Citation:

YOKLEY, K., M. V. EVANS, AND J. E. SIMMONS. ESTABLISHING CHANGES IN METABOLISM OF CARBON TETRACHLORIDE IN THE PRESENCE OF TRICHLOROETHYLENE IN THE RAT THROUGH THE USE OF PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING. Presented at Society of Toxicology Annual Meeting, Charlotte, NC, March 25 - 29, 2007.

Description:

Toxicological interactions of chemicals can affect metabolism, often decreasing overall associated metabolic rates; and changes in metabolism can be evaluated through the use of mathematical models. Trichloroethylene (TCE) and carbon tetrachloride (CCl₄) are common contaminants in water and at superfund sites. A closed inhalation (or gas uptake) system was used to collect metabolic data using F344 rats at various initial concentrations of TCE and CCl₄. The initial concentrations used for the exposures were: 25 ppm CCl₄ and 1000 ppm TCE, 25 ppm CCl₄ and 100 ppm TCE, 100 ppm CCl₄ and 500 ppm TCE, 100 ppm CCl₄ and 1000 ppm TCE, and 1000 ppm CCl₄ and 500 ppm TCE. This particular binary mixture pair is an example of metabolic synergy as opposed to the more common metabolic inhibition expected during exposure to multiple chemicals. A previously developed physiologically based pharmacokinetic (PBPK) model of carbon tetrachloride in the rat was verified to fit with gas uptake data for CCl₄ alone (with initial concentrations of 25 ppm, 100 ppm, 250 ppm, and 1000 ppm) and then used to simulate chamber concentration predictions for the aforementioned mixtures. In order to fit chamber concentration data for CCl₄ when administered with TCE, the parameter of the maximum rate of metabolism (V_max) was increased. An increase of 2.8 times the V_max value from the original model of carbon tetrachloride alone produced reasonable predictions for mixture data with higher concentrations (500 ppm or 1000 ppm) of TCE, and an increase of 1.4 times the original V_max worked well at predicting CCl4 chamber concentration for mixtures with 100 ppm TCE. The increase in V_max suggests that metabolism of carbon tetrachloride is amplified by the presence of trichloroethylene and that this amplification is dose-dependant. (This abstract does not reflect EPA policy. Research support for Karen Yokley is provided by grants EPA T829472 and EPA CT833237.)

Record Details:

Record Type:DOCUMENT( PRESENTATION/ ABSTRACT)

Product Published Date:03/26/2007

Record Last Revised:03/29/2007

Record ID: 159083

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Planning Links:

planid :233

myp :AT

myp_title :Air Toxics

ltg :AT-5

ltg_title :Redu Uncert in AT risks

progproj :A5

Goal :1

Goal Title :Clean Air

obj :106

obj_title :Science and Research

subobj :10602

subobj_title :Air Pollution Research

apgfy :2009

APG :14

APG Title :Cumulative Risks -Collect data and develop methods and models for characterizing and predicting multipollutant, multipathway exposures and the toxicity of HAP mixtures based on mode of action to reduce uncertainty in OAR and other client risk assessments

apmfy :2006

APM :61

APM Title :Characterize acute noncancer health effects and develop PBPK models for the binary interactions of trichloroethylene plus carbon tetrachloride and trichloroethylene plus chloroform