EU-ToxRisk Final Symposium

Case studies

EU-ToxRisk publications

EU-ToxRisk Final Symposium

DAY 1

 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

Martijn Mone/Giorgia Pallocca 

The EU-ToxRisk case study approach  PDF

Sylvia Escher/Susanne H.Bennekou

Prediction of microvesicular liver steatosis – a RAx CS: the regulatory impact  PDF

Sylvia Escher

Prediction of microvesicular liver steatosis – a RAx CS: the applied technology  PDF

Sylvia Escher

RAx CS to predict developmental and reproductive toxicity: the regulatory impact  PDF

Dinant Kroese

RAx CS to predict developmental and reproductive toxicity: the applied technology  PDF

Dinant Kroese

Use of integrated approaches to assess neurotoxicity: the regulatory impact  PDF

Bob van de Water

Use of integrated approaches to assess neurotoxicity: the applied technology  PDF

Bob van de Water

High-concern toxicity profile screening: the regulatory impact  PDF

Bob van de Water

High-concern toxicity profile screening: the applied technology  PDF

Bob van de Water

NGRA approach for insecticides induced-DNT: the regulatory impact  PDF

Susanne H. Bennekou

Approach for insecticides induced-DNT: the applied technology NGRA  PDF

Susanne H. Bennekou

Case Study on multi-organ metabolism: the regulatory impact  PDF

Paul Jennings

Case Study on multi-organ metabolism: the applied technology

Paul Jennings

Poster session II: from test system development to commercialization

Technology

An overview of the EU-ToxRisk technologies and sustainable derived datasets  PDF

Johannes Schimming/Martijn Mone

Computational prediction tools used and developed in the project  PDF

Manuel Pastor

PBPK methods used and established in the project  PDF

Iain Gardner

High throughput transcriptomics methods established in the project  PDF

Bob van de Water

High throughput cell reporter tools used and developed in the project  PDF

Catherine Verfaillie

EU-ToxRisk test methods comparison in CSy  PDF

Marcel Leist

Advanced test methods developed in the EU-ToxRisk project  PDF

Wolfgang Moritz

From in vitro to human. Translational strategies in EU-ToxRisk  PDF

Ian Cotgreave

EU-ToxRisk computational methods based on qAOP  PDF

Frederic Bois

Databasing and data sustainability: the EU-ToxRisk approach for data reuse  PDF

Ugis Sarkans

 

Read-Across Strategy

Impact #2: Improved toxicological knowledge to advance read-across procedures  PDF

Hennicke Kamp/Dinant Kroese/Sylvia Escher

The EU-ToxRisk Read-Across Advisory Document  PDF

Hennicke Kamp/Dinant Kroese/Sylvia Escher

 

Commercialization

Impact #3: Commercial exploitation of developed toxicological tests & services  PDF

Bart van de Burg/Barry Hardy

The EU-ToxRisk Commercialization Partnership  PDF

Barry Hardy

The EU-ToxRisk Syngenta Case Study  PDF

Rabea Graepel/Damiano

Dermal Exposure to Propylparaben: joint RAx case study with Cosmetics Europe  PDF

Gladys Ouedraogo

Poster session : Regulatory Impact

Impact #4: Advancement of international co-operation in toxicology  PDF

Giorgia Pallocca/Martijn Mone 

Communication strategy to harmonize research and regulatory needs  PDF

Giorgia Pallocca/Martijn Mone

The ToxTemp document  PDF

Marcel Leist

EU-ToxRisk’s sustainability plan  PDF  

Bob van de Water

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

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]


OECD IATA report

Report [link]; Annex II [link]; Annex III [link]


Contributors

ITEM, UL, UM, RISE, INERIS, BDS, TNO, DC, IRFMN, SYMCYP, VUA, UOF, UNIVIE, HULAFE, UCPH, CRX, IS, UHEI, L’OREAL, LHASA.

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]


OECD IATA report

Report [link]; Annex II [link]; Annex III [link]


Contributors

TNO, UKN, UM, INERIS, BDS, IFADO, SIMCYP, LUMC, ROCHE, UHEI, NC3Rs, UNIVIE, RISE.

Peroxisome proliferation / Organic anion transporter interference

Keywords

REACH, read-across, RDT, systemic toxicity, NAM, metabolomics


Objective

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]


OECD IATA report

Report [link], Annex I [link]


Contributors

UL, UKN, BASF, Unilever, RISE, KI, BDS, ITEM, VU, UPF, UNIVIE, HULAFE, CRX, DTU, L’Oreal

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]


OECD IATA report

Report [link]; Annex I [link]


Contributors

UL, UKN, BASF, Unilever, RISE, KI, BDS, ITEM, VU, UPF, UNIVIE, HULAFE, CRX, DTU, L’Oreal

Liver toxicity

Keywords

RDT, liver toxicity, NAM


Objective

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:

  1. To predict blood concentrations of chemicals that cause an increased risk of hepatotoxicity and to identify concentration ranges that can be considered harmless.
  2. 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.


Publications

Berggren et al. (2017) [link]


OECD IATA report

Report [link]


Contributors

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.


Contributors

ITEM, UL, BDS, VU, LUMC, HULAFE, IRFM, CRX, SIMCYP.

High-concern toxicity profile screening

Keywords

RDT/DART ab initio


Objective

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.


Contributors

UL, UKN, BASF, Unilever, BDS, TNO, ITEM, EWC, IRFMN, LUMC, UPF, EMBL-EBI, UNIVIE, HULAFE, CRX, L’Oreal, LHASA, VU, RISE.

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]


Contributors

DTU, UKN INERIS, BIOT, SIMCYP, UHEI, VU, SU.

Multi-organ metabolism (MOM)

Keywords

REACH, RTD, hepatotoxicity, nephrotoxicity, metabolism, kinetics


Objective

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.

EU-ToxRisk publications 

Publications of the EU-ToxRisk project

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  • Identifying multi-scale translational safety biomarkers using a network-based systems approach
    2023 | iScience
    Callegaro Giulia
    Callegaro Giulia, Schimming Johannes P, Piñero González Janet, Kunnen Steven J., Wijaya Lukas S., Trairatphisan Panuwat, van den Berk Linda, Beetsma Kim, Furlong Laura I., Sutherland Jeffrey J., Mollon Jennifer, Stevens James L., van de Water Bob
    DOI: 10.1016/j.isci.2023.106094  RISK-HUNT3R
    PMID: 36895646
    READ MORE
  • Collaborative SAR Modeling and Prospective In Vitro Validation of Oxidative Stress Activation in Human HepG2 Cells
    2023 | Journal of Chemical Information and Modeling
    Béquignon Olivier J.M.
    Béquignon Olivier J.M., Gómez-Tamayo José C., Lenselink Eelke B., Wink Steven, Hiemstra Steven, Lam Chi Chung, Gadaleta Domenico, Roncaglioni Alessandra, Norinder Ulf, van de Water Bob, Pastor Manuel, van Westen Gerard J.P.
    DOI: 10.1021/acs.jcim.3c00220  RISK-HUNT3R
    PMID: 37616385
    READ MORE
  • Identification of the bacterial metabolite aerugine as potential trigger of human dopaminergic neurodegeneration
    2023 | Environment International
    Ückert Anna-Katharina
    Ückert Anna-Katharina, Rütschlin Sina, Gutbier Simon, Wörz Nathalie Christine, Miah Mahfuzur R., Martins Airton C., Hauer Isa, Holzer Anna-Katharina, Meyburg Birthe, Mix Ann-Kathrin, Hauck Christof, Aschner Michael, Böttcher Thomas, Leist Marcel
    DOI: 10.1016/j.envint.2023.108229  RISK-HUNT3R
    PMID: 37797477
    READ MORE
  • A quantitative AOP of mitochondrial toxicity based on data from three cell lines
    2022 | Toxicology in Vitro
    Tebby Cleo
    Tebby Cleo, Wang Gao, Delp Johannes, Carta Giada, van der Stel Wanda, Leist Marcel, Jennings Paul, van de Water Bob, Bois Frederic Y
    DOI: 10.1016/j.tiv.2022.105345  RISK-HUNT3R
    PMID: 35278637
    READ MORE
  • 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
    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
    DOI: 10.1021/acs.jproteome.1c00779  RISK-HUNT3R
    PMID: 34982937
    READ MORE
  • Specific attenuation of purinergic signaling during bortezomib-induced peripheral neuropathy
    2022 | International Journal of Molecular Sciences
    Holzer Anna-Katharina
    Holzer Anna-Katharina, Suciu Ilinca, Goj Thomas, Karreman Christiaan, Leist Marcel
    DOI: 10.1101/2022.02.17.479688  RISK-HUNT3R
    PMID: 35409095
    READ MORE
  • Zebrafish embryo neonicotinoid developmental neurotoxicity in the FET test and behavioral assays
    2022 | ALTEX
    von Hellfeld Rebecca
    von Hellfeld Rebecca, Ovcharova Viktoriia, Bevan Samantha, Lazaridi Maria-Agapi, Bauch Caroline, Walker Paul, Hougaard Bennekou Susanne, Forsby Anna, Braunbeck Thomas
    DOI: 10.14573/altex.2111021  RISK-HUNT3R
    PMID:
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  • 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
    Tricot Tine, Thibaut Hendrik J., Abbasi Kayvan, Boon Ruben, Helsen Nicky, Kumar Manoj, Neyts Johan, Verfaillie Catherine M
    DOI: 10.3390/biomedicines10020268  RISK-HUNT3R
    PMID: 35203482
    READ MORE
  • Application of high-throughput transcriptomics for mechanism-based biological read-across of short-chain carboxylic acid analogues of valproic acid
    2022 | ALTEX
    Vrijenhoek Nanette G.
    Vrijenhoek Nanette G., Wehr Matthias, Kunnen Steven J., Wijaya Lukas S., Callegaro Giulia, Moné Martijn J., Escher Sylvia E., van de Water Bob
    DOI: 10.14573/altex.2107261  RISK-HUNT3R
    PMID:
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  • HiPSC-Derived Hepatocyte-like Cells Can Be Used as a Model for Transcriptomics-Based Study of Chemical Toxicity
    2022 | Toxics
    Ghosh Sreya
    Ghosh Sreya, De Smedt Jonathan, Tricot Tine, Proença Susana, Kumar Manoj, Nami Fatemeharefeh, Vanwelden Thomas, Vidal Niels, Jennings Paul, Kramer Nynke I., Verfaillie Catherine M
    DOI: 10.3390/toxics10010001  RISK-HUNT3R
    PMID:
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  • 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
    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
    DOI: 10.1007/s00204-021-03160-7  RISK-HUNT3R
    PMID:
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  • The hepatocyte export carrier inhibition assay improves the separation of hepatotoxic from non-hepatotoxic compounds
    2022 | Chemico-Biological Interactions
    Brecklinghaus Tim
    Brecklinghaus Tim, Albrecht Wiebke, Kappenberg Franziska, Duda Julia, Vartak Nachiket, Edlund Karolina, Marchan Rosemarie, Ghallab Ahmed, Cadenas Cristina, Guenther Georgia, Leist Marcel, Zhang Mian, Gardner Iain, Reinders Jörg, Russel Frans GM., Foster Alison J., Williams Dominic P., Damle-Vartak Amruta, Grandits Melanie, Ecker Gerhard F, Kittana Naim, Rahnenführer Jörg, Hengstler Jan G.
    DOI: 10.1016/j.cbi.2021.109728  RISK-HUNT3R
    PMID: 34717914
    READ MORE
  • 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.
    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
    DOI: 10.1016/j.tiv.2021.105269  RISK-HUNT3R
    PMID: 34757180
    READ MORE
  • 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
    von Hellfeld Rebecca, Pannetier Pauline, Braunbeck Thomas
    DOI: 10.1007/s11356-021-16354-4  RISK-HUNT3R
    PMID:
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  • 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
    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
    DOI: 10.1007/s00204-021-03160-7  RISK-HUNT3R
    PMID:
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  • Transcriptomic Cross-Species Analysis of Chronic Liver Disease Reveals Consistent Regulation Between Humans and Mice
    2022 | Hepatology Communications
    Holland Christian H.
    Holland Christian H., Ramirez Flores Ricardo O., Myllys Maiju, Hassan Reham, Edlund Karolina, Hofmann Ute, Marchan Rosemarie, Cadenas Cristina, Reinders Jörg, Höhme Stefan, Seddek Abdel-Latif, Dooley Steven, Keitel Verena, Godoy Patricio, Begher-Tibbe Brigitte, Trautwein Christian, Rupp Christian, Mueller Sebastian, Longerich Thomas, Hengstler Jan G., Saez-Rodriguez Julio, Ghallab Ahmed
    DOI: 10.1002/hep4.1797  RISK-HUNT3R
    PMID:
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  • Towards an advanced testing strategy for genotoxicity using image-based 2D and 3D HepG2 DNA damage response fluorescent protein reporters
    2022 | Mutagenesis, Volume 37, Issue 2, April 2022, Pages 130–142
    ter Braak Bas
    ter Braak Bas, Niemeijer Marije, Wolters Liesanne, le Dévédec Sylvia, Bouwman Peter, van de Water Bob
    DOI: 10.1093/mutage/geab031  RISK-HUNT3R
    PMID:
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  • Combining In Vivo Data with In Silico Predictions for Modeling Hepatic Steatosis by Using Stratified Bagging and Conformal Prediction
    2021 | Chem. Res. Toxicol
    Jain Sankalp
    Jain Sankalp, Norinder Ulf, Escher Sylvia E., Zdrazil Barbara
    DOI: 10.1021/acs.chemrestox.0c00511  RISK-HUNT3R
    PMID:
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  • A quantitative in vivo assay for craniofacial developmental toxicity of histone deacetylases
    2021 | Toxicology Letters
    Koch Bjorn
    Koch Bjorn, Spaink Herman, Meijer Annemarie H
    DOI: 10.1016/j.toxlet.2021.02.005  RISK-HUNT3R
    PMID:
    READ MORE
  • Evaluation of the global performance of eight in silico skin sensitization models using human data
    2021 | Altex
    Golden Emily
    Golden Emily, Macmillan Donna S., Dameron Greg, Kern Petra, Hartung Thomas, Maertens Alexandra
    DOI: https://doi.org/10.14573/altex.1911261  RISK-HUNT3R
    PMID:
    READ MORE
  • Acute effects of the imidacloprid metabolite desnitro-imidacloprid on human nACh receptors relevant for neuronal signaling
    2021 | Archives of Toxicology
    Loser Dominik
    Loser Dominik, Grillberger Karin, Hinojosa Maria G., Blum Jonathan, Hauser Karin, Danker Timm, Johansson Ylva, Möller Clemens, Nicke Annette, Bennekou Suzanne H., Gardner Iain, Bauch Caroline, Walker Paul, Forsby Anna, Ecker Gerhard F, Kraushaar Udo, Leist Marcel
    DOI: 10.1007/s00204-021-03168-z  RISK-HUNT3R
    PMID:
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  • Neurotoxic effects in zebrafish embryos by valproic acid and nine of its analogues: the fish-mouse connection?
    2021 | Archives of Toxicology
    Brotzmann Katharina
    Brotzmann Katharina, Wolterbeek André, Kroese E. Dinant, Braunbeck Thomas
    DOI: 10.1007/s00204-020-02928-7  RISK-HUNT3R
    PMID:
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  • Neurodevelopmental toxicity assessment of flame retardants using a human DNT in vitro testing battery
    2021 | Cell Biology and Toxicology
    Klose Jördis
    Klose Jördis, Pahl Melanie, Bartmann Kristina, Bendt Farina, Blum Jonathan, Dolde Xenia, Förster Nils, Holzer Anna-Katharina, Hübenthal Ulrike, Keßel Hagen Eike, Koch Katharina, Masjosthusmann Stefan, Schneider Sabine, Stürzl Lynn-Christin, Woeste Selina, Rossi Andrea, Covaci Adrian, Behl Mamta, Leist Marcel, Tigges Julia, Fritsche Ellen
    DOI: 10.1007/s10565-021-09603-2  RISK-HUNT3R
    PMID: 33969458
    READ MORE
  • PLoS Computational Biology
    2021 | PLoS Computational Biology
    Hanspers Kristina
    Hanspers Kristina, Kutmon Martina, Coort Susan L., Digles Daniela, Dupuis Lauren J., Ehrhart Friederike, Hu Finterly, Lopes Elisson N., Martens Marvin, Pham Nhung, Shin Woosub, Slenter Denise N., Waagmeester Andra, Willighagen Egon L., Winckers Laurent A., Evelo Chris T., Pico Alexander R.
    DOI: 10.1371/journal.pcbi.1009226  RISK-HUNT3R
    PMID:
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  • ELIXIR and Toxicology: a community in development
    2021 | F1000Research
    Martens Marvin
    Martens Marvin, Stierum Rob, Schymanski Emma L., Evelo Chris T., Aalizadeh Reza, Aladjov Hristo, Arturi Kasia, Audouze Karine, Babica Pavel, Berka Karel, Bessems Jos, Blaha Ludek, Bolton Evan E., Cases Montserrat, Damalas Dimitrios Ε., Dave Kirtan, Dilger Marco, Exner Thomas, Geerke Daan P., Grafström Roland, Gray Alasdair, Hancock John M., Hollert Henner, Jeliazkova Nina, Jennen Danyel, Jourdan Fabien, Kahlem Pascal, Klanova Jana, Kleinjans Jos C S, Kondic Todor, Kone Boï, Lynch Iseult, Maran Uko, Martinez Cuesta Sergio, Ménager Hervé, Neumann Thomas, Nymark Penny, Oberacher Herbert, Ramirez Noelia, Remy Sylvie, Rocca-Serra Philippe, Salek Reza M., Sallach Brett, Sansone Susanna-Assunta, Sanz Ferran, Sarimveis Haralambos, Sarntivijai Sirarat, Schulze Tobias, Slobodnik Jaroslav, Spjuth Ola, Tedds Jonathan, Thomaidis Nikolaos, Weber Ralf J.M., van Westen Gerard J.P., Wheelock Craig E., William Antony J., Witters Hilda, Zdrazil Barbara, Županič Anže, Willighagen Egon L.
    DOI: 10.12688/f1000research.74502.1  RISK-HUNT3R
    PMID:
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  • A fully defined matrix to support a pluripotent stem cell derived multi-cell-liver steatohepatitis and fibrosis model
    2021 | Biomaterials
    Kumar Manoj
    Kumar Manoj, Toprakhisar Burak, van Haele Matthias, Antoranz Asier, Boon Ruben, Chesnais François, De Smedt Jonathan, Tricot Tine, Idoype Teresa Izuel, Canella Marco, Tilliole Pierre, De Boeck Jolan, Bajaj Manmohan, Bosisio Francesca Maria, Roskams Tania, van Grunsven Leo A., Verfaillie Catherine M
    DOI: 10.1016/j.biomaterials.2021.121006  RISK-HUNT3R
    PMID:
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  • 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.
    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
    DOI: 10.1007/s00204-021-03127-8  RISK-HUNT3R
    PMID:
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  • Identifying novel transcript biomarkers for hepatocellular carcinoma (HCC) using RNA-Seq datasets and machine learning
    2021 | BMC Cancer 21, 962 (2021)
    Gupta Rajinder
    Gupta Rajinder, Kleinjans Jos C S, Caiment Florian
    DOI: https://doi.org/10.1186/s12885-021-08704-9  RISK-HUNT3R
    PMID:
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  • Factors that Influence the Quality of Metabolomics Data in in Vitro Cell Toxicity Studies: A Systematic Survey
    2021 | Research Square
    Moreno-Torres Marta
    DOI: https://doi.org/10.21203/rs.3.rs-724307/v1  RISK-HUNT3R
    PMID:
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  • 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
    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
    DOI: https://doi.org/10.14573/altex.2103051  RISK-HUNT3R
    PMID:
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  • 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
    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
    DOI: https://doi.org/10.1007/s00204-021-03036-w  RISK-HUNT3R
    PMID:
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  • Flame: An Open Source Framework for Model Development, Hosting, and Usage in Production Environments
    2021 | Journal of Cheminformatics
    Pastor Manuel
    Pastor Manuel, Gómez-Tamayo José Carlos, Sanz Ferran
    DOI: https://doi.org/10.21203/rs.3.rs-107430/v1  RISK-HUNT3R
    PMID:
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  • Generation and characterization of iPSC-derived renal proximal tubule-like cells with extended stability
    2021 | Scientific Reports volume 11, Article number: 11575 (2021)
    Chandrasekaran Vidya
    Chandrasekaran Vidya, Carta Giada, da Costa Pereira Daniel, Gupta Rajinder, Murphy Cormac, Feifel Elisabeth, Kern Georg, Lechner Judith, Cavallo Anna Lina, Gupta Shailesh, Caiment Florian, Kleinjans Jos C S, Gstraunthaler Gerhard, Jennings Paul, Wilmes Anja
    DOI: https://doi.org/10.1038/s41598-021-89550-4  RISK-HUNT3R
    PMID:
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  • Neurodevelopmental toxicity assessment of flame retardants using a human DNT in vitro testing battery
    2021 | Cell Biology and Toxicology (2021)
    Klose Jördis
    Klose Jördis, Pahl Melanie, Bartmann Kristina, Bendt Farina, Blum Jonathan, Dolde Xenia, Förster Nils, Holzer Anna-Katharina, Hübenthal Ulrike, Keßel Hagen Eike, Koch Katharina, Masjosthusmann Stefan, Schneider Sabine, Stürzl Lynn-Christin, Woeste Selina, Rossi Andrea, Covaci Adrian, Behl Mamta, Leist Marcel, Tigges Julia, Fritsche Ellen
    DOI: https://doi.org/10.1007/s10565-021-09603-2  RISK-HUNT3R
    PMID:
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  • Stimulation of de novo glutathione synthesis by nitrofurantoin for enhanced resilience of hepatocytes
    2021 | Cell Biology and Toxicology (2021)
    Wijaya Lukas S.
    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
    DOI: https://doi.org/10.1007/s10565-021-09610-3  RISK-HUNT3R
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  • Directed differentiation of human induced pluripotent stem cells to hepatic stellate cells
    2021 | Nature Protocols
    Vallverdu Julia
    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
    DOI: 10.1038/s41596-021-00509-1  RISK-HUNT3R
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  • 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.
    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
    DOI: https://doi.org/10.1016/j.bcp.2021.114591  RISK-HUNT3R
    PMID:
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  • A human stem cell-derived test system for agents modifying neuronal N-methyl-D-aspartate-type glutamate receptor Ca2+-signalling
    2021 | Archives of Toxicology volume 95, pages 1703–1722 (2021)
    Klima Stefanie
    Klima Stefanie, Brüll Markus, Spreng Anna-Sophie, Suciu Ilinca, Falt Tjalda, Schwamborn Jens C., Waldmann Tanja, Karreman Christiaan, Leist Marcel
    DOI: https://doi.org/10.1007/s00204-021-03024-0  RISK-HUNT3R
    PMID:
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  • Physiologically Relevant Estrogen Receptor Alpha Pathway Reporters for Single-Cell Imaging-Based Carcinogenic Hazard Assessment of Estrogenic Compounds
    2021 | Toxicological Sciences, Volume 181, Issue 2, June 2021, Pages 187–198
    Duijndam Britt
    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
    DOI: https://doi.org/10.1093/toxsci/kfab037  RISK-HUNT3R
    PMID:
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  • 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
    ter Braak Bas, Niemeijer Marije, Boon Ruben, Parmentier Céline, Baze Audrey, Richert Lysiane, Huppelschoten Suzanna, Wink Steven, Verfaillie Catherine M, van de Water Bob
    DOI: 10.1016/j.tiv.2021.105107  RISK-HUNT3R
    PMID:
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  • Functional alterations by a subgroup of neonicotinoid pesticides in human dopaminergic neurons
    2021 | Archives of Toxicology volume 95, pages 2081–2107 (2021)
    Loser Dominik
    Loser Dominik, Hinojosa Maria G., Blum Jonathan, Schaefer Jasmin, Brüll Markus, Johansson Ylva, Suciu Ilinca, Grillberger Karin, Danker Timm, Möller Clemens, Gardner Iain, Ecker Gerhard F, Bennekou Suzanne H., Forsby Anna, Kraushaar Udo, Leist Marcel
    DOI: https://doi.org/10.1007/s00204-021-03031-1  RISK-HUNT3R
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  • Effective exposure of chemicals in in vitro cell systems: A review of chemical distribution models
    2021 | Toxicology in Vitro Volume 73, June 2021, 105133
    Proença Susana
    Proença Susana, Escher Beate I., Fischer Fabian C., Fisher Ciarán, Grégoire Sébastien, Hewitt Nicky J., Nicol Beate, Paini Alicia, Kramer Nynke I.
    DOI: https://doi.org/10.1016/j.tiv.2021.105133  RISK-HUNT3R
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  • Statement on advancing the assessment of chemical mixtures and their risks for human health and the environment
    2020 | Environment International
    Drakvik Paula E
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