Project Summary (2000-2005)

The goal of this project is to investigate why certain PCBs are activated to genotoxins in vivo and others are not. Previous research has shown that PCBs are metabolized to forms that bind to DNA, and that metabolism of PCBs produces reactive oxygen species resulting in DNA strand breaks and 8-oxodeoxyguanosine formation in DNA. Employing the Solt-Farber protocol, project investigators identified 4-chlorobiphenyl as an initiator of hepatocarcinogenesis in the rat. Researchers are studying the metabolic activation pathway of 4-chlorobiphenyl with cell culture and in vivo methods, and determining the primary sequence changes in oncogenes and tumor suppressor genes in rats. The genotoxic profiles of the metabolites of 4-chlorobiphenyl are being described. The changes in DNA arising from oxidative stress during PCB toxicity are being identified to develop biomarkers of exposure, susceptibility, and toxicity to PCBs. These mechanistic and biomonitoring issues are forming a basis for quantitative human health risk assessment for these important Superfund Chemicals.