Using urinary biomarkers to elucidate dose-related patterns of human benzene metabolism

Kim, Sungkyoon; Vermeulen, Roel; Waidyanatha, Suramya; Johnson, Brent A.; Lan, Qing; Rothman, Nathaniel; Smith, Martyn T.; Zhang, Luoping; Li, Guilan; Shen, Min; Yin, Shu; Rappaport, Stephen M.

doi:10.1093/carcin/bgi297

Cited by 109 publications

(179 citation statements)

References 47 publications

Supporting

Mentioning

163

Contrasting

Unclassified

Order By: Relevance

“…We recently reported dose-specific urine concentrations of the major urinary metabolites of benzene (i.e., phenol, catechol, hydroquinone, and E,E-muconic acid) and a minor metabolite [S-phenylmercapturic acid (SPMA)] in 250 benzene-exposed and 139 control workers from Tianjin, China (9). After grouping subjects according to their benzene exposures (30 subjects per group), median metabolite levels increased nonlinearly with increasing median benzene concentrations between 0.03 and 20 ppm, whereas median dose-specific levels of total metabolites (Amol/L/ppm benzene) decreased about 10-fold.…”

Section: Introductionmentioning

confidence: 99%

Modeling Human Metabolism of Benzene Following Occupational and Environmental Exposures

Kim

Vermeulen

Waidyanatha

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

Self Cite

107

View full text Add to dashboard Cite

We used natural spline (NS) models to investigate nonlinear relationships between levels of benzene metabolites (E,Emuconic acid, S-phenylmercapturic acid, phenol, hydroquinone, and catechol) and benzene exposure among 386 exposed and control workers in Tianjin, China. After adjusting for background levels (estimated from the 60 control subjects with the lowest benzene exposures), expected mean trends of all metabolite levels increased with benzene air concentrations from 0.03 to 88.9 ppm. Molar fractions for phenol, hydroquinone, and E,E-muconic acid changed continuously with increasing air concentrations, suggesting that competing CYP-mediated metabolic pathways favored E,Emuconic acid and hydroquinone below 20 ppm and favored phenol above 20 ppm. Mean trends of dose-specific levels (Mmol/L/ppm benzene) of E,E-muconic acid, phenol, hydroquinone, and catechol all decreased with increasing benzene exposure, with an overall 9-fold reduction of total metabolites. Surprisingly, about 90% of the reductions in dosespecific levels occurred below about 3 ppm for each major metabolite. Using generalized linear models with NSsmoothing functions (GLM + NS models), we detected significant effects upon metabolite levels of gender, age, and smoking status. Metabolite levels were about 20% higher in females and decreased between 1% and 2% per year of life. In addition, levels of hydroquinone and catechol were greater in smoking subjects. Overall, our results indicate that benzene metabolism is highly nonlinear with increasing benzene exposure above 0.03 ppm, and that current human toxicokinetic models do not accurately predict benzene metabolism below 3 ppm. Our results also suggest that GLM + NS models are ideal for evaluating nonlinear relationships between environmental exposures and levels of human biomarkers. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2246 -52)

show abstract

Section: Introductionmentioning

confidence: 99%

Modeling Human Metabolism of Benzene Following Occupational and Environmental Exposures

Kim

Vermeulen

Waidyanatha

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

Self Cite

107

View full text Add to dashboard Cite

show abstract

“…Toluene and benzene are two important aromatic compounds in JP-8. Biotransformation of these two aromatic compounds has been thoroughly studied, and the applicability of their metabolites as possible biomarkers of exposure in humans has been discussed (Kim et al 2006;Manini et al 2004; Qu et al 2000). Another important component of JP-8 is 2-(2-methoxyethoxy)ethanol; this is added to the fuel as an anti-icing agent and is formulated at a consistent concentration of 0.1%.…”

Section: Hhs Public Accessmentioning

confidence: 99%

Evaluation and Comparison of Urinary Metabolic Biomarkers of Exposure for the Jet Fuel JP-8

B’Hymer

Krieg²,

Cheever³

et al. 2012

Journal of Toxicology and Environmental Health, Part A

View full text Add to dashboard Cite

A study of workers exposed to jet fuel propellant 8 (JP-8) was conducted at U.S. Air Force bases and included the evaluation of three biomarkers of exposure: S-benzylmercapturic acid (BMA), Sphenylmercapturic acid (PMA), and (2-methoxyethoxy)acetic acid (MEAA). Postshift urine specimens were collected from various personnel categorized as high (n = 98), moderate (n = 38) and low (n = 61) JP-8 exposure based on work activities. BMA and PMA urinary levels were determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/ MS), and MEAA urinary levels were determined by gas chromatography-mass spectrometry (GC-MS). The numbers of samples determined as positive for the presence of the BMA biomarker (above the test method's limit of detection [LOD = 0.5 ng/ml]) were 96 (98.0%), 37 (97.4%), and 58 (95.1%) for the high, moderate, and low (control) exposure workgroup categories, respectively. The numbers of samples determined as positive for the presence of the PMA biomarker (LOD = 0.5 ng/ml) were 33 (33.7%), 9 (23.7%), and 12 (19.7%) for the high, moderate, and low exposure categories. The numbers of samples determined as positive for the presence of the MEAA biomarker (LOD = 0.1 μg/ml) were 92 (93.4%), 13 (34.2%), and 2 (3.3%) for the high, moderate, and low exposure categories. Statistical analysis of the mean levels of the analytes demonstrated MEAA to be the most accurate or appropriate biomarker for JP-8 exposure using urinary concentrations either adjusted or not adjusted for creatinine; mean levels of BMA and PMA were not statistically significant between workgroup categories after adjusting for creatinine.Biomarkers of exposure are important tools for use in exposure assessment and toxicological research. As the term implies, biomarkers of exposure are those related to exposure and the internal levels of some agent or chemical. A well-chosen biomarker of exposure should have several qualities. Primarily, the biomarker should be specific for the exposure of interest; some metabolites are common to multiple parent chemical substances and therefore may not be suitably specific biomarkers. Second, the biomarker needs to be associated with the et al. 2003). The fuel is formulated to meet military performance specifications, and therefore, the overall chemical composition varies from batch to batch with the exception of an anti-icing component (NRC 2003). With the many constituent chemicals present at varying concentrations, the best or most accurate biomarker for JP-8 exposure has not been extensively addressed in the literature, and this was the main objective of the current study. Three potential biomarkers of JP-8 exposure were compared since a previous study had investigated only one of these potential biomarkers (B'Hymer et al. 2012). HHS Public AccessThe specifications for JP-8 include a maximum olefin content of 5%, a maximum aromatic content of 22%, and a maximum sulfur content of 0.3%. On average, the composition is approximately 33-61% alkanes, 10-45% cycloalkanes, 12-22%...

show abstract

“…The most widely-used sample preparation procedure employs solid phase extraction (SPE) with ion exchange resins [13][14][15][16][17][18]. This procedure reduces the quantities of solvents required and provides better recoveries, as well as clearer extracts, compared to the non-extraction procedure [19,20].…”

Section: Introductionmentioning

confidence: 99%

Method for the Determination of Benzene Metabolite t,t-Muconic Acid in Urine by HPLC-UV with an Ion Exclusion Column

et al. 2016

View full text Add to dashboard Cite

Abstract:The benzene metabolite trans,trans-muconic acid (tt-MA) is widely used as a biological indicator of exposure to this xenobiotic. An analytical method was developed and validated for the determination of urinary tt-MA using solid phase extraction onto a Strata SAX cartridge. The analysis was performed by HPLC with an Aminex HPX-87H ion exclusion column and a UV diode array detector. The sample preparation conditions were optimized using a 2 4´1 factorial design.Comparison of the slopes of standard analytical curves prepared in aqueous solution and urine showed that the biological matrix suppressed the tt-MA signal by around 50%, so the analytical curves were prepared with tt-MA standard at low concentrations in pooled urine. The analytical curves in the range of 5-500 µg¨L´1 showed determination coefficients values (R 2 ) > 0.99 for tt-MA standard in water and R 2 > 0.98 for tt-MA standards in pooled urine. The coefficients of variation obtained using seven replicates were lower than 3.6%, and recoveries of tt-MA from solutions containing 5, 25, 50 and 100 µg¨L´1 of the analyte were in the range 85%-90%, demonstrating the satisfactory precision and accuracy of the method. The limits of detection and quantification were 0.11 and 0.36 µg¨L´1, respectively. The benefits of this new method developed is the possibility of complete chromatographic peak separation for the determination of tt-MA at baseline, without matrix components' interference as normally found in the C18 column. This is the first time that this chromatographic column has been used for the analysis of tt-MA in urine.

show abstract

Using urinary biomarkers to elucidate dose-related patterns of human benzene metabolism

Cited by 109 publications

References 47 publications

Modeling Human Metabolism of Benzene Following Occupational and Environmental Exposures

Modeling Human Metabolism of Benzene Following Occupational and Environmental Exposures

Evaluation and Comparison of Urinary Metabolic Biomarkers of Exposure for the Jet Fuel JP-8

Method for the Determination of Benzene Metabolite t,t-Muconic Acid in Urine by HPLC-UV with an Ion Exclusion Column

Contact Info

Product

Resources

About