Superfund Research Program
The Role of Oxidative Stress in Toxicology and Carcinogenesis
Project Leader: James A. Swenberg
Grant Number: P42ES005948
Funding Period: 1995-2018
Project Summary (2006-2011)
The research in this project utilizes newly developed biomarkers of oxidative stress to evaluate the mode of action and dose response of hazardous chemicals of importance to Superfund sites. These studies primarily address effects of polyhalogenated and polycyclic aromatic hydrocarbons including dibenzo(a,l)pyrene (DBF), RGBs and dioxin. These studies analyze snap frozen tissues from two of the largest and best characterized carcinogenicity bioassays: the NTP Toxic Equivalency Factor studies on PCBs and dioxin in rats; and the ED0.i DBF study in rainbow trout. Dr. Swenberg's team hypothesizes that oxidative stress is an important mode of action for toxicity and carcinogenesis. These studies are being accomplished by comparing a comprehensive series of biomarkers for oxidative DNA damage that includes lesions removed by long and short patch base excision repair and utilizes different glycosylases, as well as by nucleotide excision repair. The studies examine dose-response relationships for oxidative DNA damage and compare this with P450 induction, cell proliferation, and in the case of DBF, 32P-postlabeling studies of bulky DNA adducts. In addition, the project is conducting similar research on fish from the Hudson River and less polluted waterways that have exposures to different mixtures and amounts of PAHs, PCBs and dioxins. In collaboration with the NYU SBRP, laboratory exposures to similar mixtures of hazardous chemicals are being conducted to investigate the development of resistance to PCBs toxicity and differences in life stage susceptibility to these agents. Finally, they are continuing their basic research on oxidative DNA damage and repair to further their understanding of the biology of DNA damage and repair, and its implications for environmental health and individual susceptibility. The long term goals are to develop an in-depth understanding of how these chemicals cause toxicity and under what conditions they elicit responses. These data will fill critical gaps in knowledge that will impact the basis of low dose extrapolation and improve the scientific basis of risk assessment and the setting of remediation standards. Project investigators interact with each of the other scientific projects of this program by performing biomarker analyses, providing data or determining the ability of various environmental chemicals or their metabolites to cause oxidative DNA damage. The research also make heavy use of both the Chemistry and Analytical Core and the Mathematical and Statistical Analysis and Modeling Core.