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[POSTER] Uptake and systemic relative effect potencies (REPS) of 4-PECDF, PCB-126, PCB-118 and PCB-156 in female C57/BL6 mice after acute exposure

Research Area: Uncategorized Year: 2013
Type of Publication: In Proceedings
Authors:
  • van Ede, K.I.
  • Andersson, P.L.
  • Gaisch, K.P.J.
  • van den Berg, M.
  • van Duursen, M.B.M.
Book title: The Toxicologist
Organization: Society of Toxicology
BibTex:
Abstract:
Risk assessment of mixtures of chlorinated dioxins (PCDDs), furans (PCDFs) and biphenyls (PCBs) is performed using the Toxic Equivalency Factors (TEFs) that are derived from multiple relative effect potencies (REPs) linking administered dose levels to toxic/biologic effects. Increasing evidence suggests that using administered dose levels instead of systemic levels (e.g. liver or plasma concentrations), may lead to misinterpretation of risk. In this study, REPs of 4-PeCDF, PCB-126, PCB-118 and PCB-156 were determined in female mice three days after a single oral dose. REPs were calculated relatively to the EC20 of TCDD, based on cytochrome P450 1A1 (EROD) activity in liver samples and gene expression of CYP1A1, 1A2 and 1B1 in liver and peripheral blood lymphocytes (PBL) using administered dose, systemic liver tissue levels and systemic plasma levels. Lipid adjusted compound concentrations in liver and plasma increased linearly with the administered dose. At all concentrations, PCB-118 and PCB-156 showed the lowest liver/plasma concentration ratio of ~2, and 4-PeCDF the highest (485 at 100µg/kg bw), indicating high accumulation of 4-PeCDF in the liver. Using the administered dose, REPs for the various endpoints ranged between 0.01 – 0.2 for 4-PeCDF (WHO-TEF 0.3), 0.005 – 0.04 for PCB-126 (WHO-TEF 0.1), 0.000005 – 0.00003 for PCB-118 (WHO-TEF 0.00003) and 0.00001 – 0.00003 for PCB-156 (WHO-TEF 0.00003). Recalculating the REPs using systemic plasma levels showed a 4- to 9-fold increase in REPs for 4-PeCDF and 2-fold for PCB-126. In contrast, plasma-based REPs for PCB-118 and PCB-156 where slightly lower than the REPs based on administered dose. Recalculating the REPs using systemic liver levels resulted in a decrease of the REPs for 4-PeCDF and PCB-126 and an increase for PCB-118 and PCB-156. Generally, calculated REPs where below the WHO-TEFs, yet differences were observed between administered dose or systemic REPs. However, the SYSTEQ-derived REPs fall within a 10-fold uncertainty that is taken into account for the WHO-TEF. Additional rat and human in vitro data will be used to further confirm and/or explore these findings.
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SYSTEQ is funded under the FP7-ENVIRONMENT programme of the European Commission.