New approach methodologies (NAMs) for human-relevant biokinetics predictions

Punt, Ans; Bouwmeester, Hans; Blaauboer, Bas J.; Coecke, Sandra; Hakkert, Betty C.; Hendriks, Delilah; Jennings, Paul; Kramer, Nynke I.; Neuhoff, Sibylle; Masereeuw, Rosalinde; Paini, Alicia; Peijnenburg, Ad; Rooseboom, Martijn; Shuler, Michael L.; Sorrell, Ian; Spee, Bart; Strikwold, Marije; Meer, Andries D. van der; Zande, Meike van der; Vinken, Mathieu; Yang, Huan; Bos, Peter; Heringa, Minne B.

doi:10.14573/altex.2003242

Cited by 40 publications

(29 citation statements)

References 113 publications

(172 reference statements)

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“…The results obtained do not apparently favor one of the two in vitro models and it can be concluded that both model systems can be equally well used to study human intestinal epithelial responses, thus selection may depend on the endpoint of interest. For instance, to derive uptake rates for pharmacokinetic modelling the robust and routinely used Transwell models might be the preferred approach 54 , while to emulate complex interactions in the intestine organ-on-chip models might be the preferred model [55][56][57] . It should be kept in mind that some specific gene functions are differently modulated in each model.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome comparisons of in vitro intestinal epithelia grown under static and microfluidic gut-on-chip conditions with in vivo human epithelia

Kulthong

Hooiveld

Duivenvoorde

et al. 2021

Sci Rep

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Gut-on-chip devices enable exposure of cells to a continuous flow of culture medium, inducing shear stresses and could thus better recapitulate the in vivo human intestinal environment in an in vitro epithelial model compared to static culture methods. We aimed to study if dynamic culture conditions affect the gene expression of Caco-2 cells cultured statically or dynamically in a gut-on-chip device and how these gene expression patterns compared to that of intestinal segments in vivo. For this we applied whole genome transcriptomics. Dynamic culture conditions led to a total of 5927 differentially expressed genes (3280 upregulated and 2647 downregulated genes) compared to static culture conditions. Gene set enrichment analysis revealed upregulated pathways associated with the immune system, signal transduction and cell growth and death, and downregulated pathways associated with drug metabolism, compound digestion and absorption under dynamic culture conditions. Comparison of the in vitro gene expression data with transcriptome profiles of human in vivo duodenum, jejunum, ileum and colon tissue samples showed similarities in gene expression profiles with intestinal segments. It is concluded that both the static and the dynamic gut-on-chip model are suitable to study human intestinal epithelial responses as an alternative for animal models.

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Section: Discussionmentioning

confidence: 99%

Transcriptome comparisons of in vitro intestinal epithelia grown under static and microfluidic gut-on-chip conditions with in vivo human epithelia

Kulthong

Hooiveld

Duivenvoorde

et al. 2021

Sci Rep

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“…In vitro methods can contribute to the refinement of the default UFs, while complying with the 3Rs principle of the reduction, refinement and replacement of animal testing (Russell and Burch 1959). Although the use of an interspecies differences UF may be eliminated when human cells and/or tissue are used in the transition towards an alternative risk assessment without animal experiments, it can still be useful to investigate these interspecies differences to gain confidence in the alternative method used and compare with an animal in vivo data (Punt et al 2020). To refine the UF for human variability, i.e.…”

Section: Introductionmentioning

confidence: 99%

Acetylcholinesterase inhibition in electric eel and human donor blood: an in vitro approach to investigate interspecies differences and human variability in toxicodynamics

et al. 2020

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In chemical risk assessment, default uncertainty factors are used to account for interspecies and interindividual differences, and differences in toxicokinetics and toxicodynamics herein. However, these default factors come with little scientific support. Therefore, our aim was to develop an in vitro method, using acetylcholinesterase (AChE) inhibition as a proof of principle, to assess both interspecies and interindividual differences in toxicodynamics. Electric eel enzyme and human blood of 20 different donors (12 men/8 women) were exposed to eight different compounds (chlorpyrifos, chlorpyrifos-oxon, phosmet, phosmet-oxon, diazinon, diazinon-oxon, pirimicarb, rivastigmine) and inhibition of AChE was measured using the Ellman method. The organophosphate parent compounds, chlorpyrifos, phosmet and diazinon, did not show inhibition of AChE. All other compounds showed concentration-dependent inhibition of AChE, with IC50s in human blood ranging from 0.2–29 µM and IC20s ranging from 0.1–18 µM, indicating that AChE is inhibited at concentrations relevant to the in vivo human situation. The oxon analogues were more potent inhibitors of electric eel AChE compared to human AChE. The opposite was true for carbamates, pointing towards interspecies differences for AChE inhibition. Human interindividual variability was low and ranged from 5–25%, depending on the concentration. This study provides a reliable in vitro method for assessing human variability in AChE toxicodynamics. The data suggest that the default uncertainty factor of ~ 3.16 may overestimate human variability for this toxicity endpoint, implying that specific toxicodynamic-related adjustment factors can support quantitative in vitro to in vivo extrapolations that link kinetic and dynamic data to improve chemical risk assessment.

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“…The need to recreate this level of complexity, combined with a parallel drive to decrease dependence on animal experiments (for ethical, cost and reliability reasons), has led to intensive efforts in both academia and industry to generate more representative in vitro models of the PT. Recent indepth articles have reviewed this rapidly expanding field in detail [49,50], but the main areas of active research include more differentiated human-derived cell lines [51,52], reprogrammed stem cells [53], kidney organoids [54,55] and microfluidic devices (so-called kidney-on-a-chip) [56,57]. Each approach has advantages and disadvantages [49], for example organoids can partially mimic the threedimensional environment of the normal kidney, allowing the study of cross-talk between PT cells and surrounding interstitial cells in response to injury.…”

Section: New In Vitro Proximal Tubule Models To Screen For Drug Toxicitymentioning

confidence: 99%

Drug toxicity in the proximal tubule: new models, methods and mechanisms

2021

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The proximal tubule (PT) reabsorbs most of the glomerular filtrate and plays an important role in the uptake, metabolism and excretion of xenobiotics. Some therapeutic drugs are harmful to the PT, and resulting nephrotoxicity is thought to be responsible for approximately 1 in 6 of cases of children hospitalized with acute kidney injury (AKI). Clinically, PT dysfunction leads to urinary wasting of important solutes normally reabsorbed by this nephron segment, leading to systemic complications such as bone demineralization and a clinical scenario known as the renal Fanconi syndrome (RFS). While PT defects can be diagnosed using a combination of blood and urine markers, including urinary excretion of low molecular weight proteins (LMWP), standardized definitions of what constitutes clinically significant toxicity are lacking, and identifying which patients will go on to develop progressive loss of kidney function remains a major challenge. In addition, much of our understanding of cellular mechanisms of drug toxicity is still limited, partly due to the constraints of available cell and animal models. However, advances in new and more sophisticated in vitro models of the PT, along with the application of high-content analytical methods that can provide readouts more relevant to the clinical manifestations of nephrotoxicity, are beginning to extend our knowledge. Such technical progress should help in discovering new biomarkers that can better detect nephrotoxicity earlier and predict its long-term consequences, and herald a new era of more personalized medicine.

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New approach methodologies (NAMs) for human-relevant biokinetics predictions

Cited by 40 publications

References 113 publications

Transcriptome comparisons of in vitro intestinal epithelia grown under static and microfluidic gut-on-chip conditions with in vivo human epithelia

Transcriptome comparisons of in vitro intestinal epithelia grown under static and microfluidic gut-on-chip conditions with in vivo human epithelia

Acetylcholinesterase inhibition in electric eel and human donor blood: an in vitro approach to investigate interspecies differences and human variability in toxicodynamics

Drug toxicity in the proximal tubule: new models, methods and mechanisms

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