Biomarkers of exposure versus effect: improving the scientific basis for risk assessment
Project 1 Leader: James Swenberg, UNC-Chapel Hill
Carcinogenicity is the major human health risk associated with the regulation of chemicals present at Superfund Sites. Evidence in humans suggests that cancer is a multi-step disease resulting from genetic alterations to DNA. A major mechanism resulting in genetic alterations to DNA is the induction of mutation. In addition to chemicals that directly bind to DNA and induce mutations, DNA damage can also occur by reactive oxygen species (ROS), one of the primary Modes of Action (MOA) for mutagenesis and carcinogenesis.
Dr. Swenberg’s team is now examining the role of oxidative stress and its associated DNA damage for the following highly persistent polyhalogenated hydrocarbons, namely Tetrachlorodibenzo-p-dioxin (dioxin, TCDD), PCBs, and pentachlorodibenzofuran (PeCDF) and mixtures thereof, using liver and lung samples from rats.
His team is also examining the role of endogenous DNA damage in causing background mutations by studying DNA damage responses to endogenous reactive chemicals. The cells in animals, humans, and cell culture are subjected to continuous endogenous DNA damage arising mainly from oxidative stress and other intracellular processes. The working hypothesis is that background mutations are induced by endogenous mutagenic DNA damage and that exposure to an exogenous chemical can either introduce different DNA lesions, resulting in a different spectrum of mutations, or it might introduce DNA damage identical to endogenous DNA lesions. This hypothesis will be tested by modulating exposures to endogenous chemicals, evaluating mutation frequencies and mutational spectra.
This research will clarify the role of oxidative stress in the toxicity and carcinogenicity of TCDD and PCBs and demonstrate the role of endogenous DNA adducts in mutagenesis. Using these data, critical dose-response relationships necessary for science-based cancer risk assessments will be evaluated.