BENZENE POISONING, A RISK FACTOR FOR HEMATOLOGICAL MALIGNANCY, IS ASSOCIATED WITH THE NQ01 C-609-]T MUTATION AND RAPID FRACTIONAL EXCRETIONOF CHLORZOXAZONE

Benzene is a ubiquitous occupational hematotoxin and leukemogen, but p eople vary in their response to this toxic agent, To evaluate the impa ct of interindividual variation in enzymes that activate (i.e., CYP2E1 ) and detoxify (i.e., NQO1) benzene and its metabolites, we carried ou t a case-control study in Shanghai, China, of occupational benzene poi soning (BP; i.e., hematotoxicity), which we show is itself strongly as sociated with subsequent development of acute nonlymphocytic leukemia and the related myelodysplastic syndromes (relative risk, 70.6; 95% co nfidence interval, 11.4-439.3). CYP2E1 and NQO1 genotypes were determi ned by PCR-RFLP, and CYP2E1 enzymatic activity was estimated by the fr actional excretion of chlorzoxazone (fe(6-OH)) for 50 cases of BP and 50 controls, Subjects with both a rapid fe6--OH and two copies of the NQO1 C-609-->T mutation had a 7.6-fold (95% confidence interval, 1.8-3 1.2) increased risk of BP compared to subjects with a slow fe(6-OH) wh o carried one or two wild-type NQO1 alleles, In contrast, the CYP2E1 P stI/RsaI polymorphism did not influence BP risk. This is the first rep ort that provides evidence of human susceptibility to benzene-related disease. Further evaluation of susceptibility for hematotoxicity and h ematological malignancy among workers with a history of occupational e xposure to benzene is warranted.