| 1. |
- Chelcea, Ioana C., 1994-
(författare)
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Computational methods for assessing chemical risk : focusing on toxicokinetic modelling in zebrafish (danio rerio)
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 2. |
- Chelcea, Ioana C., et al.
(författare)
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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
- 2022
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 56:14, s. 10216-10228
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Chelcea, Ioana C., 1994-, et al.
(författare)
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Physiology-informed toxicokinetic model for the zebrafish embryo test developed for bisphenols
- 2023
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Ingår i: Chemosphere. - : Elsevier. - 0045-6535 .- 1879-1298. ; 345
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Tidskriftsartikel (refereegranskat)abstract
- Zebrafish embryos (ZFE) is a widely used model organism, employed in various research fields including toxicology to assess e.g., developmental toxicity and endocrine disruption. Variation in effects between chemicals are difficult to compare using nominal dose as toxicokinetic properties may vary. Toxicokinetic (TK) modeling is a means to estimate internal exposure concentration or dose at target and to enable extrapolation between experimental conditions and species, thereby improving hazard assessment of potential pollutants. In this study we advance currently existing TK models for ZFE with physiological ZFE parameters and novel experimental bisphenol data, a class of chemicals with suspected endocrine activity. We developed a five-compartment model consisting of water, plastic, chorion, yolk sack and embryo in which surface area and volume changes as well as the processes of biotransformation and blood circulation influence mass fluxes. For model training and validation, we measured internal concentrations in ZFE exposed individually to BPA, bisphenol AF (BPAF) and Z (BPZ). Bayesian inference was applied for parameter calibration based on the training data set of BPZ. The calibrated TK model predicted internal ZFE concentrations of the majority of external test data within a 5-fold error and half of the data within a 2-fold error for bisphenols A, AF, F, and tetrabromo bisphenol A (TBBPA). We used the developed model to rank the hazard of seven bisphenols based on predicted internal concentrations and measured in vitro estrogenicity. This ranking indicated a higher hazard for BPAF, BPZ, bisphenol B and C (BPB, BPC) than for BPA.
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| 4. |
- Hamers, Timo, et al.
(författare)
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Transthyretin-Binding Activity of Complex Mixtures Representing the Composition of Thyroid-Hormone Disrupting Contaminants in House Dust and Human Serum
- 2020
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Ingår i: Journal of Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 128:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: House dust contains many organic contaminants that can compete with the thyroid hormone (TH) thyroxine (T-4) for binding to transthyretin (TTR). How these contaminants work together at levels found in humans and how displacement from TTR in vitro relates to in vivo T-4-TTR binding is unknown. OBJECTIVES: Our aims were to determine the TTR-binding potency for contaminant mixtures as found in house dust, maternal serum, and infant serum; to study whether the TTR-binding potency of the mixtures follows the principle of concentration addition; and to extrapolate the in vitro TTR-binding potency to in vivo inhibition levels of T-4-TTR binding in maternal and infant serum. METHODS: Twenty-live contaminants were tested for their in vitro capacity to compete for TTR-binding with a fluorescent FITC-T-4 probe. Three mixtures were reconstituted proportionally to median concentrations for these chemicals in house dust, maternal serum, or infant serum from Nordic countries. Measured concentration-response curves were compared with concentration-response curves predicted by concentration addition. For each reconstituted serum mixture, its inhibitor-TTR dissociation constant (K-i) was used to estimate inhibition levels of T-4-TTR binding in human blood. RESULTS: The TTR-binding potency of the mixtures was well predicted by concentration addition. The similar to 20% inhibition in FITC-T-4 binding observed for the mixtures reflecting median concentrations in maternal and infant serum was extrapolated to 1.3% inhibition of T-4-TTR binding in maternal and 1.5% in infant blood. For nontested mixtures reflecting high-end serum concentrations, these estimates were 6.2% and 4.9%, respectively. DISCUSSION: The relatively low estimated inhibition levels at median exposure levels may explain why no relationship between exposure to TTR-binding compounds and circulating T-4 levels in humans has been reported, so far. We hypothesize, however, that 1.3% inhibition of T-4-TTR binding may ultimately be decisive for reaching a status of maternal hypothyroidism or hypothyroxinemia associated with impaired neurodevelopment in children.
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| 5. |
- Kortenkamp, Andreas, et al.
(författare)
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Removing Critical Gaps in Chemical Test Methods by Developing New Assays for the Identification of Thyroid Hormone System-Disrupting Chemicals-The ATHENA Project
- 2020
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 21:9
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Tidskriftsartikel (refereegranskat)abstract
- The test methods that currently exist for the identification of thyroid hormone system-disrupting chemicals are woefully inadequate. There are currently no internationally validated in vitro assays, and test methods that can capture the consequences of diminished or enhanced thyroid hormone action on the developing brain are missing entirely. These gaps put the public at risk and risk assessors in a difficult position. Decisions about the status of chemicals as thyroid hormone system disruptors currently are based on inadequate toxicity data. The ATHENA project (Assays for the identification of Thyroid Hormone axis-disrupting chemicals: Elaborating Novel Assessment strategies) has been conceived to address these gaps. The project will develop new test methods for the disruption of thyroid hormone transport across biological barriers such as the blood-brain and blood-placenta barriers. It will also devise methods for the disruption of the downstream effects on the brain. ATHENA will deliver a testing strategy based on those elements of the thyroid hormone system that, when disrupted, could have the greatest impact on diminished or enhanced thyroid hormone action and therefore should be targeted through effective testing. To further enhance the impact of the ATHENA test method developments, the project will develop concepts for better international collaboration and development in the area of thyroid hormone system disruptor identification and regulation.
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| 6. |
- Smith, Sanne J., et al.
(författare)
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Electrochemical Oxidation for Treatment of PFAS in Contaminated Water and Fractionated Foam─A Pilot-Scale Study
- 2023
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Ingår i: ACS - ES & T Water. - : American Chemical Society (ACS). - 2690-0637. ; 3:4, s. 1201-1211
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Tidskriftsartikel (refereegranskat)abstract
- Per- and polyfluoroalkyl substances (PFAS) are persistent synthetic contaminants that are present globally in water and are exceptionally difficult to remove during conventional water treatment processes. Here, we demonstrate a practical treatment train that combines foam fractionation to concentrate PFAS from groundwater and landfill leachate, followed by an electrochemical oxidation (EO) step to degrade the PFAS. The study combined an up-scaled experimental approach with thorough characterization strategies, including target analysis, PFAS sum parameters, and toxicity testing. Additionally, the EO kinetics were successfully reproduced by a newly developed coupled numerical model. The mean total PFAS degradation over the designed treatment train reached 50%, with long- and short-chain PFAS degrading up to 86 and 31%, respectively. The treatment resulted in a decrease in the toxic potency of the water, as assessed by transthyretin binding and bacterial bioluminescence bioassays. Moreover, the extractable organofluorine concentration of the water decreased by up to 44%. Together, these findings provide an improved understanding of a promising and practical approach for on-site remediation of PFAS-contaminated water.
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