Please note that the video has been divided into chapters to facilitate navigation between presentations.
Welcome words from the EU-ToxRisk project coordinator– Bob van de Water (Leiden University) PDF; VIDEO
Opening remarks on the EU-ToxRisk project, an EC Horizon 2020 initiative– Christian Desaintes (EC DG Research & Innovation) PDF;VIDEO
Part I : New technologies and approaches for toxicology
How has EU-ToxRisk impacted on innovative science research outreach – Thomas Steger Hartmann (Bayer) PDF ;VIDEO
iPSC-derived hepatocyte spheroids for liver disease and toxicity assessment – Catherine Verfaillie (University Leuven) PDF;VIDEO
Biology-inspired microphysiological systems: the asset of multi-organ co-cultures – Uwe Marx (TissUse) PDF;VIDEO
Interactions with the Tox21 program – Joshua Harrill(U.S. EPA) PDF ;VIDEO
The case of a high-concern toxicity profile screening – Bob van de Water (Leiden University) PDF ;VIDEO
Application of NAMs to detect multisite metabolism– Paul Jennings (VU University Amsterdam) PDF
Application of an AOP approach in a RAx safety assessment: the case of mitochondrial complex I inhibitors – Marcel Leist (University of Konstanz) PDF ;VIDEO
Which NAM testing scope is good enough for risk identification/characterization? – Sylvia Escher (ITEM Fraunhofer)VIDEO
Part II: Implementation of NAM-based approaches in risk assessment workflows
How has EU-ToxRisk impacted on NAM implementation in industry? –Andrew White (Unilever) PDF ;VIDEO
A case study combining read-across and NAM, the example of propyl-paraben in systemic toxicity, from A to Z –Gladys Ouedraogo (L’Oreal)
Commercialization Platform: perspectives from partners– Barry Hardy (Edelweiss Connect) PDF ;VIDEO
Podium discussion: an overview on the impact of the EU-ToxRisk strategy from different perspectives – I. Cotgreave, T. S-Hartmann, M. Sachana, G. Kass, C. Desaintes VIDEO
DAY 2
Please note that the video has been divided into chapters to facilitate navigation between presentations.
Part III: Driving regulatory acceptance of NAMs
How will EU-ToxRisk impact on NAM regulatory acceptance? – Matthias Herzler (BfR) PDF ;VIDEO
EU-ToxRisk RAx advisory Document – Hennicke Kamp (BASF) PDF ;VIDEO
Interactions with the OECD IATA Case Study programme – Magdalini Sachana (OECD) PDF ;VIDEO
EU-ToxRisk and EFSA: A common journey towards NGRA – George Kass (EFSA) PDF ;VIDEO
NGRA of developmental neurotoxicity liabilities of neonicotinoid insecticides – Susanne H. Bennekou (Danish Technical University) PDF ;VIDEO
Interactions with other projects/initiatives: the PARC initiative – Mirjam Luijten (RIVM) PDF ;VIDEO
European Commission perspective on EU-ToxRisk – Maurice Whelan (JRC) PDF ;VIDEO
Ab initio risk assessment – case studies using the EU-ToxRisk toolbox – Andrew White (Unilever)
Poster session I: the EU-ToxRisk Case Studies
Impact #1: Toxicological testing to better predict human risk PDF
Impact #5: Reduced use of laboratory animals in safety testing PDF
Andy White/Tom Cull/Giorgia Pallocca
The EU-ToxRisk dissemination activities…in figures PDF
Giorgia Pallocca
fas|fa-random|
Case studies
Case Studies of the EU-ToxRisk project
Prediction of microvesicular liver steatosis – a read-across case study with short branched carboxylic acids
Keywords
REACH, read-across, RDT, systemic toxicity, NAM, uncertainty, mode of action
Objective
In-vivo evidence indicates that short branched carboxylic acids –such as the drug valproic acid (VPA)– induce microvesicular liver steatosis in animals and humans. Would an analogue compound induce the same adverse outcome? To investigate this, we investigated a category of branched carboxylic acids by characterizing their toxicology profile with an in-vitro test battery. This study aimed to explore how far biological data from NAMs can be used in a read-across scenario to prove a shared mode of action and similar toxicokinetics.
Testing Strategy
Based on available in-vivo data of three structurally related analogues, the target compound 2-ethylbutyric acid (2-EBA) was assumed to be a liver toxicant with special concern for hepatic steatosis. Toxicokinetics and toxicodynamics properties of 2-EBA were analysed and compared to a category of structurally highly similar carboxylic acids that vary only with regard to their aliphatic side chain length. To characterize the toxicodynamics, published signalling pathways/AOPs leading to steatosis were compiled from literature and described in an AOP network. Two high-throughput reporter gene assays (CALUX and stress pathway responses in HepG2) were used to measure some of the described molecular initiating events (MIEs). Furthermore, three liver models were used to measure lipid accumulation as a direct in-vitro surrogate for in-vivo steatosis. It was shown that the number of activated MIEs and the induction of lipid accumulation increased with the side chain length of the tested carboxylic acids, whereas short-chain analogues like 2-EBA remained inactive up to the highest tested dose in vitro. The low activity of short-chain analogues was in good agreement with known in-vivo animal data. To characterize the toxicokinetics, a PBPK model was developed and parameterized with in-vitro ADME data. Bioavailable concentrations were predicted and QIVIVE extrapolation was performed using PBPK-based reverse dosimetry. Overall, the NAM data proved the initial read-across hypothesis to be valid by showing a consistent trend concerning toxicokinetics and toxicodynamics within grouped compounds.
Publications
van Vugt-Lussenburg et al. 2018 [link]; Leist et al. 2017 [link]; Tolosa et al. 2017 [link]; Fisher et al. 2018 [link]; Gadaleta et al. 2018 [link]; Wink et al. 2018 [link]; Niemeijer et al. 2018 [link]; Escher et al. 2022 [link]; Escher et al. 2019 [link]; Rovida et al. 2021 [link]
Prediction of developmental and reproductive toxicity (DART): a read-across case study with short branched carboxylic acids
Keywords
REACH, read-across, DART
Objective
2-Methylhexanoic acid (MHA) is mostly used as a food additive. Developmental and reproductive toxicity (DART) data for MHA were taken to be lacking. The aim was to find structural analogues for which DART data is available and to attempt to show that a NAM-based read-across would rightly predict the DART profile of MHA.
Testing Strategy
MHA and its selected chemical analogues were tested in a battery of in-vitro tests relevant to developmental toxicity, including the zebrafish embryotoxicity test (ZET), the mouse embryonic stem cell test (mEST), an iPSC-based neurodevelopmental model (UKN1), and a series of CALUX reporter assays. Also, toxicokinetic models were developed and applied to calculate effective cellular concentrations and associated in-vivo exposure doses. The applied NAM-based read-across was used to predict the in-vivo developmental toxicity of MHA from the developmental toxicity data of selected source chemicals. This data would also allow us to further explore the relationship between structure and developmental toxicity within this series of aliphatic carboxylic acids. We also investigated the potential to inhibit histone deacetylase in these test models, as this enzyme is postulated to be the molecular target initiating neural tube defects, an observed developmental toxicity for some of these analogues. NAM results showed that VPA, PHA, EHA, and 4-ene-VPA were correctly predicted as in-vivo developmental toxicants, and EBA and DMPA as non-developmental toxicants. The results indicate that MHA, which is a non-developmental toxicant, cannot be classified as fully negative based on this NAM-based read-across.
Publications
Shinde et al. 2016 [link]; Waldman et al. 2016 [link]; van Vugt-Lussenburg et al. 2018 [link]; Fisher et al. 2017 [link]; Simeon et al. 2020 [link]; Escher et al. 2019 [link]; Brotzmann et al. 2021 [link]; Koch et al. 2021 [link]; Escher et al. 2019 [link]; Rovida et al. 2021 [link]
The phenoxy acetic/propionic acid herbicides form a group of structurally similar herbicides are known to induce similar systemic toxicity in rat studies. The main toxicological effects observed are liver toxicity due to peroxisome proliferation as well as kidney toxicity associated with oxidative stress. Since the liver effects are mediated through activation of peroxisome proliferation, other non-herbicidal peroxisome proliferators – such as phthalates or pharmaceutical peroxisome proliferators– were tested to evaluate the NAMs in terms of general detection of peroxisome proliferation.
Testing Strategy
Data from CALUX assays, HepG2 metabolomics, and stress responses showed that the biological effects observed can be linked to the toxicological mode of action in the liver. The metabolite profile indicated changes in lipid metabolism as had been seen for peroxisome proliferators in vivo. The data for the herbicides were well in line with published in vivo findings (van Ravenzwaay et al., 2016) and demonstrated that the in vitro data might be used to substantiate a read-across based on in vitro methodologies. PBPK modelling for the compounds and test substances will be performed.
Publications
Van Ravenzwaay et al. 2016 [link]; Escher et al. [link]
Contributors
BASF, RISE, KI, BDS, ITEM, DC, MUI, VU.
Repeated dose toxicity (RDT)/ Developmental and reproductive toxicity (DART) – Mitochondrial toxicity. The case of the strobilurin fungicides.
Keywords
REACH, read-across, RDT, DART, NAM, AOP
Objective
A large group of pesticides used in the agrochemical sector targets mitochondria functionality. The synthetic strobilurin fungicides, derived from the naturally occurring strobilurin A and B, belong to this group. Strobilurin fungicidal mode of action is known. The chemical binds to the quinol oxidation site of cytochrome b of complex III (CIII) of the mitochondria. The degree of in vivo inhibition of the mitochondrial respiratory system depends on the respiratory activity and thereby tissues like the brain can be more susceptible if exposed. Evidence of potential neurotoxicity was also shown in in vitro studies. The objective of this case is to characterise potential CIII-mediated neurotoxicity of target compound azoxystrobin by NAM-enhanced read-across. The objective is to answer the question: ‘Can the absence of a neurotoxic potential of azoxystrobin-mediated inhibition of complex III of mitochondria be predicted by toxicodynamic and toxicokinetic NAM data?’
Testing Strategy
Source compounds selected in this case study are other strobilurin fungicides. Existing regulatory in vivo data was collected for the source and target compounds with a focus on ADME, neurotoxicity, as well as target organ toxicity data. Source compounds showed no signs of neurotoxicity, neither in neurotoxicity studies nor in other RDT studies. Overall, based on the generated data on kinetics and effect data, there is no evidence for a stronger neurotoxic potential of azoxystrobin mediated by a CIII inhibitory mode of action as compared to the source compounds. Since source compounds did not elicit neurotoxicity in vivo, we concluded that also the target compound azoxystrobin is not a neurotoxicant.
Publications
Wink et al. 2018 [link]; Hiemstra et al. 2019 [link]; Delp et al. 2018 [link]; Terron et al. 2019 [link]; van der Stel W et al. 2020 [link]; Fisher et al. 2017 [link]; Delp et al. 2019 [link]; Hemmerich et al. 2020 [link]; Troger et al. 2020 [link]; Delp et al. 2019 [link]; Delp et al. 2018 [link]; Delp et al. 2021 [link]; Hemmerich et al. 2020 [link]; van der Stel et al. 2021 [link]; van der Stel et al. 2020 [link]; Troger et al. et al. 2020 [link]; Vrijenhoek et al. 2022 [link]; Escher et al. 2019 [link]; Rovida et al. 2021 [link]
Repeated dose toxicity (RDT)/ Developmental and reproductive toxicity (DART) – Mitochondrial toxicity. The case of mitochondrial complex I inhibitors: deguelin and rotenone.
Keywords
REACH, read-across, RDT, DART, NAM, AOP
Objective
There is an anticipated hazard for agrochemicals that inhibit complex I of the mitochondrial respiratory chain to cause toxicity to the nigrostriatal neurons leading to symptoms that reflect Parkinson's disease. This effect has been comprehensively described in an OECD-validated AOP (Terron et al. 2019). This case study aims to assess the application of an AOP approach in a read-across safety assessment of structurally related mitochondrial complex I inhibitors, deguelin, and rotenone. Epidemiological studies indicate that exposure of workers to rotenone is statistically associated with an increased incidence of Parkinson's disease; moreover, rotenone is known to induce parkinsonian phenotypes in experimental animals. Therefore, rotenone was used as the source substance. Deguelin can induce parkinsonian-like phenotypes in rats. Whether deguelin has such a parkinsonian hazard liability in humans is currently unclear and therefore deguelin was the target substance for this case study.
Testing Strategy
Based on the AOP, structural modelling approaches were applied to define the binding of rotenone and deguelin to mitochondrial complex I, the molecular initiating event of the AOP. Then, previously established and routinely applied assays that reflect the various key events in this AOP were defined. Multiple human-based in vitro test systems to monitor mitochondrial effects of rotenone and deguelin were additionally integrated. To assess the effect on neuron toxicity, high-content imaging approaches to measure degeneration of neuronal neurites were applied. Finally, both biokinetic evaluation of cellular exposure to rotenone and deguelin, as well as PBPK modelling, were used to evaluate the relevance of observed effects in vitro towards a likely in vivo exposure situation. Both substances inhibit complex I activity and cause mitochondrial dysfunction. Similarly, rotenone is also more potent than deguelin in disrupting neurites. The target compound deguelin displayed a similar mode-of-action as rotenone, but with minor potency. The case study showed how practical application of an AOP approach through the integration of specific technologies and test systems might find broader application in a read-across safety assessment of structurally related substances.
Publications
Wink et al. 2018 [link]; Hiemstra et al. 2019 [link]; Delp et al. 2018 [link]; Terron et al. 2019 [link]; van der Stel W et al. 2020 [link]; Fisher et al. 2017 [link]; Delp et al. 2019 [link]; Hemmerich et al. 2020 [link]; Troger et al. 2020 [link]; Delp et al. 2019 [link]; Delp et al. 2018 [link]; Delp et al. 2021 [link]; Hemmerich et al. 2020 [link]; van der Stel et al. 2021 [link]; van der Stel et al. 2020 [link]; Troger et al. et al. 2020 [link]; Vrijenhoek et al. 2022 [link]; Escher et al. 2019 [link]; Rovida et al. 2021 [link]
Drug-induced liver injury (DILI) cannot be accurately predicted by animal models. Also, currently available in vitro methods do not allow for the estimation of hepatotoxic doses or the determination of an acceptable daily intake (ADI). To overcome this limitation, an in vitro/in silico method was established that predicts the risk of human DILI concerning oral doses and blood concentrations. Despite intensive research, it is currently not possible to reliably predict whether repeated exposure to a certain dose of a chemical leads to an increased risk of hepatotoxicity or can be considered harmless.
The main objectives of this case study are:
To predict blood concentrations of chemicals that cause an increased risk of hepatotoxicity and to identify concentration ranges that can be considered harmless.
To predict oral doses of chemicals that cause an increased risk of hepatotoxicity (reverse modelling).
Testing Strategy
The developed novel in vitro/in silico method can be used to estimate DILI risk if the maximal blood concentration of the test compound is known. Moreover, an ADI can be estimated even for compounds without information on blood concentrations. To systematically optimize the in vitro system, two novel test performance metrics were introduced: the toxicity separation index (TSI), which quantifies how well a test differentiates between hepatotoxic and non-hepatotoxic compounds, and the toxicity estimation index (TEI), which measures how well hepatotoxic blood concentrations in vivo can be estimated. In vitro test performance was optimized for a training set of compounds, based on TSI and TEI, to identify the most performing concentrations and incubation time. Additionally, metrics were moderately improved by adding gene expression to the test battery and evaluation of pharmacokinetic parameters were evaluated. With a support vector machine-based classifier, the cross-validated sensitivity, specificity, and accuracy for hepatotoxicity prediction were highly relevant, respectively 100, 88, and 93%. Currently, the novel in vitro/in silico method is validated in a set of >200 test compounds. A constantly ongoing activity in this project is the identification of key events of DILI that can be tested in vitro in order to integrate them into our in vitro test battery.
Publications
Albrecht et al. 2019 [link]; Gu et al. 2018 [link]; Leist et al. 2017 [link]; Sachinidis et al. 2019 [link]; Ghallab et al. 2018 [link]; Jansen et al. 2016 [link]; Kappenberg et al. 2021 [link]; Gupta et al. 2020 [link]; Kappenberg et al. [link]; Krebs et al. 2020 [link]; Hengstler et al. 2020 [link]; Fasbender et al. 2020 [link]; Ruoß et al. 2020 [link]; Campos et al. 2020 [link]; Ghallab et al. 2019 [link]
Contributors
IFADO, UL, UKN, UM, UNILEVER, RISE, KI, CE, TNO, ITEM, DC, SimCyp, EBI, UNIVIE, UCPH, TissUse, JHSPH, IS, L’Oreal.
Popcorn lung – a read-across case study on diketones class group
Keywords
Read-across, RDT, REACH, respiratory disease, NAM
Objective
The alpha-diketone diacetyl (2,3- butadiene) is known to induce the so-called “popcorn lung” condition. This disease was frequently observed among microwave popcorn manufacturing employees who inhaled the butter flavour vapour of diacetyl. This condition represents an obstructive pulmonary disease in which the airway epithelium is the initial target of injury. The disease is called bronchiolitis obliterans and is characterized by fibroproliferative airway lesions. In this case study, the effects of alpha-diketone have been investigated together with two structurally similar groups (β and γ diketone) which seem to have a different mode of action based on available information. This approach can show how far selected NAMs are also able to differentiate the α, β, and γ diketone specific toxicity in the selected in vitro test systems. The three groups of structurally related compounds are sufficiently data-rich to allow the exploration of NAMs to adequately perform chemical hazard identification and herewith replacing the regulatorily required animal study. EU-ToxRisk tools were applied to predict toxicokinetics properties of the target compounds (e.g. PBPK and metabolism). Furthermore, we explored to which extent chemical similarity can be enriched by biological data, e.g. derived from omics investigations or cellular readouts.
Testing Strategy
All case study compounds were evaluated in fluorescent cell stress reporter assay high-throughput screens. Alpha diketones are known to have a high electron affinity and can transfer electrons and, thus, can induce ROS and oxidative stress. Αlpha-diketones as well as the beta-diketone 2,4-pentanedione were shown to induce activation of oxidative stress and DNA damage response pathways. The air-liquid interface (ALI) exposure setup for diacetyl and analogues was preferred in further experiments since dose control is ensured by online measurements of volatile test atmosphere employing FT-IR spectroscopy. Cultures of primary airway epithelial cells (PBECs) as well as human precision cut lung slices (PCLuS) were set up for ALI exposures. Additionally, transcriptomics as well as cytokine data are currently being analysed. Kinetic studies with diacetyl aiming at the determination of diacetyl uptake and intracellular concentrations are ongoing.
Contributors
ITEM, UL, UKN, DC, SimCyp, LUMC, Mario Negri IRCCS
Parabens
Keywords
Cosmetics regulation, industry-sponsored case study, read-across, ab-initio
Objective
This case study aims at establishing a proof-of-concept approach for the use of NAM-enhanced read-across in a next-generation risk assessment context. Parabens are esters of para-hydroxybenzoic acid (pHBA) that are widely used as preservatives in diverse product sectors including agrochemical, pharmaceutical, food, and cosmetics. In this case study, the use of in silico information, in vitro toxicodynamic (toxicogenomics, endocrine activity) and toxicokinetic data were combined to support biological similarity among analogues and establish potency trends to inform the selection of the best source chemical from within a category. This approach, along with consideration of aggregate exposure, was here used in an example safety assessment of low-toxicity chemicals. The chemical category under consideration is short linear chain parabens.
Testing Strategy
The external dermal cosmetic exposure to four parabens of primary interest (methyl, ethyl, propyl, and butyl) was analysed. Deterministic external exposure values were used to predict human plasma systemic exposure to the compounds. A comprehensive human in vitro dataset was obtained, which enabled PBPK modelling of systemic plasma concentrations of the parent compounds following dermal exposure in humans. This data comprised human skin penetration data; biotransformation data in skin, liver, enterocytes (Caco-2 cells), and plasma, which characterized major metabolites and intrinsic clearance rates; plus plasma protein binding. The parabens are readily hydrolysed to p-hydroxy benzoic acid in presence of metabolic activation. The human ADME parameters were used to develop PBPK-based multi-compartment models of human systemic plasma parabens concentrations following dermal external exposure to compounds. Parabens were shown to lack specific target organ toxicity at very high doses in repeated dose toxicity studies. However, they are active in some uterotrophic assays and were assigned a conservative point of departure (PoD) by the Scientific Committee for Consumer Safety. Also, data have emerged in the literature that show parabens exhibit low activity in in vitro assays relevant for endocrine activity. These in vitro assays suggest that parabens (the parent compounds but not the main metabolite) possess very weak activity on some nuclear receptors involved in endocrine homeostasis, many orders of magnitude lower than natural estrogens/androgens. In this case study, NAMs have been applied to explore this oestrogenic activity as an approach to inform on biological similarity and relative potency of the category members. This relative potency is then used to adjust the conservative PoD derived from butylparaben to carry out a theoretical risk assessment for propylparaben based on read-across. For the read-across risk assessment, a margin of safety was derived using internal concentrations: margin of internal exposure –MoiE- which is protective of human health. In conclusion this case study demonstrated the value added by NAMs in identifying, characterizing analogues, in informing similarities/differences on toxicokinetic and toxicodynamic properties and in the calculation of the internal margin of safety.
L’OREAL, UL, P&G, BASF, Unilever, Clariant, INERIS, CE, BDS, TNO, ITEM, LHASA, University of Liverpool.
Multi-target organ toxicity
Keywords
REACH, RDT, LOEL
Objective
The majority of toxic chemicals cause their most sensitive toxicological effects in liver, kidney or the respiratory tract in studies with repeated exposure. Nevertheless, there are compounds that show other types of toxicity. However, even if unaffected at the lowest observed effect level (LOEL), there is a 95% probability that effects on liver or kidney are observed in vivo at the next higher dose. The objective of this case study is to gain knowledge on how toxicological data derived from neuro, lung, liver, or kidney in vitro models can be used to predict the LOEL of test compounds and whether an additional safety factor will be needed.
Testing Strategy
In this case study, compounds that show specific toxicity effects in target organs different from the EU-ToxRisk test method panel have been selected for testing. In this way, knowledge will be gained in how far we can use the results of neuro/lung/liver or kidney models to predict the LOEL of such compounds. This case study applies cross-system testing and a 3-tiered approach: hypothesis generation, test cellular assays, PBPK modeling. Finally, data will be analyzed and the next tests will be refined based on the information gained in the first phase.
Currently, for an enormous proportion of REACH registrations, no safety information is available. This particularly applies to 'lower tonnage' chemicals. Here there is a need to prioritize chemicals based on the likelihood of safety issues. The main objective of the case study is to demonstrate the overall feasibility of high-throughput NAM hazard-based information to identify substances of high-toxicity concern.
Testing Strategy
The driving hypothesis is that only toxic substances will strongly impact cell biology. This would be reflected by the activation of specific transcriptional networks that will provide mechanistic mode-of-action information. We anticipate that high-throughput NAM approaches could provide this mechanistic insight and thereby allow to rank substances based on their mode-of-action. To demonstrate the feasibility to prioritize chemicals for further safety assessment, a training set of high tonnage compounds, for which in vivo safety data is available, will be used. These compounds will all be tested in dose-response scenarios in high-throughput test systems to assess the impact on the cell biology, and include: in silico approaches (metabolism, QSAR, target prediction); high-throughput reporter assays; targeted transcriptomics in selected cell types. All compounds will be ranked and we will relate our findings to the available in vivo adversity and potency information.
Next-generation risk assessment of developmental neurotoxicity liabilities of neonicotinoid insecticides
Keywords
DART, OECD DNT TG426, IATA
Objective
In 2013, the European Food Safety Authority (EFSA) published a scientific opinion raising concerns regarding the DNT potential based on newer mechanistic in vitro data and insufficient hazard characterization based on available in vivo DNT tests of two neonicotinoid pesticides, acetamiprid and imidacloprid. This action has resulted in a proposal for revision of the human reference values. The objective of the case study is the development of an IATA to support hazard identification/characterization of selected neonicotinoids and to validate the biological plausibility and sufficiency of data from available datasets.
Testing Strategy
Data on neonicotinoid compounds in a combination of NAMs have been contextualized in an IATA. The selected NAMs span from molecular receptor docking, gene expression, assays covering endpoints involved in key neurodevelopmental processes as well as zebrafish embryos, and PBPK modelling. Many endpoints of the in vitro test battery were not affected by high concentrations (up to 100 µM) of neonicotinoids. However, the functional properties of neurons were affected by a subset of test compounds in similar directions as observed with the well-known DNT toxicant nicotine. The case study now focuses on a more detailed molecular characterization of the observed hazard and potency estimates. Results across the testing battery expand the knowledge of available in vivo data and can, therefore, contribute to a better risk assessment. This approach aligns with the OECD program on „OECD DNT guidance on the interpretation of in vitro DNT data that can be used in an IATA", a global effort to test up to 120 DNT compounds in an in vitro test battery, generation of a database, and generation of IATA cases supporting endorsed guidance.
Publications
Loser et al. 2021 [link]; Loser et al. 2021 [link]; Loser et al. 2021 [link]
Halogenated alkenes are a family of chemicals that have been widely used in various industrial applications, like pesticides, solvents, and dry cleaning, and pose a significant hazard to human health. Occupational investigations and animal studies have indeed demonstrated that halogenated alkenes – especially trichloroethylene (TCE), perchloroethylene (PER), and hexachlorobutadiene (HCBD) – can cause various types of toxicity, including hepatotoxicity and nephrotoxicity. Mechanistic in vivo and in vitro animal studies have demonstrated that the renal toxicity of these chemicals is not caused by the parent compounds but is a result of several enzymatic reactions (GST, GGT, dipeptidase, and β-lyase) at hepatic and renal levels. The resulting reactive metabolites will lead to oxidative stress and mitochondrial dysfunction, which are considered key events in renal proximal tubule toxicity. The case study aims to develop a quantitative model for halogenated alkene metabolism, distribution and target organ toxicity for halogenated alkenes, focusing on TCE.
Testing Strategy
An integrative workflow that includes in vitro hepatic studies for biotransformation of parent compounds, monitorisation of renal metabolism of hepatic conjugates and toxicity testing in hepatic, renal, and neuro in vitro systems has been developed. NAMs have been integrated into the testing approach. An in vitro model was developed utilizing human liver preparations, human recombinant enzymes, synthetic chemistry, and the human renal cell proximal tubule cell line RPTEC/TERT1. Metabolism stages and eventual mitochondrial toxicity have been evaluated in this system. LC-MS based analytical methods were applied to monitor the kinetics of parent compounds and tested metabolites which will also provide data for the support of an improved physiologically based pharmacokinetic (PBPK) model for human in vivo TCE, PER, and HCBD exposures.
Publications
Zgheib et al. 2018 [link]; Limonciel et al. 2018 [link]; van der Stel et al. 2020 [link]; Aschauer et al. 2015 [link]; Capinha et al. 2021 [link]; Capinha et al. 2021 [link]
Contributors
VU, UL, UKN, BIOT, EwC, IRFMN, SIMCYP.
fas|fa-random|
EU-ToxRisk publications
Publications of the EU-ToxRisk project
Author
All authors
Aalizadeh Reza
Abbas Aya A.
Abbasi Kayvan
Adams Timothy
Aguayo-Orozco Alejandro
Aguilar-Bravo Beatriz
Ahmed Yasser A.
Aichem Michael
Akabane Takafumi
Akkerman Renate
Aladjov Hristo
Albrecht Wiebke
Alcalà Morera Ariadna
Ali Ahmed
Allen Dave
Altenburger Rolf
Amberg Alexander
Andersson Tommy B.
Angeli Karine
Angrish Michelle
Annys Erwin
Antoranz Asier
Aoki Yasunobu
Ariño Silvia
Armstrong Lyle
Arturi Kasia
Aschauer Lydia
Aschner Michael
Ates Gamze
Athar Awais
Attoff Kristina
Audouze Karine
Avci Hasan X
Azzouzi Salah
Babica Pavel
Backhaus Thomas
Bahadori Tina
Baharvand Hossein
Baier Vanessa
Bajaj Manmohan
Baker Elizabeth
Bal-Price Anna
Banhart Benjamin K
Barouki Robert
Bartmann Kristina
Barton-Maclaren Tara
Basiri Mohsen
Bauch Caroline
Baumann Lisa
Baze Audrey
Beaumont Maria
Begher-Tibbe Brigitte
Behbehani Mehri
Behl Mamta
Behr Anne-Cathrin
Behrangi Ehsan
Beilmann Mario
Beken Sonja
Bellak Tamas
Beltman Joost B
Bender Hans
Bendt Farina
Benfenati Emilio
Bennekou Suzanne H.
Berckmans Pieter
Bergemann Jörg
Berggren Elisabet
Bergman Åke
Berka Karel
Berthelot Sylvie
Berthold Michael R.
Bessems Jos
Bevan Samantha
Beyss Martin
Birk Barbara
Bischoff Luc J. M.
Bitsch Annette
Blaha Ludek
Blank Lars M
Blaya Delia
Bluethgen Nils
Blum Jonathan
Blüthgen Nils
Bobis-Wozowicz Sylwia
Bock Istvan
Boei Jan J
Bois Frederic Y
Bolton Evan E.
Bondarenko Olesja
Boon Ruben
Boonen Harrie
Bopp Stephanie K
Bordag Natalie
Borlinghaus Hanna
Bosisio Francesca Maria
Botelho Danielle
Botham Philip
Bouwman Peter
Boyer Scott
Brack Werner
Braeuning Albert
Brajnik Maja
Brandel Jeremy
Brauers Karen
Braun Theresa S.
Braunbeck Thomas
Brazma Alvis
Brecklinghaus Tim
Brendler-Schwaab Susanne
Briggs Katharine
Britschgi Markus
Brookes Anthony J
Brotzmann Katharina
Brunak Søren
Brunner Thomas
Brüll Markus
Buck-Wiese Marie
Buhrke Thorsten
Burgoon Lyle D.
Busquet Francois
Cadenas Cristina
Cai Qing
Caiment Florian
Callegaro Giulia
Caloni Francesca
Campos Gisela
Canella Marco
Carta Giada
Cases Montserrat
Castel Jose
Castell Jose V
Castell José
Cathomen Toni
Cavallo Anna Lina
Ceccatelli Sandra
Cediel Andrea
Cediel Ulloa Andrea Paola
Cerff Martin
Chandrasekaran Abinaya
Chandrasekaran Vidya
Chandrasekera P. Charukeshi
Chau David
Chaudhry Qasim
Chen Alice
Chen Yemiao
Cherianidou Anna
Chesnais François
Chesne Christophe
Chesnut Megan
Chorley Brian N
Chovancova Petra
Cirit Murat
Clayton Rick
Coecke Sandra
Coll Mar
Conde Isabel
Coonen Maarten L J
Coort Susan L.
Copple Ian M.
Corthout Nikky
Corvi Raffaella
Covaci Adrian
Covaro Marco
Crofton Kevin M
Cronin Mark T. D.
Culot Maxime
Currie Richard
Curtiss Cameron
Czich Andreas
Dal Negro Gianni
Dalla Costa Silvia
Damalas Dimitrios Ε.
Dameron Greg
Damle-Vartak Amruta
Damm Georg
Danen Erik
Daneshian Mardas
Danker Timm
Dankers Anita
Darici Salihanur
Dastidar Sumitava
Daston George
Dave Kirtan
David Rhiannon
De Boeck Jolan
De Knecht Joop
De Smedt Jonathan
Dear Gordon
Deferme Lize
Dehne Eva-Maria
Delannois Frédérique
Delp Johannes
Demeneix Barbara
Dent Matt
Desaintes Christian
Desprez Bertrand
Dhalluin Stephane
Di Monte Donato A
Dickens David
Dietrich Daniel R.
Dinnyés András
Dolde Xenia
Donato M Teresa
Dooley Steven
Dorne Jean Lou
Drakvik Paula E
Drasdo Dirk
Dreser Nadine
Drewell Christopher
Duda Julia
Duijndam Britt
Dunkern Torsten
Dupuis Lauren J.
Durieux Isabell
EFSA WG EPI1 Members
Eakins Julie
Ebbels Timothy
Ebbert Kristina
Ecker Gerhard F
Edlund Karolina
Efremova Liudmila
Eggermont Kristel
Ehrhart Friederike
Ekins Sean
El Taghdouini Adil
Ellinger-Ziegelbauer Heidrun
Ellis Ewa C.
Elson Joanna L.
Escher Beate I.
Escher Sylvia E.
Eschment Melanie
Eskes Chantra
Estrada-Tejedor Roger
Evelo Chris T.
Ewart Lorna
Exner Thomas
Ezendam Janine
Faas Marijke M
Fatma El Zahraa Ammar Mohamed
Fernandez Murga Maria Leonor
Ferrari Thomas
Fischer Fabian C.
Fisher Ciarán
Fitzpatrick Suzanne C
Florian Fromm
Fluri David A
Forsby Anna
Fritsche Ellen
Fuchs Regine
Förster Sunniva
Gadaleta Domenico
Gardner Iain
Gaspar John Antonydas
Georgiadis Nikolaos
Gerhold David
Ghallab Ahmed
Glaab Enrico
Godoy Patricio
Gourmelon Anne
Graepel Rabea
Greene Nigel
Grinberg Marianna
Gstraunthaler Gerhard
Gutbier Simon
Guzmán Antonio
Gätgens Jochem
Gómez-Lechón Maria José
Hackermüller Jörg
Hammad Seddik
Hampe Jochen
Hardy Barry
Hartung Thomas
Hasiwa Nina
Hatley Oliver
Hengstler Jan
Hengstler Jan G.
Henry Margit
Hernandez Antonio F
Hersey Anne
Hescheler Jürgen
Hiemstra Steven W
Higton David
Hoelting Lisa
Hogberg Helena T
Holzer Anna-Katharina
Hougaard Bennekou Susanne
Huppelschoten Suzanne
Höhme Stefan
Inutsuka Takashi
Jacques Pascale
Jagtap Smita
Jamei Mehdi
Jansen Peter L.M.
Jennings Paul
Jover Ramiro
Kamp Hennicke
Kanda Yasunari
Kauffmann Hans-Martin
Kelm Jens M
Kempa Stefan
Kerins Anna
Kern Georg
Kindinger Ilona
Kleinstreuer Nicole
Kleinöder Thomas
Klima Stefanie
Klip Janna E
Knapen Dries
Kobolák Julianna
Koch Bjorn
Koedoot Esmee
Krebs Alice
Kroese E. Dinant
Kuijper Isoude A
König André
Lako Majlinda
Lakshmipathy Uma
Lammens Lieve
Legler Daniel F
Lehmann Martin
Lein Pamela J
Leist Marcel
Leite Sofia
Li Abby
Liebing Julia
Limonciel Alice
Lombardo Anna
Luechtefeld Thomas
López-Riera Mireia
Mack Amanda
Maclennan Richard
Mahony Catherine
Mantovani Alberto
Marc Philippe
Marchan Rosemarie
Martens Marvin
Marzo Marco
McFarland Richard
Meganathan Kesavan
Meier Florian
Meijer Annemarie H
Meisig Johannes
Mestres Jordi
Meyer Christoph
Mombelli Enrico
Monnet-Tschudi Florianne
Mundi William R
Muster Wolfgang
Nembo Erastus
Niedenführ Sebastian
Niemeijer Marije
Noel Sabrina
Northeved Helle
Nuria Jiménez
Nyffeler Johanna
Nöh Katharina
Oesch Franz
Ouedraogo Gladys
Paini Alicia
Pallocca Giorgia
Pamies David
Pape Regina
Pastor Manuel
Perdichizzi Stefania
Piersma Aldert H
Pinches Marc
Pinto-Gil Kevin
Pistollato Francesca
Pognan François
Poole Alan
Posch Wilfried
Purvanov Vladimir
Pérez Gabriela
Rahnenführer Jörg
Ramirez Tzutzuy
Raska Ivan
Raskova Maria
Rauch Caroline
Reaves Elissa
Reif Raymond
Rempel Eugen
Richarz Andrea-Nicole
Rowlands Craig
Sachana Magdalini
Sachinidis Agapios
Saiz Javier
Sajot Nicolas
Salem Harry
Sanz Ferran
Sauer Ursula G
Schaap Frank G
Schildknecht Stefan
Schmidt Béla Z.
Schreiber Falk
Schwarz Michael
Seiler Andrea
Shinde Vaibhav
Silvester Steve
Simeonov Anton
Smirnova Lena
Srinivasan Sureshkumar Perumal
Stacey Glyn N.
Steger-Hartmann Thomas
Stoeber Regina
Strigun Alexander
Sutherland Jeffrey J.
Taboureau Olivier
Tagle Danilo A.
Tarazona Jose V
Tebby Cleo
Tedds Jonathan
Teglasi Annamaria
Terron Andrea
Testa Giuseppe
Testai Emanuela
Tetard David
Thibaut Hendrik J.
Thiel Christoph
Thomaidis Nikolaos
Tieu Kim
Tigges Julia
Tikhonov Andrew
Tilliole Pierre
Timmer Jens
Tollefsen Knut E
Tolosa Laia
Tolosa Pardo Laia
Toma Cosimo
Tonevitsky Alexander
Toprakhisar Burak
Toropov Andrey A.
Toropova Alla P.
Torres Andón Fernando
Trairatphisan Panuwat
Tralau Tewes
Trapecar Martin
Trautwein Christian
Tredwell Gregory D.
Trefzer Timo
Tricot Tine
Trier Xenia
Troger Florentina
Tsyb Sergej
Táncos Zsuzsanna
Ullrich Anett
Vadigepalli Rajanikanth
Valencia Alfonso
Valentin Jean-Pierre
Vallverdu Julia
Van Den Bosch Ludo
Van Goethem Freddy
Van Rossom Rob
Van den Hof Wim F P M
VanSteenhouse Harper C.
Vanhove Jolien
Vanslembrouck Veerle
Vanuytsel Kim
Vanwelden Thomas
Vartak Nachiket
Vemuri Mohan C
Verbruggen Tim
Verfaillie Catherine M
Vergauwen Lucia
Verhulst Stefaan
Verlohner Andreas
Vermeulen Nico P E
Vidal Niels
Vinken Mathieu
Viviani Barbara
Vladetic Alexandra
Vlasveld Matthijs
Vock Esther
Vrieling Harry
Vrijenhoek Nanette G.
Vulto Paul
Waagmeester Andra
Waldmann Tanja
Walk Tilmann
Walker Paul
Wang Gao
Wang Wen Bo
Warhurst A. Michael
Watanabe Kengo
Watson David K
Watzele Manfred
Weaver Richard
Weber Ralf J.M.
Wehr Matthias
Weiß Thomas S
Westerink Remco H S
Westmoreland Carl
Wheelock Craig E.
Whelan Maurice
White Andrew
Wichard Joerg
Widera Agata
Wiecek Witold
Wijaya Lukas S.
Wilflingseder Doris
Wilks Martin F
William Antony J.
Williams Dominic P.
Willighagen Egon L.
Willy Jeffrey
Wilmes Anja
Wilschut Annette
Wink Steven
Witters Hilda
Wittmann Valentin
Woeste Selina
Wolber Gerhard
Wolf Armin
Wolfs Esther
Wolterbeek André
Wolters Jarno E J
Wolters Liesanne
Worth Andrew
Yamada Takashi
Yamazaki Daiju
Yamazaki Kunihiko
Yang Chihae
Yang Huan
Yauk Carole
Yeakley Joanne M.
Yin Dezhong
Yuko Sekino
Zamora Ismael
Zana Melinda
Zaragoza Ángela
Zasada Christin
Zaza Ayham
Zdrazil Barbara
Zeigerer Anja
Zgheib Elias
Zhang Fang
Zhang Mian
Zhao Liang
Zhou Xiaobing
Zimmer Bastian
Zimmermann Lea
Zvonimir Zvonar
Zühlke Sebastian
da Costa Pereira Daniel
de Bont Hans
de Kok Theo M.
de Vos Paul
de Vrij Femke
de Zeeuw Elisabeth
den Hollander Wouter
eTOX
ter Braak Bas
van Aerts Leon
van Breda Simone G J
van Gils Jos
van Grunsven Leo A.
van Haele Matthias
van Herwijnen Marcel
van Klaveren Jacob
van Os Bram
van Ravenzwaay Ben
van Ravenzwaay Bennard
van Thriel Christoph
van Vugt-Lussenburg Barbara M A
van Westen Gerard J.P.
van de Water Bob
van den Berk Linda
van den Eijnden-van Raaij Janny
van den Hoorn Tineke
van den Nieuwendijk Karen
van der Burg Bart
van der Laan Jan Willem
van der Lei Johan
van der Stel Wanda
van der Voet Hilko
von Hellfeld Rebecca
Ückert Anna-Katharina
Županič Anže
Year
All years
2016
2017
2019
2018
2020
2021
2022
Journal
All Journal
Archives of Toxicology
Expert Opinion on Drug Metabolism & Toxicology
Alternatives to Laboratory Animals
Altex
Chem Res Toxicol
Chemico-Biological Interactions
Computational Toxicology
Critical Reviews in Toxicology
Current Pharmaceutical Design
Environmental Sciences Europe
Environmental Toxicology and Pharmacology
Food and Chemical Toxicology
Frontiers in Cellular Neuroscience
Frontiers in Pharmacology
Hepatotolgy
International Journal of Molecular Sciences
iScience
Journal of Computer-Aided Molecular Design
Mutat Res Gen Tox En
Nature Reviews Drug Discovery
Regulatory Toxicology and Pharmacology
Science of the Total Environment
Scientific Reports
Stem Cell Reports
The Toxicologist Supplement to Toxicological Sciences
Toxicology and Applied Pharmacology
Toxicology in Vitro
Toxicology Letters
Toxicology Research
Trends in Biotechnology
Trends in Pharmacological Sciences
Biochemical Pharmacology
Bioinformatics
Biomaterials
Biomedicines
BMC Cancer
Cell Biology and Toxicology
Cell Death & Differentiation
Cell Stem Cell
Cells
Computational Toxicology: Risk Assessment for Chemicals
EFSA Journal
Environment International
Environmental Science and Pollution Research
F1000Research
Frontiers in Genetics
Future Science
HAL Archives
Journal of Chemical Information and Modeling
Journal of Cheminformatics
Journal of Proteome Research
Methods in Molecular Biology
Molecular Informatics
Molecular nutrition & Food Research
Mutagenesis
Nature Protocols
npj Systems Biology and Applications
Nucleic Acids Research
Pharmaceutical Research
PLoS Computational Biology
PLoS One
Reproductive Toxicology
Research Square
Toxicological Sciences
Toxics
Sort By Year
A quantitative AOP of mitochondrial toxicity based on data from three cell lines
2022 | Toxicology in Vitro
Tebby Cleo, Wang Gao, Delp Johannes, Carta Giada, van der Stel Wanda, Leist Marcel, Jennings Paul, van de Water Bob, Bois Frederic Y
A Novel UPLC-MS Metabolomic Analysis-Based Strategy to Monitor the Course and Extent of iPSC Differentiation to Hepatocytes
2022 | Journal of Proteome Research
Moreno-Torres Marta, Kumar Manoj, García-Llorens Guillem, Quintás Guillermo, Tricot Tine, Boon Ruben, Tolosa Laia, Toprakhisar Burak, Chesnais François, Verfaillie Catherine M, Castell Jose V
Metabolically Improved Stem Cell Derived Hepatocyte-Like Cells Support HBV Life Cycle and Are a Promising Tool for HBV Studies and Antiviral Drug Screenings
2022 | Biomedicines
Tricot Tine, Thibaut Hendrik J., Abbasi Kayvan, Boon Ruben, Helsen Nicky, Kumar Manoj, Neyts Johan, Verfaillie Catherine M
Mapping the cellular response to electron transport chain inhibitors reveals selective signaling networks triggered by mitochondrial perturbation
2022 | Archives of Toxicology
van der Stel Wanda, Yang Huan, Vrijenhoek Nanette G., Schimming Johannes P., Callegaro Giulia, Carta Giada, Darici Salihanur, Delp Johannes, Forsby Anna, White Andrew, le Dévédec Sylvia, Leist Marcel, Jennings Paul, Beltman Joost B, van de Water Bob, Danen Erik
Keywords: Mitochondrial toxicity ETC complex inhibitors High-content imaging TempO-Seq DILI
Integrate mechanistic evidence from new approach methodologies (NAMs) into a read-across assessment to characterise trends in shared mode of action
2022 | Toxicology in Vitro
Escher Sylvia E., Aguayo-Orozco Alejandro, Benfenati Emilio, Bitsch Annette, Brotzmann Katharina, Bois Frederic Y, van der Burg Bart, Castel Jose, Exner Thomas, Gadaleta Domenico, Gardner Iain, Goldmann Daria, Hatley Oliver, Golbamaki Nazanin, Graepel Rabea, Jennings Paul, Limonciel Alice, Long Anthony, Maclennan Richard, Mombelli Enrico, Norinder Ulf, Jain Sankalp, Santos Capinha Liliana, Taboureau Olivier, Tolosa Laia, Vrijenhoek Nanette G., van Vugt-Lussenburg Barbara M A, Walker Paul, van de Water Bob, Wehr Matthias, White Andrew, Zdrazil Barbara, Fisher Ciarán
Specificity of time- and dose-dependent morphological endpoints in the fish embryo acute toxicity (FET) test for substances with diverse modes of action: the search for a “fingerprint”
2022 | Environmental Science and Pollution Research
von Hellfeld Rebecca, Pannetier Pauline, Braunbeck Thomas
Mapping the cellular response to electron transport chain inhibitors reveals selective signaling networks triggered by mitochondrial perturbation
2022 | Archives of Toxicology
van der Stel Wanda, Yang Huan, Vrijenhoek Nanette G., Schimming Johannes P., Callegaro Giulia, Carta Giada, Darici Salihanur, Delp Johannes, Forsby Anna, White Andrew, le Dévédec Sylvia, Leist Marcel, Jennings Paul, Beltman Joost B, van de Water Bob, Danen Erik
Keywords: Mitochondrial toxicity; ETC complex inhibitors; High-content imaging; TempO-Seq; DILI
Fluorescent tagging of endogenous Heme oxygenase-1 in human induced pluripotent stem cells for high content imaging of oxidative stress in various differentiated lineages
2021 | Archives of Toxicology volume 95, pages 3285–3302 (2021)
Snijders Kirsten E., Fehér Anita, Táncos Zsuzsanna, Bock Istvan, Teglasi Annamaria, van den Berk Linda, Niemeijer Marije, Bouwman Peter, le Dévédec Sylvia, Moné Martijn J., Van Rossom Rob, Kumar Manoj, Wilmes Anja, Jennings Paul, Verfaillie Catherine M, Kobolák Julianna, ter Braak Bas, Dinnyés András, Van Den Bosch Ludo
Keywords: Oxidative stress; Reporter cells; Induced pluripotent stem cells; In vitro toxicology; Endogenous gene tagging; High content imaging
New approach methods (NAMs) supporting read-across: Two neurotoxicity AOP-based IATA case studies
2021 | ALTEX - Alternatives to animal experimentation, 38(4), pp. 615–635
van der Stel Wanda, Carta Giada, Eakins Julie, Delp Johannes, Suciu Ilinca, Forsby Anna, Cediel Ulloa Andrea Paola, Attoff Kristina, Troger Florentina, Kamp Hennicke, Gardner Iain, Zdrazil Barbara, Moné Martijn J., Ecker Gerhard F, Pastor Manuel, Gómez-Tamayo José Carlos, White Andrew, Danen Erik, Leist Marcel, Walker Paul, Jennings Paul, Bennekou Suzanne H., van de Water Bob
Keywords: in vitro mitochondrial toxicity neurotoxicity PBK-modelling uncertainty analysis
The in vitro assessment of the toxicity of volatile, oxidisable, redox-cycling compounds: phenols as an example
2021 | Archives of Toxicology volume 95, pages2109–2121 (2021)
Tolosa Laia, Martinez-Sena Teresa, Schimming Johannes P., Moro Erika, Escher Sylvia E., ter Braak Bas, van de Water Bob, Miranda M. A., van Vugt-Lussenburg Barbara M A, Castell Jose V
Keywords: Developmental neurotoxicity; Flame retardants; Human cell–based testing battery; 3D in vitro model; New approach methodologies; Hazard assessment
Stimulation of de novo glutathione synthesis by nitrofurantoin for enhanced resilience of hepatocytes
2021 | Cell Biology and Toxicology (2021)
Wijaya Lukas S., Rau Carina, Braun Theresa S., Marangoz Serif, Spegg Vincent, Vlasveld Matthijs, Albrecht Wiebke, Brecklinghaus Tim, Kamp Hennicke, Beltman Joost B, Hengstler Jan G., van de Water Bob, Leist Marcel, Schildknecht Stefan
Directed differentiation of human induced pluripotent stem cells to hepatic stellate cells
2021 | Nature Protocols
Vallverdu Julia, Martínez García de la Torre Raquel A., Mannaerts Inge, Verhulst Stefaan, Smout Ayla, Coll Mar, Ariño Silvia, Rubio-Tomás Teresa, Aguilar-Bravo Beatriz, Martínez-Sánchez Celia, Blaya Delia, Verfaillie Catherine M, van Grunsven Leo A., Sancho-Bru Pau
Integration of temporal single cell cellular stress response activity with logic-ODE modeling reveals activation of ATF4-CHOP axis as a critical predictor of drug-induced liver injury
2021 | Biochemical Pharmacology
Wijaya Lukas S., Trairatphisan Panuwat, Gabor Attila, Niemeijer Marije, Keet Jason, Alcalà Morera Ariadna, Snijders Kirsten E., Wink Steven, Yang Huan, Schildknecht Stefan, Stevens James L., Bouwman Peter, Kamp Hennicke, Hengstler Jan G., Beltman Joost B, Leist Marcel, le Dévédec Sylvia, Saez-Rodriguez Julio, van de Water Bob
Duijndam Britt, Goudriaan Annabel, van den Hoorn Tineke, van der Stel Wanda, le Dévédec Sylvia, Bouwman Peter, van der Laan Jan Willem, van de Water Bob
Keywords: Estrogen receptor alpha, fluorescent reporters, live-cell imaging, single cell
Systematic transcriptome-based comparison of cellular adaptive stress response activation networks in hepatic stem cell-derived progeny and primary human hepatocytes
2021 | Toxicology in Vitro
ter Braak Bas, Niemeijer Marije, Boon Ruben, Parmentier Céline, Baze Audrey, Richert Lysiane, Huppelschoten Suzanna, Wink Steven, Verfaillie Catherine M, van de Water Bob
Statement on advancing the assessment of chemical mixtures and their risks for human health and the environment
2020 | Environment International
Drakvik Paula E, Altenburger Rolf, Aoki Yasunobu, Backhaus Thomas, Bahadori Tina, Barouki Robert, Brack Werner, Cronin Mark T. D., Demeneix Barbara, Bennekou Suzanne H., van Klaveren Jacob, Kneuer Carsten, Kolossa-Gehring Marike, Lebret Erik, Posthuma Leo, Reiber Lena, Rider Cynthia, Ruegg Joelle, Testa Giuseppe, van der Burg Bart, van der Voet Hilko, Warhurst A. Michael, van de Water Bob, Yamazaki Kunihiko, Öberg Mattias, Bergman Åke
Multiparametric assessment of mitochondrial respiratory inhibition in HepG2 and RPTEC/TERT1 cells using a panel of mitochondrial targeting agrochemicals
2020 | Archives of Toxicology
van der Stel Wanda, Carta Giada, Eakins Julie, Darici Salihanur, Delp Johannes, Forsby Anna, Hougaard Bennekou Susanne, Gardner Iain, Leist Marcel, Danen Erik H J, Walker Paul, van de Water Bob, Jennings Paul
Biology-inspired Microphysiological systems to advance patient benefit and animal welfare in drug development
2020 | Altex
Marx Uwe, Akabane Takafumi, Andersson Tommy B., Baker Elizabeth, Beilmann Mario, Beken Sonja, Brendler-Schwaab Susanne, Cirit Murat, David Rhiannon, Dehne Eva-Maria, Durieux Isabell, Ewart Lorna, Fitzpatrick Suzanne C, Frey Olivier, Griffith Linda G., Hamilton Geraldine A., Hartung Thomas, Hoeng Julia, Hogberg Helena T, Hughes David J., Ingber Donald E., Iskandar Anita, Kanamori Toshiyuki, Kojima Hajime, Kuehnl Jochen, Leist Marcel, Li Bo, Loskill Peter, Mendrick Donna L., Neumann Thomas, Pallocca Giorgia, Rusyn Ivan, Smirnova Lena, Steger-Hartmann Thomas, Tagle Danilo A., Tonevitsky Alexander, Tsyb Sergej, Trapecar Martin, van de Water Bob, van den Eijnden-van Raaij Janny, Vulto Paul, Watanabe Kengo, Wolf Armin, Zhou Xiaobing, Roth Adrian
The EU-ToxRisk method documentation, data processing and chemical testing pipeline for the regulatory use of new approach methods
2020 | Archives of Toxicology
Krebs Alice, van Vugt-Lussenburg Barbara M A, Waldmann Tanja, Albrecht Wiebke, Boei Jan J, ter Braak Bas, Brajnik Maja, Braunbeck Thomas, Brecklinghaus Tim, Exner Thomas, Fisher Ciarán, Fluri David A, Forsby Anna, Hengstler Jan G., Holzer Anna-Katharina, Janstova Zofia, Jennings Paul, Kisitu Jaffar, Kobolák Julianna, Kumar Manoj, Limonciel Alice, Lundqvist Jessica, Mihalik Balázs, Moritz Wolfgang, Pallocca Giorgia, Cediel Ulloa Andrea Paola, Pastor Manuel, Rovida Costanza, Sarkans Ugis, Schimming Johannes P, Schmidt Béla Z., Stoeber Regina, Strassfeld Tobias, van de Water Bob, Wilmes Anja, van der Burg Bart, Verfaillie Catherine M, von Hellfeld Rebecca, Vrieling Harry, Vrijenhoek Nanette G, Leist Marcel
Sillé Fenna C. M., Karakitsios Spyros, Kleensang Andre, Koehler Kirsten, Maertens Alexandra, Miller Gary W, Prasse Carsten, Quiros-Alcala Lesliam, Ramachandran Gurumurthy, Rappaport Stephen M., Rule Ana M, Sarigiannis Denis, Smirnova Lena, Hartung Thomas
Setting the stage for next-generation risk assessment with non-animal approaches: the EU-ToxRisk project experience
2020 | Archives of Toxicology
Moné Martijn J., Pallocca Giorgia, Escher Sylvia E., Exner Thomas, Herzler Matthias, Hougaard Bennekou Susanne, Kamp Hennicke, Kroese E. Dinant, Leist Marcel, Steger-Hartmann Thomas, van de Water Bob
Adverse effects in the fish embryo acute toxicity (FET) test: a catalogue of unspecific morphological changes versus more specific effects in zebrafish (Danio rerio) embryos
2020 | Environmental Sciences Europe
von Hellfeld Rebecca, Brotzmann Katharina, Baumann Lisa, Strecker Ruben, Braunbeck Thomas
Towards grouping concepts based on new approach methodologies in chemical hazard assessment: the read-across approach of the EU-ToxRisk project
2019 | Archives of Toxicology
Escher Sylvia E., Kamp Hennicke, Bennekou Suzanne H., Bitsch Annette, Fisher Ciarán, Graepel Rabea, Hengstler Jan G., Herzler Matthias, Knight Derek, Leist Marcel, Norinder Ulf, Ouedraogo Gladys, Pastor Manuel, Stuard Sharon B., White Andrew, Zdrazil Barbara, van de Water Bob, Kroese E. Dinant
A systematic analysis of Nrf2 pathway activation dynamics during repeated xenobiotic exposure
2019 | Archives of Toxicology
Bischoff Luc J. M., Kuijper Isoude A, Schimming Johannes P, Wolters Liesanne, ter Braak Bas, Langenberg Jan P., Noort Daan, Beltman Joost B, van de Water Bob
Current EU research activities on combined exposure to multiple chemicals
2019 | Environment International
Bopp Stephanie K, Barouki Robert, Brack Werner, Dalla Costa Silvia, Dorne Jean Lou, Drakvik Paula E, Faust Michael, Karjalainen Tuomo K, Kephalopoulos Stylianos, van Klaveren Jacob, Kolossa-Gehring Marike, Kortenkamp Andreas, Lebret Erik, Lettieri Teresa, Nørager Sofie, Ruegg Joelle, Tarazona Jose V, Trier Xenia, van de Water Bob, van Gils Jos, Bergman Åke
Characterisation of the NRF2 transcriptional network and its response to chemical insult in primary human hepatocytes: implications for prediction of drug-induced liver injury
2019 | Archives of Toxicology
Copple Ian M., den Hollander Wouter, Callegaro Giulia, Mutter Fiona E., Maggs James L., Schofield Amy L., Rainbow Lucille, Fang Yongxiang, Sutherland Jeffrey J., Ellis Ewa C., Ingelman-Sundberg Magnus, Fenwick Stephen W., Goldring Christopher E., van de Water Bob, Stevens James L., Park B. Kevin
Paradigm shift in safety assessment using new approach methods: The EU-ToxRisk strategy
2019 | Current Opinion in Toxicology Volume 15, June 2019, Pages 33-39
Graepel Rabea, ter Braak Bas, Escher Sylvia E., Fisher Ciarán, Gardner Iain, Kamp Hennicke, Kroese E. Dinant, Leist Marcel, Moné Martijn J., Pastor Manuel, van de Water Bob
High-throughput confocal imaging of differentiated 3D liver-like spheroid cellular stress response reporters for identification of drug-induced liver injury liability
2019 | Archives of Toxicology volume 93, pages 2895–2911 (2019)
Hiemstra Steven, Ramaiahgari Sreenivasa C., Wink Steven, Callegaro Giulia, Meerman John, Jennen Danyel, van den Nieuwendijk Karen, Dankers Anita, Snoeys Jan, de Bont Hans, Price Leo, van de Water Bob
A structure-activity relationship linking non-planar PCBs to functional deficits of neural crest cells: new roles for connexins
2018 | Archives of Toxicology
Nyffeler Johanna, Chovancova Petra, Dolde Xenia, Holzer Anna-Katharina, Purvanov Vladimir, Kindinger Ilona, Kerins Anna, Higton David, Silvester Steve, van Vugt-Lussenburg Barbara M A, Glaab Enrico, van der Burg Bart, Maclennan Richard, Legler Daniel F, Leist Marcel
Validation of gene expression profiles from cholestatic hepatotoxicants in vitro against human in vivo cholestasis
2018 | Toxicology in Vitro
Van den Hof Wim F P M, Coonen Maarten L J, van Herwijnen Marcel, Brauers Karen, Jennen Danyel, Olde Damink Steven W M, Schaap Frank G, Kleinjans Jos C S
Model-based identification of TNFα-induced IKKβ-mediated and IκBα-mediated regulation of NFκB signal transduction as a tool to quantify the impact of drug-induced liver injury compounds
2018 | npj Systems Biology and Applications
Oppelt Angela, Kaschek Daniel, Huppelschoten Suzanna, Sison-Young Rowena, Zhang Fang, Buck-Wiese Marie, Herrmann Franziska, Malkusch Sebastian, Krüger Carmen L., Meub Mara, Merkt Benjamin, Zimmermann Lea, Schofield Amy L., Jones Robert P., Malik Hassan, Schilling Marcel, Heilemann Mike, van de Water Bob, Goldring Christopher E., Park B. Kevin, Timmer Jens, Klingmüller Ursula
Bile Microinfarcts in Cholestasis Are Initiated by Rupture of the Apical Hepatocyte Membrane and Cause Shunting of Bile to Sinusoidal Blood
2018 | Hepatology
Ghallab Ahmed, Hofmann Thomas, Sezgin Selahaddin, Vartak Nachiket, Hassan Reham, Zaza Ayham, Godoy Patricio, Schneider Kai Markus, Guenther Georgia, Ahmed Yasser A., Abbas Aya A., Keitel Verena, Kuepfer Lars, Dooley Steven, Lammert Frank, Trautwein Christian, Spiteller Michael, Drasdo Dirk, Hofmann Alan F., Jansen Peter L.M., Hengstler Jan G., Reif Raymond
Comparison of base-line and chemical-induced transcriptomic responses in HepaRG and RPTEC/TERT1 cells using TempO-Seq
2018 | Archives of Toxicology
Limonciel Alice, Ates Gamze, Carta Giada, Wilmes Anja, Watzele Manfred, Shepard Peter J., VanSteenhouse Harper C., Seligmann Bruce, Yeakley Joanne M., van de Water Bob, Vinken Mathieu, Jennings Paul
Relevance of the incubation period in cytotoxicity testing with primary human hepatocytes
2018 | Archives of Toxicology
Gu Xiaolong, Albrecht Wiebke, Edlund Karolina, Kappenberg Franziska, Rahnenführer Jörg, Leist Marcel, Moritz Wolfgang, Godoy Patricio, Cadenas Cristina, Marchan Rosemarie, Brecklinghaus Tim, Tolosa Pardo Laia, Castell Jose V, Gardner Iain, Han Bo, Hengstler Jan G., Stoeber Regina
A new semi-automated workflow for chemical data retrieval and quality checking for modeling applications
2018 | Journal of Cheminformatics
Gadaleta Domenico, Lombardo Anna, Toma Cosimo, Benfenati Emilio, Tredwell Gregory D., Wilmes Anja, Aschauer Lydia, Siskos Alexandros P., Sachinidis Agapios, Keun Hector C., Kopp-Schneider Annette, de Kok Theo M., Kleinjans Jos C S, Jennings Paul
OECD/EFSA workshop on developmental neurotoxicity (DNT): The use of non-animal test methods for regulatory purposes
2017 | Altex
Fritsche Ellen, Crofton Kevin M, Hernandez Antonio F, Hougaard Bennekou Susanne, Leist Marcel, Bal-Price Anna, Reaves Elissa, Wilks Martin F, Terron Andrea, Sachana Magdalini, Gourmelon Anne
Ab initio chemical safety assessment: A workflow based on exposure considerations and non-animal methods
2017 | Computational Toxicology
Berggren Elisabet, White Andrew, Ouedraogo Gladys, Paini Alicia, Richarz Andrea-Nicole, Bois Frederic Y, Exner Thomas, Leite Sofia, van Grunsven Leo A., Worth Andrew, Mahony Catherine
Comprehensive Landscape of Nrf2 and p53 Pathway Activation Dynamics by Oxidative Stress and DNA Damage
2017 | Chem Res Toxicol
Hiemstra Steven W, Niemeijer Marije, Koedoot Esmee, Wink Steven, Klip Janna E, Vlasveld Matthijs, de Zeeuw Elisabeth, van Os Bram, White Andrew, van de Water Bob
Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals: example lists and criteria for their selection and use
2016 | Altex
Aschner Michael, Ceccatelli Sandra, Daneshian Mardas, Fritsche Ellen, Hasiwa Nina, Hartung Thomas, Hogberg Helena T, Leist Marcel, Li Abby, Mundi William R, Piersma Aldert H, Bal-Price Anna, Seiler Andrea, Westerink Remco H S, Zimmer Bastian, Lein Pamela J
Definition of transcriptome‑based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP‑Toxukn and STOP‑Toxukk tests