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Theme C WorkshopsWC1: Transgenic Animal Issues W2: Euthanasia Guidelines and Practices WC2: Euthanasia of Laboratory Animals: What is Best for Animal and Experiment? Animals in laboratories or breeding facilities are killed for different reasons, e.g., during experiments, for donation of organs or blood, illness, age, upon reaching humane endpoints, or as surplus stock. Most laws and guidelines require animals to be killed humanely with a minimum of physical and mental suffering. The most important criterion for euthanasia in terms of animal welfare is the ability to induce loss of consciousness without adverse effects, such as pain, distress, or anxiety. Special attention should be paid to fetuses/neonates and cold-blooded vertebrates, as they are less sensitive to hypoxia and anoxia. Pros and cons of some euthanasia methods will be discussed. WC2: Establishing Science-based Animal Care and Euthanasia Policy When the Data are Incomplete Since the first edition of the Guide for the Care and Use of Laboratory Animals, veterinary professionals have strived to develop professional standards that are grounded in valid scientific knowledge of animals and their welfare. With euthanasia guidelines as a case study, this seminar will show how incomplete and conflicting data can be translated into policy recommendations only when supplemented with wide extrapolations, untested theoretical assumptions, and value judgments. A research and policy agenda is offered that encourages IACUC's and policy makers to reconsider how statistics are used in animal welfare studies, to objectively assess the role of human skill in recommending best practices, and to standardize research methodologies. Importantly, IACUC's must always remember in their deliberations that any cost-benefit assessment of animal welfare costs includes a large margin of uncertainty, both in the hoped-for benefits of the research and the welfare costs to the animals. WC2: Laboratory Rodent Aversion to Agents of Anesthesia and Euthanasia Gaseous agents are used for both anesthetizing and killing animals. Very few studies have investigated directly the effect on the animals other than interpreting their behavior. This is fraught with difficulty given that some species (and even strains within a species) show tonic immobility when exposed to an external threat, whereas others employ violent and intense escape activities. This would explain the mixed claims of humaneness. We examined the responses of rats and mice of two strains to a voluntary exposure of several gases at various concentrations taken to reflect their common usage for induction and maintenance of anesthesia, and for killing. Gases included: isoflurane, halothane, enflurane, sevoflurane, desflurane, argon, carbon monoxide, and carbon dioxide in various combinations with argon and with humidification and oxygen. We looked at the time taken for animals to reach unconsciousness (as at that point they would not feel any pain, discomfort, or distress), corticosterone levels, and incidence and extent of lung hemorrhage. Measures of aversion include time to withdraw from a gas mixture, re-entry time, and total dwelling time. Our results show that carbon dioxide at all concentrations and combinations was extremely aversive compared with all the other agents. It induced higher corticosterone levels and lung hemorrhage, whereas the fluorinated gases were better in all respects, but significant differences were observed at different concentrations. Argon was intermediate. Recommendations for euthanasia and anesthesia can now be made by the animal! WC3: Reducing the Use of Dogs and Other Non-Rodent Species in Safety Testing WC3: The Set Study on the Use of Dogs as Second Species in Regulatory Testing of Pesticides, Part II: Subacute, Subchronic, and Chronic Studies in the Dog The Foundation for the Promotion of Research on Replacement and Complementary Methods to Reduce Animal Testing (Stiftung SET) in Mainz, Germany, initiated an evaluation of the use of dogs as the second species in regulatory testing of pesticides. The study was conducted by ZEBET, and the raw data were provided by the German Pesticides Manufacturer's Association (IVA = Industrieverband Agrar). Data on 172 substances (fungicides, herbicides, insecticides, and other pesticides) submitted during the past forty years to the German Federal institute for the health Protection of Consumers and Veterinary Medicine (BgVV) have been analyzed in a coded form to determine if the specific toxicological information that is provided by chronic studies in dogs (52/104 weeks) gives essential information in addition to subchronic (13 weeks) or subacute (4 weeks) studies in the same species. Analysis or organ-specific toxic effects revealed for pesticides that chronic long-term studies (52/104 weeks) in dogs do not provide specific information in addition to 26-week studies in the same species. WC3: An Approach to Minimize Dog Use in Regulatory Toxicology: Production of a Best Practice Guide to Study Design The primary non-rodent species used in toxicology is the dog. For ethical and scientific reasons, its use has been discussed widely, concluding that there is real potential to achieve a significant reduction in its use1. An Industry/Animal Welfare initiative commenced in 2000, with the aim of evaluating and, where possible, putting into practice scientifically valid approaches to minimize dog use in regulatory toxicology. The Steering Group categorized potential reduction approaches into three distinct areas, one of which is the production of a best practice guide in aspects of study design, including: group sizes, use of control animals, single sex studies, and design of MTD studies. Progress in the preparation of the guide will be presented and discussed. 1Broadhead et al. (2000) Human Experimental Toxicology. 19, pp. 440-447. WC3: Justification of the Non-Rodent Species Used in Pharmaceutical Toxicology Pharmaceuticals must be tested in rodents and non-rodents (except in exceptional circumstances) to ensure their safe use in humans. The selection of the appropriate non-rodent species in pharmaceutical toxicology has been a major topic of discussion between the industry, the product regulatory agencies, and the national authorities responsible for animal welfare. The non-rodent most generally used at present for repeat dose general toxicology studies is the dog, although sometimes a monkey (the cynomolgus macaque or marmoset), a pig (often a miniature breed) or, rarely, the ferret is selected. The selection is based on regulatory requirements, ethics, the scientific requirement to obtain the best possible prediction of the human response and animal husbandry and technical issues. Because the decision is often a complex one, it is important to regularly review the factors that have to be taken into account. The current practices used by industry in its selection of non-rodent species in pharmaceutical toxicology are discussed. It is hoped that this paper will stimulate an informed debate amongst government regulators, animal welfare groups, and the industry. Industry has recognized society's concern over the use of the primate and dog in research, but there does need to be improved liaison between the product regulators at the international level with animal welfare regulators to justify a broader range of species and to explore ways of sharing data. WC4: Practical Assessment of Harms and Benefits for Ethics Committees WC4: Comprehensive Assessment of Experimental Harms The comprehensiveness of assessments of experimental harms and the actions taken to minimize them are measures of the researcher's acceptance of ethical responsibility for all features of each experiment that affect animals adversely. A system, refined from its original 1993 form, has been devised to assist in this process. Five domains of potential welfare compromise are identified. Domain 1 is water deprivation/food deprivation/malnutrition; 2 is environment challenge, 3 is disease/injury/functional impairment, and 4 is anxiety/fear/pain/distress. A proposal would be examined systematically in all domains, and the degree of compromise in each rated on a 5-step non-numerical scale--O, A, B, C, X. Anxiety/fear/pain/distress arising from compromise in domains 1-4 would be cumulated into domain 5. The overall rating would commonly be that given to domain 5, but if it were low or unknown, it would be given to the highest rating in the other domains. Each experimental group in a study would be rated so that compromise overall would be neither over- nor under-estimated. Both the researcher and the animal ethics committee would rate each group in these terms. WC4: Practical Difficulties in Balancing Harms and Benefits in the Production of Genetically Modified Animals Every ethical review process presupposes a set of ethical criteria, proper procedures, and a consistent legal framework. In 1998, the Dutch parliament adopted a decree to regulate the ethical review procedure regarding the production and use of genetically modified animals. Due to the policy of public disclosure of all relevant documents and providing a legal trajectory for public objections, extensive ethical arguments, pro and con, are well documented. The paper will list and analyze the misconceptions when one tries to apply the "classical" ethical framework of harms and benefits to animal experiments in the context of biotechnology. For instance: What is the object? The foster mothers, the manipulated egg cell, or the adult mice in the experiments? The public considers the whole methodology ethically relevant. And, what is the domain of benefits? A promising construct to be incorporated in the genome, the healthy birth and surviving knock out, or a successful experiment with adult GM mice? In the same way, the question for relevant alternatives in the "classic" sense of the Three R's seems to shift completely. WC5: Xenotransplantation Speakers: Alan Berger, Animal Protection Institute, USA; Louisa Chapman, CDC, USA; John McArdle, ARDF, USA; Jon Richmond, Home Office, UK Although the basic concept and medical promise of xenotransplantation appears simple, clinical and scientific realization has proven elusive, with success unlikely in the immediate future. Speakers in this workshop will discuss the current European perspective on xenotransplantation; the range of clinical protocols under consideration and the health problems they are designed to address; alternative approaches with an emphasis on reducing the need for transplantation while increasing the supply and utilization of human organs; and animal welfare considerations associated with xenotransplantation research and potential clinical applications. PCP-C1: Is Animal Research Necessary in the 21st Century? Speakers: Ray Greek (USA) and Michael Festing (UK) PCP-C2: A Different View of Animal Research Bruegel's Two Monkeys, or, Why Finding Alternatives to Animal Tests Matters Progress in finding alternatives to animal tests continues to be painfully slow, and pain is certainly the operative word for animals involved in the tests. U.S. government agencies are not simply being slow, they are not moving forward at all. For example, the U.S. Environmental Protection Agency has been directed by Congress to spend a small amount of its budget on non-animal test method development, yet it has not done so, and the in vivo percutaneous absorption test continues to be used, despite the existence of an approved non-animal method. A movement is building that may compel industry to stop hiding behind the regulators and take action. There are excellent reasons, intimidation not being the only one, to stop fighting such advances. For ethical, practical, business, and other reasons, it is time to enthusiastically embrace an effective approach to finding, advocating, and adopting non-animal test methods.
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