The Importance of Pharmacokinetics in Determining the Relative Potency of 2,3,7,8-Tetrachlorodibenzo-p-dioxin and 2,3,7,8-Tetrachlorodibenzofuran

The Importance of Pharmacokinetics in Determining the Relative Potency of 2,3,7,8-Tetrachlorodibenzo-p-dioxin and 2,3,7,8-Tetrachlorodibenzofuran. Devito, M. J., and Birnbaum, L. S. (1995). Fundam. Appl. Toxicol.24, 145-148.Polychlorinated dibenzo-p-dioxins and dibenzofurans induce exthoxyresorufin-O-deethylase (EROD) activity, a marker for CYP1A1. Differences in potency of these compounds can be attributed to differences in their affinity for the Ah receptor as well as differences in pharmacokinetics. To test the role of pharmacokinetics in the in vivo potency of these chemicals, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,3,7,8-tetrachlorodibenzufuran (TCDF) were administered to female B6C3F1 mice for 4 or 13 weeks of treatment and EROD activity in liver and skin was determined. The doses were designed to be equally potent based on the published Toxic Equivalency Factor (TEF) values for these compounds. Mice received either 150 ng TCDD/kg/day or 1500 ng TCDF/kg/day, 5 days/week for either 4 or 13 weeks. At 4 weeks, hepatic EROD was induced 11- and 7-fold by TCDD and TCDF, respectively. These data indicate that the published TEFs accurately estimated the relative potency of TCDF after 4 weeks of treatment. After 13 weeks, hepatic EROD was induced 41- and 6-fold by TCDD and TCDF, respectively. The TEFs did not accurately estimate the relative inductive potency of these compounds when compared after 13 weeks of treatment. The inability of the TEFs to predict the relative potency of these compounds after 13 weeks of treatment may be due in part to the differences in the pharmacokinetic properties of each congener. The half-life of TCDF and TCDD is approximately 2 and 15 days, respectively. Steady-state levels of TCDD were not attained by 4 weeks, which is reflected in the increase in hepatic EROD between 4 and 13 weeks. In contrast, steady-state levels of TCDF were reached within 4 weeks. Thus, induction of hepatic EROD remained constant from 4 to 13 weeks. Similar results were observed for skin EROD activity. These data demonstrate that estimates of the relative potency of two chemicals is dependent upon the dosing regimen and the time of euthanization. Thus TEFs derived from short-term assays may not adequately predict the relative potencies of this class of compounds following chronic exposure.