New approach methodologies: A quantitative in vitro to in vivo extrapolation case study with PFASs

Fragki, Styliani; Louisse, Jochem; Bokkers, Bas; Luijten, Mirjam; Peijnenburg, Ad; Rijkers, Deborah; Piersma, Aldert H.; Zeilmaker, Marco J.

doi:10.1016/j.fct.2022.113559

Cited by 9 publications

(5 citation statements)

References 80 publications

(163 reference statements)

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“…To obtain in vivo relative potencies based on in vitro toxicity data, information on toxicokinetics should be included in the assessment. In that regard, we have been working on the quantitative in vitro to in vivo extrapolation (QIVIVE) of the toxicity data of PFOA, PFNA, PFHxS, and PFOS, translating cell-associated PFAS levels to oral equivalent doses using physiologically based kinetic (PBK) modeling, providing information that will be of use in the assessment of relative potencies of PFASs in humans (Fragki et al 2023 ).…”

Section: Discussionmentioning

confidence: 99%

Determination of in vitro hepatotoxic potencies of a series of perfluoroalkyl substances (PFASs) based on gene expression changes in HepaRG liver cells

et al. 2023

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Per- and polyfluoroalkyl substances (PFASs) are omnipresent and have been shown to induce a wide range of adverse health effects, including hepatotoxicity, developmental toxicity, and immunotoxicity. The aim of the present work was to assess whether human HepaRG liver cells can be used to obtain insight into differences in hepatotoxic potencies of a series of PFASs. Therefore, the effects of 18 PFASs on cellular triglyceride accumulation (AdipoRed assay) and gene expression (DNA microarray for PFOS and RT-qPCR for all 18 PFASs) were studied in HepaRG cells. BMDExpress analysis of the PFOS microarray data indicated that various cellular processes were affected at the gene expression level. From these data, ten genes were selected to assess the concentration–effect relationship of all 18 PFASs using RT-qPCR analysis. The AdipoRed data and the RT-qPCR data were used for the derivation of in vitro relative potencies using PROAST analysis. In vitro relative potency factors (RPFs) could be obtained for 8 PFASs (including index chemical PFOA) based on the AdipoRed data, whereas for the selected genes, in vitro RPFs could be obtained for 11–18 PFASs (including index chemical PFOA). For the readout OAT5 expression, in vitro RPFs were obtained for all PFASs. In vitro RPFs were found to correlate in general well with each other (Spearman correlation) except for the PPAR target genes ANGPTL4 and PDK4. Comparison of in vitro RPFs with RPFs obtained from in vivo studies in rats indicate that best correlations (Spearman correlation) were obtained for in vitro RPFs based on OAT5 and CXCL10 expression changes and external in vivo RPFs. HFPO-TA was found to be the most potent PFAS tested, being around tenfold more potent than PFOA. Altogether, it may be concluded that the HepaRG model may provide relevant data to provide insight into which PFASs are relevant regarding their hepatotoxic effects and that it can be applied as a screening tool to prioritize other PFASs for further hazard and risk assessment.

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Section: Discussionmentioning

confidence: 99%

Determination of in vitro hepatotoxic potencies of a series of perfluoroalkyl substances (PFASs) based on gene expression changes in HepaRG liver cells

et al. 2023

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“… In the model for PFNA and PFHxS the tissue/blood partition coefficients were adjusted for liver and kidney according to Fragki et al [26] . In the Table 2 , Table 3 the input parameters for PFNA and PFHxS are reported as taken from Fragki et al [26] . …”

Section: Methodsmentioning

confidence: 99%

“…In the case of PFNA and PFHxS, tissue-blood partition coefficients were used for PFOA and PFOS, respectively, with the exception of liver and kidney, were data used were derived from rodent studies [approach followed as by 26]. Again here, transporter maximum capacity for renal tubular reabsorption is fitted in order to achieve the desired half-life in humans [26] . However, due to the absence of suitable human biomonitoring data, the PFNA and PFHxS models could not be verified directly on such data [26] .…”

Section: Methodsmentioning

confidence: 99%

“…Again here, transporter maximum capacity for renal tubular reabsorption is fitted in order to achieve the desired half-life in humans [26] . However, due to the absence of suitable human biomonitoring data, the PFNA and PFHxS models could not be verified directly on such data [26] . No further model validation for PFNA and PFHxS was performed here.…”

Section: Methodsmentioning

confidence: 99%

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Advancing PFAS risk assessment: Integrative approaches using agent-based modelling and physiologically-based kinetic for environmental and health safety

Iulini,

Russo,

Crispino

et al. 2024

Computational and Structural Biotechnology Journal

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“…To facilitate the quantitative in vitro -to- in vivo extrapolation (QIVIVE) for PFAS, the concentration–response curves from in vitro bioassays should be derived with free concentrations of PFAS to obtain freely dissolved effect concentrations, which can be compared to the actual PFAS levels that human are exposed to (i.e., freely dissolved concentrations in human plasma). − Fetal bovine serum (FBS) is typically used as the nutrient supply in an in vitro cell-based bioassay, while fish and mice are common in vivo animal models. To make the results from the different in vitro and in vivo models comparable and to allow extrapolation to humans, plasma binding of PFAS among different species needs to be known, but it has not been assessed for PFAS systematically so far.…”

Section: Introductionmentioning

confidence: 99%

Species Difference? Bovine, Trout, and Human Plasma Protein Binding of Per- and Polyfluoroalkyl Substances

Qin,

Escher,

Huchthausen

et al. 2024

Environ. Sci. Technol.

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Per-and polyfluoroalkyl substances (PFAS) strongly bind to proteins and lipids in blood, which govern their accumulation and distribution in organisms. Understanding the plasma binding mechanism and species differences will facilitate the quantitative in vitro-to-in vivo extrapolation and improve risk assessment of PFAS. We studied the binding mechanism of 16 PFAS to bovine serum albumin (BSA), trout, and human plasma using solid-phase microextraction. Binding of anionic PFAS to BSA and human plasma was found to be highly concentration-dependent, while trout plasma binding was linear for the majority of the tested PFAS. At a molar ratio of PFAS to protein ν < 0.1 mol PFAS /mol protein , the specific protein binding of anionic PFAS dominated their human plasma binding. This would be the scenario for physiological conditions (ν < 0.01), whereas in in vitro assays, PFAS are often dosed in excess (ν > 1) and nonspecific binding becomes dominant. BSA was shown to serve as a good surrogate for human plasma. As trout plasma contains more lipids, the nonspecific binding to lipids affected the affinities of PFAS for trout plasma. Mass balance models that are parameterized with the protein−water and lipid−water partitioning constants (chemical characteristics), as well as the protein and lipid contents of the plasma (species characteristics), were successfully used to predict the binding to human and trout plasma.

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New approach methodologies: A quantitative in vitro to in vivo extrapolation case study with PFASs

Cited by 9 publications

References 80 publications

Determination of in vitro hepatotoxic potencies of a series of perfluoroalkyl substances (PFASs) based on gene expression changes in HepaRG liver cells

Determination of in vitro hepatotoxic potencies of a series of perfluoroalkyl substances (PFASs) based on gene expression changes in HepaRG liver cells

Advancing PFAS risk assessment: Integrative approaches using agent-based modelling and physiologically-based kinetic for environmental and health safety

Species Difference? Bovine, Trout, and Human Plasma Protein Binding of Per- and Polyfluoroalkyl Substances

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