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
Project Summary (2011-2018)
This project utilizes newly developed assays for a series of DNA adducts, Biomarkers of Exposure, and analyses of mutations, Biomarkers of Effect, to evaluate the mode of action and dose response of hazardous chemicals of importance to Superfund sites. Expansion of this project’s earlier studies on PCBs and TCDD are better defining dose and time responses for oxidative stress. The research group now has liver and lung samples from 13, 30 and 52 week tissues from in vivo exposures to pentachlorodibenzofuran (PeCDF), PCB 118 and a mixture of TCDD, PeCDF and PCB 126 from NTP Toxic Equivalency Factor (TEF) studies.
The researchers are measuring their battery of oxidative DNA adducts as Biomarkers of Exposure to fully characterize the extent and timing of oxidative stress. These studies are helping them understand the relationships between endogenous DNA adducts and carcinogenesis for this important set of nongenotoxic chemicals. DNA adducts, as Biomarkers of Exposure, can also result in mutations, Biomarkers of Effect, if DNA replication takes place before repair. Unlike DNA adducts, mutations cannot be repaired and are heritable in the progeny of the originally mutated cell. They have reported that endogenous DNA adducts are always present in genomic DNA. Thus, this nonzero background of endogenous DNA damage may cause a nonzero spontaneous background mutation rate. The researchers are developing new methods for studying mutations using the PIG gene in DT-40 cells and will employ this system to evaluate the dose-response for mutations resulting from chemicals that can be formed in cells and tissues. They are also examining dose-response relationships for three reactive intermediates of Superfund chemicals. This research, in addition to characterizing Biomarkers of Exposure, helps them to better understand differences between Biomarkers of Exposure and Effect. Thus, the most informative scientific data can be used to derive future cancer risk assessments, rather than relying on default science policy decisions that may not provide any additional protection to public health, but pose expensive and often nonattainable clean-up levels for Superfund sites. Finally, the research group is collaborating with Drs. Rebecca Fry and Michael Aitken to identify critical DNA response pathways and examine bioremediation products.