Tissue distribution of dioxin-like compounds: Potential impacts on systemic relative potency estimates

•Distribution of Dioxin-like compounds (DLCs) is similar after single or subchronic dosing.•Comparable responding concentrations for TCDD after single or subchronic dosing.•Hepatic sequestration for dioxins, furans, and non-ortho PCBs notable in rodents.•Little or no hepatic sequestration in humans at environmental exposure levels.•These differences may impact selection of systemicREPs for human risk assessment.

Relative effect potencies (REPs) for dioxins and dioxin-like compounds based on tissue concentration or internal dose (systemicREPs) can be considered of high relevance for human risk assessment. Within the EU-project SYSTEQ, systemicREPs for 1,2,3,7,8-pentachlorodibenzodioxin (PeCDD), 2,3,4,7,8,-pentachlorodibenzofuran (4-PeCDF), 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126), 2,3′,4,4′,5-pentachlorobiphenyl (PCB 118) and 2,3,3′,4,4′,5-hexachlorobiphenyl (PCB 156) were calculated based on a plasma, adipose tissue or liver concentration in Sprague Dawley rats and C57bl/6 mice three days after a single oral dose. Compound-specific distribution as well as differences in accumulation and elimination can influence the tissue concentration and thereby the relative potency estimate of a congener. Here, we show that distribution patterns are generally similar for the tested congeners between the SYSTEQ dataset and other studies using either a single dose or subchronic dosing. Furthermore, the responding concentration for TCDD in single dose studies is comparable to the responding concentrations reported in subchronic studies. In contrast with data for laboratory rodents, available distribution data for humans in the general population display little or no hepatic sequestration. Because hepatic sequestration due to CYP1A2 protein binding may affect the amount of congener that is bioavailable for the AhR to produce hepatic responses, estimates of relative potencies between congeners with differing degrees of hepatic sequestration based on hepatic responses may be misleading for application to human risk assessment. Therefore, extra-hepatic concentration in blood serum/plasma or adipose tissue together with a biological extra-hepatic response might give a more accurate prediction of the relative potency of a congener for human responses under environmental conditions.