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Stephen M. Rappaport,¹ Sungkyoon Kim,^2,* Qing Lan,³ Roel Vermeulen,⁴ Suramya Waidyanatha,² Luoping Zhang,¹ Guilan Li,⁵ Songnian Yin,⁵ Richard B. Hayes,³ Nathaniel Rothman,³ and Martyn T. Smith¹

¹School of Public Health, University of California at Berkeley, Berkeley, California, USA; ²School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; ³National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, USA; ⁴Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands; ⁵Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China

Abstract
Background: Recent evidence has shown that humans metabolize benzene more efficiently at environmental air concentrations than at concentrations > 1 ppm. This led us to speculate that an unidentified metabolic pathway was mainly responsible for benzene metabolism at ambient levels.

Objective: We statistically tested whether human metabolism of benzene is better fitted by a kinetic model having two pathways rather than one.

Methods: We fit Michaelis-Menten-like models to levels of urinary benzene metabolites and the corresponding air concentrations for 263 nonsmoking Chinese females. Estimated benzene concentrations ranged from less than 0.001 ppm to 299 ppm, with 10th and 90th percentile values of 0.002 ppm and 8.97 ppm, respectively.

Results: Using values of Akaike’s information criterion obtained under the two models, we found strong statistical evidence favoring two metabolic pathways, with respective affinities (benzene air concentrations analogous to K_m values) of 301 ppm for the low-affinity pathway (probably dominated by cytochrome P450 enzyme 2E1) and 0.594 ppm for the high-affinity pathway (unknown) . The exposure-specific metabolite level predicted by our two-pathway model at nonsaturating concentrations was 184 µM/ppm of benzene, a value close to an independent estimate of 194 µM/ppm for a typical nonsmoking Chinese female. Our results indicate that a nonsmoking woman would metabolize about three times more benzene from the ambient environment under the two-pathway model (184 µM/ppm) than under the one-pathway model (68.6 µM/ppm) . In fact, 73% of the ambient benzene dose would be metabolized via the unidentified high-affinity pathway.

Conclusion: Because regulatory risk assessments have assumed nonsaturating metabolism of benzene in persons exposed to air concentrations well above 10 ppm, our findings suggest that the true leukemia risks could be substantially greater than currently thought at ambient levels of exposure—about 3-fold higher among nonsmoking females in the general population.

Key words: benzene, biomonitoring, cancer risk, cytochrome P450, metabolism. Environ Health Perspect 117:946–952 (2009) . doi:10.1289/ehp.0800510 available via http://dx.doi.org/ [Online 19 February 2009]

Address correspondence to S.M. Rappaport, School of Public Health, University of California, Berkeley, CA 94720-7356 USA. Telephone: (510) 642-4355. Fax: (510) 642-0427. E-mail: srappaport@berkeley.edu

*Current address: School of Public Health, Seoul National University, Seoul, Korea.

We are indebted to M. Dosemici, who compiled some of the benzene exposure data used in this investigation ; to M. Shin, who helped assemble a portion of the database ; and to P. Egeghy, L. Nylander-French, K. Gwin, and I. Hertz-Picciotto, who contributed to a previous study from which we used data to estimate benzene uptake at sub-parts-per-million exposure levels. We also appreciate the helpful comments of M. Andersen, who reviewed a draft of the manuscript, and of S. Selvin, who provided helpful discussion regarding the statistical analyses.

This research was supported by the National Institute for Environmental Health Sciences through grants P42ES05948 and P30ES10126 to S.M.R. and RO1ES06721 and P42ES04705 to M.T.S. and by funds from the intramural research program of the National Institutes of Health, National Cancer Institute.

S.M.R. has received consulting and expert testimony fees from law firms representing plaintiffs’ cases involving exposure to benzene, and he has received research support from the American Petroleum Institute and the American Chemistry Council. G.L. has received funds from the American Petroleum Institute for consulting on benzene-related health research. M.T.S. has received consulting and expert testimony fees from law firms representing both plaintiffs and defendants in cases involving exposure to benzene. The other authors declare they have no competing financial interests.

Received 19 December 2008 ; accepted 18 February 2009.