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PubMed1981

Distribution and elimination of 14C-xylene in rat.

Male rats were exposed to about 45 ppm of radioactively labeled xylene in the inspired air for 1--8 h. The distribution and elimination of xylene and metabolites in different organs and tissues were studied. To get an idea of the ratio between unmetabolized and metabolized xylene in organs and tissues, a supplementary study was performed in which five male rats were exposed to about 250 ppm of radioactively labeled xylene. The concentration of xylene and metabolites in the subcutaneous fat, where the largest amounts were found, displayed a sharp rise during the first 4 h of exposure in comparison with the following 4 h. Both during exposure and the decay phase the concentration of xylene and its metabolites in the cerebrum, cerebellum and muscles paralleled the arterial blood concentration and amounted to about 40% of the arterial blood value for xylene. The coefficient between the concentration of unmetabolized xylene in subcutaneous fat and inspiratory air was calculated to be 525 after 8 h of exposure.

Animals↗
PubMed1980

Effects of xylene and alcohol on vestibular and visual functions in man.

Ten healthy male volunteers were exposed for 4 h to two concentrations [6 and 11.5 mumol/l (636 and 1,218 mg/m3)] of m-xylene or/and given single doses (0.4 and 0.8 g/kg) of ethyl alcohol. Exposure to two xylene concentrations combined with the higher dose (0.8 g/kg) of alcohol was also conducted. Vestibular functions (positional nystagmus with electronystagmography, body balance) and visual function (flicker fusion) were measured. Both alcohol doses increased body sway and the intensity of nystagmus more than either concentration of xylene did, but they had little effect on visual functions. The effects of alcohol on vestibular functions were dose-dependent. The effects of xylene alone on the vestibular system were rather small, and those on the visual functions negligible. The combined effect of alcohol and the lower concentration of xylene (6 mumol/l) on body sway was additive, but the higher xylene concentration (11.5 mumol/l) antagonized the effect of alcohol on body sway and positional nystagmus. Two subjects experienced nausea and vomited exposure to alcohol and the higher xylene concentration. Mild impairment in visual functions was noted in the combined exposure. Alcohol significantly increased the blood m-xylene concentrations, a finding that suggests that their antagonism was pharmacodynamic rather than pharmacokinetic.

Adult↗
PubMedDate not supplied

Variability in the enzyme properties of Pseudomonas aeruginosa strain 2x oxidizing p-xylene.

A culture of Pseudomonas aeruginosa 2x was observed for its spontaneous variability for growth on p-xylene and the intermediate products of its metabolism. The highest variability was found for ability to grow on p-xylene and pyrocatechol, and a variability an order of magnitude lower was found for ability to grow on protocatechuate and p-toluate. No variability was found for the character "ability to grow on p-hydroxybenzoate." The activity of the key enzymes for the oxidation of p-xylene was studied in p-xylene-negative strains. The difference between the p-xylene-positive wild type strain and the spontaneous p-xylene-negative strains was found to be linked to changes in the regulatory mechanisms for several enzymes: p-xylene methylhydroxylase and the enzymes involved in the breakdown of the aromatic ring. In addition, the appearance of p-xylene-negative strains was linked with a significant fall in the specific activity of all enzymes, except pyrocatechuase, which was replaced by metapyrocatechuase on a number of substrates.

4-Hydroxybenzoate-3-Monooxygenase↗
PubMed1990

The effect of xylene exposure on the liver.

The author, with the xylene exposure of mice, rats and rabbits (sc, ip, per os, inhalation), as well as with xylene inhalation following the partial hepatectomy of rats, or the ligation of their common bile duct, wanted to find out whether xylene did have a selective or elective hepatotoxic effect. Using morphological (routine histological, enzyme-histochemical, electron microscopical, morphometrical), biochemical, clinical and analytical-chemical methods, it was found, that the xylene increased the activity of the hepatic biotransformation system, its adaptation to the xylene exposure; the xylene had neither selective, nor elective hepatotoxic effect in the examined species. The effect of xylene increasing the biotransformation ability of the liver is not inhibited by partial hepatectomy and ligation of the common bile duct; the so-called enzyme induction, which evolves at the effect of xylene, hinders the mitotic activity following the partial hepatectomy (defensive ability against xenobiotics takes priority over regeneration).

Aminopyrine N-Demethylase↗
PubMedDate not supplied

The biotransformation of p-xylene to a toxic aldehyde.

Rats given a single ip injection of p-xylene suffered 65% loss of pulmonary microsomal p-xylene hydroxylase activity. The activity was protected by pretreating the rats with phenobarbital, which increased hepatic p-xylene hydroxylase and cytosolic aldehyde dehydrogenase activities, but had no effect on alcohol dehydrogenase activity in hepatic cytosol. Pretreatment of rats with pyrazole caused a 60% inhibition of liver alcohol dehydrogenase but had no effect on liver aldehyde dehydrogenase activity. This treatment partially protected the pulmonary microsomal p-xylene hydroxylase from inactivation by p-xylene. Experiments in vitro showed that inactivation of cytochrome P-450 by p-xylene required the metabolic conversion of p-xylene to p-tolualdehyde. The reactive intermediate (p-tolualdehyde) required the presence of NADPH to carry out the inactivation. Inasmuch as lung tissues cannot form p-tolualdehyde (because of the low activity of p-methylbenzyl alcohol dehydrogenase), it is assumed that the inactivation of lung enzymes in vivo following exposure to p-xylene was due to the aldehyde intermediate which is formed in the liver and transported to the lung.

Aldehydes↗
PubMed1982

[Evaluation of inhalation toxicity of organic solvent xylene in pregnant rats].

The objective of the present experimental study was the assessment of organism susceptibility to the toxic xylene effect during gestation period, with a view to elaborating recommendations for female work protection. The experiments were carried out in a comparative aspect in 60 pregnant and 60 virgin, sexually matured female albino rats, exposed to 1850 and 467.8 mg/m3 technical xylene in inhalation chambers--levels 40 and 10 times higher than MAC of the solvent, in the course of 21 days (period of gestation of rats), 5 hours daily, 5 times a week. The assessment of inhalation toxicity of xylene is based on the data from the complex biochemical investigations in serum, liver, brain, myocardium and aorta, supported by pathomorphological studies. Xylene disturbs the balance of serum lipid fractions with both levels of inhalation effect and has a manifested hepatotoxic and cardiovascular effect to pregnant animals. Less manifested disorders in serum lipid profile, liver and the brain of the female, non-pregnant rats, were established with the administration of high xylene concentrations only, suggesting the higher vulnerability of the pregnant organism to the toxic xylene effect. Recommendations for early labour readjustment of pregnant women engaged in xylene production are presented on the base of the data obtained about the disorders of vital functions of organism during gestation period, supported by epidemiological observations and the presence of experimentally established specific embryotoxic effect of xylene at MAC levels.

Air Pollutants↗
PubMed1997

Isolation and Metabolic Characterization of a Pseudomonas stutzeri Mutant Able To Grow on the Three Isomers of Xylene.

From an o-xylene-degrading Pseudomonas stutzeri strain (OX1), we previously isolated mutant M1, which had acquired the ability to grow on m-xylene and p-xylene but lost the ability to utilize the ortho isomer. From M1 cultures we have now isolated a revertant strain (R1) which grows on o-xylene and retains the ability to grow with the meta and para isomers regardless of the selective pressure applied. In P. stutzeri R1, o-xylene is degraded through two successive monooxygenations of the aromatic ring, while m-xylene and p-xylene catabolism proceeds through the progressive oxidation of a methyl substituent, although unquantifiable amounts of these two substrates are transformed into the corresponding dimethylphenols, which are not utilized for further growth. The two catabolic pathways are inducible by all three xylene isomers.

Journal Article↗
PubMed1995

Musk xylene induces and inhibits mouse hepatic cytochrome P-450 2B enzymes.

The purpose of this work was to characterize the effects of musk xylene on mouse hepatic microsomal enzyme activities. Male B6C3F1 mice were dosed for 7 days at 0 or 200 mg musk xylene/kg after which microsomes were prepared. Musk xylene treatment increased liver weight by 40%, caused hepatocellular hypertrophy and increased total cytochrome P-450 2-fold over control. Microsomes from musk xylene-treated mice showed increased activity for the dealkylation of ethoxy- and methoxyresorufin, results consistent with increased CYP1A1 and 1A2 protein levels determined by Western blotting. No increase in pentoxyresorufin-O-dealkylation activity was seen, but musk xylene treatment markedly increased CYP2B protein levels. Preliminary in vitro studies showed that musk xylene inhibited mouse CYP2B enzymes (IC50 approximately 1 microM), but did not affect the activities of CYP1A1 or 1A2. This inhibition was not NADPH-dependent. These results indicate that, in mice, musk xylene causes generalized hepatic changes similar to classical CYP2B inducers. However, musk xylene is also a potent inhibitor of the CYP2B enzymes.

Animals↗
PubMed1978

Biochemical and toxicological effects of short-term, intermittent xylene inhalation exposure and combined ethanol intake.

Intermittent inhalation of 300 ppm of xylene vapour 6 h daily for 2 weeks caused a marked accumulation of the solvent in the perirenal fat. Simultaneous ethanol ingestion reduced the solvent load significantly although the perirenal xylene concentration increased in both test groups between the first and second week of exposure. Xylene inhalation enhanced hepatic and renal ethoxycoumarin 0-deethylase activity about 1.5-fold. The combination of inhaled xylene and peroral ethanol showed a markedly potentiated effect on microsomal ethoxycoumarin 0-deethylase activity especially in the kidneys. The enhanced monooxygenase activity was compatible with the decreased body solvent burden. Therefore, simultaneous ethanol intake might significantly modify the toxicological hazard in xylene exposure. Slightly increased proteolysis was detected in brain of animals in the xylene-ethanol experiment after the second week. Brain RNA content decreased after 2 weeks of exposure in the ethanol consuming animals. Xylene inhalation enhanced cerebral DT-diaphorase activity in both groups after 2 weeks of exposure. Ethanol intake also potentiated the behavioural effects caused by the solvent inhalation.

Animals↗
PubMed1984

Urinary disposition of ethylbenzene and m-xylene in man following separate and combined exposure.

Four volunteer subjects were exposed to 150ppm (655 mg/m3) of ethylbenzene and 150ppm (655 mg/m3) of m-xylene both separately and in combination. The biotransformation of the solvents was studied on the basis of the metabolites found in the urine. The metabolic conversion of both m-xylene and ethylbenzene proceeded mainly through oxidation of side chains. Ring oxidation seemed to be of minor importance; in the case of ethylbenzene it accounted for 4.0% (combined share of 4-ethylphenol, p- and m-hydroxyacetophenones) and in case of m-xylene for 2.5% (2,4-dimethylphenol), respectively. Mandelic and phenylglyoxylic acids amounted to 90% of the ethylbenzene metabolites, whereas m-xylene were excreted to 97% in the form of m-methylhippuric acid. Almost equimolar amounts in the form of metabolites of both solvents were found in the urine during 24h from the onset of exposure. Most of the ethylbenzene metabolites were excreted at substantially slower rates than those of m-xylene. The combined exposure resulted in a mutual inhibition of the metabolism of ethylbenzene and m-xylene, which was demonstrated by delayed excretion and decreased amounts of metabolites excreted. No sign of alteration in the urinary metabolite patterns of either ethylbenzene or m-xylene could be detected.

Adult↗
PubMed2001

Isolation and characterization of a thermotolerant bacterium Ralstonia sp. strain PHS1 that degrades benzene, toluene, ethylbenzene, and o-xylene.

A thermotolerant bacterium, designated as PHS1, was isolated from a hot spring in Pohang, Korea, on the basis of its ability to grow on benzene, toluene, ethylbenzene, and xylenes (BTEX) as a sole carbon source. Strain PHS1 is a gram-negative, rod-shaped aerobe and grows optimally at 42 degrees C and pH 7.2. According to 16 S rDNA analysis, strain PHS1 showed highest similarity to Ralstonia eutropha (previously named Alcaligenes eutrophus). Unlike its closest known Ralstonia species, however, strain PHS1 was able to utilize toluene, ethylbenzene, o-xylene, and both m- and o-cresol. The degradation of o-xylene by strain PHS1 is particularly important, since o-xylene is a compound of considerable environmental interest, owing to its recalcitrance; and very few microorganisms have been reported to utilize o-xylene as a sole carbon source. It was found that strain PHS1 transformed o-xylene to 2,3-dimethylphenol through direct oxygenation of the aromatic ring. The unique properties of strain PHS1, such as thermotolerance and the ability to degrade o-xylene, may have important implications for the treatment of BTEX-contaminated industrial effluents.

Benzene↗
PubMed1987

Effect of xylene inhalation on fixed-ratio responding in rats.

The effect of xylene inhalation was studied on operant behavior under a fixed-ratio (FR24) schedule in rats. Experiments were performed while rats were being exposed to xylene vapor in an inhalational (flow-through) behavioral chamber. Rats were exposed successively to three graded concentrations (113, 216 and 430 ppm) of xylene vapor each for 2 hr in range-finding studies during 6 1/4-hr sessions. The reinforcement rate which is correlated with FR responding was shown to be decreased at hr 1, hr 3 and hr 5. However at hr 2, hr 4 and hr 6 the reinforcement rate in rats increased approaching the control levels, thereby indicating development of tolerance. When rats were exposed to one of the three graded concentrations of xylene for 2 hr on separate days, they also showed a decrease in the reinforcement rate at hr 1; development of acute tolerance was also noted in this schedule. Exposure to the lowest (98.5 ppm) level of xylene used during 5-hr sessions caused no significant decrease in the reinforcement rate. This study thus attempts to identify a minimum effective concentration of xylene and indicates the development of acute tolerance to behavioral effect of xylene.

Administration, Inhalation↗
PubMed1983

Induction of cytochrome P-450 in the rat liver after exposure to xylenes, dose-response relationship and dependence on endocrine factors.

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.

Animals↗
PubMed1992

Subacute ethanol consumption reverses p-xylene-induced decreases in axonal transport.

Human exposure to organic solvents is often complicated by ethanol ingestion and the literature is replete with demonstrations of metabolic interactions between ethanol and organic solvents at a pharmacokinetic level. Because of the possible modulation of xylene toxicity by ethanol consumption, the present group of studies characterizes the effect of ethanol on the p-xylene-induced decrease in axonal transport in the rat optic system previously reported by our laboratory. Long-Evans, hooded, male rats were divided randomly into two groups: those receiving 10% ethanol in their drinking water and those receiving water only. These two groups were further subdivided into two groups which were either exposed by inhalation to 1600 ppm p-xylene for 6 h/day, 5 days/week for 8 exposure-days or were treated identically except that they were exposed to air while in the inhalation chambers. The ethanol-drinking rats were given ethanol 6 days prior to and on the days of the inhalation exposure. Immediately after removal from the inhalation chambers on the last exposure day, the animals were injected intraocularly with [35S]methionine and [3H]fucose to measure the synthesis and rapid axonal transport of proteins and glycoproteins, respectively, in the retinal ganglion cells. The animals were sacrificed 20 h later, and the amount of radioactivity in different areas of the retinal ganglion cells was determined by liquid scintillation counting. As in previous experiments, the xylene exposure group showed a significant reduction in axonal transport of proteins and glycoproteins, whereas the ethanol exposure alone produced no significant reductions in the transport of either proteins or glycoproteins. In the animals receiving both ethanol and xylene, however, the ethanol treatment prevented the decreased transport characteristic of the xylene only animals, i.e. in all areas of the optic projections the level of transport were similar to the level present in the control groups. These data suggest that the xylene-induced reduction in rapid axonal transport was reversed (or prevented) by subacute ethanol consumption.

Alcohol Drinking↗
PubMedDate not supplied

Acute exposures to p-xylene and toluene alter visual information processing.

Long-Evans hooded rats were exposed to single doses of toluene (PO) at 0, 250, 500 and 1000 mg/kg, to p-xylene (PO) at 0, 125, 250, 500, 1000 and 2000 mg/kg, and to inhalation of p-xylene for 4 hr at 0, 800 or 1600 ppm. The functional integrity of the visual system was evaluated using flash-evoked potentials (FEPs). The data indicated a significant depression in amplitude of FEP peak N3 at 250 mg/kg and higher dosages of toluene and p-xylene. A similar depression in peak N3 amplitude was observed following inhalation exposure to 1600 ppm p-xylene. The effects produced by oral administration of 500 mg/kg p-xylene or toluene lasted at least 8 hr, while the effect of inhaled p-xylene dissipated within 75 min of removal from the exposure. FEP peak N3 is presumed to be related to arousal, such that increases in arousal from a relaxed state should decrease amplitude. Rats administered amphetamine in dosages of 0.6, 1.2 and 2.5 mg/kg (known to increase arousal) also had reduced N3 amplitude. The effects of p-xylene and toluene on FEPs, while indicative of altered processing of visual information, may be secondary to changes in arousal or excitability.

Amphetamine↗
PubMed2003

Sex differences in the toxicokinetics of inhaled solvent vaporsin humans 1. m-Xylene.

The aim of this study was to evaluate possible sex differences in the inhalation toxicokinetics of m-xylene vapor. Seventeen healthy volunteers (nine women and eight men) were exposed to m-xylene (200 mg/m3) and to clean air (control exposure) on different occasions during 2 h of light physical exercise (50 W). The chosen level corresponds to the occupational exposure limit (8-h time weighted average) in Sweden. m-Xylene was monitored up to 24 h after exposure in exhaled air, blood, saliva, and urine by headspace gas chromatography. m-Methylhippuric acid (a metabolite of m-xylene) was analyzed in urine by high-performance liquid chromatography. Body fat and lean body mass (LBM) were estimated from sex-specific equations using bioelectrical impedance, body weight, height, and age. Genotypes and/or phenotypes of cytochromes P450 2E1 and 1A1, glutathione transferases M1 and P1, and epoxide hydrolase were determined. The toxicokinetic profile in blood was analyzed using a two-compartment population model. The area under the concentration-time curve (AUC) of m-xylene in exhaled air postexposure was larger in women than in men. In addition, the excretion via exhaled air was significantly higher in women when correcting for body weight or LBM. In contrast, the men had a significantly higher volume of distribution, excretion of m-methylhippuric acid in urine, and AUC of m-xylene in urine. The toxicokinetic analyses revealed no differences between subjects of different metabolic genotypes or phenotypes. In conclusion, the study indicates small sex differences in the inhalation toxicokinetics of m-xylene, which can be explained by body build.

Administration, Inhalation↗
PubMed2005

A physiologically based toxicokinetic model of inhalation exposure to xylenes in Caucasian men.

Widespread exposure to the volatile aromatic hydrocarbons, ortho-, meta-, and para-xylene occurs in many industries including the manufacture of plastics, pharmaceuticals, and synthetic fibers. This paper describes the development of a physiologically based toxicokinetic model using biomonitoring data to quantify the kinetics of ortho-, meta-, and para-xylenes. Serial blood concentrations of deuterium-labeled xylene isomers were obtained over 4 days after 37 controlled, 2h inhalation exposures to different concentrations of the isomers. Peak toxicant concentrations in blood occurred in all subjects at the termination of exposure. Systemic clearance averaged 116 L/h+/-34 L/h, 117 L/h+/-23 L/h, and 129 L/h+/-33 L/h for ortho-, para-, and meta-xylene, respectively. The half-life of each toxicant in the terminal phase (>90 h post-exposure) was fit by the model, yielding values of 30.3+/-10.2 h for para-xylene, 33.0+/-11.7 h for meta-xylene and 38.5+/-18.2 h for ortho-xylene. Significant isomeric differences were found (p<0.05) for toxicant half-life, clearance and extrahepatic metabolism. Inter-individual variability seen in this study suggests that airborne concentration guidelines may not protect all workers. A Biological Exposure Index is preferred for this purpose since it is integrative and reflective of inter-individual kinetic variability.

Adipose Tissue↗
PubMed1990

Effects of soil on the dermal bioavailability of m-xylene in male rats.

Bioavailability of a chemical absorbed through the skin from contaminated soil may differ from that seen following exposure to the pure chemical. The objective of this research was to qualitatively and quantitatively assess the absorption, distribution, excretion, and metabolism of soil-adsorbed m-xylene versus pure m-xylene so that the potential for public health risk following dermal exposure could be evaluated. In this study a shallow glass cap covering a 13-cm2 area was fixed to the shaved skin of each male rat (6-10 rats per group) followed by the addition of 225 microliters of m-xylene containing 20 muCi of m-[14C]xylene alone or with one of two soils. Maximum plasma levels of radioactivity were highest for pure m-xylene while the values for the sandy and clay soil groups were approximately equal. Although clay soil statistically decreased the rate of absorption, the half-lives of elimination and the area under the plasma concentration time curve were not changed by either soil. The major route of excretion in the pure and sandy groups was via expired air followed by urine. However, in the presence of clay soil, the percentage of the initial dose in expired air was similar to that in urine. Forty-eight hours after treatment, skin application sites in both soil treatment groups contained amounts of radioactivity significantly higher than those of m-xylene treatment alone. In the presence of clay soil a statistical increase in m-xylene-derived radioactivity was also observed in fat beneath the treated skin area. Metabolite analysis by HPLC indicated that methylhippuric acid was the main urinary metabolite followed by xylenol and the parent compound in all groups.

Administration, Topical↗