Benzene has been classified as a human carcinogen with hematoxicity by International Agency for Research on Cancer (IARC). The urinary benzene metabolites, trans,trans-moconic acid (ttMA) and S-phenylmercapturic acid (SPMA), are considered as sensitive and specific benzene exposure biomarkers. The American Conference of Governmental Industrial Hygienists (ACGIH) has set biological exposure indexes values (BEIs) for ttMA and SPMA as 500 and 25 ug g-1 creatinine respectively for biological monitoring. The previous analytical methods for quantitation of these two urinary metabolites require tedious manual sample preparation process and/or have high method detection limits (MDLs). For routine analysis, it is important to improve its quantitative analytical method.
Additionally, glutathione S-transferase (GST) genetic polymorphism that is considered a biomarker of susceptibility may influence the excretion levels of ttMA and SPMA. The association between dose-related production of urinary benzene metabolites and benzene exposure level was reported. However, the association between the dose-related productions of urinary benzene metabolites and GST genetic polymorphism were not found in the literature.
The issues of the dissertation contain (1) development of analytical method for quantitation of urinary ttMA and SPMA without tedious manual sample preparation process and with high sensitivity, and (2) investigation of the association between the GST genetic polymorphism (a biomarker of susceptibility), and dose-related production of urinary ttMA and SPMA (biomarkers of exposure). The development process of analytical method contains the following 3 parts. First, the analytical method with an on-line clean-up system for quantitation of urinary SPMA was developed. Second, the analytical method was modified for simultaneous quantitation of urinary ttMA and SPMA. Third, the automatic analytical method was validated.
For development of analytical method for SPMA quantitation, an on-line clean-up device coupled with electrospray ionization tandem mass spectrometry (ESI-MS/MS) was developed. The analytical system was fully automatic. No tedious manual sample clean-up procedures were required. The automatic analytical method was modified for simultaneous quantitation of urinary ttMA and SPMA. The MDL of the modified analytical method was ppb-level, which can be used for large-scale monitoring of environmental or occupational benzene exposure. For validation of the analytical method, the calibration curve, detection limit, recovery, precision, accuracy and the stability of sample storage for the system have been characterized. For both of ttMA and SPMA, the intra- and inter-day precision values were considered acceptable well below 25 % at the various spiked concentrations. The intra- and inter-day apparent recovery values were also considered acceptable (apparent recovery > 90 %). The ttMA accuracy was estimated by urinary standard reference material (SRM). The accuracy reported in terms of relative error (RE) was 5.0 % ± 2.0 % (n=3). Without tedious manual sample preparation procedure, the analytical system was able to quantify simultaneously ttMA and SPMA in less than 20 minutes per sample.
The analytical method was further applied to investigation of association between the GST genetic polymorphism and dose-related production of urinary ttMA and SPMA. Seventy male workers in a chemical factory were measured for their benzene exposure levels and provided blood and urine specimens at the end of work-shift for analyses of ttMA and SPMA. Among the GST genotypes, including GSTM1, GSTT1, and GSTP1, the results showed that only GSTT1 genotype was related to the level and dose-related production of SPMA. While using SPMA for evaluating benzene exposure, the results suggest that the GSTT1 genetic polymorphism, especially in a comparison study between two populations with different GSTT1 genotype frequencies, should be considered. Additionally, the BEI value of SPMA should be set on the basis of levels of subjects with GSTT1 deficient genotypes for protection of all subjects.

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