Uncertainty analysis in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) cancer dose-response for three occupational cohorts

Abstract

While the U.S. EPA has issued a draft report with a 1% TCDD effective dose (ED01) of 87.9pg/kg/day based on continuous integration of key scientific evidence, a detailed and comprehensive uncertainty analysis has not been well documented. In this study, a new estimate for ED01 was derived based on uncertainty analysis by quantitatively assessing the potential bias arising from the selection of kinetic models, dose-response models and cohorts. The cumulative serum lipid concentration (CSLC) and cumulative body burden (CBB) were reconstructed as dose metrics using a concentration- and age-dependent pharmacokinetic model (CADM), physiologically based pharmacokinetic model (PBPK), and age-dependent half-life model (FV), and the reconstructed dose metrics based on CADM and PBPK were generally higher than those based on the FV model. Three dose-response curves (linear, multiplicative and power) were used to link dose metrics and cancer risk to estimate ED01, and the linear model resulted in the lowest ED01, followed by the power model and multiplicative model, for the same cohort. Meanwhile, ED01 based on the CADM model was the highest, followed by those based on the PBPK model and first-order model. Finally, the ED01 was estimated to be 17.03±7.83pg/kg/day by statistically analyzing the distribution of ED01 values based on various kinetic models, cohorts and dose-response models. The study presented here strengthens the scientific basis for understanding the potential health implications of TCDD exposure.

Keywords: Cancer; Dioxin; Dose–response model; Effective dose; Kinetic model.