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USING IN VIVO GAS UPDATE STUDIES TO ESTIMATE METABOLIC RATE CONSTANTS FOR CCL CHEMICALS: 1,1-DICHLOROPROPANE AND 2,2-DICHLOROPROPANE
Citation:
Mitchell, C T., M V. Evans, AND E M. Kenyon. USING IN VIVO GAS UPDATE STUDIES TO ESTIMATE METABOLIC RATE CONSTANTS FOR CCL CHEMICALS: 1,1-DICHLOROPROPANE AND 2,2-DICHLOROPROPANE. Presented at Society of Toxicology, Baltimore, MD, March 21-25, 2004.
Description:
USING IN VIVO GAS UPTAKE STUDIES TO ESTIMATE METABOLIC RATE CONSTANTS FOR CCL CHEMICALS: 1,1-DICHLOROPROPENE AND 2,2-DICHLOROPROPANE.
Mitchell, C T, Evans, M V, Kenyon, E M. NHEERL, U.S. EPA, ORD, ETD, RTP, NC
The Safe Drinking Water Act Amendments of 1996 required the US EPA to develop Candidate Contaminant Lists (CCL), to aid in the setting of priorities for the Agency's drinking water research program. 1,1-Dichloropropene (1,1-DCPe) and 2,2-dichloropane (2,2-DCP) are two of the high priority chemicals identified from the first CCL. Since both are volatile organic compounds, the gas uptake technique was used to estimate rates of metabolism. The gas uptake system is a closed inhalation chamber system in which an initial bolus injection of chemical is made into the chamber, and allowed to decline to obtain a set of decay curves. Individual male F344 rats (200-250g) were exposed to initial chamber concentrations of 50 ppm, 200 ppm, 500 ppm, or 1200 ppm of either 2,2-DCP or 1,1-DCP for up to six hours (n=4 rats/exposure level/chemical). Each rat was exposed only once to a single concentration of each chemical. Partition coefficients were estimated using a published quantitative structure-property relationship methodology (Beliveau et al., 2003). These partition coefficients were used with the PBPK model to generate estimates of VmaxC (mg/hr/kg) and Km (mg/L). Optimized VmaxC and Km were 4.9 and 3.17, respectively, for 2,2-DCP. Optimized VmaxC and Km were 5.76 and 0.31, respectively, for 1,1-DCPe. The shape of the gas uptake curves for 2,2-DCP compared to 1,1-DCPe and the V/K ratios suggest that 2,2-DCP is more slowly metabolized. These metabolic rate estimates are critical parameters for PBPK models that can ultimately be used for animal to human extrapolation. They are also a vital part of a developing data base comparing in vivo to in vitro methods for determination of metabolic rate parameters. (This abstract does not reflect EPA policy).