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Effect of inhalation of xylene on intracranial self-stimulation behavior in rat
Abstract
The effect of the inhalation of xylene on intracranial self-stimulation behavior was studied in rats in a flow-through (dynamic) inhalational behavioral chamber. Rats were exposed successively to four graded concentrations (102, 192, 419 and 623 ppm) of xylene vapor during 2-hr sessions on different days. The rate of lever-pressing showed a dose-dependent decrease during exposure to 192, 419 and 623 ppm of xylene. The 4-hr exposure to the smallest concentration (106 ppm) of xylene failed to show any effect on self-stimulation behavior. During a 5-day 2 hr/day exposure, the decrease in response observed on the 1st day was further accentuated with a nadir on the 3rd day; from the 4th day onwards, the depressant effect was attenuated showing the development of tolerance.
... Mice dosed at 1000 mg/kg in a day were consistently hyperactive for 5 to 30 min after dosing (Crookes et al., 1993). Wimolwattanapun et al. (1987) reported that 2-h exposure of rats to xylene (192, 419, or 623 ppm) resulted in dose-dependent reductions in intracranial self-stimulation (ICSS), possibly implicating xylene exposures in reduced levels of motivation. ...
Over 1.3 million civilian and military personnel are occupationally exposed to hydrocarbon fuels, emphasizing gasoline, jet fuel, diesel fuel, or kerosene. These exposures may occur acutely or chronically to raw fuel, vapor, aerosol, or fuel combustion exhaust by dermal, respiratory inhalation, or oral ingestion routes, and commonly occur concurrently with exposure to other chemicals and stressors. Hydrocarbon fuels are complex mixtures of 150-260+ aliphatic and aromatic hydrocarbon compounds containing varying concentrations of potential neurotoxicants including benzene, n-hexane, toluene, xylenes, naphthalene, and certain n-C9-C12 fractions (n-propylbenzene, trimethylbenzene isomers). Due to their natural petroleum base, the chemical composition of different hydrocarbon fuels is not defined, and the fuels are classified according to broad performance criteria such as flash and boiling points, complicating toxicological comparisons. While hydrocarbon fuel exposures occur typically at concentrations below permissible exposure limits for their constituent chemicals, it is unknown whether additive or synergistic interactions may result in unpredicted neurotoxicity. The inclusion of up to six performance additives in existing fuel formulations presents additional neurotoxicity challenge. Additionally, exposures to hydrocarbon fuels, typically with minimal respiratory or dermal protection, range from weekly fueling of personal automobiles to waist-deep immersion of personnel in raw fuel during maintenance of aircraft fuel tanks. Occupational exposures may occur on a near daily basis for from several months to over 20 yr. A number of published studies have reported acute or persisting neurotoxic effects from acute, subchronic, or chronic exposure of humans or animals to hydrocarbon fuels, or to certain constituent chemicals of these fuels. This review summarizes human and animal studies of hydrocarbon fuel-induced neurotoxicity and neurobehavioral consequences. It is hoped that this review will support ongoing attempts to review and possibly revise exposure standards for hydrocarbon fuels.
Behavioral effects of ethanol inhalation were studied on two fixed-ratio (FR) liquid-reinforced schedules and a continuous reinforcement (CRF) schedule intracranial self-stimulation (SS) in rats using the inhalational behavioral chamber designed in our laboratory. In the FR-24 schedule ethanol caused a decrease of reinforcement rate at 161 ppm and higher concentrations. In the FR-50 schedule decreases of the rate were observed at 102 ppm and 203 ppm. In the SS behavior ethanol produced a decrease in the rate of reinforcement at 603 ppm and higher concentrations. In rats of this schedule, blood ethanol concentrations were measured to be 393 micrograms/ml and 545 micrograms/ml after exposure to 600 ppm and 1200 ppm of ethanol respectively. Acute tolerance to ethanol was observed in these experiments, particularly in the FR-24 schedule. Thus ethanol inhalation could produce adequate blood concentrations so as to produce behavioral effects.
Xylenes, or dimethylbenzenes, are among the highest-volume chemicals in production. Common uses are for gasoline blending, as a solvent or component in a wide variety of products from paints to printing ink, and in the production of phthalates and polyester. They are often encountered as a mixture of the three dimethyl isomers, together with ethylbenzene. As part of its mandate, the Agency for Toxic Substances and Disease Registry (ATSDR) prepares toxicological profiles on hazardous chemicals found at Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) National Priorities List (NPL) sites that are of greatest concern for public health purposes. These profiles comprehensively summarize toxicological and environmental information. This article constitutes the release of the bulk of this profile (ATSDR, 1995) into the mainstream scientific literature. An extensive listing of known human and animal health effects, organized by route, duration, and end point, is presented. Toxicological information on toxicokinetics, biomarkers, interactions, sensitive subpopulations, reducing toxicity after exposure, and relevance to public health is also included. Environmental information encompasses physical properties, production and use, environmental fate, levels seen in the environment, analytical methods, and a listing of regulations. ATSDR, as mandated by CERCLA (or Superfund), prepares these profiles to inform and assist the public.
On January 3, 1980 an outbreak of illness occurred in 15 employees of a small community hospital. Symptoms included headache, nausea, vomiting, and dizziness or vertigo; the duration of illness ranged from 2 to 48 hours. The employees who became ill all worked in areas of the hospital served by one central ventilation system. None of the 180 persons working in other parts of the hospital developed symptoms requiring medical care. Less than 1 hour before the outbreak occurred, 1 liter of liquid xylene had been discarded down a sink drain in the pathology laboratory. Simulation experiments confirmed that xylene vapor could have been drawn into the room that contained the fan unit of the ventilation system. This outbreak illustrates an unusual route of exposure to a widely used laboratory chemical.
Rats were exposed for 5 days (6 hr/day) to one of four concentrations of a mixture of m-xylene (XYL) and ethylbenzene (EB) in the air (0 + 0, 75, + 25, 300 + 100, or 600 + 200 ppm). XYL and EB were found in the fat after the 5th day of exposure in the same molar ratio (3:1) as in the inspired air. The urine of the rats in each group was collected in two daily portions. The excretion of urinary thioethers increased linearly up to 12-fold. The urinary excretion of the major metabolites of XYL (methylhippuric acid, dimethylphenols, and methylbenzyl alcohol) and EB (hippuric, mandelic, phenylglyoxylic, and phenaceturic acids, and 1-phenylethanol) were measured. XYL metabolites were excreted faster than EB metabolites in a manner pronounced with repetitive exposure and increasing dose. If the urinary elimination was expected to show the same molar ratio as in the inspired air (3:1), then total XYL metabolites were recovered in amounts lower than those of EB (about 2:1). The metabolite pattern of XYL showed no difference between mixed and pure equimolar exposures, whereas the pattern of EB metabolites was variable. The major problem met in quantitation of total output of EB was the estimation of metabolites (hippuric and phenaceturic acids) also formed endogenously. The apparent metabolic capacity for urinary solvent disposition vs the atmospheric concentration showed nonlinear correlation after a single mixed exposure. From the 2nd day onward, the metabolite excretion rates abruptly increased more than expected with the 600 + 200 ppm dose. This dose also increased microsomal drug-metabolizing activity in the liver. In conclusion, the mutual effects characteristic for mixed exposure to XYL + EB were, in a conspicuous manner, enhanced with the dose.
Male rats were exposed to different concentrations of xylenes for 3 days. Small but statistically significant increases in cytochrome P-450 content, NADPH-cytochrome c reductase activity and O-deethylation of 7-ethoxyresorufin in liver microsomes were detected already at an exposure level of 75 ppm. Morphological studies of livers from rats exposed to relatively high concentrations of xylenes for 5 days showed marked proliferation of smooth ER with little changes of the rough ER. No pathological alterations were observed. Castration of male rats influenced the response to xylene exposure only to a minor extent. Hypophysectomy alone was shown to cause significant increases in cytochrome P-450 and cytochrome b5 content and epoxide hydrolase activity. Induction of cytochrome P-450 dependent enzymatic activities after exposure to xylenes was reduced but qualitatively similar to that obtained with normal male rats whereas the induction of epoxide hydrolase activity was prevented. The difference in response to exposure to xylenes between male and female rats was mainly quantitative in nature. Polyacrylamide gel electrophoresis of liver microsomes from animals exposed to xylenes in the presence of SDS showed increases in protein bands comigrating with cytochrome P-450 PB-B2 and epoxide hydrolase purified from phenobarbital treated rats. It is concluded that in the rat exposure to xylenes mimics the effects of phenobarbital treatment as judged by both biochemical and morphological criteria and that the pituitary seems to have a regulatory function with regard to the induction of several drug-metabolizing enzymes.
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.
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.
Effects of various doses of L-DOPA were tested on self-stimulation behaviour in rats with electrodes implanted in the posterior hypothalamus (PH) or area ventralis tegmentum (A10 area) as well as on the concentration of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in the caudate nucleus (CN), diencephalon-midbrain (DM) and pons-medulla (PM). L-DOPA (50, 100 and 150 mg/kg. i.p.) showed a biphasic action on self-stimulation responding with an initial decrease for 40–60 min, followed by an increase for about an hour or more in rats with both PH and A10 electrodes. Both effects were more marked in rats with A10 electrodes. The effects of these doses on spontaneous motor activity were not significant. L-DOPA markedly increased DA levels in the CN and DM, and moderately decreased 5-HT, without significantly altering NE levels in the DM and PM. It appears that L-DOPA-induced changes in self-stimulation responding cannot be correlated with the increase of DA levels in the CN and DM. It is possible that this behaviour involves a system of several neurotransmitters, including biogenic amines and acetylcholine, and a sudden increase of one, such as DA, causes an imbalance in the multitransmitter system and disrupts the behaviour.
The suggested hygienic standard of 0.46 mg/liter (110 ppm) for mixed xylenes is based solely on sensory response of human subjects because of the relatively low toxicity of the vapor. The Lt50 was 92 min for rats that inhaled 46 mg/liter (11,000 ppm) of mixed xylenes, a concentration which approaches air saturated at room temperature. The LC50 for rats in a 4-hr inhalation period was 29 mg/liter (6700 ppm). Cats succumbed within 2 hr at 41 mg/liter (9500 ppm) with signs suggestive of central nervous system effect. No statistically significant differences from control groups, receiving only the uniformly shared dilution air, occurred among groups of beagles and rats that inhaled measured concentrations 6 hr/day, 5 days/wk for 13 wk at levels of 3.5(810), 2.0(460), and 0.77 mg/liter (180 ppm). The odor threshold was determined by a panel of six people to be on the order of 0.0045 mg/liter or 1 ppm. In a 15-min inhalation period, the only common sign of discomfort at 2.0 mg/liter (460 ppm) was eye irritation in four of six subjects. Some transitory olfactory fatigue occurred with recovery in 10 min.
Xylene, a widely used industrial solvent, is a mixture of the ortho-, meta-, and paraisomers. In this study we examined the effects of each individual isomer, as well as a commercial-grade mixture of xylenes, on two behavioral measures: (1) operant performance of 15 mice trained to lever-press under a DRL (differential reinforcement of low rates) 10-sec schedule, and (2) motor performance of mice on an inverted screen test. The 15-min operant sessions immediately followed 30-min exposures to solvent vapors (500 to 7000 ppm), or air, in static inhalation chambers. All mice were exposed to each isomer in a counterbalanced order, and the mixture was given last in all cases. Ortho-, meta-, para-, and mixed xylenes produced similar biphasic effects on response rates, and concentration-dependent decreases in reinforcement rates. The lowest significantly effective concentration for each isomer on any variable was 1400 ppm, where increases in response rates occurred. Half-maximal response rate decreases were produced by 5179 ppm (ortho-xylene) to 6176 ppm (meta-xylene). The temporal distribution of responses was only moderately disrupted, even at high concentrations. In other groups of mice, motor coordination was also disrupted by the xylenes in a concentration-dependent manner. Half-maximal effective concentrations were 2676 ppm (para-xylene) to 3790 ppm (meta-xylene). Minimally effective concentrations were 2000 to 3000 ppm, higher than those seen in the operant studies. Xylene produced pronounced behavioral actions following acute exposure and no substantial differences in overall effects, and only slight potency differences, were obtained between the individual isomers or the commercial mixture.
In their neurotropic intoxication research work the authors made an application of maze technique so as to complement other test procedures. Rats were given small doses of xylene to bring about a subacute intoxication. When established, this intoxication was found to cause a set-back in learning and a lability in realizing skill acquired under developing xylene effect while it did not interfere with crystallized, well-trained stereotypes of behaviour.
Inhalation exposure to m-xylene at 100-400 ppm caused some changes of psychophysiological performance of volunteer subjects, e.g. impairment of body balance and increase of reaction times. With repetitive exposure, tolerance developed within a few days with regard to most of these effects. At steady-state and under conditions of increased xylene absorption, blood xylene concentration was directly related to the rate of xylene uptake. Acute xylene effects on the central nervous system were correlated with blood xylene concentrations and their occurrence also seemed to depend on a rapid rise of blood xylene level. Thus, exposure to a fluctuating xylene concentration with high uptake rates during the peak concentration caused more pronounced effects than a corresponding exposure to a constant concentration. Physical exercise may also greatly raise the uptake rates and enhance the effects. Kinetic data showed that well perfused tissues such as the brain will reach xylene equilibrium within some minutes and brain xylene concentration probably closely follows blood xylene levels. A very brief period of increased xylene absorption, not exceeding a few minutes, is not likely to bring about effective brain levels of xylene, however. Post-exposure excretion of xylene from most tissues takes place rapidly (elimination half-time about 0.5-1.0 h within the first hours). Consequently, acute xylene effects are probably short-lived. Xylene stored in adipose tissue is eliminated slowly but its mobilization results in only low blood levels. Compared to effects by moderate doses of alcohol (blood alcohol concentration 6.5-15.2 mmol 1.-1) xylene effects were clearly weaker, suggesting the practical inference that exposure to xylene may not be as serious an occupational and motoring hazard as social drinking.
Nine healthy male students were exposed to singular atmospheric concentrations of m-xylene (8.2 mumol/l; 200 ppm) or 1,1,1-trichloroethane (TCE) (8.2 and 16.4 mumol/l; 200 and 400 ppm), and also to a combination of xylene (8.2 mumol/l) and TCE (16.4 mumol/l) for 4 h per day at 6-day intervals. The effects of the atmospheric xylene and TCE concentrations on psychophysiological functions such as reaction time, body balance and CFF thresholds were studied. The exposures to xylene alone and to the lower TCE concentrations usually tended to improve the performances, whereas the higher TCE concentration alone or in combination with xylene tended to have an opposite effect, although statistically significant changes in performance, as compared to the control values, were rare. The results thus suggest a biphasic effect of TCE on the central nervous system (CNS), slight stimulation of the CNS at lower and depression at higher TCE concentrations. The results also revealed that xylene and TCE together exhibited neither kinetic interaction nor synergistic nor antagonistic effects on the CNS functions studied.