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Final Progress Reports: University of North Carolina-Chapel Hill: Biomarkers of Exposure versus Effect: Improving the Scientific Basis for Risk Assessment

Superfund Research Program

Biomarkers of Exposure versus Effect: Improving the Scientific Basis for Risk Assessment

Project Leader: James A. Swenberg
Grant Number: P42ES005948
Funding Period: 1995-2018
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Final Progress Reports

Year:   2017  2005  1999 

Important advances were made in several areas during the 1999-2000 funding period. Project investigators demonstrated the potential of administering stable isotopes to differentiate between identical endogenous and exogenous DNA adducts by exposing rats by inhalation to [13C2]-vinyl chloride (VC). This demonstrated that exposure to 10 ppm VC for 5 days caused a 2-3 fold increase in N2,3-ethenoguanine (EG) over that of controls and that even high exposures to [13C2]-VC did not saturate DNA repair, as evidenced by increased endogenous EG. Researchers also developed very sensitive LC-MS/MS methods for 7-hydroxyethylguanine, another endogenous DNA adduct. Using the DNA abasic site (AP) assay that was developed last year, oxidative stress was found to cause the direct loss of bases and the formation of 5'-cleaved AP sites. These DNA lesions were poor substrates for polymerase b and were not repaired in HeLa cells. Thus, they may represent a new biomarker of oxidative DNA damage. It is of interest to note that 5'-cleaved AP represent about 70% of the endogenous AP sites in control rodent and human tissue and that AP sites are the most common form of DNA damage, being present at 50,000-200,000 per cell. Finally, the researchers demonstrated that quinone protein and DNA adducts form from PCBs. The same metabolites cause oxidative stress and it was demonstrated that oxidative DNA damage was ~100 times more frequent than direct DNA damage.

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