Relative Cancer Potencies of Selected Dioxin-Like Compounds on a Body-Burden Basis: Comparison to Current Toxic Equivalency Factors (TEFs)

Abstract

Recent National Toxicology Program (NTP) cancer bioassay data for 2,3,7,8-tetrachlorodibenzo-p‐dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126), and a mixture of these three compounds offer opportunities to assess the accuracy of current World Health Organization (WHO) 1998 toxic equivalency factors (TEFs) for these compounds under a variety of assumptions. An evaluation of the current TEF values for these compounds using body burden in nanograms per kilogram as the dose metric is presented. Average lifetime body burdens were estimated for all compounds at all dose groups based on measured tissue concentrations at 4 time points during the 2-yr NTP studies. Poly-3 adjusted tumor incidences for hepatocellular adenomas, cholangiocarcinomas, and the two tumors combined were modeled using a quantal multistage model and the Hill model with lifetime average body burden as the dose metric. Benchmark doses for a 10% response (BMD₁₀) for each compound and the mixture were estimated. With TCDD as the reference standard, relative potency (REP) estimates were derived from ratios of the BMD₁₀ estimates for PCB 126, 4-PeCDF, and for the toxic equivalent (TEQ) mixture. On a body-burden basis, PCB 126 and 4-PeCDF were 2- to 3-fold and 10- to 12-fold less potent than predicted based on the WHO TEFs, respectively, while the TEQ mixture was approximately 3- to 5-fold less potent than predicted by the TEFs. The current WHO TEF values, which were derived from data on noncancer endpoints evaluated on an administered dose basis, overpredict the carcinogenic potency of these compounds on a body-burden basis compared to TCDD.

This analysis was partially funded by the General Electric Company.

Notes

This analysis was partially funded by the General Electric Company.

^aCorn oil gavage, 5 d/wk.

^bTissue weights not reported for wk 104; values from wk 53 were used in these calculations.

^cAs assumed in NTP pharmacokinetic modeling (NTP, 2004a).

^dCalculated using Eq. (1).

^eCalculated using Eq. (2).

^aCorn oil gavage, 5 d/wk.

^bPoly-3 survival adjustment applied (Bailar & Portier, 1988).

^cUnits are ng TEQ/kg.

^aThe observed tumor incidences are too low to define a fit for the Hill model.

^aWHO 1998 TEF values.

^bRelative potency = BMD_TCDD/BMD_Compound.

^cModel fit undefined.

^dUnits are ng TEQ/kg.