Excretion Of Methylhippuric Acid Research Articles

Visual functions of workers exposed to organic solvents in petrochemical industries.

Aim:The purpose of this study was to evaluate the visual functions of workers exposed to organic solvents in petrochemical industries.Materials and Methods:Thirty workers from the petroleum refinery and 30 age-matched controls (mean age) were recruited. Visual functions and occupational exposure levels were assessed among both the groups. Visual acuity, contrast sensitivity, color vision, and visual fields were evaluated at the workplace. The biological samples, namely blood and urine, were collected at the workplace and transported to the laboratory for analysis. The urinary excretion of hippuric and methylhippuric acid as well as creatinine was measured by high performance liquid chromatography.Results:The mean age of the workers and controls were 39.7 ± 7.6 years and 38.6 ± 8.1, years respectively. The mean years of experience of the workers were 15.6 ± 6.8 years. Visual acuity was >0.01 LogMAR among both the control and case groups. The contrast sensitivity was reduced at 12cpd among workers. Comparison between groups was done using independent sample t-test. The mean difference in color confusion index was 0.11 ± 0.05 (P = 0.037*). The mean difference in visual fields was −0.31 ± 0.36 dB (P = 0.933). The mean difference in urinary hippuric acid level (urinary metabolite of toluene) between the groups was 0.19 ± 0.96 g/g creatinine (P = 0.049FNx01). The mean difference in the excretion of methylhippuric acid (urinary metabolite of xylene) was 0.06 ± 0.04g/g creatinine (P = 0.154). We also found that exposure was a significant risk factor for color vision defect with an odds ratio of 4.43 (95% CI: 1.36–14.4); P = 0.013.Conclusion:The study results showed that contrast sensitivity and color vision were affected among workers in petrochemical industry.

New approaches to the metabolism of xylenes: verification of the formation of phenylmercapturic acid metabolites of xylenes.

It was the aim of this study to ascertain whether xylenes form phenylmercapturic acids via aromatic epoxides in the human metabolism. Aromatic epoxides are suspected to exert mutagenic properties. Therefore we developed an LC/MS/MS procedure for the determination of these mercapturic acids. Using this method we were able to detect dimethylphenylmercapturic acid (DPMA) in urine samples of persons occupationally exposed to xylenes. The unequivocal LC/MS/MS detection of phenylmercapturic acid metabolites of xylene thanks to authentic standards was verified with an independent GC/MS method. Xylene concentrations in the air of the workplaces ranged between 0.7 and 58.1 ppm (median 12.6 ppm). The excretion of methylhippuric acid in the urine samples of the workers (n=27) ranges from 19.8 to 2332.5 mg/l (median 450.9 mg/l). DPMA was detected in only 9 samples of 27 exposed persons. According to a rough calculation DPMA is only formed in a ratio of 0.0003% respective to the xylene main metabolite MHA. That means that even under occupationally relevant xylene exposure potential mutagenic potencies should be negligible. DPMA in urine is not sensitive enough for general biomonitoring purposes due to the low ratio of excretion. MHA should therefore be used for biomonitoring from now on. Furthermore, our results show that irrespective of the structure of xylene isomers there is no preferences in metabolism.

Urinary methylhippuric acid isomer levels after occupational exposure to a xylene mixture

The quantitative relationship between exposure to xylene vapor and urinary excretion of methylhippuric acid (MHA) isomers were studied in the second half of a working week. The participants in the study were 121 male workers engaged in dip-coating of metal parts who were predominantly exposed to three xylene isomers. The intensity of exposure measured by diffusive sampling during an 8-h shift was such that the geometric mean vapor concentration was 3.8 ppm for xylenes (0.8 ppm for o-xylene, 2.1 ppm for m-xylene, and 0.9 ppm for p-xylene), 0.8 ppm for toluene, and 0.9 ppm for ethylbenzene. Urine samples were collected at the end of the shift and analyzed for metabolities by HPLC. The statistical analysis showed that there is a linear relationship between the intensity of exposure to xylenes and the concentration of MHA in urine, that the regression line passes very close to the origin, and that the increment in observed (i.e., noncorrected) MHA concentrations as a function of increasing xylene concentration was 17.8 mg x l-1 ppm-1. Further examination on the basis on individual xylene isomers showed that the slopes of the regression lines for o- and m-isomers were similar (i.e., 17.1 and 16.6 mg l-1 ppm-1, respectively), whereas that for p-xylene was larger (21.3 mg l-1 ppm-1).

Metabolic interaction and disposition of methyl ethyl ketone andm-xylene in rats at single and repeated inhalation exposures

1. Rats were exposed to m-xylene (300 ppm) and methyl ethyl ketone (MEK, 600 ppm) vapour, separately and in combination. 2. Repeated exposures to m-xylene enhanced liver drug-metabolizing capacity, whereas MEK showed no effects. After mixed exposure the cytochrome P-450-dependent monooxygenase activities were additively or synergistically induced. 3. In the presence of MEK the overall metabolism of xylene was strongly inhibited both after single and repeated exposures, an effect accompanied by elevation of xylene concentration in blood (18-29%) and fat (25-32%). 4. The 24-h excretion of the urine metabolites of m-xylene was decreased by 22-24% in mixed exposures: the excretion of methylhippuric acid was decreased (29%), but that of 2,4-dimethylphenol increased (9-35%). 5. After repeated inhalation exposures the excretion of xylene metabolites in urine was consistently higher, whereas the concentrations of xylene in fat (but not the concentration of MEK) were lower than after a single treatment, conceivably due to accelerated metabolic clearance of xylene. 6. Thioether excretion in urine was enhanced in xylene-treated rats (7-13-fold), but was not influenced by the induced changes in the metabolism of xylene. Xylene inhalation caused liver GSH to decrease slightly (10%), as did inhalation of MEK, but the latter did not enhance the excretion of thioethers. 7. MEK is a potent inhibitor of the side-chain oxidation of m-xylene producing methylhippuric acid, but not of its ring oxidation to 2,4-dimethylphenol, and exhibits a synergistic inducing effect on liver enzymes responsible for the oxidation of m-xylene. The increased ring oxidation of m-xylene was not associated with increased production of reactive metabolites indicated by GSH-depletion or thioether formation.

Coexposure of man to m-xylene and methyl ethyl ketone. Kinetics and metabolism.

In a study of the kinetics and metabolic interaction of xylene and methyl ethyl ketone (MEK) eight male volunteers were exposed to m-xylene (100 ppm) and MEK (200 ppm). The exposures to the two compounds were carried out both separately and in combination. Respiratory uptake and blood concentration, as well as urinary metabolites (methyl hippuric acid and 2,3-butanediol), were monitored. Coexposure to xylene and MEK resulted in inhibited xylene metabolism. The xylene concentration in blood increased significantly, and the urinary excretion of methyl hippuric acid decreased. The combined exposure did not cause any change in the concentration of MEK in the blood or the excretion of 2,3-butanediol in the urine. Exposure to MEK 20 h before the m-xylene exposure had no detectable effect on the kinetics of m-xylene.

Correlation of xylene exposure and methyl hippuric acid excretion in urine among paint industry workers.

Different calculations of methyl hippuric acid excretion in urine were correlated to the time-weighted average (TWA) of the xylene exposure of a complete workday for 40 paint industry workers exposed to 12 different solvents. The 8-h TWA xylene exposure varied between 0 and 865 (median 69) mg/m3. The amount of methyl hippuric acid excreted in about 24 h showed only a slightly higher linear correlation to the xylene exposure than the amount of methyl hippuric acid excreted per hour during the latter part of the workshift among the 37 subjects exposed to TWA xylene air concentrations of 0-200 mg/m3. It was concluded that the methyl hippuric acid excretion rate during the latter part of the workshift can be used for crude xylene exposure categorizations.

Acute solvent-ethanol interactions with special reference to xylene.

Acute ethanol ingestion inhibits the metabolism of the common industrial solvents trichloroethylene and dimethylformamide. The solvents in turn may interact with ethanol metabolism as shown by an accumulation of acetaldehyde and occasional symptoms of alcohol intolerance. It was recently found that mutual metabolic interaction occurs even in the context of ethanol ingestion (0.8 g/kg in single dose) combined with subsequent inhalation exposure to m-xylene (6.0 & 11.5 mmol/m3 (140 & 280 ppm), over 4 h). Ethanol impaired the metabolic clearance of m-xylene, raised the blood xylene concentration, and decreased the urinary excretion of methylhippuric acid. Thus, ingestion of ethanol is a noticeable source of error in the biological monitoring of xylene uptake. Some people appear to be susceptible to combined ethanol-xylene exposure and may develop nausea and dermal flush.

Metabolic interaction between m-xylene and ethanol.

Ingestion of a moderate dose of ethanol (0.8 g/kg) by volunteers prior to 4-h inhalation exposure to m-xylene (6.0 or 11.5 mmol/m3) caused marked alterations in xylene kinetics. After ethanol intake the blood xylene level rose about 1.5-2.0-fold and urinary methylhippuric acid excretion declined by about 50% suggesting that ethanol decreased the metabolic clearance of xylene by about one half during xylene inhalation. This effect was noticeable up until a few hours after completed xylene exposure. Urinary excretion of 2,4-xylenol, the minor m-xylene metabolite, was generally not decreased by ethanol and sometimes the reverse seemed to be the case. The disturbance of xylene kinetics can be hypothesized to be caused mainly by ethanol-mediated inhibition of microsomal metabolism. When four volunteers who ingested ethanol prior to m-xylene inhalation at the higher concentration were monitored for blood acetaldehyde, transiently raised levels were found without notable effects on ethanol elimination. This observation may explain why some individuals experienced dizziness and nausea during the combined ethanol-xylene exposure.

Kinetics of m-xylene in man – general features of absorption, distribution, biotransformation and excretion in repetitive inhalation exposure

Sedentary volunteer subjects were exposed to an m-xylene concentration of about 3.9 mmol/m3 over five successive days, 6 h/d. It was noted that about 60% of the inhaled xylene was retained in the lungs. The estimated daily uptake of xylene was recovered nearly quantitatively as methylhippuric acid in the urine. Other pathways of xylene excretion played a minor role. The rate of 2,4-xylenol excretion shortly after a day's exposure was about 1-2% of that for methylhippuric acid excretion, and pulmonary excretion of unchanged xylene amounted to about 4% of the estimated uptake. In the blood, xylene was mainly associated with serum proteins, and only small amounts resided in the cells. Postexposure excretion of xylene in expired air and the urinary excretion of methylhippuric acid were initially rapid (elimination half-time about 1 h), and after an intermediate phase it attained, some 6-16 h after the exposure, a slow phase of elimination (half-time about 20 h). These observations are congruent with the concept that xylene is distributed to at least two main tissue compartments in the body. The slow elimination takes place from tissues with a high xylene solubility and a small perfusion, for example, adipose tissue; in this compartment cumulation of xylene occurs over repeated exposures. Under the conditions studied no signs of saturation of the metabolic pathways or renal excretion were noted.

Evaluation of occupational exposure to xylene by blood, exhaled air and urine analysis.

Occupational xylene exposure in the breathing zone of 15 painters was measured during three consecutive workdays. The applicability of the use of different biological samples was tested by the monitoring of xylene concentrations in blood and exhaled air, and urinary methylhippuric acid excretion as well. The best relation to the time-weighted average of xylene exposure was obtained for urinary methylhippuric acid concentration at the end of the workday; an amount of 665 mg/g of creatinine corresponded to 50 ppm of xylene. The amount of methylhippuric acid in a morning sample at the end of the work week, on the other hand, correlated to the mean exposure of the three preceding days. Xylene concentrations in exhaled air and blood sampled after the workday correlated poorly to the exposure of the preceding day. The urinary elimination of methylhippuric acid after the finished work week showed two distinct phases of excretion, with different biological half-times (1.9-5.3 h for the first 10 h after exposure and 16.5-48.4 h for the next two days).

Percutaneous absorption of m-xylene in man.

Percutaneous absorption of m-xylene was studied in volunteer experiments by means of monitoring xylene concentrations in blood and in exhaled air, and urinary methylhippuric acid excretion. Compared to normal working practices a rather extreme skin exposure, i.e. immersion of both hands in liquid xylene resulted in an estimated absorption of 35 mg xylene in 15 min which equals an estimated pulmonary retention within the same time period at TLV air.level of 100 ppm. The observed absorption rate for m-xylene was approximately 2 μg/cm2/min. The penetration of xylene was fairly rapid, peak concentrations appearing in the draining venous blood 4–6 min after exposure. Further absorption took place for five hours, however, after the termination of exposure and the removal of the contaminant by alcohol and water rinsing. It was found, as expected, that venous blood from a contaminated area exhibits a much higher concentration of the contaminant than mixed venous blood. To exclude this error in biological monitoring of xylene (and other skin penetrating solvents) exposure, exhaled air determinations are recommended. As a sporadic finding in the investigation, a symptom-free subject with previous history of atopic dermatitis developed toxic eczema of the hands after xylene exposure and exhibited a three times greater absorption of the compound than the average for the rest of the group.