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Physiologically Based Toxicokinetic Modeling of Bisphenols in Zebrafish (Danio rerio) Accounting for Variations in Metabolic Rates, Brain Distribution, and Liver Accumulation
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Box 7028, Sweden.
Department of Environment & Health, Vrije Universiteit Amsterdam, HV Amsterdam, Netherlands.
Department of Environment & Health, Vrije Universiteit Amsterdam, HV Amsterdam, Netherlands.
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2022 (English)In: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 56, no 14, p. 10216-10228Article in journal (Refereed) Published
Abstract [en]

Bisphenol A (BPA) is an industrial chemical, which has raised human health and environmental concerns due to its endocrine-disrupting properties. BPA analogues are less well-studied despite their wide use in consumer products. These analogues have been detected in water and aquatic organisms around the world, with some analogues showing toxic effects in various species including fish. Here, we present novel organ-specific time-course distribution data of bisphenol Z (BPZ) in female zebrafish (Danio rerio), including concentrations in the ovaries, liver, and brain, a rarely sampled organ with high toxicological relevance. Furthermore, fish-specific in vitro biotransformation rates were determined for 11 selected bisphenols. A physiologically based toxicokinetic (PBTK) model was adapted for four of these bisphenols, which was able to predict levels in the gonads, liver, and brain as well as the whole body within a 2-5-fold error with respect to experimental data, covering several important target organs of toxicity. In particular, predicted liver concentrations improved compared to currently available PBTK models. Predicted data indicate that studied bisphenols mainly distribute to the carcass and gonads and less to the brain. Our model provides a tool to increase our understanding on the distribution and kinetics of a group of emerging pollutants.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2022. Vol. 56, no 14, p. 10216-10228
Keywords [en]
biotransformation, bisphenols, endocrine disruptors, PBTK, zebrafish
National Category
Environmental Sciences
Identifiers
URN: urn:nbn:se:umu:diva-198331DOI: 10.1021/acs.est.2c01292ISI: 000830801200001PubMedID: 35797464Scopus ID: 2-s2.0-85134721270OAI: oai:DiVA.org:umu-198331DiVA, id: diva2:1685296
Funder
Swedish Research Council Formas, 2017-00675Swedish Research Council, 2017-01036Available from: 2022-08-02 Created: 2022-08-02 Last updated: 2023-02-06Bibliographically approved
In thesis
1. Computational methods for assessing chemical risk: focusing on toxicokinetic modelling in zebrafish (danio rerio)
Open this publication in new window or tab >>Computational methods for assessing chemical risk: focusing on toxicokinetic modelling in zebrafish (danio rerio)
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Beräkningsmetoder för att bedöma kemikalierisker : med fokus på toxikokinetiska processer i zebrafisk (danio rerio)
Abstract [en]

New chemicals are constantly produced and large data gaps exist on hazards of currently used industrial chemicals, stressing the need for rapid, ethically sound and cost-efficient hazard assessment methods. Traditional methods for effect assessment based on animal testing, do not meet these requirements and thus the toxicology field has been moving towards the development of new approach methodologies which include in vitro approaches but also computational methods. The current work has mainly focused on computational tools but also employed in vitro and in vivo methodologies for the development and validation of the in silico approaches.

We firstly explored chemical variation of emerging chemicals as a basis for selecting sub-groups of per- and polyfluoroalkyl substances (PFASs) and bisphenols for Papers I and II. These compounds can be used for future testing and as case study compounds for in silico tools development. The PFASs selection showed compounds with large differences in structure and highlighted the lack of knowledge for large parts of the PFASs chemical domain. This likely is the main driver of the low predictive accuracy of some current fate models and the need for expanding their applicability domains. 

In Paper II we investigated the toxicokinetics of selected bisphenols in a commonly studied model organism, the zebrafish (Danio rerio), and developed a physiologically-based toxicokinetic model. Novel data for fish biotransformation was derived and showed lower rates than those measured in humans, providing valuable insight for both model parameterization and for chemical safety assessment using fish. The model also demonstrated the ability to predict and rank hazard of these bisphenols in terms of organ-specific bioaccumulation making it a useful tool for chemical screening and prioritization efforts. The results indicate that bisphenols AP, C and Z as well as tetrabromo bisphenol A may have larger potential for bioaccumulation than the widely used bisphenol A (BPA), indicating that these compounds do not constitute safer industrial substitutions.  

Lastly, we present in Paper III the development of a toxicokinetic model for the zebrafish embryo life-stage. Since the zebrafish embryo test is widely applied in toxicology research, the developed model provides a tool to better understand how varying testing conditions may affect dose at target thus providing a means to compare internal effect concentrations. Additionally, we applied the model in combination with data on estrogenic activity in order to rank the relative hazard of investigated bisphenols, which showed that bisphenols AF, C, B and Z may be more hazardous than BPA.

Overall the developed computational tools showed good predictive performance and improvements in parameterization, thus providing tools for understanding dose at target and toxicokinetic variation of emerging substances. Furthermore, the thesis presents novel data and findings for per- and polyfluoroalkyl substances and bisphenols, which are environmental pollutants of emerging concern of relevance for future hazard assessments and substitution processes.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2023. p. 53
Keywords
PBTK, Toxicokinetics, Endocrine disruptors, bisphenols, zebrafish, embryo
National Category
Other Chemistry Topics Computational Mathematics
Research subject
Toxicology
Identifiers
urn:nbn:se:umu:diva-204535 (URN)978-91-7855-990-9 (ISBN)978-91-7855-991-6 (ISBN)
Public defence
2023-03-03, Lilla Hörsalen, KBC byggnad KBE301, Linnaeus väg 10, Umeå, 09:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council, 2017-01036
Available from: 2023-02-10 Created: 2023-02-06 Last updated: 2023-02-06Bibliographically approved

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Chelcea, Ioana C.Andersson, Patrik L.

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