specific REPs can vary across species due to intrinsic differences in e.g. efficacy. In particular, the species-differences in REP of the non-ortho substituted PCB 126 have been subject of much scientific debate (Nagayama et al., 1985; Silkworth et al., 2005; Sutter et al., 2010; Van Duursen et al., 2003; 2005; Zeiger et al., 2001). In addition, some PCDDs and PCDFs, such as 4-PeCDF, 123478-HxCDF and 1,2,3,6,7,8-hexachlorodibenzofuran (123678-HxCDF) also show species-specific differences in REPs (Nagayama et al., 1985; Sutter et al., 2010).
In chapters 5 and 6 of this thesis, species-specific differences in REPs between human and rodents have been investigated for twenty DLCs in primary cell systems (human peripheral blood lymphocytes (PBL) and mouse splenocytes) as well as in chemicalactivated luciferase expression (DR-CALUX速) cell lines (mouse, rat, guinea pig and human). The calculated REPs from human in vitro models for 1234678-HpCDD, 4-PeCDF, 123478-HxCDF, 1234789-HpCDF and PCB 126 deviate significantly from the rodent derived REPs. To illustrate these differences between human and rodent derived REPs more clearly, we combined the REPs from both chapters and compared these with the 2004 REP database (Haws et al., 2006), on which the current WHO-TEFs are based together with newly published human data. For PCB 126, the WHO-TEF of 0.1 is consistent with the median of REPs of 86 in vivo and 29 in vitro REPs obtained from 20 and 19 studies, respectively (Haws et al., 2006). These in vivo REPs comprise of 23 mouse- and 63 rat-based REPs, the latter mainly consisting of in vivo studies from the National toxicology program (NTP) using female Sprague-Dawley rats (National Toxicology Program, 2006c). Especially, REPs for PCB 126 from rat studies are consistently close to 0.1 (Haws et al., 2006). However, a wider distribution exists for the mouse-based in vivo REPs in this database. The median in vitro REP from rodents for PCB 126 is with 0.09, very similar to the median in vivo REP of 0.1.
Only 8 of the 29 in vitro REPs for PCB 126 within this 2004 REP database are derived from studies in human cells (Drenth et al., 1998; Pang et al., 1999; Van Duursen et al., 2003; Zeiger et al., 2001). Compared with the rodent data, the human in vitro REPs are clearly much lower with a median REP of 0.009 (range 0.0007-0.02) (Figure 3A). Since 2005, another five in vitro studies with human primary PBLs, hepatocytes, keratinocytes or human hepatoblastoma cells (HepG2) were conducted that determined the relative potency of PCB 126, with REPs ranging from 0.00009 to 0.11 (Carlson et al., 2009; Silkworth et al., 2005; Sutter et al., 2010; Van Duursen et al., 2005; Westerink et al., 2008). When we compare our data with data from the 2004 REP database and newly published literature, it is evident that both our rodent and human in vitro REPs are 182