Latest Publications

@article{larsson_consensus_2015,

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.},

author = {Malin Larsson and Martin Berg and Petra Brenerová and Majorie B. M. Duursen and Karin I. Ede and Christiane Lohr and Sandra Luecke-Johansson and Miroslav Machala and Sylke Neser and Kateřina Pěnčíková and Lorenz Poellinger and Dieter Schrenk and Simona Strapáčová and Jan Vondráček and Patrik L. Andersson},

doi = {10.1021/tx500434j},

issn = {1520-5010 0893-228X},

year  = {2015},

date = {2015-04-01},

journal = {Chemical research in toxicology},

volume = {28},

number = {4},

pages = {641–650},

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.},

note = {Place: United States},

keywords = {Animals, Aryl Hydrocarbon/*physiology, Benzofurans/chemistry/*toxicity, Computer Simulation, Dibenzofurans, Humans, In Vitro Techniques, Polychlorinated, Polychlorinated Biphenyls/chemistry/*toxicity, Polychlorinated Dibenzodioxins/*analogs & derivatives/chemistry/toxicity, Quantitative Structure-Activity Relationship, Rats, Receptors, Rodentia},

pubstate = {published},

tppubtype = {article}

}

@article{ghorbanzadeh_vitro_2014,

title = {In vitro and in silico derived relative effect potencies of ah-receptor-mediated effects by PCDD/Fs and PCBs in rat, mouse, and guinea pig CALUX cell lines.},

author = {Mehdi Ghorbanzadeh and Karin I. Ede and Malin Larsson and Majorie B. M. Duursen and Lorenz Poellinger and Sandra Lücke-Johansson and Miroslav Machala and Kateřina Pěnčíková and Jan Vondráček and Martin Berg and Michael S. Denison and Tine Ringsted and Patrik L. Andersson},

doi = {10.1021/tx5001255},

issn = {1520-5010 0893-228X},

year  = {2014},

date = {2014-07-01},

journal = {Chemical research in toxicology},

volume = {27},

number = {7},

pages = {1120–1132},

abstract = {For a better understanding of species-specific relative effect potencies (REPs), responses of dioxin-like compounds (DLCs) were assessed. REPs were calculated using chemical-activated luciferase gene expression assays (CALUX) derived from guinea pig, rat, and mouse cell lines. Almost all 20 congeners tested in the rodent cell lines were partial agonists and less efficacious than 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). For this reason, REPs were calculated for each congener using concentrations at which 20% of the maximal TCDD response was reached (REP20TCDD). REP20TCDD values obtained for PCDD/Fs were comparable with their toxic equivalency factors assigned by the World Health Organization (WHO-TEF), while those for PCBs were in general lower than the WHO-TEF values. Moreover, the guinea pig cell line was the most sensitive as indicated by the 20% effect concentrations of TCDD of 1.5, 5.6, and 11.0 pM for guinea pig, rat, and mouse cells, respectively. A similar response pattern was observed using multivariate statistical analysis between the three CALUX assays and the WHO-TEFs. The mouse assay showed minor deviation due to higher relative induction potential for 2,3,7,8-tetrachlorodibenzofuran and 2,3,4,6,7,8-hexachlorodibenzofuran and lower for 1,2,3,4,6,7,8-heptachlorodibenzofuran and 3,3',4,4',5-pentachlorobiphenyl (PCB126). 2,3,7,8-Tetrachlorodibenzofuran was more than two times more potent in the mouse assay as compared with that of rat and guinea pig cells, while measured REP20TCDD for PCB126 was lower in mouse cells (0.05) as compared with that of the guinea pig (0.2) and rat (0.07). In order to provide REP20TCDD values for all WHO-TEF assigned compounds, quantitative structure-activity relationship (QSAR) models were developed. The QSAR models showed that specific electronic properties and molecular surface characteristics play important roles in the AhR-mediated response. In silico derived REP20TCDD values were generally consistent with the WHO-TEFs with a few exceptions. The QSAR models indicated that, e.g., 1,2,3,7,8-pentachlorodibenzofuran and 1,2,3,7,8,9-hexachlorodibenzofuran were more potent than given by their assigned WHO-TEF values, and the non-ortho PCB 81 was predicted, based on the guinea-pig model, to be 1 order of magnitude above its WHO-TEF value. By combining in vitro and in silico approaches, REPs were established for all WHO-TEF assigned compounds (except OCDD), which will provide future guidance in testing AhR-mediated responses of DLCs and to increase our understanding of species variation in AhR-mediated effects.},

note = {Place: United States},

keywords = {Animals, Aryl Hydrocarbon/agonists/*metabolism, Benzofurans/*pharmacology, Biological, Biological Assay, Cell Line, Computer Simulation, Dibenzofurans, Dose-Response Relationship, Drug, Guinea Pigs, Luciferases/metabolism, Mice, Models, Polychlorinated, Polychlorinated Biphenyls/*pharmacology, Polychlorinated Dibenzodioxins/*analogs & derivatives/pharmacology, Quantitative Structure-Activity Relationship, Rats, Receptors, Tumor},

pubstate = {published},

tppubtype = {article}

}