title: Consensus toxicity factors for polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls combining in silico models and extensive in vitro screening of AhR-mediated effects in human and rodent cells.
abstract: Consensus toxicity factors (CTFs) were developed as a novel approach to establish toxicity factors for risk assessment of dioxin-like compounds (DLCs). Eighteen polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/Fs), and biphenyls (PCBs) with assigned World Health Organization toxic equivalency factors (WHO-TEFs) and two additional PCBs were screened in 17 human and rodent bioassays to assess their induction of aryl hydrocarbon receptor-related responses. For each bioassay and compound, relative effect potency values (REPs) compared to 2,3,7,8-tetrachlorodibenzo-p-dioxin were calculated and analyzed. The responses in the human and rodent cell bioassays generally differed. Most notably, the human cell models responded only weakly to PCBs, with 3,3',4,4',5-pentachlorobiphenyl (PCB126) being the only PCB that frequently evoked sufficiently strong responses in human cells to permit us to calculate REP values. Calculated REPs for PCB126 were more than 30 times lower than the WHO-TEF value for PCB126. CTFs were calculated using score and loading vectors from a principal component analysis to establish the ranking of the compounds and, by rescaling, also to provide numerical differences between the different congeners corresponding to the TEF scheme. The CTFs were based on rat and human bioassay data and indicated a significant deviation for PCBs but also for certain PCDD/Fs from the WHO-TEF values. The human CTFs for 2,3,4,7,8-pentachlorodibenzofuran, 1,2,3,4,7,8-hexachlorodibenzofuran, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin, and 1,2,3,4,7,8,9-heptachlorodibenzofuran were up to 10 times greater than their WHO-TEF values. Quantitative structure-activity relationship models were used to predict CTFs for untested WHO-TEF compounds, suggesting that the WHO-TEF value for 1,2,3,7,8-pentachlorodibenzofuran could be underestimated by an order of magnitude for both human and rodent models. Our results indicate that the CTF approach provides a powerful tool for condensing data from batteries of screening tests using compounds with similar mechanisms of action, which can be used to improve risk assessment of DLCs.
authors: †Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
authors: Malin
authors: M
authors: Larsson
authors: ‡Endocrine Toxicology Group, Institute for Risk Assessment Sciences, Utrecht University, P.O. Box 80177, NL-3508 TD Utrecht, The Netherlands.
authors: Martin
authors: M
authors: van den Berg
authors: #Department of Chemistry and Toxicology, Veterinary Research Institute, 621 32 Brno, Czech Republic.
authors: Petra
authors: P
authors: Brenerová
authors: ‡Endocrine Toxicology Group, Institute for Risk Assessment Sciences, Utrecht University, P.O. Box 80177, NL-3508 TD Utrecht, The Netherlands.
authors: Majorie B M
authors: MB
authors: van Duursen
authors: ‡Endocrine Toxicology Group, Institute for Risk Assessment Sciences, Utrecht University, P.O. Box 80177, NL-3508 TD Utrecht, The Netherlands.
authors: Karin I
authors: KI
authors: van Ede
authors: ⊥Department of Food Chemistry and Environmental Toxicology, University of Kaiserslautern, Kaiserslautern 67663, Germany.
authors: Christiane
authors: C
authors: Lohr
authors: §Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden.
authors: Sandra
authors: S
authors: Luecke-Johansson
authors: #Department of Chemistry and Toxicology, Veterinary Research Institute, 621 32 Brno, Czech Republic.
authors: Miroslav
authors: M
authors: Machala
authors: ⊥Department of Food Chemistry and Environmental Toxicology, University of Kaiserslautern, Kaiserslautern 67663, Germany.
authors: Sylke
authors: S
authors: Neser
authors: #Department of Chemistry and Toxicology, Veterinary Research Institute, 621 32 Brno, Czech Republic.
authors: Kateřina
authors: K
authors: Pěnčíková
authors: §Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden.
authors: Lorenz
authors: L
authors: Poellinger
authors: ⊥Department of Food Chemistry and Environmental Toxicology, University of Kaiserslautern, Kaiserslautern 67663, Germany.
authors: Dieter
authors: D
authors: Schrenk
authors: #Department of Chemistry and Toxicology, Veterinary Research Institute, 621 32 Brno, Czech Republic.
authors: Simona
authors: S
authors: Strapáčová
authors: #Department of Chemistry and Toxicology, Veterinary Research Institute, 621 32 Brno, Czech Republic.|∥Department of Cytokinetics, Institute of Biophysics AS CR, 612 65 Brno, Czech Republic.
authors: Jan
authors: J
authors: Vondráček
authors: †Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
authors: Patrik L
authors: PL
authors: Andersson
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000737:chemistry / Q000633:toxicity*; D003198:Computer Simulation; D000072338:Dibenzofurans, Polychlorinated; D006801:Humans; D066298:In Vitro Techniques; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000633:toxicity*; D000072317:Polychlorinated Dibenzodioxins / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D012377:Rodentia
chemical_list: D001572:Benzofurans; D000072338:Dibenzofurans, Polychlorinated; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D011078:Polychlorinated Biphenyls