Suitability of S-phenyl mercapturic acid and trans-trans-muconic acid as biomarkers for exposure to low concentrations of benzene.

Abstract

Phenol is not reliable as a biomarker for exposure to benzene at concentrations below 5 ppm (8-hr time-weighted average [TWA]). S-Phenylmercapturic acid (S-PMA) and trans-trans-muconic acid (tt-MA), two minor urinary metabolites of benzene, have been proposed as biomarkers for low-level exposures. The aim of this study was to compare their suitability as biomarkers. S-PMA and tt-MA were determined in 434 urine samples collected from 188 workers in various settings in the petrochemical industry and from 52 control workers with no occupational exposure to benzene. Benzene concentrations in the breathing zone of the potentially exposed workers were assessed by personal air monitoring. Strong correlations were found between S-PMA and tt-MA concentrations in end-of-shift samples and between either of these parameters and airborne benzene concentrations. Exposure to 1 ppm benzene (8-hr TWA) leads to an average concentration in end-of-shift samples of 21 mol S-PMA and 1.5 mmol tt-MA per mol creatinine. Of an inhaled dose of benzene, on average 0.11% (range 0.05-0.26%) was excreted as S-PMA with an apparent elimination half-life of 9.1 (standard error [SE] 0.7) hr and 3.9% (range 1.9-7.3%) as tt-MA with a half-life of 5.0 (SE 0.5) hr. Due to its longer elimination half-life, S-PMA proved a more reliable biomarker than tt-MA for benzene exposures during 12-hr shifts. Specificity of S-PMA, but not tt-MA, was sufficient to discriminate between the 14 moderate smokers and the 38 nonsmokers from the control group. The mean urinary S-PMA was 1.71 (SE 0.27) in smokers and 0.94 (SE 0.15) mol/mol creatinine in nonsmokers (p = 0.013). The mean urinary tt-MA was 0.046 (SE 0.010) in smokers and 0.029 (SE 0.013) mmol/mol creatinine in nonsmokers (p = 0.436). The inferior specificity of tt-MA was due to relatively high background values of up to 0.56 mmol/mol creatinine, which may be found in nonexposed individuals and limits the use of tt-MA to concentrations of benzene over 1 ppm (8-hr TWA). We conclude that S-PMA is superior to tt-MA as a biomarker for low-level benzene exposures because it is more specific, enabling reliable determination of benzene exposures down to 0.3 ppm (8-hr TWA), and because its longer half-life makes it more suited for biological monitoring of operators working in shifts longer than 8 hr.

Urinary Phenylmercapturic Acid as a Marker of Occupational Exposure to Benzene.

“…Nevertheless, the observation as a whole suggests that the effect should be small if present. Thus, the present survey not only supports the opinion that PMA is a good biomarker of benzene exposure 8,9,[15][16][17][18][19] , but has demonstrated that PMA is useful even under the condition of co-exposure to other aromatics and most probably to other solvents in general. The latter observation suggests that, as a benzene exposure marker, PMA is superior to mono-to tri-hydroxylated benzenes [phenol 27) , quinol 27) and catechol 27) , 1,2,4-benzenetriol 11) ] and t,t-muconic acid 13) , because the excretion of these urinary benzene metabolites other than PMA are all known to be suppressed by coexposure to other aromatics.…”

“…Major findings available in literature on quantitative relationship of PMA in end-of-shift urine with TWA benzene exposure 8,9,[15][16][17][18][19] are summarized in Table 4. The reported values for PMA corresponding to 1 ppm benzene cluster around 40 µg/g cr with two extremes of 12 and 58 µg/g cr.…”

“…This study group has been studying on urinary biomarkers of occupational exposure to benzene such as catechol 10) , quinol 10) , 1,2,4-benzenetriol 11,12) as well as t,t-muconic acid 13) in addition to a traditional marker of phenol 14) . Urinary phenylmercapturic acid (PMA; N-acetyl-S-phenyl-L-cysteine), a N-acetylcysteine conjugate of benzene, has also been evaluated as a marker of exposure to low-level benzene 8,9,[15][16][17][18][19][20] , but the analytical methods employed are rather complex, e.g., requiring derivatization or clean-up through columns before instrumental analysis [21][22][23][24][25] such as gas chromatography-mass spectrometry 15) or liquid chromatography-mass spectrometry 26) , and application of the methods to routine occupational health services appear to be not practical.…”

Evaluation of benzene exposure in adults and urinary s-phenylmercapturic acid in children living in Adelaide, South Australia

“…Measurement of metabolite in urine prefer to analysis of benzene at blood because collection of urine is painless, easy to obtain, low in cost and easily performed even at subjects are far away from laboratory. An alternative approach involves measurement of the metabolites of benzene in urine including phenol, trans, trans-muconic acid (TTMA) and s-phenylmercapturic acid (SPMA) (ACGIH, 2005;Inoue et al 2000;Boogaard et al, 1996). TTMA and SPMA were proposed to replace phenol in biological monitoring of benzene (Boogaard et al, 1996;ACGIH, 2005) Benzene in the human system is subsequently oxidized to benzene oxide and in turn conjugated with glutathione to form SPMA that is excreted in the urine (15).…”

“…An alternative approach involves measurement of the metabolites of benzene in urine including phenol, trans, trans-muconic acid (TTMA) and s-phenylmercapturic acid (SPMA) (ACGIH, 2005;Inoue et al 2000;Boogaard et al, 1996). TTMA and SPMA were proposed to replace phenol in biological monitoring of benzene (Boogaard et al, 1996;ACGIH, 2005) Benzene in the human system is subsequently oxidized to benzene oxide and in turn conjugated with glutathione to form SPMA that is excreted in the urine (15). SPMA derives solely from benzene metabolism and is a sensitive and specific biomarker of exposed benzene in low level (Van Sitter et al, 1993, Ghittori et al, 1996.…”