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Jennings P.,Innsbruck Medical University | Schwarz M.,University of Tubingen | Landesmann B.,EU Joint Research Centre | Maggioni S.,Istituto di Ricerche Farmacologiche Mario Negri | And 4 more authors.
Archives of Toxicology | Year: 2014

There is an urgent need for the development of alternative methods to replace animal testing for the prediction of repeat dose chemical toxicity. To address this need, the European Commission and Cosmetics Europe have jointly funded a research program for ‘Safety Evaluation Ultimately Replacing Animal Testing.’ The goal of this program was the development of in vitro cellular systems and associated computational capabilities for the prediction of hepatic, cardiac, renal, neuronal, muscle, and skin toxicities. An essential component of this effort is the choice of appropriate reference compounds that can be used in the development and validation of assays. In this review, we focus on the selection of reference compounds for liver pathologies in the broad categories of cytotoxicity and lipid disorders. Mitochondrial impairment, oxidative stress, and apoptosis are considered under the category of cytotoxicity, while steatosis, cholestasis, and phospholipidosis are considered under the category of lipid dysregulation. We focused on four compound classes capable of initiating such events, i.e., chemically reactive compounds, compounds with specific cellular targets, compounds that modulate lipid regulatory networks, and compounds that disrupt the plasma membrane. We describe the molecular mechanisms of these compounds and the cellular response networks which they elicit. This information will be helpful to both improve our understanding of mode of action and help in the selection of appropriate mechanistic biomarkers, allowing us to progress the development of animal-free models with improved predictivity to the human situation. © 2014, Springer-Verlag Berlin Heidelberg. Source


Katsumiti A.,University of the Basque Country | Gilliland D.,EU Joint Research Centre | Arostegui I.,University of the Basque Country | Cajaraville M.P.,University of the Basque Country
Aquatic Toxicology | Year: 2014

CdS quantum dots (QDs) show a great promise for treatment and diagnosis of cancer and for targeted drug delivery, due to their size-tunable fluorescence and ease of functionalization for tissue targeting. In spite of their advantages it is important to determine if CdS QDs can exert toxicity on biological systems. In the present work, cytotoxicity of CdS QDs (5. nm) at a wide range of concentrations (0.001-100. mg Cd/L) was screened using neutral red (NR) and thiazolyl blue tetrazolium bromide (MTT) assays in isolated hemocytes and gill cells of mussels (Mytilus galloprovincialis). The mechanisms of action of CdS QDs were assessed at sublethal concentrations (0.31-5. mg Cd/L) in the same cell types through a series of functional in vitro assays: production of reactive oxygen species (ROS), catalase (CAT) activity, DNA damage, lysosomal acid phosphatase (AcP) activity, multixenobiotic resistance (MXR) transport activity, Na-K-ATPase activity (only in gill cells) and phagocytic activity and damage to actin cytoskeleton (only in hemocytes). Exposures to CdS QDs lasted for 24. h and were performed in parallel with exposures to bulk CdS and ionic Cd. Ionic Cd was the most toxic form to both cell types, followed by CdS QDs and bulk CdS. ROS production, DNA damage, AcP activity and MXR transport were significantly increased in both cell types exposed to the 3 forms of Cd. CAT activity increased in hemocytes exposed to the three forms of Cd while in gill cells only in those exposed to ionic Cd. No effects were found on hemocytes cytoskeleton integrity. Effects on phagocytosis were found in hemocytes exposed to bulk CdS and to CdS QDs at concentrations equal or higher than 1.25. mg Cd/L but not in those exposed to ionic Cd, indicating a particle-specific effect on phagocytosis. In conclusion, cell-mediated immunity and gill cell function represent significant targets for CdS QDs toxicity. © 2014 Elsevier B.V. Source


Matinga M.N.,P.O Box 31632 | Pinedo-Pascua I.,EU Joint Research Centre | Vervaeke J.,EU Joint Research Centre | Monforti-Ferrario F.,EU Joint Research Centre | Szabo S.,EU Joint Research Centre
Energy Policy | Year: 2014

This paper uses Q methodology to reveal stakeholder perceptions on how best to address energy issues in Africa. We sampled a group of stakeholders involved in various energy sub-sectors to uncover perspectives on how to achieve and promote access to modern energy, energy efficiency and renewable energy in Africa, whether the perceptions could be correlated to educational or geographical background and implications such patterns could have on policies and current dialogues.We found that all stakeholders agree on the need to prioritise sustainability but had different views on how to achieve sustainable energy for all in Africa, depending on the relevance given to each energy driver. Stakeholders could be categorised into four groups: (I) preference of large-scale high-impact projects; (II) supporters of targeted sectoral solutions with preference for small-scale technology and microfinance; (III) supporters of centralised solutions with preference for grid extension, and (IV) supporters of local entrepreneurship with scepticism about centralised solutions. The results show that differences in stakeholders' perceptions can be associated with respondents' educational but not geographical background. This implies that dialogues on energy in Africa should focus on inter-disciplinary understanding while further examining the trans-continent consensus that appears to have been established. © 2013 Elsevier Ltd. Source


Vanmaercke M.,Catholic University of Leuven | Vanmaercke M.,Research Foundation Flanders FWO | Kettner A.J.,University of Colorado | van Den Eeckhaut M.,EU Joint Research Centre | And 8 more authors.
Progress in Physical Geography | Year: 2014

Current models aiming to simulate contemporary sediment yield (SY) implicitly assume that tectonic effects are either irrelevant or are reflected by catchment topography. In this study we analyse the relation between SY and seismic activity, a component of tectonic processes. Results show a spatial correlation between SY and seismic activity expressed as the estimated peak ground acceleration (PGA) with a 10% exceedance probability in 50 years. PGA has a significant impact on the spatial variation of SY, even after correcting for cross-correlations with topography, lithology or other factors that may influence SY. Based on three distinct data sets, we demonstrate that this effect is significant both for small catchments in Europe (0.3-3940 km2) and for large river systems worldwide (1580-6.15×106 km2) and that seismic activity may be even more important for explaining regional variation in SY than land use or many other commonly considered factors (e.g. catchment area, climate). We show that explicitly considering seismic activity may lead to SY-estimates that easily deviate a factor 2 or more compared to estimates that do not consider seismic activity. This is not only the case for highly seismically active regions: also in regions with a weak to moderate seismic regime seismic activity helps explaining regional patterns in SY. We argue that these findings have important implications for a better understanding of SY and its sensitivity to human impacts, as well as for our comprehension of sediment fluxes at longer timescales. © The Author(s) 2014. Source


Gocht T.,University of Tubingen | Berggren E.,EU Joint Research Centre | Ahr H.J.,Bayer AG | Cotgreave I.,Swedish Toxicology Science Research Center Swetox | And 14 more authors.
Altex | Year: 2015

SEURAT-1 is a European public-private research consortium that is working towards animal-free testing of chemical compounds and the highest level of consumer protection. A research strategy was formulated based on the guiding principle to adopt a toxicological mode-of-action framework to describe how any substance may adversely affect human health. The proof of the initiative will be in demonstrating the applicability of the concepts on which SEURAT-1 is built on three levels: (i) Theoretical prototypes for adverse outcome pathways are formulated based on knowledge already available in the scientific literature on investigating the toxicological modes-of-action leading to adverse outcomes (addressing mainly liver toxicity); (ii) adverse outcome pathway descriptions are used as a guide for the formulation of case studies to further elucidate the theoretical model and to develop integrated testing strategies for the prediction of certain toxicological effects (i.e., those related to the adverse outcome pathway descriptions); (iii) further case studies target the application of knowledge gained within SEURAT-1 in the context of safety assessment. The ultimate goal would be to perform ab initio predictions based on a complete understanding of toxicological mechanisms. In the near-term, it is more realistic that data from innovative testing methods will support read-across arguments. Both scenarios are addressed with case studies for improved safety assessment. A conceptual framework for a rational integrated assessment strategy emerged from designing the case studies and is discussed in the context of international developments focusing on alternative approaches for evaluating chemicals using the new 21st century tools for toxicity testing. Source

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