https://www.altex.org/index.php/altex/issue/feed ALTEX - Alternatives to animal experimentation 2018-07-15T12:18:23+02:00 Sonja von Aulock editor@altex.org Open Journal Systems <p><strong>The journal ALTEX – Alternatives to Animal Experimentation publishes open access academic articles on the development and implementation of alternatives to the use of animals for scientific purposes and informs on international developments in this field. </strong></p> <p>ALTEX is the official organ of&nbsp;<a href="http://caat.jhsph.edu/" target="_blank" rel="noopener">CAAT</a>, <a href="https://www.biologie.uni-konstanz.de/leist/caat-europe/">CAAT-Europe</a>, the Doerenkamp-Zbinden Chairs and <a href="http://altweb.jhsph.edu/about_us/t4.html">t<sup>4</sup></a>.</p> https://www.altex.org/index.php/altex/article/view/1132 Editorial 2018-07-10T15:35:34+02:00 Franz P. Gruber fpg@altex.org 2018-07-09T15:21:50+02:00 ##submission.copyrightStatement## https://www.altex.org/index.php/altex/article/view/1134 Animal testing and its alternatives – the most important omics is economics 2018-07-10T15:35:34+02:00 Lucy Meigs editor@altex.org Lena Smirnova editor@altex.org Costanza Rovida editor@altex.org Marcel Leist marcel.leist@uni-konstanz.de Thomas Hartung thartun1@jhu.edu <p>For a long time, the discussion about animal testing <em>vs </em>its alternatives centered on animal welfare. This was a static warfare, or at least a gridlock, where life scientists had to take a position and make their value choices and hardly anyone changed sides. Technical advances have changed the frontline somewhat, with <em>in vitro </em>and <em>in silico </em>methods gaining more ground. Only more recently has the economic view begun to have an impact: Many animal tests are simply too costly, take too long, and give misleading results.<br>As an extension and update to previous articles in this series written a decade ago, we reanalyze the economic landscape of especially regulatory use of animal testing and this time also consider respective alternative tests. Despite some ambiguity and data gaps, which we have filled with crude estimates, a picture emerges of globally regulated industries that are subject to stark geographic and sectorial differences in regulation, which determine their corre­sponding animal use. Both animal testing and its alternatives are industries in their own right, offering remarkable business opportunities for biotech and IT companies as well as contract research organizations. In light of recent revelations as to the reproducibility and relevance issues of many animal tests, the economic consequences of incorrect results and the reasons for still maintaining often outdated animal test approaches are discussed.</p> 2018-07-09T15:51:12+02:00 ##submission.copyrightStatement## https://www.altex.org/index.php/altex/article/view/353 Recommendation on test readiness criteria for new approach methods in toxicology: Exemplified for developmental neurotoxicity 2018-07-10T15:35:34+02:00 Anna Bal-Price Anna.PRICE@ec.europa.eu Helena T. Hogberg hhogber2@jhu.edu Kevin M. Crofton Crofton.Kevin@epa.gov Mardas Daneshian Mardas.Daneshian@uni-konstanz.de Rex E. FitzGerald rex.fitzgerald@unibas.ch Ellen Fritsche Ellen.Fritsche@uni-duesseldorf.de Tuula Heinonen Tuula.Heinonen@staff.uta.fi Susanne Hougaard Bennekou suhou@mst.dk Stefanie Klima stefanie.klima@uni-konstanz.de Aldert H. Piersma aldert.piersma@rivm.nl Magdalini Sachana Magdalini.SACHANA@oecd.org Timothy J. Shafer shafer.tim@epa.gov Andrea Terron Andrea.TERRON@efsa.europa.eu Florianne Monnet-Tschudi Florianne.Tschudi-Monnet@unil.ch Barbara Viviani viviani.barbara@icloud.com Tanja Waldmann tanja.waldmann@uni-konstanz.de Remco H. S. Westerink r.westerink@uu.nl Martin F. Wilks martin.wilks@unibas.ch Hilda Witters hilda.witters@vito.be Marie-Gabrielle Zurich Marie-Gabrielle.ZurichFontanellaz@unil.ch Marcel Leist Marcel.Leist@uni-konstanz.de <p>Multiple non animal-based test methods have never been formally validated. In order to use such new approach methods (NAMs) in a regulatory context, criteria to define their readiness are necessary. The field of developmental neurotoxicity (DNT) testing is used to exemplify the application of readiness criteria. The costs and number of untested chemicals are overwhelming for in vivo DNT testing. Thus, there is a need for inexpensive, high-throughput NAMs, to obtain initial information on potential hazards, and to allow prioritization for further testing. A background on the regulatory and scientific status of DNT testing is provided showing different types of test readiness levels, depending on the intended use of data from NAMs. Readiness criteria, compiled during a stakeholder workshop, uniting scientists from academia, industry and regulatory authorities are presented. An important step beyond the listing of criteria, was the suggestion for a preliminary scoring scheme. On this basis a (semi)-quantitative analysis process was assembled on test readiness of 17 NAMs with respect to various uses (e.g. prioritization/screening, risk assessment). The scoring results suggest that several assays are currently at high readiness levels. Therefore, suggestions are made on how DNT NAMs may be assembled into an integrated approach to testing and assessment (IATA). In parallel, the testing state in these assays was compiled for more than 1000 compounds. Finally, a vision is presented on how further NAM development may be guided by knowledge of signaling pathways necessary for brain development, DNT pathophysiology, and relevant adverse outcome pathways (AOP).</p> 2018-07-09T15:35:13+02:00 ##submission.copyrightStatement## https://www.altex.org/index.php/altex/article/view/1000 Advanced Good Cell Culture Practice for human primary, stem cell-derived and organoid models as well as microphysiological systems 2018-07-10T15:35:34+02:00 David Pamies david.pamies@unil.ch Anna Bal-Price editor@altex.org Christophe Chesné editor@altex.org Sandra Coecke editor@altex.org Andras Dinnyes editor@altex.org Chantra Eskes editor@altex.org Regina Grillari editor@altex.org Gerhard Gstraunthaler editor@altex.org Thomas Hartung thartun1@jhu.edu Paul Jennings editor@altex.org Marcel Leist marcel.leist@uni-konstanz.de Ulrich Martin editor@altex.org Robert Passier editor@altex.org Jens C. Schwamborn editor@altex.org Glyn N. Stacey editor@altex.org Heidrun Ellinger-Ziegelbauer editor@altex.org Mardas Daneshian editor@altex.org <p>A major reason for the current reproducibility crisis in the life sciences is the poor implementation of quality control measures and reporting standards. Improvement is needed, especially regarding increasingly complex <em>in vitro</em> methods. Good Cell Culture Practice (GCCP) was an effort from 1996 to 2005 to develop such minimum quality standards also applicable in academia. This paper summarizes recent key developments in <em>in vitro</em> cell culture and addresses the issues resulting for GCCP, e.g., the development of induced pluripotent stem cells (iPSCs) and gene-edited cells. It further deals with human stem-cell-derived models and bioengineering of organotypic cell cultures, including organoids, organ-on-chip and human-on-chip approaches. Commercial vendors and cell banks have made human primary cells more widely available over the last decade, increasing their use but also requiring specific guidance as to GCCP. The characterization of cell culture systems including high-content imaging and high-throughput measurement technologies increasingly combined with more complex cell and tissue cultures represent a further challenge for GCCP. The increasing use of gene editing techniques to generate and modify <em>in vitro</em> culture models also requires discussion of its impact on GCCP. International (often varying) legislations and market forces originating from the commercialization of cell and tissue products and technologies are further impacting on the need for the use of GCCP. This report summarizes the recommendations of the second of two workshops, held in Germany in December 2015, aiming to map the challenge and organize the process or developing a revised GCCP 2.0.</p> 2018-07-09T15:46:53+02:00 ##submission.copyrightStatement## https://www.altex.org/index.php/altex/article/view/706 Investigation of ruminant xenobiotic metabolism in a modified rumen simulation system (RUSITEC) 2018-07-10T15:35:35+02:00 Barbara Birk barbara.birk@basf.com Alexander Staehle alexander.staehle@gmail.com Mathias Meier mathias.meier@basf.com Markus Palm markus.palm@basf.com Dorothee Funk-Weyer dorothee.funk@basf.com Gerhard Breves Gerhard.Breves@tiho-hannover.de Harald Seulberger harald.seulberger@basf.com <p>The approval of plant protection agents requires xenobiotic metabolism and residue studies in rats, farm animals and plants (e.g., EU regulation 1107/2009) performed according to OECD guidelines. The intestinal metabolism of ruminants can produce specific residues, which must be investigated in detail. This is usually done by performing additional <em>in vivo </em>studies. The aim of the present work is to assess whether a modified <em>in vitro </em>rumen simulation system (RUSITEC) can generate this information. Rumen constituents from sheep were incubated over 8 days. The pH (6.70 ± 0.07), the redox potential (301 mV ± 30 mV), the microbial composition, and β-glucosidase activity were monitored. After an equilibration period of four or five days the fermenters were probed with 14C-labelled triazole derivatives, i.e., common metabolites of azole fungicides. Only triazole-alanine was cleaved to 1,2,4-triazole, while triazole-acetic acid and triazole-lactic acid remained stable for up to 96 hours. The two glucosides octyl-β-D-glucopy­ranoside and polydatin, which are common residues found in plants, were both rapidly cleaved in the <em>in vitro </em>rumen system. The data shows that the modified RUSITEC system is stable, viable and maintains metabolic capacity over a longer period of time (at least 8 days). This makes many animal experiments obsolete and represents a significant contribution to the 3Rs (refine, reduce, replace). The modification of the RUSITEC system enables safe use of unlabeled but also of radiolabeled test compounds.</p> 2018-07-09T16:28:06+02:00 ##submission.copyrightStatement## https://www.altex.org/index.php/altex/article/view/248 A standardized method based on pigmented epidermal models evaluates sensitivity against UV-irradiation 2018-07-10T15:35:35+02:00 Freia F. Schmid editor@altex.org Florian Groeber-Becker florian.kai.groeber-becker@isc.fraunhofer.de Stefanie Schwab editor@altex.org Sibylle Thude editor@altex.org Matthias Goebeler editor@altex.org Heike Walles editor@altex.org Jan Hansmann editor@altex.org <p>To protect the human skin from extensive solar radiation, melanocytes produce melanin and disperse it via mela­nosomes to keratinocytes in the basal and suprabasal layers of the human epidermis. Moreover, melanocytes are associated with pathological skin conditions such as vitiligo and psoriasis. Thus, an <em>in vitro </em>skin model that comprises a defined cutaneous pigmentation system is highly relevant in cosmetic, pharmaceutical and medical research. Here, we describe how the epidermal melanin unit can be established <em>in vitro</em>. Primary human melanocytes were introduced into an open source reconstructed epidermis. Following 14 days at the air liquid interface, a differentiated epidermis had formed and the melanocytes were located in the basal layer. The functionality of the epidermal melanin unit could be shown by the transfer of melanin to the surrounding keratinocytes, and a significantly increased melanin content of models stimulated with either UV-radiation or the melanin precursor dihydroxyphenylalanine (DOPA). An UV50 assay was developed to test the protective effect of melanin. In analogy to the IC50 value in risk assessment, the UV50 value facilitates a quantitative investigation of harmful effects of natural UV-radiation to the skin <em>in vitro</em>. Employing this test, we could demonstrate that the melanin content correlates with the resilience against simulated sunlight, which comprises 2.5% UVB and 97.5% UVA. Besides demonstrating the protective effect of melanin <em>in vitro</em>, the assay was used to determine the protective effect of a consumer product in a highly standardized setup.</p> 2018-07-09T17:18:13+02:00 ##submission.copyrightStatement## https://www.altex.org/index.php/altex/article/view/762 In vitro and in silico liver models: Current trends, challenges and opportunities 2018-07-10T15:35:36+02:00 Andrey Poloznikov andrey.poloznikov@gmail.com Irina Gazaryan igazaryan@pace.edu Maxim Shkurnikov mshkurnikov@gmail.com Sergey Nikulin sergenomail-fupm@yahoo.com Oxana Drapkina drapkina@bk.ru Ancha Baranova abaranov@gmu.edu Alexander Tonevitsky tonevitsky@mail.ru <p>Most common drug development failures originate from either bioavailability problems or unexpected toxic effects. The culprit is often the liver, which is responsible for biotransformation of the majority of xenobiotics. Liver may be modeled using liver-on-a-chip devices, which may include established cell lines, primary human cells, and stem cell-derived hepatocyte-like cells. The choice of biological material along with its processing and maintenance greatly influence both the device performance and the resultant toxicity predictions. Impediments to the development of liver-on-a-chip technology include problems with standardization of cells, limitations imposed by culturing, and the necessity to develop more complicated fluidic contours. Recent breakthroughs in the development of cell-based reporters, including ones with fluorescent labels, permit monitoring of the behavior of the cells embedded into the liver-on-a-chip devices. Finally, a set of computational approaches has been developed to model both toxic responses and the homeostasis of human liver as a whole; these approaches pave the way to enhance the <em>in silico </em>assessment of potential toxicity.</p> 2018-07-09T17:25:53+02:00 ##submission.copyrightStatement## https://www.altex.org/index.php/altex/article/view/1005 Regulatory acceptance of read-across 2018-07-10T15:35:36+02:00 Megan Chesnut editor@altex.org Takashi Yamada editor@altex.org Timothy Adams editor@altex.org Derek Knight editor@altex.org Nicole Kleinstreuer editor@altex.org George Kass editor@altex.org Thomas Luechtefeld editor@altex.org Thomas Hartung thartun1@jhu.edu Alexandra Maertens editor@altex.org 2018-07-09T18:09:53+02:00 ##submission.copyrightStatement## https://www.altex.org/index.php/altex/article/view/821 From 3Rs to 3D: In vitro alternative models for replacement 2018-07-10T15:35:37+02:00 Andras-Laszlo Nagy editor@altex.org Cornel Catoi editor@altex.org Carmen Socaciu editor@altex.org Adela Pintea editor@altex.org Nechita A. Oros editor@altex.org Cristina Coman editor@altex.org Dumitrita Rugina editor@altex.org Cristian T. Matea editor@altex.org Teodora Mocan editor@altex.org Teresa Coccini editor@altex.org Uliana De Simone editor@altex.org Isabella De Angelis editor@altex.org Alessia Bertero editor@altex.org Yula Sambuy editor@altex.org Francesca Caloni francesca.caloni@unimi.it 2018-07-09T17:42:48+02:00 ##submission.copyrightStatement## https://www.altex.org/index.php/altex/article/view/1034 The 3Rs Competence Centre (3RCC) – better research with less animal testing? 2018-07-10T15:35:37+02:00 Julika Fitzi-Rathgen julika.fitzi@tierschutz.com 2018-07-09T17:50:46+02:00 ##submission.copyrightStatement## https://www.altex.org/index.php/altex/article/view/1130 Promoting 3Rs in Finland 2018-07-15T12:18:23+02:00 Hanna Vuorenpää hanna.k.vuorenpaa@gmail.com 2018-07-09T17:53:51+02:00 ##submission.copyrightStatement## https://www.altex.org/index.php/altex/article/view/1054 Corners 2018-07-10T15:35:37+02:00 Sonja von Aulock editor@altex.org 2018-07-09T17:56:40+02:00 ##submission.copyrightStatement## https://www.altex.org/index.php/altex/article/view/1133 Essential components of methods papers 2018-07-10T15:35:37+02:00 Marcel Leist marcel.leist@uni-konstanz.de Jan G. Hengstler editor@altex.org <p>Methods papers are important for the progress of biomedical research, as they provide the essential tools to explore new questions and help to better answer old ones. However, it is often not clear how a methods paper differs from a methods protocol. Confusion between these two very different types of publication is widespread. The resultant misun­derstanding contributes to a relatively poor reputation of methods research in biology despite the fact that many Nobel prizes have been awarded specifically for method development. Here, the key components of a methods paper are summarized: (i) methods description, (ii) performance standards, (iii) applicability domains, (iv) evidence for advances compared to the state-of-the-art, (v) exemplification of the method by practical application. In addition, information domains are discussed that are desirable but may be provided on a case-by-case basis or over the course of a series of papers: (vi) method robustness, (vii) accuracy and (viii) precision measures, including various quantifications of method performance, and (ix) measures of uncertainty, including a sensitivity analysis. Finally, elements of the overall framing of the method description are highlighted. These include the scientific, technical and, e.g., toxicological rationale for the method, and also the prediction model, i.e., the procedure used to transform primary data into new information.</p> 2018-07-09T18:01:42+02:00 ##submission.copyrightStatement## https://www.altex.org/index.php/altex/article/view/1135 Imprint 2018-07-10T15:35:37+02:00 Sonja von Aulock editor@altex.org 2018-07-09T18:08:04+02:00 ##submission.copyrightStatement## https://www.altex.org/index.php/altex/article/view/1136 Cover 2018-07-10T15:35:37+02:00 Sonja von Aulock editor@altex.org 2018-07-09T19:34:47+02:00 ##submission.copyrightStatement##