Established in 1998, the FRAME Reduction Committee (FRC) (now the FRAME Reduction Steering Committee [FRSC]) has continued to pursue its aim of reducing the number of animals used in biomedical science. Through its expertise in statistics, experimental design, animal welfare and research on alternatives, it has contributed to raising awareness of the need for reduction and the means of achieving and demonstrating it. In recognising the need for training of scientists to appreciate and understand the concept of reduction, the FRSC has organised dedicated workshops and training schools. Some of the Committee’s major achievements are described, and, bearing in mind the current year-on-year increases in the number of scientific procedures on animals, its future activities are outlined.
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Years 1988, 1993, 1994 and 1995 show that the impact factor of ATLA has improved significantly over this period, as has the ranking of the journal in relevant sectors of journal publishing. The results further suggest that in vitro toxicology is evolving into a separate discipline and that ATLA is increasingly being seen as one of the key journals for this discipline. However, ATLA’s coverage extends beyond in vitro toxicology. It is a vital and unique resource for the promotion of the Three Rs in fields where no other influential specialised journals on alternatives are currently being published.
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Jiaqi Lu, Kathryn Bayne and Jianfei Wang
In the past few years, new social passions have sparked on the Chinese mainland. At the centre of these burgeoning passions is a focus on animal welfare, animal treatment, and even animal rights, by the public and academic sectors. With China’s rapid economic changes and greater access to information from around the world, societal awareness of animal issues is rising very fast. Hastening this paradigm shift were several highly public incidents involving animal cruelty, including exposés on bear bile harvesting for traditional Chinese medicine, the thousands of dogs rescued from China’s meat trade, and the call to boycott shark fin soup and bird nest soup. This article outlines the current status of campaigning by animal advocates in China (specifically the animal rights movement) from three interlinked perspectives: wildlife conservation, companion animal protection, and laboratory animal protection. By reviewing this campaigning, we attempt to present not only the political and social impact of the concept of animal rights, but also the perceptions of, and challenges to, animal rights activities in China.
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Validation of the Hepatocyte-like HPCT-1E3 Cell Line as an In Vitro Model for the Prediction of Acute In Vivo Toxicity
Sandra Halwachs, Cathleen Lakoma and Walther Honscha
In a pilot study, we tested 20 randomly-selected chemicals for their cytotoxicity toward the HPCT-1E3 cell model, in order to prove the ability of this in vitro model to predict human acute in vivo toxicity. The study revealed that, in contrast to most other in vitro models, results from the HPCT-1E3 cellbased system show better correlation with the more-relevant human acute lethal doses, whereas results from most other systems have a high predictivity for human lethal serum concentrations. For the prevalidation of the HPCT-1E3 model as a surrogate for regulatory acute in vivo toxicity tests, we have now expanded the list of tested chemicals to 57 substances, and have compared the results with data from the HepG2 cell assay. Again, a better correlation of HPCT-1E3 IC50 values with human oral lethal doses, as comparedto correlation with human lethal serum concentrations, was observed after the pooling of all the tested substances (r2 = 0.53 [P < 0.001] and r2 = 0.41 [P = 0.009], respectively). Therefore, the HPCT-1E3 in vitro model may be a valuable tool for prediction of human oral toxicity, and may help to further reduce the number of animals used for in vivo toxicity tests.
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David E. Leahy, Ruth Duncan, Hans J. Ahr, Martin K. Bayliss, A. (Bert) G. de Boer, Ferenc Darvas, Julia H. Fentem, Jeffrey R. Fry, Robert Hopkins, J. Brian Houston, Johan Karlsson, Gregory L. Kedderis, Margaret K. Pratten, Pilar Prieto, Dennis A. Smith and Donald W. Straughan
This is the report of the twenty-second of a series of workshops organised by the European Centre for the Validation of Alternative Methods (ECVAM). The workshop on Pharmacokinetics in Early Drug Research was held in Bath, UK, on 27–29 March 1996, under the co-chairmanship of David Leahy (ZENECA Pharmaceuticals, Macclesfield, UK) and Ruth Duncan (School of Pharmacy, London, UK). The aims of the workshop were to: a) review the current methodology for providing early pharmacokinetic and related information; b) define current best practice and identify those problem areas where scientific and technological advances could significantly improve the efficiency of drug discovery; and c) recommend further work which should be conducted in these high priority areas.
Toxicity of 20 Chemicals from the MEIC Programme Determined by Growth Inhibition of L-929 Fibroblast-like Cells
Lena Järkelid, Per Kjellstrand, Evi Martinson and Anders Wieslander
The Multicentre Evaluation of In vitro Cytotoxicity (MEIC) programme is an international project aimed at evaluating the relevance of in vitro tests in predicting human toxicity. We have screened 20 chemicals (MEIC codes 31–50) from the programme, by using a cytotoxicity test based on growth inhibition of the mouse fibroblast-like L-929 cell line. Inhibition of cell growth was determined by the neutral red uptake method, which is well established and is used for screening the cytotoxicity of chemicals and plastics for pharmaceuticals and medical devices. The concentrations causing 50% inhibition of cell growth after a 72-hour exposure period varied from 3.1µM for hexachlorophene, to 1.4mM for caffeine. This is within the same range as results recently obtained with five other cell models. However, with some chemicals (chloroform, carbon tetrachloride and dichloromethane), no reliable results were obtained. These substances could not be dissolved in a reproducible way in any of the solvents used and, furthermore, they were highly volatile, which led to difficulties in maintaining the concentrations.
The Trustees of FRAME
Comment – A Critical Review of Anaesthetised Animal Models and Alternatives for Military Research, Testing and Training, with a Focus on Blast Damage, Haemorrhage and Resuscitation
Robert D. Combes
Military research, testing, and surgical and resuscitation training, are aimed at mitigating the consequences of warfare and terrorism to armed forces and civilians. Traumatisation and tissue damage due to explosions, and acute loss of blood due to haemorrhage, remain crucial, potentially preventable, causes of battlefield casualties and mortalities. There is also the additional threat from inhalation of chemical and aerosolised biological weapons. The use of anaesthetised animal models, and their respective replacement alternatives, for military purposes — particularly for blast injury, haemorrhaging and resuscitation training — is critically reviewed. Scientific problems with the animal models include the use of crude, uncontrolled and non-standardised methods for traumatisation, an inability to model all key trauma mechanisms, and complex modulating effects of general anaesthesia on target organ physiology. Such effects depend on the anaesthetic and influence the cardiovascular system, respiration, breathing, cerebral haemodynamics, neuroprotection, and the integrity of the blood–brain barrier. Some anaesthetics also bind to the NMDA brain receptor with possible differential consequences in control and anaesthetised animals. There is also some evidence for gender-specific effects. Despite the fact that these issues are widely known, there is little published information on their potential, at best, to complicate data interpretation and, at worst, to invalidate animal models. There is also a paucity of detail on the anaesthesiology used in studies, and this can hinder correct data evaluation. Welfare issues relate mainly to the possibility of acute pain as a side-effect of traumatisation in recovered animals. Moreover, there is the increased potential for animals to suffer when anaesthesia is temporary, and the procedures invasive. These dilemmas can be addressed, however, as a diverse range of replacement approaches exist, including computer and mathematical dynamic modelling of the human body, cadavers, interactive human patient simulators for training, in vitro techniques involving organotypic cultures of target organs, and epidemiological and clinical studies. While the first four of these have long proven useful for developing protective measures and predicting the consequences of trauma, and although many phenomena and their sequelae arising from different forms of trauma in vivo can be induced and reproduced in vitro, non-animal approaches require further development, and their validation and use need to be coordinated and harmonised. Recommendations to these ends are proposed, and the scientific and welfare problems associated with animal models are addressed, with the future focus being on the use of batteries of complementary replacement methods deployed in integrated strategies, and on greater transparency and scientific cooperation.