Benzene Poisoning, a Risk Factor for Hematological Malignancy, Is Associated with the NQO1 609C—÷T Mutation and Rapid Fractional Excretion of Chlorzoxazone'

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 case control 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 re lated myelodysplastic syndromes (relative risk, 70.6; 95% confidence interval, 11.4—439.3). CYP2EJ and NQOJ genotypes were determined by PCR-RFLP, and CYP2E1 enzymatic activity was estimated by the frac tional excretion of chlorzoxazone (fe@H) for 50 cases of BP and 50 controls. Subjects with both a rapid fe@OH and two copies of the NQOJ @°@C—*T mutationhad a 7.6-fold (95% confidenceinterval, 1.8—31.2) increased risk of BP compared to subjects with a slow fe60@ who carried one or two wild-type NQOJ alleles. In contrast, the CYP2E1 PsiI/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.