5
Topics for Further Investigation and Recommendations

RESEARCH DIRECTIONS

The constant generation of technological and scientific advances provides us with the means to answer scientific inquiries in all fields with greater accuracy and precision. One can therefore reasonably expect further reductions in the causes of laboratory animal distress without compromising scientific or regulatory principles, if the scientific community continues to approach this subject with the diligence, imagination, and compromise demonstrated to date. Interdisciplinary projects and translational research foci in particular offer many avenues to explore toward identifying and reducing distress in research animals. The following suggestion list is the distillate of many diverse opinions rather than firm directions for the future and is presented in no particular order for the reader’s consideration:

  • Are there molecular or other markers of distress (e.g., fMRI and PET scans of blood flow through the brain) that reflect an animal’s physiological and perhaps even mental state (Gingrich 2006)? Is it possible to obtain those markers easily and harmlessly? Can they indicate the relative predisposition to distress of different species, different genetic strains of the same species, or even individual animals? If the answer is yes to any of these questions, such markers would provide powerful new tools for the intertwined fields of distress research and animal welfare research.

  • Tools (such as microarrays) used in genomics and proteomics research could contribute toward an integrated picture of the



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5 Topics for Further Investigation and Recommendations RESEARCH DIRECTIONS The constant generation of technological and scientific advances pro- vides us with the means to answer scientific inquiries in all fields with greater accuracy and precision. One can therefore reasonably expect further reductions in the causes of laboratory animal distress without compromis- ing scientific or regulatory principles, if the scientific community continues to approach this subject with the diligence, imagination, and compromise demonstrated to date. Interdisciplinary projects and translational research foci in particular offer many avenues to explore toward identifying and reducing distress in research animals. The following suggestion list is the distillate of many diverse opinions rather than firm directions for the future and is presented in no particular order for the reader’s consideration: • Are there molecular or other markers of distress (e.g., fMRI and PET scans of blood flow through the brain) that reflect an animal’s physiological and perhaps even mental state (Gingrich 2006)? Is it possible to obtain those markers easily and harmlessly? Can they indicate the relative predisposition to distress of different species, different genetic strains of the same species, or even individual ani- mals? If the answer is yes to any of these questions, such markers would provide powerful new tools for the intertwined fields of distress research and animal welfare research. • Tools (such as microarrays) used in genomics and proteomics research could contribute toward an integrated picture of the 8

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88 RECOGNITION AND ALLEVIATION OF DISTRESS IN LABORATORY ANIMALS physiology and pathophysiology of stress and distress. Modeling this knowledge across species and strains would both enlarge our understanding of distress and enable translational approaches to human diseases as well as improvements in animal welfare. The absence of a consensus definition of distress affects the evaluation of distress and its impact on animal welfare in veterinary, scientific, and legislative contexts; integrative research approaches could be immensely helpful in this area. • The development of possible distress predictors could serve as the basis for a predictive scoring system for laboratory animals, similar to the system used for the severity of illness in human intensive care units (Knaus et al. 1985, 1991). The ability to perform stan- dardized, quantitative, and comprehensive evaluations of animals in poor health or in distress would enable teams to make decisions about continued treatment versus euthanasia faster and with greater consensus. Such a system would further assist important decisions about the adoption and/or refinement of humane endpoints before the initiation of experiments, especially if the clinical assessment is validated through postmortem examinations. As shown in the Appendix, score sheets can be used to identify any number of abnormal signs, some of which will help diagnose the cause of the abnormality or will be relevant to individual research protocols. While some of the clinical observations and test results would be common among various experiments, the creation of a standard- ized predictive scoring system for distress is predicated upon a definition of distress and identification of the crucial parameters that accompany its clinical presentation. • New research could delineate the mechanisms of possible asso- ciations between stress/distress and disease behaviors or abnormal behaviors (e.g., stereotypies). Collaborative investigation is neces- sary to identify the neural processes, systems, and pathways that regulate active or passive coping in stressful situations, “permit” development of distress, or enable abnormal behaviors. Because stereotypies may adversely affect research outcomes and lead to invalidated studies and the need for repetitions, research is essential to determine, among other things, whether their presence could serve as a reliable indicator of animal welfare. • With the genetic manipulation of increasing numbers of animal species and the creation of new animal types (e.g., “humanized” mice) to better mimic human pathophysiology and disease, it is cru- cial to have a deeper and complete understanding of how the char- acteristics of an organism (such as gender or age) or its manipulated genotype can influence the development of distress (for an example

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8 TOPICS FOR FURTHER INVESTIGATION AND RECOMMENDATIONS of behavioral assessment of transgenic mice see Appendix). More- over, the improvements in husbandry that support the successful creation of transgenic and genetically modified (GM) colonies, could provide clues for refinement of breeding and husbandry pro- cedures in the non-GM laboratory animal world. This knowledge will enable further investigation into the conditions under which stress or distress do (or do not) alter the course of a disease. • Should IACUCs, preclinical study safety officers, and scientific journal editors establish criteria by which historically acceptable control animals would suffice for statistical comparisons in certain situations? If otherwise scientifically and methodologically valid (more information on the challenges of using historical controls in Chapter 4), such a change would reduce the number of con- trol animals used in potentially or intentionally distress-inducing protocols. Standardization and awareness of key Three Rs-related words and concepts among editors and reviewers would promote their application, especially in refinements. In a similar spirit, could the often useful but underappreciated approach of humans serving as the “animal” model be similarly informative for animal distress situations (Niemi 2006)? For example, could progress in human psychopharmacology enable the extrapolation of new drugs or indications to prevent or relieve distress in laboratory animals? • It is essential to continue the review of currently approved eutha- nasia methods, discussion of the duration of an animal’s distress before loss of consciousness, and research on the applicability of the Three Rs. For example, what refinements in the euthanasia of large populations of animals (e.g., mice) would be nondistressing to the animal as well as cost-effective and safe? The use of high concen- trations of carbon dioxide is similarly contentious, as it is perceived by some as likely to be painful while it is also clearly aversive. As a euthanasia agent it may also be distressful even though conscious- ness probably ceases in less than a minute. Furthermore, debate has focused on the use of cervical dislocation, decapitation, and neck cutting as more appropriate methods of euthanasia with respect to the time needed for the animal to lose consciousness (Hawkins et al. 2006; EFSA 2006; AVMA 2007). Last, scientific interventions should also address the serious emotional effects on personnel who habitually perform euthanasia. • Are there established parameters for a truly optimal husbandry sys- tem for each species of laboratory animal and for the genetic lines within those species? Animal care facility managers may wonder, for example, if it is more humane to disturb mice that normally sleep in the daytime for daily health assessments versus observ-

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0 RECOGNITION AND ALLEVIATION OF DISTRESS IN LABORATORY ANIMALS ing them passively, even though the latter approach might result in missing something serious. While there exists a growing body of scientific evidence (for example see Bayne et al. 2002; EEC 1986; Kaliste 2004; Morton 2002), it is important to approach continuing attempts to establish what is in the best interests of animals with rigorous scientific interdisciplinary methods. Even experts such as veterinarians, ethologists, and animal welfare sci- entists have to guard against the twin traps of anthropomorphism and anthropocentrism when interpreting such data (Bradshaw and Casey 2007). • The use of experimental designs currently used for human research may offer new insights and opportunities in studies that depend on laboratory animals and should be further explored. Epidemiological approaches can help identify management and biological factors involved in the etiology of problem behaviors (McGreevy et al. 1995; Nicol et al. 2003), and matched-pair designs may allow for smaller sample sizes because of their powerful capacity (Würbel and Garner 2007). RECOMMENDATIONS The following recommendations are the intellectual product of this Committee’s deliberations; however, we acknowledge some overlap with the recent report of the Working Group on Animal Distress in the Labora- tory (Brown et al. 2006). 1. The Three Rs (refinement, reduction, and replacement) should be the standard for identifying, modifying, avoiding, and minimizing most causes of distress in laboratory animals. While research on distress and methods of alleviating distress (e.g., the development of anesthesia or analgesia) may unavoidably cause animal suffering, the optimum goal of research and veterinary teams should be to reduce and alleviate distress in laboratory animals to the minimum necessary to achieve the scientific objective. 2. Protocols should include efforts to improve housing and hus- bandry conditions through the judicious employment of strategies for enrichment, animal training, and socialization. Well-trained, competent, and attentive research and animal care personnel are crucial in providing relief from unintended distress that originates from the care and use of laboratory animals.

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1 TOPICS FOR FURTHER INVESTIGATION AND RECOMMENDATIONS 3. Institutional support for and embrace of a commitment to animal welfare of the laboratory animals is essential. veterinarians and animal care personnel who work with research animals on a daily basis should have adequate time and contact with the animals to properly evaluate their well-being. Funding for training programs is crucial to the training and development of specialized laboratory animal veterinarians and animal behaviorists and should increase, because in addition to such objective measurements as weight loss or lack of grooming, clinical judgment is vital to effective assess- ments of stress and distress. 4. Appropriate statistical methodologies are an essential tool for the avoidance, minimization, and alleviation of distress. 5. There should be a clearinghouse (or some other venue such as a website or a specialized peer-reviewed journal) for publication of research on the effects of enrichment strategies on parameters such as physiology, distress, and endpoints for all laboratory animals (one useful example is the Primate Enrichment Database hosted by the Animal Welfare Institute).1 Although a variety of journals (such as Lab Animal, Applied Animal Behaiour Science, Animal Welfare, Laboratory Animals, Contemporary Topics in Lab- oratory Animal Science, Comparatie Medicine) publish research pertaining to animal welfare, the highly specialized nature of the field makes it difficult for the larger scientific community to remain informed about recent advances and ongoing debates. Biomedical research journals should be more open to submissions from sci- entists whose research focuses on animal welfare issues so that concerns about research interference or unjustified expenses can be debated on scientific, ethical, or regulatory grounds. 6. Obtaining funding for welfare research is often difficult, especially when project applications compete against other fields of science due to lack of an appropriate/separate research oversight body. In the United Kingdom the funds available for welfare research have increased dramatically with the founding of the National Center for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs).2 In the United States, the National Institutes of Health, Environmental Protection Agency, and other federal insti- tutions have occasionally provided funding to develop or validate 1 http://www.awionline.org/SearchResultsSite/enrich.aspx. 2 NC3Rs website: www.nc3rs.org.uk.

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2 RECOGNITION AND ALLEVIATION OF DISTRESS IN LABORATORY ANIMALS nonanimal or nonvertebrate alternatives. Funding for laboratory animal welfare research, however, is usually available only in small amounts from nongovernmental organizations such as the Animal Welfare Institute, the Johns Hopkins Center for Alternatives to Animal Testing, the American College of Laboratory Animal Medicine, and the American Association for Laboratory Animal Science. given the impact of better animal welfare on science as well as the growing public interest in the treatment of labora- tory animals, federal agencies and large foundations that support biomedical and behavioral research should make funds available specifically for the avenues of investigation listed above and for other related topics. 7. Animal welfare scientists and researchers and scientists who use animal models should communicate with each other more frequently in order to compare objectives and progress and to identify opportunities for collaboration. Neutral groups and/or other established research and science policy entities can provide platforms and venues for such exchanges. REFERENCES AVMA (American Veterinary Medical Association). 2007. 2007 AVMA Guidelines on Euthanasia. Bayne, K. A. L., J. A. Mench, B. V. Beaver, and D. B. Morton. 2002. Laboratory Animal Behavior. In: Laboratory Animal Science, ACLAM series 2nd Ed. New York: Academic Press. 1240-1264 pp. Bradshaw, W. S. and R. A. Casey. 2007. Anthropomorphism and anthropocentrism as influ- ences in the quality of life of companion animals. Anim Welf 16 (suppl): in press. Brown, M., L. Carbone, K. M. Conlee, M. S. Dawkins, I. J. Duncan, D. Fraser, G. Griffin, V. A. Hampshire, L. A. Lambert, J. A. Mench, D. Morton, J. Richmond, B. E. Rollin, A. N. Rowan, M. L. Stephens, and H. Würbel. 2006. Report of the Working Group on Animal Distress in the Laboratory. Lab Animal 35(8):26-30. EEC (European Economic Commission). 1986. Council Directive 86/609/EEC on the Protection of Animals Used for Experimental and Other Scientific Purposes. Available at: ec.europa. eu/food/fs/aw/aw_legislation/scientific/86-609-eec_en.pdf. Accessed August 2007. EFSA (European Food Safety Authority Scientific Panel on Animal Health and Welfare). 2006. The welfare aspects of the main systems of stunning and killing applied to commercially farmed deer, goats, rabbits, ostriches, ducks, geese and quail. EFSA J 326:1-18. Gingrich, J. A. 2006. Oxidative stress is the new stress. Nat Med 11(12):1281-1282. Hawkins, P., L. M. Felton, P. L. Van Loo, M. Maconochie, D. J. Wells, N. Dennison, R. Hubrecht, and M. Jennings. 2006. Report of the 2005 RSPCA/UFAW Rodent Welfare Group Meeting. Lab Anim 35(9):10. Hawkins, P., L. Playle, H. Golledge, M. Leach, R. Banzett, A. Coene, J. Cooper, P. Danneman, P. Flecknell, R. Kirkden, L. Niel, and M. Raj. 2006. Newcastle Consensus Meeting on Carbon Dioxide Euthanasia of Laboratory Animals. Available at: www.nc3rs.org.uk/ downloaddoc.asp?id=416&page=292&skin=0. Accessed January 30, 2008.

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3 TOPICS FOR FURTHER INVESTIGATION AND RECOMMENDATIONS Kaliste, E., ed. 2004. The Welfare of Laboratory Animals. Dordrecht/London: Kluwer Academic Publishers. Knaus, W. A., J. E. Zimmerman, D. P. Wagner, E. A. Draper, and D. E. Lawrence. 1985. APACHE II—A severity of disease classification system. Crit Care Med 13:818-829. Knaus, W. A., D. P. Wagner, E. A. Draper, J. E. Zimmerman, M. Bergner, P. G. Bastos, C. A. Sirio, D. J. Murphy, T. Lotring, A. Damiano, et al. 1991. The APACHE III prognostic system. Risk prediction of hospital mortality for critically ill hospitalized adults. Chest 100(6):1619-1636. McGreevy, P. D., P. J. Cripps, N. P. French, L. E. Green, and C. J. Nicol. 1995. Management factors associated with stereotypic and redirected behavior in the thoroughbred horse. Equine Vet J 27(2):86-91. Morton, D. B. 2002. Behaviour of rabbits and rodents. In The Ethology of Domestic Animals— An Introductory Text, P. Jensen, ed. Oxford: CABI Wallingford. 193-209 pp. Nicol, C. J., C. Potzsch, K. Lewis, and L. E. Green. 2003. Matched concurrent case-control study of risk factors for feather pecking in hens on free-range commercial farms in the UK. Br Poultry Sci 44(4):515-523. Niemi, S. M. 2006. Making comparative medicine more so. J Am Vet Med Assoc 228(2):199-200. Weisstaub, N. V., M. Zhou, A. Lira, E. Lambe, J. Gonzalez-Maeso, J. P. Hornung, E. Sibille, M. Underwood, S. Itohara, W. T. Dauer, M. S. Ansorge, E. Morelli, J. J. Mann, M. Toth, G. Aghajanian, S. C. Sealfon, R. Hen, and J. A. Gingrich. 2006. Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors in mice. Science 313(5786):536-540. Würbel, H. and J. P. Garner. 2007. Refinement of rodent research through environmental enrichment and systematic randomization. NC3Rs 9:1-9.

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