Superfund Research Program
Development and Application of Biomarkers of Exposure
Project Leader: Stephen M. Rappaport (University of California-Berkeley)
Grant Number: P42ES005948
Funding Period: 1995 - 2011
The major accomplishments during the last year involved investigation of biomarkers of exposure to benzene which is a ubiquitous environmental contaminant. Although benzene is known to cause cancer in both humans and rodents, the mechanism of carcinogenesis remains elusive. The complexity of the metabolism of benzene and the myriad of effects that the various metabolites exert have precluded the formulation of a clear model of genotoxicity. The liver is the primary site of metabolism of benzene. However, bone marrow, the target tissue in humans, contains enzymes which are capable of either producing DNA-reactive species or activating those produced elsewhere.
The work to determine the mechanism by which benzene induces genotoxicity in the bone marrow has focused largely on the phenolic metabolites, phenol, catechol and hydroquinone; the latter can be oxidized by bone-marrow enzymes to the genotoxic species, 1,2- and 1,4-benzoquinone, respectively. Although there is extensive evidence that these phenolic metabolites are toxic, questions have emerged concerning the specific roles of these species in producing human leukemia. For example, levels of phenol, catechol and hydroquinone in the blood and urine of workers have been found to correlate poorly with exposure to benzene, especially at lower air concentrations. This motivated researchers to develop a new assay to measure protein adducts of another benzene metabolite, benzene oxide, in blood proteins of persons exposed to benzene. The new assay is considerably more sensitive and simpler than previous assays, and opens the possibility for use in large-scale epidemiological investigations. The new method for measuring benzene oxide adducts was applied to hemoglobin from 20 benzene-exposed workers (median: 31 ppm benzene) and 20 unexposed controls in Shanghai, China, as part of a larger cross-sectional study of benzene biomarkers conducted by the National Cancer Institute. Preliminary analyses show that median benzene oxide-hemoglobin adduct levels increased with exposure to benzene. This is the first direct evidence that benzene oxide adducts of Hb are produced in humans.