Estimation of occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin using a minimal physiologic toxicokinetic model.

Abstract

In this study we investigated estimation of occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) based on a minimal physiologic toxicokinetic model in humans. Our purpose was to obtain a mathematical tool for dose-response studies based on human data. We first simplified an existing model of TCDD kinetics in humans and estimated its parameters (i.e., liver elimination and background input of TCDD) using repeated measures of serum dioxin taken in Vietnam veterans (Ranch Hand data and data from an unexposed reference group). We carried out computer simulation and estimation of the model parameters both under a nonlinear weighted least-squares model (naive pooled data approach) and under a nonlinear mixed-effects model. The best parameter estimates were obtained with log-transformed data under a mixed-effects model: liver elimination parameter kf = 0.022 days-1 (95% confidence interval [CI] = 0.020, 0.024), and background input rate input = 0.1251 pg/kg/day (95% CI = 0.071, 0.179). The dioxin kinetic model and its estimated parameters were then used to provide dose estimates for a cohort of workers with exposure to TCDD at chemical plants in the United States. First, the model was used to estimate the rate of occupational intake of TCDD in a subset of the cohort consisting of 253 subjects for whom one measure of serum TCDD was available. A model of change in body-mass index over time was also identified for this subsample. The occupational exposure rate was estimated by linear regression using the above values of kinetic parameters and assuming an initial condition for serum TCDD of 7 ppt, i.e., the average level found in unexposed workers. The estimate of the occupational exposure parameter was 232.7 pg/kg/day (95% CI 192, 273). This value can be applied to the full cohort to obtain for each cohort member the time course of serum dioxin concentration from which exposure indices can be derived. Sensitivity coefficients to model parameters (background input, kf, occupational exposure, and the assumed TCDD concentration at hire) allow for a convenient recalculation of the serum TCDD curve and of the derived exposure indices for different assumed values of the model parameters.