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- 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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- 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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- Johanson, G., et al.
(författare)
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Quantitative relationships of perfluoroalkyl acids in drinking water associated with serum concentrations above background in adults living near contamination hotspots in Sweden
- 2023
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Ingår i: Environmental Research. - : Elsevier BV. - 0013-9351 .- 1096-0953. ; 219
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Tidskriftsartikel (refereegranskat)abstract
- Contaminated drinking water (DW) is a major source of exposure to per- and polyfluoroalkyl substances (PFAS) at locations around PFAS production/use facilities and military airports. This study aimed to investigate quantitative relationships between concentrations in DW and serum of nine perfluoroalkyl acids (PFAAs) in Swedish adult populations living near contamination hotspots. Short-chained (PFPeA, PFHxA, PFHpA, and PFBS) and long-chained PFAAs (PFOA, PFNA, PFDA, PFHxS and PFOS) were measured in DW and serum. We matched DW and serum concentrations for a total of 398 subjects living or working in areas receiving contaminated DW and in one non-contaminated area. Thereafter, linear regression analysis with and without adjustments for co-variates was conducted. This enabled to derive (i) serum concentrations at background exposure (CB) from sources other than local DW exposure (i.e. food, dust and textiles) at 0 ng/L DW concentration, (ii) population-mean PFAA serum:water ratios (SWR) and (iii) PFAA concentrations in DW causing observable elevated serum PFAA concentrations above background variability. Median concentrations of the sum of nine PFAAs ranged between 2.8 and 1790 ng/L in DW and between 7.6 and 96.9 ng/mL in serum. DW concentration was the strongest predictor, resulting in similar unadjusted and adjusted regression coefficients. Mean CB ranged from <0.1 (PFPeA, PFHpA, PFBS) to 5.1 ng/mL (PFOS). Serum concentrations increased significantly with increasing DW concentrations for all PFAAs except for PFPeA with SWRs ranging from <10 (PFHxA, PFHpA and PFBS) to 111 (PFHxS). Observed elevated serum concentrations above background variability were reached at DW concentrations between 24 (PFOA) and 357 ng/L (PFHxA). The unadjusted linear regression predictions agreed well with serum concentrations previously reported in various populations exposed to low and high DW levels of PFOA, PFHxS and PFOS. The quantitative relationships derived herein should be helpful to translate PFAA concentrations in DW to concentrations in serum at the population level.
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