Comparison of Intake and Systemic Relative Effect Potencies of Dioxin-like Compounds in Female Mice after a Single Oral Dose

Abstract

Background: Risk assessment for mixtures of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) is performed using the toxic equivalency factor (TEF) approach. These TEF values are derived mainly from relative effect potencies (REPs) linking an administered dose to an in vivo toxic or biological effect, resulting in “intake” TEFs. At present, there is insufficient data available to conclude that intake TEFs are also applicable for systemic concentrations (e.g., blood and tissues).Objective: We compared intake and systemic REPs of 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) in female C57BL/6 mice 3 days after a single oral dose.Methods: We calculated intake REPs and systemic REPs based on administered dose and liver, adipose, or plasma concentrations relative to TCDD. Hepatic cytochrome P450 1A1–associated ethoxyresorufin-O-deethylase (EROD) activity and gene expression of Cyp1a1, 1a2 and 1b1 in the liver and peripheral blood lymphocytes (PBLs) were used as biological end points.Results: We observed up to one order of magnitude difference between intake REPs and systemic REPs. Two different patterns were discerned. Compared with intake REPs, systemic REPs based on plasma or adipose levels were higher for PeCDD, 4-PeCDF, and PCB-126 but lower for the mono-ortho PCBs 118 and 156.Conclusions: Based on these mouse data, the comparison between intake REPs and systemic REPs reveals significant congener-specific differences that warrants the development of systemic TEFs to calculate toxic equivalents (TEQs) in blood and body tissues.

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

“…As a consequence, systemic REPs for these congeners based on a skin or plasma concentration are found to be higher when compared to the intake REPs (Fig. 1 b–e) (DeVito et al 1997 ; Van Ede et al 2013 , 2014a ). For these congeners, it is clear that the systemic REPs are closer to the in vitro REPs than to the intake REPs.…”

“…In this respect, studies using primary cultures and cell lines of rodent but in particular human cells may provide relevant information that can be used for human risk assessment if based on systemic concentrations. To assess whether indeed in vitro-derived REPs are more comparable to systemic REPs, we combined intake REPs and in vitro REPs from the 2004 REP database (Haws et al 2006 ) with the very few in vivo studies in which intake REPs as well as systemic REPs were determined (Haws et al 2006 ; DeVito et al 2000 ; Van Ede et al 2013 , 2014a ). These data are presented in Fig.…”

“…The boxplots; in vivo—intake—Haws et al and in vitro—rodent—Haws et al represent data from the 2004 REP database (Haws et al 2006 ). The boxplots; in vivo—intake—this review and in vivo—systemic—this review represent data from one to four different studies in which the potency of the congener is determined based on either the administered (intake) dose or a systemic (plasma or skin) concentration (DeVito et al 1997 , 2000 ; Van Ede et al 2013 , 2014a ). The number above the boxplot represents the number of REPs.…”

“… a Current WHO-TEF (Van den Berg et al 2006 ) b 1 Budinsky et al ( 2010 ), 2 Carlson et al ( 2009 ), 3 DeVito et al ( 1997 ), 4 Endo et al ( 2003 ), 5 Haws et al ( 2006 ), 6 Larsson et al ( 2015 ), 7 Silkworth et al ( 2005 ), 8 Sutter et al ( 2010 ), 9 Van Duursen et al ( 2005 ), 10 Van Ede et al ( 2013 ), 11 Van Ede et al ( 2014a ), 12 Van Ede et al ( 2014b ), 13 Westerink et al ( 2008 ), 14 Zeiger et al ( 2001 ) …”

“…Several studies already showed that for some congeners, blood-based REPs could be significantly different from those based on oral (intake) doses. This suggests that these “intake” REPs for hazard characterization might lead to misinterpretation of the risk when applied to blood concentrations (DeVito et al 1997 , 2000 ; van Ede et al 2013 , 2014a ). Another important potential pitfall in the current WHO-TEFs comes from the fact that these are mostly based on rodent studies, but are ubiquitously applied for human risk assessment.…”