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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
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2015 (English)In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 28, no 4, 641-650 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2015. Vol. 28, no 4, 641-650 p.
National Category
Pharmacology and Toxicology Chemical Sciences
Identifiers
URN: urn:nbn:se:umu:diva-106369DOI: 10.1021/tx500434jISI: 000353429700011PubMedID: 25654323OAI: oai:DiVA.org:umu-106369DiVA: diva2:841830
Available from: 2015-07-15 Created: 2015-07-14 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Computational methods for analyzing dioxin-like compounds and identifying potential aryl hydrocarbon receptor ligands: multivariate studies based on human and rodent in vitro data
Open this publication in new window or tab >>Computational methods for analyzing dioxin-like compounds and identifying potential aryl hydrocarbon receptor ligands: multivariate studies based on human and rodent in vitro data
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) are omnipresent and persistent environmental pollutants. In particular, 29 congeners are of special concern, and these are usually referred to as dioxin-like compounds (DLCs). In the European Union, the risks associated with DLCs in food products are estimated by a weighted sum of the DLCs’ concentrations. These weights, also called toxic equivalency factors (TEFs), compare the DLCs’ potencies to the most toxic congener, 2,3,7,8-tetrachloro-dibenzo-p-dioxin (2378- TCDD). The toxicological effects of PCDD/Fs and PCBs are diverse, ranging from chloracne and immunological effects in humans to severe weight loss, thymic atrophy, hepatotoxicity, immunotoxicity, endocrine disruption, and carcinogenesis in rodents.

Here, the molecular structures of DLCs were used as the basis to study the congeneric differences in in vitro data from both human and rodent cell responses related to the aryl hydrocarbon receptor (AhR). Based on molecular orbital densities and partial charges, we developed new ways to describe DLCs, which proved to be useful in quantitative structure-activity relationship modeling. This thesis also provides a new approach, the calculation of the consensus toxicity factor (CTF), to condense information from a battery of screening tests. The current TEFs used to estimate the risk of DLCs in food are primarily based on in vivo information from rat and mouse experiments. Our CTFs, based on human cell responses, show clear differences compared to the current TEFs. For instance, the CTF of 23478-PeCDF is as high as the CTF for 2378-TCDD, and the CTF of PCB 126 is 30 times lower than the corresponding TEF. Both of these DLCs are common congeners in fish in the Baltic Sea. Due to the severe effects of DLCs and their impact on environmental and human health, it is crucial to determine if other compounds have similar effects. To find such compounds, we developed a virtual screening protocol and applied it to a set of 6,445 industrial chemicals. This protocol included a presumed 3D representation of AhR and the structural and chemical properties of known AhR ligands. This screening resulted in a priority list of 28 chemicals that we identified as potential AhR ligands.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2017. 66 p.
Keyword
dioxin-like compounds, multivariate analysis, toxic equivalency factor, quantitative structure-activity relationship, descriptors, virtual screening, in vitro, species variation, aryl hydrocarbon receptor
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-139487 (URN)978-91-7601-736-4 (ISBN)
Public defence
2017-10-19, KB.E3.01 (Lilla Hörsalen), KBC-huset, Umeå, 13:00 (English)
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Available from: 2017-09-28 Created: 2017-09-14 Last updated: 2017-10-02Bibliographically approved

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