Project Summary (1995-2000)

The goal of this project is to formulate new risk assessment methodologies for chemical mixtures by coupling physiologically based pharmacokinetics/pharmacodynamics (PBPK/PD) and experimental toxicology with statistical/mathematical modeling such as isobolographic analysis and response surface methodology. This research addresses chemical mixtures from two directions. In the "bottom up" approach, systematic interaction studies based on toxicologic mechanisms start with binary mixtures, later adding other chemicals to build a mixture. In the "top down" approach, a chemical mixture of seven common hazardous waste groundwater contaminants are being studied by successively subdividing the mixture to the level of the individual chemicals. Experimental procedures include gas uptake PBPK/PD studies, determination of selected liver enzyme levels, evaluation of hepatocellular proliferation and evaluation of molecular biomarkers of liver cell proliferation. Data from these studies are being combined with mechanistic data from companion projects 2 and 3 to help formulate a strategy for developing "predictive toxicology" methods to be used in risk assessment.