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      Alternatives to animal testing: current status and future perspectives

      editorial

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          Abstract

          On the occasion of the 20th anniversary of the Center for Alternative Methods to Animal Experiments (ZEBET), an international symposium was held at the German Federal Institute for Risk Assessment (BfR) in Berlin. At the same time, this symposium was meant to celebrate the 50th anniversary of the publication of the book “The Principles of Humane Experimental Technique” by Russell and Burch in 1959 in which the 3Rs principle (that is, Replacement, Reduction, and Refinement) has been coined and introduced to foster the development of alternative methods to animal testing. Another topic addressed by the symposium was the new vision on “Toxicology in the twenty-first Century”, as proposed by the US-National Research Council, which aims at using human cells and tissues for toxicity testing in vitro rather than live animals. An overview of the achievements and current tasks, as well as a vision of the future to be addressed by ZEBET@BfR in the years to come is outlined in the present paper.

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          Most cited references52

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          Environmental and genetic activation of a brain-adipocyte BDNF/leptin axis causes cancer remission and inhibition.

          Cancer is influenced by its microenvironment, yet broader, environmental effects also play a role but remain poorly defined. We report here that mice living in an enriched housing environment show reduced tumor growth and increased remission. We found this effect in melanoma and colon cancer models, and that it was not caused by physical activity alone. Serum from animals held in an enriched environment (EE) inhibited cancer proliferation in vitro and was markedly lower in leptin. Hypothalamic brain-derived neurotrophic factor (BDNF) was selectively upregulated by EE, and its genetic overexpression reduced tumor burden, whereas BDNF knockdown blocked the effect of EE. Mechanistically, we show that hypothalamic BDNF downregulated leptin production in adipocytes via sympathoneural beta-adrenergic signaling. These results suggest that genetic or environmental activation of this BDNF/leptin axis may have therapeutic significance for cancer. Copyright 2010 Elsevier Inc. All rights reserved.
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            Human cell type diversity, evolution, development, and classification with special reference to cells derived from the neural crest.

            Metazoans are composed of a finite number of recognisable cell types. Similar to the relationship between species and ecosystems, knowledge of cell type diversity contributes to studies of complexity and evolution. However, as with other units of evolution, the cell type often resists definition. This review proposes guidelines for characterising cell types and discusses cell homology and the various developmental pathways by which cell types arise, including germ layers, blastemata (secondary development/neurulation), stem cells, and transdifferentiation. An updated list of cell types is presented for a familiar, albeit overlooked model taxon, adult Homo sapiens, with 411 cell types, including 145 types of neurons, recognised. Two methods for organising these cell types are explored. One is the artificial classification technique, clustering cells using commonly accepted criteria of similarity. The second approach, an empirical method modeled after cladistics, resolves the classification in terms of shared features rather than overall similarity. While the results of each scheme differ, both methods address important questions. The artificial classification provides compelling (and independent) support for the neural crest as the fourth germ layer, while the cladistic approach permits the evaluation of cell type evolution. Using the cladistic approach we observe a correlation between the developmental and evolutionary origin of a cell, suggesting that this method is useful for predicting which cell types share common (multipotential) progenitors. Whereas the current effort is restricted by the availability of phenotypic details for most cell types, the present study demonstrates that a comprehensive cladistic classification is practical, attainable, and warranted. The use of cell types and cell type comparative classification schemes has the potential to offer new and alternative models for therapeutic evaluation.
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              Toxicity testing in the 21st century: bringing the vision to life.

              In 2007, the U.S. National Academy of Sciences released a report, Toxicity Testing in the 21st Century: A Vision and a Strategy, that envisions a not-so-distant future in which virtually all routine toxicity testing would be conducted in human cells or cell lines in vitro by evaluating cellular responses in a suite of toxicity pathway assays using high-throughput tests, that could be implemented with robotic assistance. Risk assessment based on results of these types of tests would shift towards the avoidance of significant perturbations of these pathways in exposed human populations. Dose-response modeling of perturbations of pathway function would be organized around computational systems biology models of the circuitry underlying each toxicity pathway. In vitro to in vivo extrapolations would rely on pharmacokinetic models to predict human blood and tissue concentrations under specific exposure conditions. All of the scientific tools needed to affect these changes in toxicity testing practices are either currently available or in an advanced state of development. A broad scientific discussion of this new vision for the future of toxicity testing is needed to motivate a departure from the traditional high dose animal-based toxicological tests, with its attendant challenges for dose and species extrapolation, towards a new approach more firmly grounded in human biology. The present paper, and invited commentaries on the report that will appear in Toxicological Sciences over the next year, are intended to initiate a dialog to identify challenges in implementing the vision and address obstacles to change.
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                Author and article information

                Contributors
                +49-30-84124538 , +49-30-84124928 , Andreas.Luch@bfr.bund.de , http://www.bfr.bund.de/
                Journal
                Arch Toxicol
                Archives of Toxicology
                Springer-Verlag (Berlin/Heidelberg )
                0340-5761
                1432-0738
                24 May 2011
                24 May 2011
                August 2011
                : 85
                : 8
                : 841-858
                Affiliations
                German Federal Institute for Risk Assessment (BfR), Center for Alternative Methods to Animal Experiments—ZEBET, 12277 Berlin, Germany
                Article
                718
                10.1007/s00204-011-0718-x
                3149673
                21607681
                56642d2c-61ca-47c6-9a7f-e2588c83332d
                © The Author(s) 2011
                History
                Categories
                Editorial
                Custom metadata
                © Springer-Verlag 2011

                Toxicology
                reduction,alternatives to animal testing,zebet,3rs,replacement,refinement
                Toxicology
                reduction, alternatives to animal testing, zebet, 3rs, replacement, refinement

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