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
Project accomplishments involved work related to the production of benzene oxide (BO) from metabolism of benzene in rodents and humans. The prevailing hypothesis of benzene-induced leukemogenesis has focused almost exclusively upon the phenolic metabolites, catechol and hydroquinone, and their oxidation products, 1,2- and 1,4-benzoquinone (BQ). An attractive feature of this hypothesis is the plausibility of transport of the BQ precursors from the liver to the bone marrow where they can be activated to the toxic quinones by peroxidases. It was thought that BO was too reactive to escape the hepatocyte. However, the discovery of BO-Hb in the blood of animals dosed with benzene called this notion into question and motivated the current focus upon BO. Project investigators confirmed that BO was present in the blood of rats dosed with benzene and that BO was surprisingly stable in human, rat and mouse blood with half-lives of 6-8 min. To investigate the disposition of BO more thoroughly in humans, sensitive assays for adducts of BO with Hb and albumin in blood were developed. Researchers found significant correlation between benzene exposure and adduct levels in both rodents and humans. Adduct measurements were used to suggest that up to 40% of the systemic BO dose reached the bone marrow. Since BO is mutagenic and carcinogenic in newborn mice, it should be considered a possible contributor to the hematotoxic and genotoxic effects associated with benzene.