Carcinogenesis Advance Access originally published online on December 8, 2005
Carcinogenesis 2006 27(4):772-781; doi:10.1093/carcin/bgi297
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Using urinary biomarkers to elucidate dose-related patterns of human benzene metabolism
School of Public Health, University of North Carolina, Chapel Hill, NC 27599, USA, 1 National Cancer Institute (NCI), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Bethesda, MD 20892, USA, 2 School of Public Health, University of California, Berkeley, CA 94720, USA and 3 Chinese Center for Disease Control and Prevention, Beijing, China
* To whom correspondence should be addressed at: CB 7431, School of Public Health, University of North Carolina, Chapel Hill, NC 27599, USA. Tel: +1 919 966 5017; Fax: +1 919 966 0521; Email: stephen_rappaport{at}unc.edu
Although the toxicity of benzene has been linked to its metabolism, the dose-related production of metabolites is not well understood in humans, particularly at low levels of exposure. We investigated unmetabolized benzene in urine (UBz) and all major urinary metabolites [phenol (PH), E,E-muconic acid (MA), hydroquinone (HQ) and catechol (CA)] as well as the minor metabolite, S-phenylmercapturic acid (SPMA), in 250 benzene-exposed workers and 139 control workers in Tianjin, China. Median levels of benzene exposure were 
1.2 p.p.m. for exposed workers (interquartile range: 0.53–3.34 p.p.m.) and 0.004 p.p.m. for control workers (interquartile range: 0.002–0.007 p.p.m.). (Exposures of control workers to benzene were predicted from levels of benzene in their urine.) Metabolite production was investigated among groups of 30 workers aggregated by their benzene exposures. We found that the urine concentration of each metabolite was consistently elevated when the group's median benzene exposure was at or above the following air concentrations: 0.2 p.p.m. for MA and SPMA, 0.5 p.p.m. for PH and HQ, and 2 p.p.m. for CA. Dose-related production of the four major metabolites and total metabolites (µmol/l/p.p.m. benzene) declined between 2.5 and 26-fold as group median benzene exposures increased between 0.027 and 15.4 p.p.m. Reductions in metabolite production were most pronounced for CA and PH <1 p.p.m., indicating that metabolism favored production of the toxic metabolites, HQ and MA, at low exposures.
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