Evaluation of relative effect potencies (REPs) for dioxin-like compounds to derive systemic or human-specific TEFs to improve human risk assessment

Abstract

Toxic equivalency factors (TEFs) are generally applied for estimating human risk of dioxins and dioxin-like compounds using systemic (e.g., blood) levels, even though these TEFs are established based on intake doses in rodent studies. This review shows that systemic relative effect potencies (REPs) can deviate substantially from intake REPs, but are similar to in vitro-derived REPs. Interestingly, the in vitro REPs for 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) and 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) are up to one order of magnitude higher than their in vivo REPs and WHO-TEFs, based on oral intake. In addition, clear species-differences in in vitro REPs were apparent for some congeners. Especially the human-derived REP for polychlorinated biphenyl 126 is one to two orders of magnitude lower than rodent REPs and its current WHO-TEF. Next, suggested adapted systemic or human-specific TEFs for these congeners were applied to calculate changes in systemic TEQ concentrations in studies from the USA, Germany and Japan and compared with either the JECFA TDI or USEPA RfD of TCDD. Overall, the effect of such TEF changes for these three congeners on total TEQ roughly balances each other out in the general population. However, results may be different for situations in which a specific group of congeners dominates. For those congeners that show a distinct deviation between either intake and systemic REPs or between rodent- and human-based in vitro REPs, we propose that especially REPs derived from human-based in vitro models are weighted more heavily in establishing systemic or human-specific TEF values to improve human health risk assessment.

Relative effect potency estimates of dioxin-like activity for dioxins, furans, and dioxin-like PCBs in adults based on cytochrome P450 1A1 and 1B1 gene expression in blood

“…We compared our human REPs with WHO-TEF values (Van den Berg et al, 2006), with consensus toxicity factors (CTF) for compounds, World Health Organization toxic equivalency factors (Larsson et al, 2015), and with published data on REPs for DLCs (Haws et al, 2006; van Ede et al, 2016). …”

“…Finally, we compared our REP data with values in the REP 2004 database (Haws et al, 2006) and the newly derived REPs published recently (van Ede et al, 2016). From the REP 2004 database we included into Table 3 the minimum, maximum, and median values published for in vivo data (see Table 8 of Haws et al, 2006).…”

“…The so far published REPs (Haws et al, 2006; van Ede et al, 2016) for PCDD, PCDF, and DL PCB congeners are based exclusively on in vitro data or on in vivo animal experiments. In contrast, we have estimated REPs by examining two human thyroid endpoints (Trnovec et al., 2013) and in the current work, expression of CYP1A1 and CYP1B1 in PBMCs in adult humans exposed to DLCs.…”

“…The decreased expression after exposure to TCDD is in agreement with the hypothesis that long-term presence of dioxin in the human body does not result in an increase in AHR pathway responsiveness or that responsiveness is eventually lost or reduced decades after the initial exposure (Baccarelli et al, 2004). An alternative explanation may be that the internal dose may be high enough for CYP 1A2 to be induced which means that much of the TCDD and other DLCs are sequestered in the liver (Aylward et al, 2005; Staskal et al, 2005; van Ede et al, 2016) instead of circulating peripherally exerting toxic activity. With 2,3,4,7,8-PeCDF, known for hepatic sequestration (Diliberto et al, 1997), we have observed much lower REPs (0.0089; 0.166; 0.0160; 0.02, see Table 3) than the 0.3 TEF (Figs.…”

“…With 2,3,4,7,8-PeCDF, known for hepatic sequestration (Diliberto et al, 1997), we have observed much lower REPs (0.0089; 0.166; 0.0160; 0.02, see Table 3) than the 0.3 TEF (Figs. 4 and 5), which possibly is related to the higher liver sequestration of this congener compared with TCDD (van Ede et al, 2016). …”