Received: September 29, 2015 Accepted: December 17, 2015 Published: December 21, 2015
Citation: Bentur Y and Lavon O (2015) Acute Inhaled Xylene Poisoning Confirmed by Methylhippuric Acid Urine Test. J Clin Toxicol 5:274. doi: 10.4172/2161-0495.1000274
Copyright: © 2015 Lavon O, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Objective: Extensive researches about biomarkers of Occupational medicamentosa-like dermatitis induced by Trichloroethylene (OMLDT) have been carried out in recent years. But dynamic change of protein biomarkers in serum has rarely been reported. The aim of our study was to explore the dynamic changing law of serum proteins/ polypeptides in different periods of OMLDT, identify potential biomarkers and provide the scientific fundamentals for monitoring the progression of the disease and screening high-risk population.
Study design: We developed an approach in the combination of magnetic beads based weak cation exchange chromatography (MB-WCX), matrix assisted laser desorption ionization time of flight mass spectrometry (MALDITOF- MS) and ClinProTools software. Based on the alternations in the polypeptides fingerprint of serum (PFS), we built diagnostic models of OMLDT, and screened the special proteins/ polypeptides biomarkers and further studied the dynamic changing law of different periods in typical OMLDT patients.
Results: We attained 72 peaks which were statistical content in OMLDT/Normal model, of which 52 peaks were differential peaks. We also obtained 69 significant peaks in OMLDT/TCE Contact model, but the differential peaks were 35. There were 21 specific peaks which were alike among the differential peaks in these two models and the change of their expression level was consistent. Among the 21 specific peaks, we found 4 peaks, which were m/z 410942675065 and 9287Da, changed nearly the same in 3 periods of 4 recurrent patients, and 2 peaks (4109 and 9173 Da) changed consistent in 3 periods of 3 stable patients. Interestingly, m/z 4109 Da appeared in both groups and the expression level was increased with the course of disease. So it may be the special serum biomarker of OMLDT. Conclusion: Overall, the results indicate specific PFS could serve as a useful tool to reflect the dynamic change of proteins/ polypeptides in different periods of OMLDT. And it may provide a new clue for clinical application.
Xylene; Poisoning; Inhalation; Methylhippuric acid; Urine
Xylene is an aromatic hydrocarbon commonly used as an industrial solvent for the manufacturing of pharmaceuticals, paints, and chemicals [1,2]. Acute xylene poisoning is difficult to confirm, as specific analytic assays are not readily available in the acute clinical setting. Methylhippuric acid is the main metabolite of xylene excreted in the urine, and is used for biomonitoring occupational exposure to xylene [1,2]. We report two patients with acute inhaled xylene poisoning whose exposure was confirmed by urinary methylhippuric acid measurement within hours from exposure.
Two young healthy male adults aged 21 and 23 years were brought to the emergency department after being found unconscious at home. According to their employer, they had been painting a closed ~10 m2 room for a few hours before collapsing. The original containers of the paint and thinner were not retrieved. En-route to the hospital their level of consciousness partially improved. On admission, they were confused and agitated, with pulse rates of 90 and 110/minute regular, blood pressures 120/78 and 142/80 mmHg, respiratory rate 20/minute, oxygen saturations 95 and 100% (room air), and mydriasis reactive to light. Electrocardiograms and chest x-rays were interpreted as normal. Complete blood count, kidney and liver functions were within normal range. Urine for metabolites of aromatic organic solvents was collected on admission and analyzed 12 hour later; samples were kept refrigerated until analysis. Methylhippuric acid and hippuric acid (a toluene metabolite) were measured in the patients’ urine by high-pressure liquid chromatography (HPLC) with an UV detector (AS-2057/2089 and UV-1570, Jasco Inc., Tokyo, Japan) using specific columns (Prodigy ODS-3 5 μm, Phenomenex®, Torrance, CA, USA). Urinary methylhippuric acid concentrations were 2.57 and 2.68 g/g creatinine (Biologic Exposure Index, BEI, 1.5 g/g creatinine) . Urinary hippuric acid (a toluene metabolite) concentrations were 0.18 and 0.46 mg/g creatinine (BEI 1.6 mg/g creatinine) . It should be noted that hippuric acid is not used anymore as a biomarker for exposure to toluene. The patients were admitted to the cardiac intensive care unit; vital signs and respiratory parameters were within normal limits and stable, and no arrhythmias were detected in continuous cardiac monitoring. Confusion and agitation resolved while drowsiness ensued. They regained full consciousness within 24 hours; at that time neurological examination was normal. Mild increases in alanine aminotransferase (80 U/L; normal value 10-40 U/L) and aspartate aminotransferase (71 U/L; normal values 10-40 U/L) were found 12 hours after exposure, returning to normal after 24 hours. The patients were discharged after 48 hours' observation with no neurological or psychiatric impairment.
We report two cases of unintentional exposure to paint thinner resulting in coma and mild liver enzyme abnormality. Both cases were diagnosed as xylene poisoning by high urinary methylhippuric acid concentrations, about 1.75 times higher than the BEI set by the American Conference of Governmental Industrial Hygienists (ACGIH) for occupational exposure to xylene .
Acute xylene poisoning is infrequently reported; most cases are industrial or occupational accidental exposures [5-9]. The clinical presentation of acute inhaled xylene toxicity includes neurological manifestations, mainly drowsiness and coma [5-9], similar to our reported patients.
Diagnosis of xylene acute exposure usually relies on medical history and clinical presentation [5-9]. Analytic assays for xylene are not readily available in the acute clinical setting. Post-mortem analysis of xylene isomers using a chromatography-mass spectrometry (GC-MS) assay was reported in few cases [8,9]. GC-MS is a complex, expensive and time-consuming assay, not regularly available in hospital laboratories. Environmental monitoring of xylene can serve as an indirect confirmation of exposure , but is less available and less relevant to acute exposure.
The presence of high concentrations of urinary methylhippuric acid, higher than the BEI, suggested the diagnosis of acute xylene inhalation in our patients. Urinary hippuric acid concentrations within the previously used BEI for toluene did not support exposure to toluene.
Xylene elimination is characterized by two phases, a relatively rapid phase and a slow one, representing a multi-compartment kinetic model . Xylene is mainly metabolized by oxidation to methylhippuric acid (95%), which is excreted in the urine [1,2]. Methylhippuric acid can be detected in the urine within 1-2 hours post exposure and for at least 24 hours later. Methylhippuric acid urinary excretion is not significantly influenced by variation in renal physiology, e.g., urine pH, rate of diuresis, and reabsorption . The assay of urinary methylhippuric acid has no known interferences, and is considered specific . All these make methylhippuric acid most suitable for biomonitoring occupational exposure to xylene. Analytic tests for methylhippuric acid are available in laboratories certified for performing occupational biomonitoring tests. HPLC with UV detector is an acceptable assay for measuring urinary methylhippuric acid . Although determination of urinary methylhippuric acid cannot affect treatment of xylene poisoning, it can serve as a reliable laboratory tool for establishing this diagnosis.
Diagnosis of acute xylene poisoning following its inhalation was suggested in our cases by urinary methylhippuric acid. It is suggested to determine urinary methylhippuric acid together with other metabolites of organic solvents (e.g., hippuric acid, trichloroacetic acid) whenever acute unintentional exposure or abuse of volatile organic compounds is suspected.
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