ATLA 42.2, April 2014

//ATLA 42.2, April 2014

Editorial: New Techniques for Producing Transgenic Animals

Coenraad Hendriksen and Horst Spielmann

New Techniques for Producing Transgenic Animals — a Mixed Blessing from Both the Scientific and Animal Welfare Perspectives. A further increase in the use of genetically-modified animals will be against the European Union policy to move away from the use of animals in biomedical research.
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ESNATS Conference — The Use of Human Embryonic Stem Cells for Novel Toxicity Testing Approaches

Costanza Rovida, Manon Vivier, Bernward Garthoff and Jürgen Hescheler

The main achievements and results of the ESNATS project (Embryonic Stem Cell-based Novel Alternative Testing Strategies) were presented at the final project conference that was held on 15 September 2013, the day before the traditional EUSAAT (European Society for Alternatives to Animal Testing) Congress in Linz, Austria. The ESNATS project was an FP7 European Integrated Project, running from 2008 to 2013, the aim of which was to develop a novel toxicity testing platform based on embryonic stem cells (ESCs), and in particular, human ESC (hESCs), to accelerate drug development, reduce related R&D costs, and propose a powerful alternative to animal tests in the spirit of the Three Rs principles. Altogether, ESNATS offered the first proof of concept that hESCs can be used to create robust, reproducible and ready-to use test assays for predicting human toxicity. In the end, essentially five test systems were developed to an adequate level for entering possible pre-validation procedures. These methods are based on hESCs, and can be combined to study the possible effects, on the human embryo, of exposure to a chemical during the early stages of development. In addition to the presentations by the main project partners, external speakers were invited to give lectures on relevant topics, both in the field of neurotoxicity and, more generally, on the applicability of hESCs in the development of advanced in vitro tests.

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A Tutorial for Analysing the Cost-effectiveness of Alternative Methods for Assessing Chemical Toxicity: The Case of Acute Oral Toxicity Prediction

Hedvig Norlen, Andrew P. Worth and Silke Gabbert

Compared with traditional animal methods for toxicity testing, in vitro and in silico methods are widely considered to permit a more cost-effective assessment of chemicals. However, how to assess the cost-effectiveness of alternative methods has remained unclear. This paper offers a user-oriented tutorial for applying cost-effectiveness analysis (CEA) to alternative (non-animal) methods. The purpose is to illustrate how CEA facilitates the identification of the alternative method, or the combination of methods, that offers the highest information gain per unit of cost. We illustrate how information gains and costs of single methods and method combinations can be assessed. By using acute oral toxicity as an example, we apply CEA to a set of four in silico methods (ToxSuite, TOPKAT, TEST, ADMET Predictor), one in vitro method (the 3T3 Neutral Red Uptake cytotoxicity assay), and various combinations of these methods. Our results underline that in silico tools are more cost-effective than the in vitro test. Battery combinations of alternative methods, however, do not necessarily outperform single methods, because additional information gains from the battery are easily outweighed by additional costs.

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A Survey of Knowledge of the Three Rs Concept Among Lecturers and Postgraduate Students in Brazil

Thales de A. e Tréz

The use of animals in science is a widespread practice, despite growing concern about its moral justification and scientific relevance. In this scenario, the Three Rs concept might be considered to be a motivation for the establishment of a new scientific approach to the use of experimental animals and to research itself. The main objective of this survey-based study was to identify the level of knowledge about this concept among lecturers (i.e. tenure-track professors) and postgraduate students in the physiological and pharmaceutical sciences in Brazilian universities. A questionnaire was completed by 185 lecturers from 16 universities, and 140 postgraduate students from five of these universities. The results indicate that the concept of the Three Rs is widespread among lecturers and students in the areas of physiology and pharmacology, throughout Brazilian universities, but that its interpretation generally attributes more importance to refinement than to reduction and replacement.

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Comment: Every Silver Lining has a Cloud

Robert D. Combes and Michael Balls

The Scientific and Animal Welfare Issues Surrounding a New Approach to the Production of Transgenic Animals

The scientific basis and advantages of using recently developed CRISPR/Cas-9 technology for transgenesis have been assessed with respect to other production methods, laboratory animal welfare, and the scientific relevance of transgenic models of human diseases in general. As the new technology is straightforward, causes targeted DNA double strand breaks and can result in homozygous changes in a single step, it is more accurate and more efficient  than other production methods and speeds up transgenesis. CRISPR/Cas-9 also obviates the use of embryonic stem cells, and is being used to generate transgenic non-human primates (NHPs). While the use of this method reduces the level of animal wastage resulting from the production of each new strain, any long-term contribution to reduction will be offset by the overall increase in the numbers of transgenic animals likely to result from its widespread usage. Likewise, the contribution to refinement of using a more-precise technique, thereby minimising the occurrence  of unwanted genetic effects, will be countered by a probable substantial increase in the production of transgenic strains of increasingly sentient species. For ethical and welfare reasons, we believe that the generation of transgenic NHPs should be allowed only in extremely exceptional circumstances. In addition, we present information, which, on both welfare and scientific grounds, leads us to question the current policy of generating ever-more new transgenic models in light of the general failure of many of them, after over two decades of ubiquitous use, to result in significant advances in the understanding and treatment of many key human diseases. Because this unsatisfactory situation is likely to be due to inherent, as well as possibly avoidable, limitations in the transgenic approach to studying disease, which are briefly reviewed, it is  concluded that a thorough reappraisal of the rationale for using genetically-altered animals in fundamental research and by the pharmaceutical industry, and for its support by funding bodies, should be undertaken. In the meantime, the use of CRISPR/Cas-9 to generate new transgenic cells in culture is to be guardedly encouraged.

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Letters to the Editor

Various authors

The Use of Second Species in Toxicology Testing
A Response to the ABPI’s Letter to the Editor on the Use of Dogs in Predicting Drug Toxicity in Humans
The CPCSEA has urged the Drug Controller General of India to End the Use of Dogs in Regulatory Testing, in the Light of New Scientific Evidence
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