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THE INFLUENCE OF VARIABLE ELIMINATION RATE AND BODY FAT MASS IN A PBPK MODEL FOR TCDD IN PREDICTING THE SERUM TCDD CONCENTRATIONS FROM VETERANS OF OPERATION RANCH HAND
Citation:
Emond, C., L S. Birnbaum, J. Michalek, AND M J. DeVito. THE INFLUENCE OF VARIABLE ELIMINATION RATE AND BODY FAT MASS IN A PBPK MODEL FOR TCDD IN PREDICTING THE SERUM TCDD CONCENTRATIONS FROM VETERANS OF OPERATION RANCH HAND. Presented at Society of Toxicology, Baltimore, MD, March 21-25, 2004.
Description:
The Influence of Variable Elimination Rate and Body Fat Mass in a PBPK Model for TCDD in Predicting the Serum TCDD Concentrations from Veterans of Operation Ranch Hand.
C Emond1,2, LS Birnbaum2, JE Michalek3, MJ DeVito2
1 National Research Council, National Academy of Sciences Washington DC, USA
2 National Health & Environmental Effects Research Laboratory,
US Environmental Protection Agency, Research Triangle Park, North Carolina
3 Air Force Research Laboratory, Brooks City-Base, Texas
Recent epidemiological studies suggest that the elimination rate of TCDD is influenced by the body burden and adipose tissue mass. Similar observations were also found in rodents. Previously published PBPK models for rodent and humans assumed a constant elimination rate. The aims of this study were 1) to examine and compare PBPK models for TCDD that had used either a constant or variable elimination of TCDD and 2) study the influence of adipose tissue fraction mass on the T? in the human. A PBPK model was developed for TCDD in rats and then extrapolated to humans. This model was described with three diffusion-limited compartments (liver, fat and rest of the body). Ah receptor-mediated induction of CYP1A2 was also described. Parameters used in this model came from the literature. The variable elimination rate was described based on the dose response for induction of CYP1A2. TCDD serum concentrations were determined in approximately 300 Veterans of Operation Ranch Hand. This cohort was divided in two groups. One was used for the optimization of the model and the other was used for model validation. In an initial analysis, body fat mass was set at 26%. The results suggest that T? could vary from less than 6 months in those with high initial body burdens (89 ng/kg) to as great as 20 years for those with background body burdens. However, adipose tissue mass also plays a role in the elimination of TCDD. Using the example above, changing the adipose mass fraction to 50%, the T? varies from 1 to 30 years, depending on the body burden. This analysis indicates that the T? of TCDD is dependent upon the body burden and the adipose tissue fraction. These results also indicate that a variable elimination rate is critical for accurate model prediction of human exposures and body burdens. This work aids in understanding the biological mechanisms of the variability for the T? of TCDD in humans. This model could be used as a predictive tool to examine the relationship between exposure and tissue concentrations in humans.