Analysis of the CYP1A1 mRNA Dose-Response in Human Keratinocytes Indicates that Relative Potencies of Dioxins, Furans, and PCBs Are Species and Congener Specific

Abstract

Reports indicate that toxic equivalency factors (TEFs) based primarily on rodent data do not accurately predict in vitro human responsiveness to certain dioxin-like chemicals (DLCs). To investigate this in cells responsive to dioxins and relevant to chloracne, normal human epidermal keratinocytes were treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and several DLCs, each with a TEF value of 0.1, representing three classes of congeners. We estimated half maximal effective concentration (EC50)-based donor-specific relative potency (REP) values for cytochrome P450 1A1 (CYP1A1) messenger RNA (mRNA) induction for TCDD, 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin (HxCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,6,7,8-hexachlorodibenzofuran (HxCDF), and 3,3',4,4',5-pentachlorobiphenyl (PCB 126). We also determined EC50-based population-level REP values (n = 4) for CYP1A1 mRNA induction for TCDD, HxCDF, and PCB 126. Furthermore, an alternative factor, the relative threshold factor (RTF) based on the low end (threshold) of the dose-response curve, was calculated. Our results demonstrated that HxCDF had a population-based REP value of 0.98, 9.8-fold higher than its assigned TEF value of 0.1. Conversely, PCB 126 had an REP value of 0.0027 and an RTF of 0.0022, 37-fold and 45-fold less than its assigned TEF of 0.1, respectively. The REP values for HxCDD and TCDF were 0.24 and 0.10, respectively, similar to their assigned value of 0.1. Therefore, although the DLCs tested in the current study all possessed the same assigned TEF value of 0.1, congener-specific differences in REPs and RTFs were observed for human keratinocytes. These congener-specific discrepancies are likely because of differences in interspecies factors that have yet to be defined.

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

“…For PCB 126, several authors describe species differences in response between rodents and humans, with human in vitro REPs being up to two orders of magnitude lower compared with the WHO-TEF (Carlson et al, 2009; Larsson et al, 2015; Silkworth et al, 2005; Sutter et al, 2010; van Duursen et al, 2005b; van Ede et al, 2014; van Ede et al, 2016). We derived a REP value (0.017) for PCB 126 from CYP 1B1 expression.…”

Pollutants in pet dogs: a model for environmental links to breast cancer

“…This fact supports a major influence of polymorphisms and power balance through competitive binding rather than a toxic critical threshold, unless if the disruption occurred in the womb owing to a similar level of exposure in utero that has changed with age, or unless if the sensitivity of dogs to these molecules is stronger than in humans. Indeed, relative potencies of dioxins and PCBs (TEF values) established from rodents and used by extension for human biomonitoring may turn to be in fact species and congener specific (Sutter et al 2010 ). P450 polymorphisms may also exist inter-species.…”

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

“…Since 2005, another seven in vitro studies with human primary PBMCs, hepatocytes, keratinocytes or HepG2 cells were conducted that determined the relative potency of PCB 126. These studies show REPs ranging from 0.00009 to 0.06 (Van Duursen et al 2005 ; Silkworth et al 2005 ; Sutter et al 2010 ; Westerink et al 2008 ; Carlson et al 2009 ; Larsson et al 2015 ; Van Ede et al 2014b ). When we combine the newly published data with those from the 2004 REP database, it is evident that in vitro REPs from different human cell systems are consistently one to two orders of magnitude lower than the current WHO-TEF.…”

“…However, if the difference in potency between species is similar for TCDD and a specific congener, this obviously does not lead to species-differences in relative effect potency. Nonetheless, distinct species-specific differences in REPs have been described for some PCDDs and PCDFs, such as 4-PeCDF, 1,2,3,4,7,8-hexachlorodibenzofuran (4-HxCDF), 1,2,3,6,7,8-hexachlorodibenzofuran (6-HxCDF), 1,2,3,4,6,7,8-heptachlorodibenzo- p -dioxin (HpCDD) and 1,2,3,4,7,8,9-heptachlorodibenzofuran (9-HpCDF) (Sutter et al 2010 ; Nagayama et al 1985 ; Van Ede et al 2014b ; Larsson et al 2015 ), but particularly the species-difference in toxicity of the non- ortho -substituted PCB 126 has been subject of much scientific debate (Nagayama et al 1985 ; Silkworth et al 2005 ; Sutter et al 2010 ; Zeiger et al 2001 ; Van Duursen et al 2003 , 2005 ; Van Ede et al 2014b ; Larsson et al 2015 ).…”

“… 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 ) …”