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PubMed1997

Toluene Elicits a Carbon Starvation Response in Pseudomonas putida mt-2 Containing the TOL Plasmid pWW0.

Pseudomonas putida mt-2(pWWO) exhibited a carbon starvation response in the presence of toluene, a utilizable carbon source. When growth-supporting (4-mg/liter), inhibitory (130-mg/liter), and lethal (267-mg/ liter) levels of toluene were provided as the sole carbon source, P. putida responded by rapidly inhibiting protein synthesis and by producing 26 new proteins, 22 of which overlapped with those induced by carbon starvation. P. putida produced the same proteins when cultures were starved by depleting their carbon source or were downshifted into a carbon-free medium. Carbon supplementation of toluene-exposed cells suppressed the production of the toluene-induced proteins. The level of toluene provided as the sole carbon source influenced the length of time that this response was observed. Following 1.5 to 3 h in a basal salts medium with 4 mg of toluene per liter, protein synthesis increased, the production of the majority of the toluene-induced proteins ceased, and the cells began to grow. In cells provided with 130 mg of toluene per liter, protein synthesis remained inhibited over a 6.5-h experimental period. At this concentration, the production of 15 toluene-induced proteins was prolonged, with nine still detectable in the profiles at 6.5 h. In cells provided with 267 mg of toluene per liter, there was a rapid loss of viability and the toluene-induced proteins were detected prior to death. In cells provided with 4 mg of toluene per liter, the carbon starvation response is transient and likely reflects a period of induction and/or adaptation prior to growth on toluene. At the toluene concentrations which inhibit growth, P. putida exhibits a prolonged starvation response despite the presence of an excess of a utilizable carbon source.

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of Vinyl Toluene (Mixed Isomers) (65%-71% meta-isomer and 32-35% para-isomer) (CAS No. 25013-15-4) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

Vinyl Toluene is used as a monomer in the plastics and surface-coating industries. NTP Toxicology and Carcinogenesis studies were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to vinyl toluene (mixed isomers: 65%-71% meta and 32%-35% para) by inhalation 6 hours per day, 5 days per week, for 15 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y cells, and Chinese hamster ovary (CHO) cells. Fifteen-Day Studies: Rats were exposed to 0, 200, 400, 800, or 1,300 ppm vinyl toluene, and mice were exposed to 0, 10, 25, 50, 100, or 200 ppm. All rats lived to the end of the studies. The mean body weights at necropsy of rats exposed to 400-1,300 ppm were 13%-19% lower than that of controls for males and 9%-13% lower for females. Most male rats exposed to 1,300 ppm had centrilobular necrosis and focal inflammatory cell infiltration of the liver, whereas minimal centrilobular vacuolization of the liver was seen in all female rats exposed to 1,300 ppm. Dysplasia of the bronchial epithelial lining, chronic bronchitis, and lymphoid hyperplasia of the lung were observed in all rats exposed to 1,300 ppm. Three of five male mice exposed to 200 ppm vinyl toluene died before the end of the studies. Four of five male mice exposed to 200 ppm had moderate-to-severe hepatocellular necrosis; all female mice exposed to 200 ppm had hyperplasia of the epithelium of the intrapulmonary bronchi and centrilobular necrosis, vacuolization, and inflammatory cell infiltrates in the liver. Thirteen-Week Studies: Rats were exposed to 0, 25, 60, 160, 400, or 1,000 ppm vinyl toluene. All rats lived to the end of the studies. The final mean body weights of rats exposed to 400-1,000 ppm were 8%-19% lower than that of controls for males and 6%-12% lower for females. Relative liver weights for rats at 1,000 ppm were significantly greater than those for controls. The severity of nephropathy was increased in male rats exposed to 160, 400, or 1,000 ppm. Compound-related lesions were not observed in female rats. Mice were exposed to 0, 10, 25, 60, or 160 ppm vinyl toluene. The final mean body weights of mice exposed to 25-160 ppm were 12%-20% lower than that of controls for males and 13%-16% lower for females. Inflammation of the lung was observed in 5/10 male and 3/9 female mice exposed to 160 ppm. Metaplasia of the nasal turbinates was seen in all exposed groups. Based on these results, 2-year studies were conducted by exposing groups of 49 or 50 rats of each sex to 0, 100, or 300 ppm vinyl toluene by inhalation, 6 hours per day, 5 days per week for 103 weeks. Groups of 50 mice of each sex were exposed to 0, 10, or 25 ppm on the same schedule. Body Weights and Survival in the Two-Year Studies: Mean body weights of male rats exposed to 300 ppm vinyl toluene and those of female rats exposed to 100 and 300 ppm were generally 4%-11% lower than those of controls. No significant differences in survival were seen between any groups of rats of either sex (male: control, 19/49; low dose, 17/50; high dose, 19/50; female: 31/50; 28/50; 26/50). Mean body weights of mice exposed to 25 ppm were 10%-23% lower than those of controls after week 8, whereas mice exposed to 10 ppm showed a weight decrement that was generally less than 10%. The survival of male mice exposed to 25 ppm was significantly greater than that of controls. No other significant differences in survival were seen between any groups of mice of either sex (male: 33/50; 30/50; 41/50; female: 36/50; 37/50; 34/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Degenerative and nonneoplastic proliferative lesions of the nasal mucosa were observed at increased incidences in exposed rats. These lesions included diffuse hyperplasia (goblet cell) of the respiratory epithelium with intraepithelial mucous cysts and focal erosion of the olfactory epithelium with cystic dilation (cysts) of the Bowman's glands. Focal respiratory epithelial metaplasia of the olfactory epithelium was seen in some exposed males, and cells with homoge) of the Bowman's glands. Focal respiratory epithelial metaplasia of the olfactory epithelium was seen in some exposed males, and cells with homogeneous eosinophilic cytoplasm in the olfactory epithelium occurred at increased incidences in exposed female rats. Neoplasms of the nasal mucosa were not seen in male or female rats. There were no chemically related increases in neoplasm incidence in exposed male or female rats. Degenerative and inflammatory lesions of the nasal mucosa were observed at increased incidences in exposed mice. These lesions included focal chronic active inflammation and diffuse hyperplasia of the respiratory epithelium. Chronic active inflammation of the bronchioles occurred in many exposed mice but not in controls. Neoplasms of the nasal passage were not observed in mice. There were no chemically related increases in neoplasm incidence in exposed male or female mice. Exposure-related decreased incidences included alveolar/bronchiolar neoplasms (control, 12/50; 10 ppm, 5/49; 25 ppm, 2/49) and malignant lymphomas (7/50; 3/50; 0/50) in males and hepatocellular neoplasms (9/48; 5/16; 2/49) in females. Genetic Toxicology: Vinyl toluene did not induce gene mutations in S. typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation (S9). Vinyl toluene was positive in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y/TK cells in the absence of S9; it was not tested with S9. Vinyl toluene did not induce sister chromatid exchanges or chromosomal aberrations in CHO cells with or without S9. Conclusions: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity for male or female F344/N rats exposed to 100 or 300 ppm vinyl toluene and no evidence of carcinogenic activity for male or female B6C3F1 mice exposed to 10 or 25 ppm. There was evidence of chemical-related toxicity to the nasal passage in both rats and mice. Synonyms: 3-vinyl toluene and 4-vinyl toluene (mixed isomers)

Journal Article↗
PubMed1996

Effects of Toluene on Microbially-Mediated Processes Involved in the Soil Nitrogen Cycle

The effects of toluene on indigenous microbial populations involved in the soil nitrogen cycle were examined. Ammonia oxidation potential (AOP) and nitrite oxidation potential (NOP) were both reduced after incubation with high toluene concentrations for 45 days, with the former activity showing greater sensitivity. KCl-extractable ammonium (NH4+ext) levels increased dramatically in soil exposed to high toluene levels, and arginine ammonification was not significantly affected. Alfalfa-amended soil incubated in the presence of 200 &mgr;g toluene ml-1 showed progressive accumulation of NH4+ext over 37 days, indicating that mineralization of plant-associated nitrogen was not hindered by toluene. AOP in treated soil was much less than in control soil on days 7 and 37, but the MPN of ammonia oxidizers in control and exposed soil were not significantly different. Soil incubated with 100 &mgr;g toluene ml-1for 28 days, vented and allowed to incubate for an additional 7 to 30 days, exhibited only slight increases in AOP and NOP, while NH4+ext returned to control levels within a week. Soil exposed to 200 &mgr;g toluene ml-1 and treated in the same manner showed no increases in either AOP or NOP, and NH4+extremained elevated for the duration of the experiment, indicating more long-term effects on soil nitrogen cycling had occurred. Ammonia oxidizer levels in control soil and soil incubated with 100 &mgr;g toluene ml-1 were not appreciably different, whereas levels of ammonia oxidizers were very low in soil exposed to 200 &mgr;g toluene ml-1 and increased only slightly by 30 days post vent. Experiments to determine how toluene affects the AOP of soil indicated a competitive inhibition mechanism, with an effective concentration causing 50% reduction in activity (EC50) of 11 &mgr;M toluene, and a competitive inhibition constant (Ki) of 0.1± 0.05 &mgr;M toluene. These results indicate the potential for toluene to adversely impact nitrogen cycling in the terrestrial ecosystem by affecting indigenous soil nitrifiers, which are sensitive to lower levels of toluene than has been previously reported.

Journal Article↗
PubMed1989

Persistent effects of neonatal toluene exposure on regional brain catecholamine levels and turnover in the adult male rat.

Effects of neonatal toluene exposure (80 ppm, day 1-7, 6 h/day) have been studied on regional brain catecholamine levels and utilization, and on serum levels of hypophyseal and adrenocortical hormones in the adult male rat. Catecholamine levels were measured by quantitative histofluorimetry in the forebrain and hypothalamus and by high pressure liquid chromatography with electrochemical detection in the substantia nigra. Catecholamine utilization was evaluated from the decrease in catecholamines seen after tyrosine hydroxylase inhibition using alpha-methyl-p-tyrosine methyl ester hydrochloride (alpha MT, 250 mg/kg, i.p., 2 h). Serum levels of thyroid stimulating hormone, corticosterone, aldosterone, prolactin and luteinizing hormone were measured by radioimmunoassays. Neonatal toluene exposure produced a reduction of dopamine levels and utilization selectively in the olfactory tubercle and substantia nigra of the adult rat. Furthermore, neonatal toluene exposure produced a significant reduction in the noradrenaline levels and utilization in the substantia nigra and an increase of noradrenaline utilization selectively in the subependymal layer of the median eminence and of the magnocellular part of the paraventricular hypothalamic nucleus. The serum hormone levels were not significantly influenced by neonatal toluene exposure as evaluated in adulthood. However, the alpha MT induced increase in serum prolactin levels was reduced following neonatal exposure to toluene. Neonatal toluene treatment was also found to alter the responses of the catecholamine neurons to subacute toluene exposure in adulthood. In some of the dopamine nerve terminal systems of the forebrain and in the dopamine cell body containing area of the substantia nigra neonatal toluene exposure appears to have made the dopamine neurons insensitive to adult subacute toluene exposure. In the hypothalamic noradrenaline nerve terminal systems, there were even reversed responses to subacute toluene exposure. The present results indicate that neonatal toluene exposure in doses at the threshold limit value produces persistent changes in dopamine and noradrenaline neurons of the forebrain, hypothalamus and substantia nigra in the presence of a relatively intact neuroendocrine system. In addition, neonatal toluene exposure appears to diminish or even counteract the responses to subacute toluene treatment in adulthood.

Administration, Inhalation↗
PubMedDate not supplied

A toluene-induced motor syndrome in rats resembling that seen in some human solvent abusers.

The purpose of these experiments was to determine the extent to which subchronic exposure of rats to toluene might cause symptoms similar to those seen in some heavy abusers of toluene-containing products. In the first exploratory experiment, weanling male Fischer-344 rats were exposed to air, toluene, n-hexane, or a mixture of toluene, n-hexane, and methyl ethyl ketone (8 h per day, 7 days per week) for 11 weeks. A mild peripheral neuropathy was revealed by measures of grip strength in the rats exposed to n-hexane alone or in the mixture, but not in the rats exposed to toluene. Instead, the rats exposed to toluene alone developed a persisting motor syndrome characterized by a shortened and widened gait and a widened landing foot splay. The rats exposed to toluene alone or in the mixture were also hearing impaired, but not the rats exposed to n-hexane alone. In the second experiment, done to confirm and extend these results, weanling male Fischer-344 rats were exposed to toluene under three different daily schedules--2,200 ppm continuously for 8 h per day; 4,400 ppm, 30 min each h, 8 h per day; or 6,200 ppm, 15 min each h, 8 h per day. The exposures were 7 days per week for 23 weeks. The motor syndrome and hearing impairment were replicated in all essential respects in all toluene-exposed groups with no appreciable differences attributable to the daily exposure schedules. The effects were still evident 15 weeks after the last exposure. Toluene inhibited weight gain in both experiments, and in the second experiment, it was found that skeletal growth (torso length, rump width) was also inhibited. Toluene did not significantly impair rotorod performance in either experiment or acquisition of a spatial-navigation task in the second experiment. No neuropathologic correlates of the persisting motor syndrome were found in either experiment when the rats were sacrificed 9 and 16 weeks after the last exposure, respectively. These results demonstrate that toluene can cause a persisting motor syndrome in rats that resembles, to some extent at least (i.e., wide-based ataxic gait), the syndrome seen in some heavy abusers of toluene-containing products.

Animals↗
PubMed2006

Toluene induces rapid and reversible rise of hippocampal glutamate and taurine neurotransmitter levels in mice.

Toluene, a widely used aromatic organic solvent, has been well characterized as a neurotoxic chemical. Although the neurobehavioral effects of toluene have been studied substantially, the mechanisms involved are not clearly understood. Hippocampus, which is one of the limbic areas of brain associated with neuronal plasticity, and learning and memory functions, may be a principal target of toluene. In the present study, to establish a mouse model for investigating the effects of acute toluene exposure on the amino acid neurotransmitter levels in the hippocampus, in vivo microdialysis study was performed in freely moving mice after a single intraperitoneal administration of toluene (150 and 300 mg/kg). Amino acid neurotransmitters in microdialysates were measured by a high performance liquid chromatography system. The extracellular levels of glutamate and taurine were rapidly and reversibly increased within 30 min after the toluene administration in a dose-dependent manner and returned to the basal level by 1h. Conversely, the extracellular level of glycine and GABA were stable, and no significant change was observed after the toluene administration. To further investigate the brain toluene level in the hippocampus of toluene-administered mice, we used a solid-phase microextraction (SPME) method and examined the time course changes of toluene in the hippocampus of living mice. The brain toluene level reached the peak at 30 min after injection and returned to the basal level after 2h. In the present study, we observed the relationship between brain toluene levels and amino acid neurotransmitter glutamate and taurine levels in the hippocampus. Therefore, we suggest that toluene may mediate its action through the glutamatergic and taurinergic neurotransmission in the hippocampus of freely moving mice.

Animals↗
PubMed2002

Degradation characteristics of toluene, benzene, ethylbenzene, and xylene by Stenotrophomonas maltophilia T3-c.

Stenotrophomonas maltophilia T3-c, isolated from a biofilter for the removal of benzene, toluene, ethylbenzene, and xylene (BTEX), could grow in a mineral salt medium containing toluene, benzene, or ethylbenzene as the sole source of carbon. The effect of environmental factors such as initial toluene mass, medium pH, and temperature on the degradation rate of toluene was investigated. The cosubstrate interactions in the BTEX mixture by the isolate were also studied. Within the range of initial toluene mass (from 23 to 70 pmol), an increased substrate concentration increased the specific degradation of toluene by S. maltophilia T3-c. The toluene degradation activity of S. maltophilia T3-c could be maintained at a broad pH range from 5 to 8. The rates at 20 and 40 degrees C were 43 and 83%, respectively, of the rate at 30 degrees C. The specific degradation rates of toluene, benzene, and ethylbenzene by strain T3-c were 2.38, 4.25, and 2.06 micromol/g-DCW/hr. While xylene could not be utilized as a growth substrate by S. maltophilia T3-c, the presence of toluene resulted in the cometabolic degradation of xylene. The specific degradation rate of toluene was increased by the presence of benzene, ethylbenzene, or xylene in binary mixtures. The presence of toluene or xylene in binary mixtures with benzene increased the specific degradation rate of benzene. The presence of ethylbenzene in binary mixtures with benzene inhibited benzene degradation. The presence of more than three kinds of substrates inhibited the specific degradation rate of benzene. All BTEX mixtures, except tri-mixtures of benzene, ethylbenzene, and xylene or mixtures of all four substrates, had little effect on the degradation of ethylbenzene by S. maltophilia T3-c. The utilization preference of the substrates by S. maltophilia T3-c was as follows: ethylbenzene was degraded fastest, followed by toluene and benzene. However, the specific degradation rates of substrates, in order, were benzene, toluene, and ethylbenzene.

Benzene↗
PubMedDate not supplied

Exhaled breath condensate as matrix for toluene detection: a preliminary study.

The study was designed to investigate whether exhaled breath condensate, obtained by cooling exhaled air in spontaneous breathing, could be a suitable matrix for toluene quantitative analyses. Nine healthy subjects were exposed for a short period (20 min) to a known concentration of toluene. Exhaled breath condensate samples were collected before and at the end of the exposure, while the environmental concentration of toluene was continuously monitored. Toluene was analysed by head-space gas-chromatography mass spectrometry, and assay repeatability was also estimated in vitro. Baseline and post-exposure measurement of hippuric acid, the urinary toluene metabolite, was performed to assess current toluene exposure. Before the exposure toluene concentrations in the exhaled breath condensate were lower than the detectable limit in all subjects, while after the exposure toluene was detectable with a median value 0.35 microg l-1 (range 0.15-0.55 microg l-1) in all the exhaled breath condensate samples. As compared with the standard calibration in distilled water, the curves obtained by exhaled breath condensate were linear and comparable with the range examined in vivo for toluene. A significant correlation was found between the environmental toluene levels and toluene in the exhaled breath condensate at the end of exposure. Furthermore, a significant relationship between increased exhaled breath condensate toluene levels and urinary hippuric acid after the exposure was found. In conclusion, exhaled breath condensate is a promising matrix for toluene assessment, although its application in humans requires further investigations.

Adult↗
PubMed2003

Anaerobic biodegradation of toluene coupled to sulfate reduction in oil-contaminated soils: optimum environmental conditions for field applications.

Degradation characteristics of toluene in enrichment culture were investigated in soil microcosms study and the optimum environmental conditions for anaerobic degradation of toluene coupled with sulfate reduction were determined for field site applications. Anaerobic sulfate-reducing bacteria were enriched from oil contaminated soil samples with toluene. Enriched consortia degraded toluene with sulfate as a terminal electron acceptor. The average degradation rate of toluene in enriched consortia ranged from 0.08 to 0.1 micromol g(-1) day(-1). Toluene degradation under sulfate-reducing condition was inhibited in the presence of molybdate alone or together with nitrate or fumarate, indicating that toluene is degraded directly by sulfate-reducing bacteria. Effects of initial toluene concentration, pH, temperature, and other hydrocarbons on toluene degradation were investigated. There is a trend of increasing rate of toluene degradation with increasing the initial mass up to 94 micromol of toluene. Toluene degradation did not affected by the presence of ethylbenzene and xylene, as a while, toluene was degraded in a slower rate in the presence of benzene. The sulfate-reducing bacteria in the enriched culture showed higher microbial activity at neutral (pH 6-8) and medium temperature (30-37 degrees C) environments.

Bacteria, Anaerobic↗
PubMed1996

Evidence for acetyl coenzyme A and cinnamoyl coenzyme A in the anaerobic toluene mineralization pathway in Azoarcus tolulyticus Tol-4.

A toluene-degrading denitrifier, Azoarcus tolulyticus Tol-4, was one of eight similar strains isolated from three petroleum-contaminated aquifer sediments. When the strain was grown anaerobically on toluene, 68% of the carbon from toluene was found as CO2 and 30% was found as biomass. Strain Tol-4 had a doubling time of 4.3 h, a Vmax of 50 micromol x min-1 x g of protein-1, and a cellular yield of 49.6 g x mol of toluene-1. Benzoate appeared to be an intermediate, since F-benzoates accumulated from F-toluenes and [14C]benzoate was produced from [14C]toluene in the presence of excess benzoate. Two metabolites, E-phenylitaconic acid (1 to 2%) and benzylsuccinic acid (<1%), accumulated from anaerobic toluene metabolism. These same products were also produced when cells were grown on hydrocinnamic acid and trans-cinnamic acid but were not produced from benzylalcohol, benzaldehyde, benzoate, p-cresol, or their hydroxylated analogs. The evidence supports an anaerobic toluene degradation pathway involving an initial acetyl coenzyme A (acetyl-CoA) attack in strain Tol-4, as proposed by Evans and coworkers (P. J. Evans, W. Ling, B. Goldschmidt, E. R. Ritter, and L. Y. Young, Appl. Environ. Microbiol. 58:496-501, 1992) for another toluene-degrading denitrifier, strain T1. Our findings support a modification of the proposed pathway in which cinnamoyl-CoA follows the oxidation of hydrocinnamoyl-CoA, analogous to the presumed oxidation of benzylsuccinic acid to form E-phenylitaconic acid. Cinnamic acid was detected in Tol-4 cultures growing in the presence of toluene and [14C]acetate. We further propose a second acetyl-CoA addition to cinnamoyl-CoA as the source of benzylsuccinic acid and E-phenylitaconic acid. This pathway is supported by the finding that monofluoroacetate added to toluene-growing cultures resulted in a significant increase in production of benzylsuccinic acid and E-phenylitaconic acid and by the finding that [14C]benzylsuccinic acid was detected after incubation of cells with toluene, [14C]acetate, and cinnamic acid. Evidence for anaerobic toluene metabolism by methyl group oxidation was not found, since benzylsuccinic acid and E-phenylitaconic acid were not detected after incubation with benzylalcohol and benzaldehyde, nor were benzylalcohol and benzaldehyde detected even in 14C trapping experiments.

Acetyl Coenzyme A↗
PubMed1994

The effects of high-dose toluene on embryonic development in the rat.

Developmental disability, intrauterine growth retardation, renal anomalies, and dysmorphic features have been described in offspring of women who abuse toluene during pregnancy. A Sprague-Dawley rat model was developed to study this clinical syndrome. During d 6-19 of gestation, 11 treated dams received daily gavage doses of toluene, 520 mg/kg body weight, diluted in corn oil, and 11 control dams received corn oil. This dose of toluene simulates the blood toluene levels obtained after an inhalation exposure to 3290 ppm toluene, an inhalation level in the lower end of the range experienced by toluene abusers. Maternal weight gain was 24% less in the toluene-exposed group (p < 0.002); however, there were no maternal deaths. The fetuses were delivered on d 19 of gestation, and 287 fetuses (148 toluene exposed, 139 control) were examined. Toluene treatment did not affect the number of implantations or stillbirths. There were no toluene-induced major congenital malformations or neuropathologic changes noted. In the toluene-treated group, the weights of the fetuses were reduced by 9.4% (p < 0.004) and placental weights were reduced by 10.3% (p < 0.01). Toluene exposure also reduced fetal organ weights as follows: brain 4.6%, heart 5.9%, liver 13.2% (p < 0.02), and kidney 13% (p < 0.05). Organ weight/body weight ratios did not differ significantly, suggesting that prenatal toluene exposure produced a generalized growth retardation.

Animals↗
PubMed1996

Skin absorption of solvent mixtures--effect of vehicles on skin absorption of toluene.

The skin absorption rates of toluene in various solvent mixtures were investigated in mice. The skin absorption rate of toluene in toluene/methanol mixtures exhibited a parabolic relationship to the mixed ratio. The maximum rate was obtained at a mixed ratio of 50% (V/V). The skin absorption rate of toluene at this point (50%) was about 4.7 times higher than that of pure toluene. The permeability coefficient (Kp) of toluene increased as the mixed ratio of methanol increased. Methanol enhanced skin absorption of toluene. The skin absorption rate of toluene in a toluene/benzene mixture was inversely proportional to the concentration of benzene. The Kp of toluene is kept constant through the mixed ratios of benzene, and benzene does not have an enhancing effect on the skin absorption of toluene contained in the toluene/benzene mixture. We examined the effects of various vehicles on the skin absorption rates of toluene in mixtures containing 50% (v/v) of toluene. Methanol was a good penetration enhancer for toluene, and its effect is similar to the effect of well-known skin penetration enhancers like DMSO, N,N-Dimethylacetamide, and N,N-Dimethylformamide. Therefore, it is necessary to take special precautions against the skin absorption of toluene when handing thinners that contain methanol.

Animals↗
PubMedDate not supplied

[Significance of urinary concentrations of S-benzyl-N-acetylcysteine (S-BMA) in subjects exposed to toluene].

Toluene is a widely diffuse solvent for oils, resins, rubber and paints, either alone or as a major component in a mixture; in the industrial environment it is currently present at concentrations of ppm. Toluene can be absorbed via the lungs or via the skin. The absorption of toluene via inhalation is related to the exposure level as well as the activities level of workers. Once absorbed into the body, toluene is metabolized in man to benzoic acid, followed by hepatic cytochrome P450 catalyzed glycine conjugation to form hippuric acid. Relatively small amounts appear in urine as o-cresol and p-cresol where they occur as glucoronide and sulfate derivate. Only a minor fraction of inhaled solvent is conjugated with glutathione with the production of S-benzyl-N-acetylcysteine (S-BMA). Several biological indicators have been proposed for evaluating toluene exposure in the workplace. These include urinary hippuric acid, toluene in blood, toluene in breath, o-cresol in urine and toluene in urine. We examined a group of 18 workers occupationally exposed to toluene, determining the concentrations of toluene in ambient air and S-BMA in urine. All urine samples were collected at the end of work shift. The renal excretion of S-BMA showed highly significant correlations with environmental data and with the other established parameters of biological monitoring of toluene. The median ambient air concentration was 15.7 ppm ranging from 2.9 to 70.3 ppm, the median concentration of S-BMA was 16.0 micrograms/g creatinine. S-BMA was detectable in urine samples of a control group of 87 subjects non occupationally exposed to toluene. Most of unexposed subjects showed S-BMA values lower than 10 micrograms/g creatinine both in smokers and in nonsmokers and no significant difference was found in samples (20) collected at three intervals during one day. Our finding further indicates that the metabolite S-BMA could be a marker of occupational toluene exposure.

Acetylcysteine↗
PubMed1996

Cascade regulation of the toluene-3-monooxygenase operon (tbuA1UBVA2C) of Burkholderia pickettii PKO1: role of the tbuA1 promoter (PtbuA1) in the expression of its cognate activator, TbuT.

Burkholderia pickettii PKO1 metabolizes toluene and benzene via a chromosomally encoded toluene-3-monooxygenase pathway. Expression of the toluene-3-monooxygenase operon (tbuA1UBVA2C) is activated by the regulator, TbuT, in the presence of toluene. We have identified the TbuT coding region downstream of the toluene-3-monooxygenase structural genes by nucleotide sequence analysis and have shown that although TbuT is similar to XylR and DmpR, two members of the NtrC family of transcriptional activators which control toluene-xylene and (methyl)phenol catabolism, respectively, it is significantly different in the domain associated with effector specificity. Using a tbuA1-lacZ fusion reporter system, we determined that TbuT is activated not only by aromatic effectors but also the chlorinated aliphatic hydrocarbon trichloroethylene. Expression of tbuT and that of the tbuA1UBVA2C operon were found to be linked by readthrough transcription of tbuT from the toluene-3-monooxygenase promoter. As a result, transcription of tbuT is low when the toluene-3-monooxygenase operon is uninduced and high when expression of tbuA1UBVA2C is induced by toluene. Thus, the toluene-3-monooxygenase promoter drives the cascade expression of both the toluene-3-monooxygenase operon and tbuT, resulting in a positive feedback circuit. Examination of the nucleotide sequence upstream of the toluene-3-monooxygenase operon for promoter-like sequences revealed a -24 TGGC, -12 TTGC sequence, characteristic of sigma54 (rpoN)-dependent promoters. Primer extension and tbuA1-lacZ fusion analyses demonstrated that this -24, -12 promoter sequence, referred to as PtbuA1, was the toluene-3-monooxygenase promoter. Upstream of PtbuA1, a DNA region with dyad symmetry exhibited homology with the XylR-binding site present upstream of the Pu promoter. Deletions within this DNA sequence resulted in complete loss of expression from PtbuA1, suggesting that this region may serve as the TbuT-binding site.

Amino Acid Sequence↗
PubMed1984

Effect of ethanol, cimetidine and propranolol on toluene metabolism in man.

In a climatic exposure chamber four healthy volunteers were exposed to 100ppm toluene, 100ppm toluene + ethanol, 100ppm toluene + cimetidine, and 100ppm toluene + propranolol for 7h each at random over four consecutive days. A control experiment and 3.5h of exposure to 200ppm toluene were also performed. Ethanol inhibited toluene metabolism by 0.5 as expressed by the urinary excretion of two of the metabolites of toluene, namely o-cresol and hippuric acid. In agreement with this, the mean alveolar concentration of toluene was greater by 1.7 during ethanol exposure; 45 min after discontinuation of exposure the increase was by 3.3. Neither cimetidine nor propranolol changed toluene metabolism significantly. The results indicate that ethanol may prolong the time interval in which toluene is retained in the human body in persons simultaneously exposed to ethanol and toluene. When using o-cresol or hippuric acid in biological monitoring of persons occupationally exposed to toluene, the consumption of ethanol should be considered.

Adult↗
PubMed1993

Immunochemical assessment of the influence of nutritional, physiological and environmental factors on the metabolism of toluene.

Factors influencing the metabolism of toluene were investigated in rats using monoclonal antibody (MAb) to cytochrome P450 (P450). At low toluene concentrations, P450 IIE1 was primarily involved in the metabolism of toluene, whereas P450 IIC11/6 was involved at high concentrations. A low-carbohydrate diet induced P450 IIE1 and resulted in an increase in toluene metabolism. The intake of fat did not influence the metabolism. A lowered protein intake decreased not only the total content of P450 but also the P450 IIC11/6. Fasting and ethanol consumption also enhanced toluene metabolism via the induction of P450 IIE1. The metabolic rate of toluene in adult male rats was 4-fold higher than in immature males and adult females at a high substrate concentration because of the high level of P450 IIC11/6 in adult males, whereas no difference was noted between adult and immature females. Although development did not influence toluene metabolism in males at a low substrate concentration, the metabolic rate in adult female rats was significantly lower than that of immature females and males; this may be due to the decrease in P450 IE1 with development. Diabetic status influenced toluene metabolism in rats by affecting several kinds of P450 isozymes. Toluene exposure also affected its own metabolism by increasing P450 IIE1 and P450 IIB 1/2, and decreasing P450 IIC11/6. A significant difference in toluene metabolism was observed among rat, mouse and human liver microsomes. Thus, when considering the factors affecting toluene metabolism, it is important to elucidate the change in specific P450 isozyme composition related to the modifications, and their affinities to toluene.

Animals↗
PubMed1993

Toluene metabolism in isolated rat hepatocytes: effects of in vivo pretreatment with acetone and phenobarbital.

Hepatocytes isolated from control, acetone- and phenobarbital-pretreated rats were used to study the metabolic conversion of toluene to benzyl alcohol, benzaldehyde, benzoic acid and hippuric acid at low (< 100 microM) and high (100-500 microM) toluene concentrations. The baseline formation rates of toluene metabolites (benzyl alcohol, benzoic acid and hippuric acid) were 2.9 +/- 1.7 and 10.0 +/- 2.3 nmol/mg cell protein/60 min at low and high toluene concentrations, respectively. In vivo pretreatment of rats with acetone and phenobarbital increased the formation of metabolites: at low toluene concentrations 3- and 5-fold, respectively; at high toluene concentrations no significant increase (acetone) and 8-fold increase (phenobarbital). Apparent inhibition by ethanol, 7 and 60 mM, was most prominent at low toluene concentrations: 63% and 69%, respectively, in control cells; 84% and 91% in acetone-pretreated cells, and 32% (not significant) and 51% in phenobarbital-pretreated cells. Ethanol also caused accumulation of benzyl alcohol. The apparent inhibition by isoniazid was similar to that of ethanol at low toluene concentrations. Control and acetone-pretreated cells were apparently resistant towards metyrapone; the decrease was 49% and 64% in phenobarbital-pretreated cells at low and high toluene concentrations, respectively. In these cells, the decrease in presence of combined ethanol and metyrapone was 95% (low toluene concentrations). 4-Methyl-pyrazole decreased metabolite formation extensively in all groups. Benzaldehyde was only found in the presence of an aldehyde dehydrogenase inhibitor. Increased ratio benzoic/hippuric acid was observed at high toluene concentrations. These results demonstrate that toluene oxidation may be studied by product formation in isolated hepatocytes. However, the influence of various enzymes in the overall metabolism could not be ascertained due to lack of inhibitor specificity.

Acetone↗
PubMed2006

New insights on toluene biodegradation by Pseudomonas putida F1: influence of pollutant concentration and excreted metabolites.

The influence of toluene concentration on the specific growth rate, cellular yield, specific CO(2), and metabolite production by Pseudomonas putida F1 (PpF1) was investigated. Both cellular yield and specific CO(2) production remained constant at 1.0 +/- 0.1 g biomass dry weight (DW) g(-1) toluene and 1.91 +/- 0.31 g CO(2) g(-1) biomass, respectively, under the tested range of concentrations (2-250 mg toluene l(-1)). The specific growth rate increased up to 70 mg toluene l(-1). Further increases in toluene concentration inhibited PpF1 growth, although inhibitory concentrations were far from the application range of biological treatment processes. The specific ATP content increased with toluene concentration up to toluene concentrations of 170 mg l(-1). 3-Methyl catechol (3-MC) was never detected in the cultivation medium despite being an intermediary in the TOD pathway. This suggested that the transformation from toluene to 3-MC was the limiting step in the biodegradation process. On the other hand, benzyl alcohol (BA) was produced from toluene in a side chain reaction. This is, to the best of our knowledge, the first reported case of methyl monoxygenation of toluene by PpF1 not harboring the pWW0 TOL plasmid. In addition, the influence of 3-MC, BA, and o-cresol on toluene degradation was investigated respirometrically, showing that toluene-associated respiration was not significantly inhibited in the presence of 10-100 mg l(-1) of the above-mentioned compounds.

Adenosine Triphosphate↗