A PBPK model describing the long-term kinetic behavior of 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD) in humans has been developed, and fitted to data from 343 veterans of Operation Ranch Hand. In the model it is assumed that TCDD in serum lipids is in dynamic equilibrium with TCDD in tissues, and that serum:tissue partitioning is directly correlated with the lipid content of the tissue. Partition coefficients estimated on this basis are consistent with published human data for TCDD. Tissue compartment sizes, most notably adipose tissue, are estimated from the height and weight of the subject, and can change over time. Clearance is modeled as directly proportional to the hepatic TCDD concentration, but the system as a whole exhibits nonlinear kinetics due to changes in body weight. For example, the model predicts a TCDD serum half-life of 17.1 years for a 170 cm/70 kg man; however, the serum half-life decreases to 9.8 years if one assumes a 5 kg weight gain over a 5-year simulation. The model also predicts that the serum TCDD concentration can increase in the absence of exposure, given rapid weight loss. The PBPK model is a better descriptor of the Ranch Hand data than the one compartment models that have typically been used for human TCDD dose estimation, as judged by residual error plots, and is expected to be suitable for estimating TCDD body burdens and serum concentrations for purposes of quantitative risk assessment.
The Toxicologist. Society of Toxicology 34th Annual Meeting, March 5-9,1995, Baltimore, Maryland