In the veterans of Operation Ranch Hand, TCDD blood concentrations were first determined starting in 1982 (Michalek et al. 1996
). The exposure occurred between 1962 and 1971, with a typical tour of duty lasting only a year. Peak blood concentrations were assumed to occur at the time of discharge from Vietnam. We documented the time of discharge for each veteran in the Ranch Hand cohort, and used these individual data in the back calculation for this study. TCDD blood concentrations were determined at four or five time points for each Veteran starting in 1982. For each TCDD measurement we used data on body weight and height for each individual to estimate the body mass index for each veteran. We used the body mass index to estimate size of the adipose tissue compartment at the time of TCDD measurement for each individual based on the approach of Deurenberg et al. (1991)
. We estimated peak TCDD blood concentrations for each individual with the PBPK model using their individual data on blood concentrations, adipose tissue mass, and the time of discharge from Vietnam. We also estimated peak blood concentrations using a classical one compartment pharmacokinetic model with a first-order elimination. The classical model assumed a TCDD half-life of 8.7 years and used the TCDD blood concentrations at 1982 (Michalek et al. 1996
) and the time of discharge as inputs into the model to estimate peak blood concentrations.
In 1982, the range of blood concentrations from 10 randomly chosen subjects, shown in , was approximately 16-fold, from 12.7 to 209 ppt. We used a classical pharmaco-kinetic approach; peak blood concentrations ranged approximately 12-fold, from 53 to 640 ppt (). Minor differences in the ranking and range of TCDD blood concentrations occur when comparing estimated peak concentrations using the one compartment classical pharmacokinetic model to blood concentrations measured in 1982. When using the PBPK model to estimate peak blood concentrations, we found a much larger range in exposures and a significant difference in the exposure rankings (). The PBPK model estimates that peak blood concentrations at the time of discharge range > 250-fold, from 138 to approximately 40,000 ppt. This large difference is due to the inclusion of a dose-dependent elimination rate in the PBPK model. At the lower exposures, the half-life of TCDD is > 10 years, and at the higher exposures the half-life is only weeks. Models fits to these data are presented in .
Model predictions of TCDD blood concentration in 10 veterans (A–J) from the Ranch Hand cohort.
The model predictions show good correlations with the measured blood concentrations in the two highly exposed women (). The model predicts a rapid decrease in the blood concentrations during the distribution phase of the first few months of exposure, followed by an elimination that appears first order at these exposures because of maximal induction of TCDD sequestration metabolism. The elimination rates in these women suggest that the overall half-life of TCDD during the first 2 years of exposure is < 3 months. In the first blood samples collected from these women, the concentrations of TCDD were 144,000 and 26,000 ppt (lipid adjusted) in patient 1 and 2, respectively (Geusau et al. 2002
). The PBPK model estimates that initial blood concentrations may have been as high as 507,000 ppt and 87,000 ppt (lipid adjusted) in patients 1 and 2, respectively. Based on this model, maximum CYP1A2 induction occurs at blood concentrations of approximately 1,250 ppt (lipid adjusted). Measured levels of TCDD in the women were approximately 20–100 folds higher than the blood concentrations that are predicted to be at maximal induction (Geusau et al. 2002
Figure 2 Time course of TCDD in blood (pg/g lipid adjusted) for two highly exposed women (patients 1 and 2). Symbols represent measured concentrations, and lines represent model predictions. These data were used as part of the model evaluation (Geusau et al. 2002 (more ...)