.01 per cent of benzene.Animal experiments indicate that toluene is more irritant and, with lower concentrations, has a somewhat stronger narcotic action than benzene but that its effect on the
Toluene is a hydrocarbon, C6H5CH3, also known as toluol and methyl benzene. It is a colorless, highly refractive inflammable liquid obtained from tolu and other resins and from coal tar. It boils at 110.4 C. and has an odor similar to that of benzene. It is insoluble in water and is miscible with alcohol, ether, chloroform, carbon disulfide and petroleum benzine. Its specific gravity is about 0.865 at 250 C. It dissolves iodine, phosphorus, sulfur and, when used in large amounts, resins and fats.Toluene constitutes 2 to 10 per cent of commercial benzene. It is used extensively as a solvent in the rubber, lacquer and munitions industries. It affords an excellent solvent for certain types of synthetic rubber because it dries rapidly. It is used as a starting material in the manufacture of trinitrotoluene.The pathologic manifestations of exposure to toluene (toluol) are a
Neurophysiological and psychological tests were administered to 107 patients - 48 men and 59 women - with a diagnosis of solvent poisoning after longstanding (mean 9.6 years for males and mean 7.6 years for females) occupational exposure. Electroencephalography (EEG) and a wide psychological test battery were applied in all cases, and electroneurographic measurements were performed in 77 subjects. Sixty-five percent of the patients showed an abnormal EEG, and excessive beta activity, not induced by drugs, was found in 54% of patients. At least one abnormally slow nerve conduction velocity (CV) was found in 48 out of 77 patients. The scores of Wechsler Adult Intelligence Scale (WAIS) subtests Digit Span (DSp) and Digit Symbol (DSy) among the men and scores of Similarities (Sim), Digit Symbol (DSy), Picture Completion (PC), and Block Design (BD) among the women were statistically significantly lower than in the Finnish standardization sample. Long duration of exposure was related to poor performance in the Santa Ana Dexterity test in both sexes, to poor visual memory among the men and to poor visuoconstructive intellectual tasks among the women. The background frequency in the EEG showed a correlation to the DSp test of WAIS and some relationship emerged also between the former and the BD, the Symmetry Drawing test, the Santa Ana Dexterity test, and the Mira test. Focal slow wave abnormalities were related to inaccurate hand movements in the psychomotor Mira test. Neurophysiological and psychological tests seem to reflect partly different aspects of neurologic effects and their combined use helps in the evaluation of hazards of solvent exposure.
Sixteen rats were chronically implanted with bipolar electrodes in the hippocampal regions containing cells generating electric θ-activity. The animals were devided into 4 groups of which 2 were exposed to 500 p.p.m. of toluene in inhalation chambers, for 8 or 16 hours per day for 5 days per week in 12 weeks respectively, and 2 served as controls. The hippocampal electric activity was recorded 48 hours after each weekly exposure, ensuring a minimal amount of toluene in the tissue during the recordings. EEG-recordings were read blindly by two experienced scientists, and the frequency of θ-waves in the exposed groups were compared to their respective control group at each recording by Student's t-test. Frequencies of θ-activity in the exposed groups were found to differ from their respective control group by variance analysis. Each point on the frequency versus time plot were further analysed by Student's t-test. Compared to the non-exposed group the eight hours daily exposed group showed an initial period of increased frequency of the regular θ-waves together with an increased incidence of θ-activity after 1–2 weeks of exposure. In the sixteen hours daily exposed rats two weeks of toluene inhalation produced a significant reduction in the θ-wave frequency. This change was also reached after eight weeks of exposure in the eight hours daily exposed group. At this moment the θ-activity was frequently disrupted by short amplitude irregular waves, a phenomen which increased gradually throughout the rest of the exposure period. The average blood concentration of toluene was 16.7 μg/ml and 17.7 μg/ml and not significantly different for the eight and sixteen hours exposed groups respectively.
An inhalational (flow-through) behavioral chamber has been designed and prepared in order to facilitate recording of the behavioral performance of a small experimental animal (e.g., rat and mouse) while the subject is being exposed to an inhalant (vapor or gas). The animal can be clearly viewed during behavioral performance inside the chamber, which consists of a cylindrical glass jar. The apparatus is made up of easily available materials (e.g., glass, metal, Teflon, etc.) that are not affected by usual industrial solvents. At the present stage of its development, three types of behavioral schedules can be performed within the chamber: 1) schedules involving brain stimulation (e.g., self-stimulation, avoidance of aversive stimulations); 2) liquid-reinforced schedules (e.g., fixed ratio, fixed interval, variable ratio, variable interval, differential reinforcement of low rates); 3) shock avoidance (classical or continuous). The schedules can be microcomputer assisted. The device is suitable for study of behavioral pharmacology and toxicology of inhalants.
Motor incoordination, euphoria and hallucinations are symptoms reported for humans voluntarily intoxicated by industrial solvents. An epileptic-like consciousness impairment has also been noted. The present paper describes a technique used for the experimental study of solvent intoxication in which toluene and benzene can be applied directly into the trachea of freely moving cats with chronically implanted electrodes. This technique permits the control of solvent dose and time of exposure. Results showed a 3 Hz spike-wave activity in the gyrus cinguli recording with both toluene or benzene intoxication. Furthermore, benzene inhalation produced generalized tonic-clonic seizures. These effects were dose related. However, a sensitization period was essential for the development of such alterations, and effects showed a tendency to shortening through chronic exposures. These alterations were correlated with behavioral disturbances such as nodding, twitching and apparent hallucinations. Results are discussed regarding the sensitization period, the optimal peak of effects, and the period of tolerance development relevant to an earlier found amygdalar activation that could be correlated with other methods inducing experimental seizures, such as repetitive stimulation of the brain (kindling).
The behavioral effects of inhalation of the vapors of volatile compounds representative of different chemical groups were studied in mice under conditions where behavior and exposure concentrations could be concurrently monitored. The magnitude and time course of the effects of toluene, halothane and ethanol inhalation on fixed-ratio (FR) responding were compared. The subjects were trained to lever-press under a FR-100 schedule of water reinforcement. Daily operant sessions took place in the exposure chambers, and solvent exposures were conducted once a week. The test exposures lasted for 20 min, and the sessions continued until the subjects resumed baseline rates of responding to give a measure of recovery. All solvents produced concentration-dependent response rate decreases, and only halothane showed any evidence of response rate increases at low concentrations. Halothane quickly produced maximal response rate-decreasing effects and recovery was rapid, while the effects of toluene became progressively greater during the exposure and recovery was prolonged. Ethanol displayed the most rapid onset and recovery of effects. Thus, these solvents produced somewhat similar effects on FR responding but displayed potency and time course differences.
Power spectral analyses were used to study cortical EEG activities during sleep-awake behavior in the rat. EEG spectra, both long-time and sequential short-time, derived from EEG during the states of wakefulness, sleep, and REM sleep were qualitatively and quantitatively different. The degree of inter- and intrasubject variability between these spectra was minimal. This experimental model with the rat should allow quantitative delineation of cortical EEG changes produced by psychotropic drugs.
Operant conditioning techniques have been shown to be sensitive to the acute effects of industrial solvents. In the first experiment, five rats trained in a multiple schedule with a fixed-ratio (FR) 10 component and a differential reinforcement of low rates (DRL) 20-sec component, with a time out 60-sec between reinforcement periods, were exposed to 0.25, 0.50, 1 and 2 ml of toluene in the experimental chamber. The effects were dose-dependent, with an increase in rate in the DRL component and a decrease in FR responding. A second experiment assessing the effects of chronic exposure to thinner in the acquisition of a timing behavior in rats showed an impairment in DRL learning after 4, 8 or 16 weeks of exposure to the solvent: however, rats having a resting period did not differ from control animals. Whereas this finding suggests a reversible impairment in the acquisition of a complex behavior, further research is needed to achieve more definitive conclusions.
This review is a critical survey and evaluation of the recent literature relevant as medical background for a discussion of hygienic threshold values for toluene.
Six rats were trained to press a lever for a liquid food reward on a multiple fixed ratio--fixed interval (FR--FI) schedule of reinforcement. When lever-pressing rates became relatively stable, the animals were exposed to 150 ppm of either acetone or toluene for duration times of 1/2, 1, 2 and 4 hr. Exposures were conducted at least three weeks apart. Acetone produced minimal changes on the FR--FI responding during the 1/2 hr exposure. During the 1 hr exposure period, both FR and FI rates increased while during the 2 hr exposure, both FR and FI responses decreased below control levels. During the 4 hr exposure FI responses approximated control levels for 2 rats and were above the control level for the third animal while FR rates were below controls for 2 of the 3 subjects. Rate changes under toluene were generally qualitatively similar to those produced by acetone. An initial enhancement of FR and FI rates occurred during the shorter exposure periods followed by a decrease in rates during the longer exposure periods.
NREM sleep in the rat has traditionally been defined by electroencephalographic (EEG) amplitudes above those of wakefulness (W) and paradoxical sleep (PS); we refer to this high-amplitude NREM sleep as "HS." We have found that approximately 5% of total time is occupied by episodes in which EEG amplitude is low, distinguishing it from HS; theta amplitude is low, distinguishing it from PS; and electromyographic (EMG) amplitude is low, distinguishing it from W. We have called these low-EEG, low-theta, low-EMG episodes "low-amplitude sleep" (LS). Three studies are done to elucidate additional characteristics of LS. Polygraphically scored 30-s epochs were matched with independent classifications of rat behavior as W, NREM, or PS; 87% of polygraphically scored LS epochs were matched with NREM sleep behavior. Response thresholds to noxious stimuli were lowest in W, intermediate and similar in LS and HS, and highest in PS. The incidence of PGO-type (ponto-geniculo-occipital) waves in W, HS, and LS were all very low in comparison with rates in PS. Thus, LS and HS exhibited similarly quiescent spontaneous behavior, similar intermediate response thresholds, and similar low rates of PGO-type activity. Accordingly, we have proposed that LS, along with HS, is an NREM sleep stage.
Behavioral toxicity of toluene has been measured in mice. Because of its small size the mouse can be confined in a 251. hermetically sealed chamber for several hours. Toluene was introduced through a port and vaporized by a hotplate. Samples of chamber air for analysis were taken through another port. A smaller mesh cage held the mouse within the larger chamber. Schedule-controlled responding was developed by arranging that a response, breaking a beam of light, was followed by milk under an FI 60-sec schedule. Responding was much more rapid in the presence of stimuli correlated with the FI schedule than when the schedule was not operating. Standard sessions consisted of alternating series of 8 consecutive FI 60-sec and interseries 30-min time-outs.
Following introduction of liquid toluene, the concentration in the chamber reached its asymptote within 60 sec. Toluene disappeared from the atmosphere of the unopened empty chamber at the rate of 0.2%/hr. When the mouse cage was in the chamber the disappearance was 1.5%/hr and when a mouse was also present it was 3.5%/hr. Effects of toluene on the behavior of the mouse reached a plateau within 30 min of continued exposure to a fixed concentration. Concentration-effect curves were constructed from the number of responses in a series of FI's following 30-min exposure to a concentration of toluene as compared to the control number on that day. In some experiments mice were exposed to a single concentration of toluene: in other experiments, more toluene was added after a series of FI so the mice were exposed to incrementally increasing concentrations. The two procedures generated similar concentration-effect curves. Toluene increased the rate of responding in most mice at levels of about 700 ppm. Higher concentrations progressively reduced responding. The ED 50 (the concentration reducing responding by 50%) averaged 1657 ppm in 10 mice.
The effects of neonatal toluene exposure on the development of cortical evoked responses to sciatic nerve and light stimulation, as well as the spontaneous Electrocorticogram (ECoG) of frontal and occipital regions, were studied in rats at different developmental ages. The major findings following the solvent exposure were a significant prolongation in the mean peak latencies of both primary and secondary cortical evoked responses the effects being more severe in the sensorimotor area than in the visual cortical region. Additionally the experimental animals did not show significant differences in the average frequencies histograms of the ECoG in both neocortical areas when compared with control littermates. The data suggest that early toluene exposure was primarily affecting those brain structures underlying locomotor abilities than those related with the functionality of the CNS visual centers.
Theta activity was investigated during the two behavioral states in which this activity occurs in the freely moving rat, namely, movement (such as exploration) and paradoxical sleep. The patterns of theta activity are basically the same in both conditions. Dorsoventral microelectrode penetration of the dorsal hippocampus shows a maximal amplitude of activity in the CA1 pyramidal layer. With further penetration, the theta activity gradually reverses phase, the reversal being complete at the hippocampal fissure. A second maximal amplitude occurs in the dorsal blade of the dentate gyrus, there being no further change of phase. The theta activity that occurs in the presence of eserine and curare was found to have a different amplitude and phase profile from that in the freely moving rat.RésuméL'activité thêta est explorée au cours des deux états comportementaux dans lesquels survient cette activité chez le rat libre de ses mouvements, c'est-à-dire le mouvement (tel qu'un mouvement d'exploration) et le sommeil paradoxal. Les patterns d'activité thêta sont en gros les mêmes dans ces deux conditions. La pénétration de micro-électrodes dorso-ventrales dans l'hippocampe dorsal montre que l'amplitude maximale de cette activité se situe dans la couche pyramidale CA1. En pénétrant plus loin, l'activité thêta s'inverse graduellement de phase, l'inversion de phase étant complète au niveau de la scissure hippocampique. Un deuxième maximum d'amplitude survient dans la lame dorsale du gyrus denté, sans que ne survienne d'autre changement de phase. L'activité thêta qui survient lorsque de l'ésérine et du curar ont été administrés montre une amplitude et un profil de phase différents de celle qui s'observe chez le rat libre de ses mouvements.
Repeated daily toluene inhalation produces circling in rats. This effect may be specific to toluence since xylene fails to elicit turning. The turning follows toluence nhalation and is not associated with histological lesions of the brain. Forced circling can be reestablished more rapidly 15 days after last toluene inhalation than 21 or 34 days thereafter These latter conditions require about as many exposures to toluene as were required to institute turning originally.
This article has no abstract; the first 100 words appear below.
INHALATION of glue vapors in an attempt to induce euphoria has recently become quite popular, particularly among teen-agers. The desired effects are probably produced by toluene, the major component of the vapors.¹ The acute Central-nervous-system symptoms after toluene inhalation are transient euphoria, exhilaration and excitement, but in high doses confusion, headache, nausea, tinnitus, ataxia, tremors and fasciculations often occur. Acute, reversible hepatic decompensation and bone-marrow suppression are also prominent effects of exposure to high concentrations of toluene.²³⁴ The severity of the acute symptoms correlates well with the concentration of toluene vapor, and specific safeguards have been established for industrial workers . . .
*From the Division of Neurology, University of California, Los Angeles, School of Medicine, and the Harbor General Hospital, Torrance (requests for reprints should be addressed to Dr. Nelson in the Division of Neurology, Harbor General Hospital).
Presented at a meeting of the Federation of Western Societies of Neurological Science, San Francisco, March 3, 1966.
We are indebted to Robert Bonkowski, Ph.D., for performing the psychometric tests and to Augustus S. Rose, M.D., for helpful comments during the preparation of the manuscript.
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LOS ANGELES AND TORRANCE, CALIFORNIA
†Formerly, chief resident in neurology, University of California, Los Angeles School of Medicine (present address, United States Naval Hospital, Oakland, California).
‡Head, Division of Neurology, Harbor General Hospital; assistant professor of medicine (neurology), University of California, Los Angeles School of Medicine.
Acute effects of a single i.p. injection of toluene on circadian rhythms of sleep-wakefulness were investigated in rats which were chronically implanted with EEG and EMG electrodes for polygraphic recordings. The toluene injection produced an initial increase in wakefulness (W) and a subsequent increase in slow-wave sleep (SWS) during the dark period. In an attempt to clarify mechanisms of these biphasic effects of toluene on sleep-wakefulness rhythms, brain monoamines and their metabolites were determined at the times of the initial increase in W and the increased SWS. The initial increase in W was associated with an increase in cortical NA, MHPG and 5-HT together with a decrease in cortical 5-hydroxyindoleacetic acid (5-HIAA), while the increased SWS during the dark period was associated with an increase in 5-HIAA and a concomitant decrease in 3-methoxy-4-hydroxyphenylglycol (MHPG). The toluene-induced changes in sleep-wakefulness seemed to be manifested at lower blood levels of toluene than the behavioral signs of central nervous system (CNS) depression. These biphasic effects of toluene on circadian sleep-wakefulness rhythms are discussed in terms of the reciprocal interactions between central 5-HT and NA neurons.
The electroencephalogram (EEG) is a promising measure in the field of neurotoxicology. It can be well quantified by techniques which can be interpreted both physically and statistically although not necessarily physiologically. Such quantification schemes are briefly discussed in this paper. However, the quantification of EEG is not trivial in either the mathematical or computational sense. The relationship of EEG to brain function or brain pathology is not very well understood by some standards, perhaps due to poor quantitative methods or erroneous assumptions about brain-behavior relationships. EEG has a similar appearance across species. Hence the measure has great promise as a cross-species indicator of neurotoxicity. Not many quantitatively sound neurotoxicological studies using EEG have been published. It must be strongly emphasized that (a) more methods development is needed before the promise of cross species generality can be realized and (b) naive and/or half-hearted attempts to use this measure are perilous.
A number of reports, particularly from Scandinavian countries, claim that painters and workers in other trades in which prolonged occupational exposure to organic solvents may occur develop a type of mental illness characterized principally by impairment of memory and co-ordination and some deterioration of personality. The condition, called ‘organic solvent disease’, is recognized as a cause of premature retirement and is classed as an occupational disease in certain countries. The conclusions of these reports have been contested and the existence of such a disease entity has been questioned. The publications reporting adverse neurological, neurophysiological and psychological disorders in solvent-exposed workers, and the methods used to determine adverse effects, have therefore been evaluated. In addition, data from animal behavioural studies have been examined but were found to have little or no relevance to the reported human disease.
Effects of methylmercury chloride (MMC) on circadian sleep-waking rhythms were examined in rats which had been chronically implanted with EEG and EMG electrodes. Bihourly distributions of wakefulness (W), slow wave sleep (SWS) and paradoxical sleep (PS) and 12-h amounts of W, SWS and PS during light and dark periods were measured before and after MMC administration for 2 successive days at 3 dose levels. A total dose of 10 mg MMC/kg body wt was found to be the threshold for inducing reversible changes in the sleep-waking patterns. A total dose of 30 mg MMC/kg produced an increase in both dark-phase SWS and PS as well as a decrease in light-phase PS at the expense of an increase in light-phase W and a delayed phase of the circadian PS rhythm. The delayed phase of the PS rhythm tended to persist after the increased SWS during the dark period returned to normal. Brain mercury concentrations were measured in order to find the dose-response relationship and the time dependence of the MMC-induced sleep disorder. The sleep-waking disorder was found to appear at lower levels of brain Hg and shorter latency than behavioral disorders of movement and postural maintenance previously reported [5-8].
This evaluative review covers the neurotoxic effects of toluene. General health effects of toluene are also discussed in more limited detail. A brief description of chemical properties and environmental prevalence is given, followed by a review of pharmacokinetic data. General health effects include lethality, growth, morbidity, liver and kidney damage and miscellaneous effects. Neurobehavioral effects include epidemiological and clinical findings, activity and sleep, performance and learning, electrophysiological and central-nervous-system (CNS) effects. Evaluation and synthesis of data is included. It was concluded that low level exposure to toluene has its primary effect on the CNS. From a systematic or general point of view it is not clear what this effect is. Both depressant and excitatory effects (possibly concentration dependent) were reported as well as other kinds of results. Other health effects were not life threatening at any exposure level short of that producing lethality. Effects were reversible even at extremely high exposure levels for very long durations. Problems in research and needed data are pointed out. Given the economic importance and ubiquity of toluene, more information about its behavioral and neurological effects is sorely needed.
Toluene appears to produce reversible effects upon liver, renal and nervous systems. Its usual route of intake is via respiration. The nervous system appears to be the most sensitive to the effects of toluene. Although there are few studies of toluene's neurotoxicity, some tenuous results can be cited. High level toluene exposures produced incoordination, ataxia, unconsciousness and eventually, death. Lower level acute exposures in man produce dizziness, exhilaration and confusion. Activity level has been inadequately studied. Schedule controlled behaviors have been reported to produce inverted U-shaped concentration-effect curves on response rate measures. Alterations at levels as low as 150 ppm have been reported when appetitive contingencies are used. Very few studies of the nervous system have been performed at levels below 1000 ppm and most of the results were inconclusive. The TLV (threshold limit value) of toluene has been set at 100 ppm for 8 hrs. No exposures on possible groups at special risk, such as perinatal, aged or impaired subjects have been made. Few studies of reversibility of effects in the nervous system have been reported. Much more work is needed before strong conclusions can be drawn.
Behavioral and electroencephalographic effects of acute and chronic administration of paint thinner in cats
- Alcaraz