Project Summary (2011-2017)

Benzene is an important industrial chemical, a component of gasoline, and a prominent contaminant at Superfund sites. Although benzene is an undisputed cause of human leukemia, many important scientific and regulatory questions remain regarding the exposure-response relationship and mechanism of action. Drs. Rappaport and Smith confirm an earlier finding that humans possess a second metabolic pathway that efficiently metabolizes benzene at low doses and determine whether enzymatic activity varies with gender and smoking status. They suspect that the enzymes CYP2F1 and CYP2A13 are responsible for the low dose metabolism of benzene. The researchers are testing this hypothesis and determining the effect of genetic variation in these enzymes on benzene metabolism and health effects among subjects with different levels of benzene exposure. The effects of variation in other candidate genes are also explored using high-throughput genotyping, fine mapping and resequencing, allowing the researchers to better predict risks of leukemia required at low levels of benzene exposure in genetically susceptible populations. The researchers are also developing biomarkers of early effect and historical exposure. They previously used microarrays to show that the blood mRNA transcriptome is exquisitely sensitive to low-level occupational benzene exposure. The researchers are developing a simple biomarker of ~10 genes, altered in expression by benzene, which may serve as a biomarker of early effect for low level benzene exposure that could readily be used in a field setting such as a Superfund site. They are also measuring changes in global and gene-specific DNA methylation and microRNA expression induced by benzene exposure in the blood cells of exposed workers. The goal is to determine if benzene can produce epigenetic changes of the type observed in leukemia, in addition to inducing chromosomal damage, thereby providing important mechanistic insight. Further, the researchers are comparing the effects of benzene on gene-specific DNA methylation and microRNA expression with previously determined changes in gene expression. Finally, they are comparing the DNA methylation profiles of blood cells from workers with current exposure to benzene with those with a past history of benzene exposure but with no current exposure and with control workers never exposed occupationally to benzene. This allows them to search for epigenetic marks that might serve as a biomarker of historical exposure to benzene. The overall goal is to use biomarkers to improve the risk assessment of benzene at Superfund sites.