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
Benzene is a ubiquitous environmental contaminant that is emitted from most waste sites on the National Priorities List sites identified by the Environmental Protection Agency. This chemical is also widely used industrially in the U.S. and throughout the world. Although past investigations have shown that benzene causes leukemia and aplastic anemia in highly exposed workers, potential effects of environmental exposure to benzene at much lower levels have been controversial. This controversy has been accentuated because, although metabolism is thought to be required for benzene to exert its toxicity, the metabolism of benzene has hardly been explored in humans. This lack of key information prompted investigators to develop and apply biomarkers of exposure to elucidate the metabolic pathways in humans exposed to benzene over a wide range of air levels. A host of biomarkers has been applied, including protein adducts of several reactive metabolites of benzene, of benzene in breath and urine, and of benzene metabolites in urine. These biomarkers have been measured in over 1000 benzene-exposed workers and controls in numerous studies, as part of collaborations with investigators at the SBRP of the University of California, Berkeley, at the National Cancer Institute (NCI), and at New York University. These studies have led to two important findings regarding the potential for benzene to cause toxic effects at low levels of exposure. First, measurements of protein adducts of benzene metabolites by investigators have shown that the metabolism of benzene becomes saturated at levels of exposure much lower than had been previously thought. This suggests that persons exposed to low environmental levels efficiently metabolize benzene and, therefore, receive proportionally greater doses of toxic metabolites than workers exposed to much higher levels. Second, biomarkers of exposure measured by investigators have been coupled with biomarkers of effect by collaborators at UC Berkeley and the NCI to show that even low-level industrial exposure to benzene causes damage to critical stem cells in the bone marrow, where benzene toxicity is observed. This important finding was recently reported in the prestigious journal Science. (Reference: Q. Lan, L. Zhang, G. Li, R. Vermeulen, R.S. Weinberg, M. Dosemeci, S.M. Rappaport, M. Shen, B.P. Alter., Y. Wu, W. Kopp, S. Waidyanatha, C. Rabkin, W. Guo, S. Chanock, R.B. Hayes, M. Linet, S. Kim, S. Yin, N. Rothman, and M.T. Smith, Hematotoxicity in Workers Exposed to Low Levels of Benzene, Science, 306: 1774-1776, 2004).