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Benzene Poisoning, a Risk Factor for Hematological Malignancy, Is Associated with the NQO1 ⁶⁰⁹CT Mutation and Rapid Fractional Excretion of Chlorzoxazone¹

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland 20892 [N. R., R. B. H., M. D., M. L., S. W.]; School of Public Health, University of California at Berkeley, Berkeley, California 94720 [M. T. S., S. C., L. Z., K. B. M., N. T-H.]; School of Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado 80262 [R. D. T., D. R.]; School of Pharmacy, University of California at San Francisco, San Francisco, California 94143 [B-a. H.]; Chinese Academy of Preventive Medicine, Beijing, People's Republic of China [G-L. L., L. X., S. Y.]; Shanghai Hygiene and Anti-Epidemic Center, Shanghai, People's Republic of China [W. L.]; and College of Pharmacy, University of Georgia, Athens, Georgia 30602 [J. T. S.]

Benzene is a ubiquitous occupational hematotoxin and leukemogen, but people vary in their response to this toxic agent. To evaluate the impact of interindividual variation in enzymes that activate (i.e., CYP2E1) and detoxify (i.e., NQO1) benzene and its metabolites, we carried out a casecontrol study in Shanghai, China, of occupational benzene poisoning (BP; i.e., hematotoxicity), which we show is itself strongly associated with subsequent development of acute nonlymphocytic leukemia and the related myelodysplastic syndromes (relative risk, 70.6; 95% confidence interval, 11.4–439.3). CYP2E1 and NQO1 genotypes were determined by PCR-RFLP, and CYP2E1 enzymatic activity was estimated by the fractional excretion of chlorzoxazone (fe_6-OH) for 50 cases of BP and 50 controls. Subjects with both a rapid fe_6-OH and two copies of the NQO1 ⁶⁰⁹CT mutation had a 7.6-fold (95% confidence interval, 1.8–31.2) increased risk of BP compared to subjects with a slow fe_6-OH who carried one or two wild-type NQO1 alleles. In contrast, the CYP2E1 PstI/RsaI polymorphism did not influence BP risk. This is the first report that provides evidence of human susceptibility to benzene-related disease. Further evaluation of susceptibility for hematotoxicity and hematological malignancy among workers with a history of occupational exposure to benzene is warranted.

¹ This study was supported in part by National Institute of Environmental Health Sciences Grants P42ES04705 and P30ES01896. S. C. and K. B. M. are trainees of the University of California Toxic Substances Program.

² To whom requests for reprints should be addressed, at NIH, National Cancer Institute EPN 418, Bethesda, MD 20892.

Received 2/13/97. Accepted 5/21/97.

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