Three Rs.

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In Vitro Models as a Platform to Investigate Traumatic Brain Injury

Ashwin Kumaria

Traumatic Brain Injury (TBI) remains a significant cause of mortality and morbidity, affecting individuals of all age groups. Much remains to be learned about its complex pathophysiology, with a view to designing effective neuroprotective strategies to protect sublethally injured brain tissue that would otherwise die in secondary injury processes. Experimental in vivo models offer the potential to study TBI in the laboratory, however, treatments that were neuroprotective in animals have, thus far, largely failed to translate in human clinical studies. In vitro models of neurotrauma can be used to study specific pathophysiological cascades — individually and without confounding factors — and to test potential neuroprotective strategies. These in vitro models include transection, compression, barotrauma, acceleration, hydrodynamic, chemical injury and cell-stretch methodologies. Various cell culture systems can also be utilised, including brain-on-a-chip, immortalised cell lines, primary cultures, acute preparations and organotypic cultures. Potential positive outcomes of the increased use of in vitro platforms to study TBI would be the refinement of in vivo experiments, as well as enhanced translation of the results into clinically meaningful neuroprotective strategies for the future. In addition, the replacement of in vivo experiments by suitable in vitro studies would lead to a welcome reduction in the numbers of animal procedures in this ethically-challenging field.

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A Multi-faceted Approach to Achieving the Global Acceptance of Animal-free Research Methods

Jodie Melbourne, Patricia Bishop, Jeffrey Brown and Gilly Stoddart

In 2015, the PETA International Science Consortium Ltd. was awarded the Lush Training Prize for its broad approach to education and training on the effective use of human-relevant, non-animal research techniques. The prize was awarded for work that included hosting workshops and webinars, initiating in-person training sessions and developing educational resources. The Consortium works closely with industry and regulatory agencies to identify and overcome barriers to the validation and use of alternatives to animal testing, by using an approach that identifies, promotes and verifies the implementation of these methods. The Consortium's recent activities toward replacing tests on animals for nanomaterials, pesticides and medical devices, are described, as examples of projects with broad applicability aimed at large-scale regulatory change.
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Exploring Waiving Opportunities for Mammalian Acute Systemic Toxicity Tests

Graepel EUSurvey

Rabea Graepel, David Asturiol, Pilar Prieto and Andrew P. Worth

A survey was carried out to explore opportunities for waiving mammalian acute systemic toxicity tests. We were interested in finding out whether data from a sub-acute toxicity test could be used to predict the outcome of an acute systemic toxicity test. The survey was directed at experts in the field of toxicity testing, and was carried out in the context of the upcoming 2018 final registration deadline for chemicals under the EU REACH Regulation. In addition to the survey, a retrospective data analysis of chemicals that had already been registered with the European Chemicals Agency, and for which both acute and sub-acute toxicity data were available, was carried out. This data analysis was focused on chemicals that were administered via the oral route. The answers to the questionnaire showed a willingness to adopt waiving opportunities. In addition, the responses showed that data from a sub-acute toxicity test or dose-range finding study might be useful for predicting chemicals that do not require classification for acute oral toxicity (LD50 > 2000mg/kg body weight). However, with the exception of substances that fall into the non-classified category, it is difficult to predict current acute oral toxicity categories.
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Stakeholder Views on the Creation and Use of Genetically-Engineered Animals in Research

Elisabeth H. Ormandy

This interview-based study examined the diversity of views relating to the creation and use of genetically-engineered (GE) animals in biomedical science. Twenty Canadian participants (eight researchers, five research technicians and seven members of the public) took part in the interviews, in which four main themes were discussed: a) how participants felt about the genetic engineering of animals as a practice; b) governance of the creation and use of GE animals in research, and whether current guidelines are sufficient; c) the Three Rs (Replacement, Reduction, Refinement) and how they are applied during the creation and use of GE animals in research; and d) whether public opinion should play a greater role in the creation and use of GE animals. Most of the participants felt that the creation and use of GE animals for biomedical research purposes (as opposed to food purposes) is acceptable, provided that tangible human health benefits are gained. However, obstacles to Three Rs implementation were identified, and the participants agreed that more effort should be placed on engaging the public on the use of GE animals in research.

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The Use of a Decision Tree Based on the Rabies Diagnosis Scenario, to Assist the Implementation of Alternatives to Laboratory Animals

Vanessa Carli Bones and Carla Forte Maiolino Molento

Brazilian federal legislation makes the use of alternatives mandatory, when there are validated methods to replace the use of laboratory animals. The objective of this paper is to introduce a novel decision tree (DT)-based approach, which can be used to assist the replacement of laboratory animal procedures in Brazil. This project is based on a previous analysis of the rabies diagnosis scenario, in which we identified certain barriers that hinder replacement, such as: a) the perceived higher costs of alternative methods; b) the availability of staff qualified in these methods; c) resistance to change by laboratory staff; d) regulatory obstacles, including incompatibilities between the Federal Environmental Crimes Act and specific norms and working practices relating to the use of laboratory animals; and e) the lack of government incentives. The DT represents a highly promising means to overcome these reported barriers to the replacement of laboratory animal use in Brazil. It provides guidance to address the main obstacles, and, followed step-by-step, would lead to the implementation of validated alternative methods (VAMs), or their development when such alternatives do not exist. The DT appears suitable for application to laboratory animal use scenarios where alternative methods already exist, such as in the case of rabies diagnosis, and could contribute to increase compliance with the Three Rs principles in science and with the current legal requirements in Brazil.

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A Training Course on Laboratory Animal Science: An Initiative to Implement the Three Rs of Animal Research in India

Kunal Pratap and Vijay Pal Singh

There is a current need for a change in the attitudes of researchers toward the care and use of experimental animals in India. This could be achieved through improvements in the provision of training, to further the integration of the Three Rs concept into scientific research and into the regulations of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA). A survey was performed after participants undertook the Federation of European Laboratory Animal Science Associations (FELASA) Category C-based course on Laboratory Animal Science (in 2013 and 2015). It revealed that the participants subsequently employed, in their future research, the practical and theoretical Three Rs approaches that they had learned. This is of great importance in terms of animal welfare, and also serves to benefit their research outcomes extensively. All the lectures, hands-on practical sessions and supplementary elements of the courses, which also involved the handling of small animals and procedures with live animals, were well appreciated by the participants. Insight into developments in practical handling and welfare procedures, norms, directives, and ethical use of laboratory animals in research, was also provided, through the comparison of results from the 2013 and 2015 post-course surveys.

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Humane Education in Brazil: Organisation, Challenges and Opportunities

Róber Bachinski, Thales Tréz, Gutemberg G. Alves, Rita de C.M. Garcia, Simone T. Oliveira, Luciano da S. Alonso, Júlio X. Heck, Claudia M.C. Dias, João M. Costa Neto, Alexandro A. Rocha, Valeska R.R. Ruiz and Rita L. Paixão

Humane education and the debate on alternatives to harmful animal use for training is a relatively recent issue in Brazil. While animal use in secondary education has been illegal since the late 1970s, animal use in higher science education is widespread. However, alternatives to animal experiments in research and testing have recently received attention from the Government, especially after the first legislation on animal experiments was passed, in 2008. This article proposes that higher science education should be based on a critical and humane approach. It outlines the recent establishment of the Brazilian Network for Humane Education (RedEH), as a result of the project, Mapping Animal Use for Undergraduate Education in Brazil, which was recognised by the 2014 Lush Prize. The network aims to create a platform to promote change in science education in Brazil, starting by quantitatively and qualitatively understanding animal use, developing new approaches adapted to the current needs in Brazil and Latin America, and communicating these initiatives nationally. This paper explores the trajectory of alternatives and replacement methods to harmful animal use in training and education, as well as the status of humane education in Brazil, from the point of view of educators and researchers engaged with the network.
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To Be Credible, Success in “Reducing the Use of Animals in Scientific Research” Must Involve the Use of Fewer Animals

Michael Balls

Much worthy effort on the Three Rs is under way in the UK, but its promise of a reduction in laboratory animal use will only be credible and laudable when the number of procedures and animals are progressively and permanently reduced.
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How Long Must They Suffer? Success and Failure of our Efforts to End the Animal Tragedy in Laboratories

Roman Kolar

Scientific findings have revealed how much we have dramatically underestimated the intellectual, social and emotional capabilities of non-human animals, including their levels of self-consciousness and ability to suffer from psychological stress. In the 21st century, the field of animal ethics has evolved as a serious scientific discipline, and nowadays largely advocates that the way we treat animals, both legally and in practice, is morally wrong. Politics and legislation have reacted to these facts, to some extent, but neither current legislation nor current practice reflect the scientific and moral state-of-the-art. Too often, the will to change things is watered down in the decision-making process, e.g. in the drafting of legislation. In the field of animal experimentation there have been many genuine efforts by various players, to advance and apply the principles behind the Three Rs. However, the fundamental problem, i.e. the overall number of animals sacrificed for scientific purposes, has increased. Clearly, if we are serious about our will to regard animal experimentation as an ethical and societal problem, we have to put much more emphasis on addressing the question of how to avoid the use of animals in science. To achieve this goal, certain issues need to be considered: a) the present system of ethical evaluation of animal experiments, including testing for regulatory purposes, needs to be reformed and applied effectively to meet the legal and moral requirements; b) animal testing must be avoided in future legislation, and existing legislation has to be revised in that regard; c) resources from animal-based research have to re-allocated toward alternatives; and d) the academic curricula must be reformed to foster and integrate ethical and animal welfare issues.
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A Step Forward in the Quality Control Testing of Inactivated Rabies Vaccines — Extensive Evaluation of European Vaccines by Using Alternative Methods to the In Vivo Potency Tests

Alexandre Servat, Sébastien Kempff, Valère Brogat, Estelle Litaize, Jean-Luc Schereffer and Florence Cliquet

The mouse challenge test still remains the reference method for the potency determination of human and animal inactivated rabies vaccines, and it is still widely used throughout the world. This test suffers from many disadvantages — it is expensive and time consuming, uses a large number of mice, causes significant animal distress, and suffers from high variability. Recently, the European Pharmacopoeia has recognised the use of a serological potency assay (SPA) as an alternative method to the challenge test. This new test is based on the determination of rabies neutralising antibody titres in vaccinated mice, by using the modified Rapid Fluorescent Focus Inhibition Test (mRFFIT). With the objective of adopting this new method for the batch release of inactivated rabies vaccines, we evaluated its performance on a large collection of rabies vaccines currently assessed in our laboratory. The Fluorescent Antibody Virus Neutralisation test (FAVNt) was used in parallel with the mRFFIT, and the results were compared to the mouse challenge test. Our results demonstrate that the SPA is capable of estimating the potency of vaccines formulated with a potency margin well above the minimum of 1IU/dose. For low potency vaccines, this new method demonstrated some limitations, due to the recurrent invalidation of the assay. We have also demonstrated the superior sensitivity of the FAVNt when compared to the mRFFIT, and the importance of minimising the risk of detecting non-responders in vaccinated mice.
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