Necessity, Use, and Care of Laboratory Dogs at the U.S. Department of Veterans Affairs (2020) / Chapter Skim
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3 Determining the Necessity of Laboratory Dogs in Biomedical Research Funded by or Conducted at the U.S. Department of Veterans Affairs
3 Determining the Necessity of Laboratory Dogs in Biomedical Research Funded by or Conducted at the U.S. Department of Veterans Affairs
Pages 39-88
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From page 39... ...
This is followed by a consideration of laboratory dog use in 10 biomedical research fields related to the VA's mission, including seven areas in which the VA currently uses laboratory dogs or has done so in the recent past (cardiovascular disease [CVD] , spinal cord injury [SCI]
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From page 40... ...
Several members of this committee recall the large number of sophisticated dog models that supported basic human and veterinary physiological research in the postwar decades, as well as dog bioassays for pharmacological and toxicological research and product discovery and development. The advent of new molecular techniques in the 1970s and 1980s likely played a role in replacing animal research models, particularly dogs.
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From page 41... ...
Research Areas with Current Laboratory Dog Use at the VA This section describes the state of research in three areas of current laboratory dog use at the VA -- CVD, SCI, and imaging. The committee reviewed current practices and recent advancements 2 The Animal Welfare Act of 1966 (U.S.
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From page 42... ...
The miniaturization of technology and the adaptation of techniques to rodents, combined with the increased use of alternative large animal models, accelerated the decline in dog use. Over time, these alternative models -- particularly the pig, goat, sheep, and non-human primate -- have come to share the cardiovascular research landscape with the laboratory dog.
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Aspects of arrhythmia The laboratory dog is used extensively for studying both atrial and ventricular arrhythmias, specifically for interrogating those physiological processes for which alternative animal models are less suitable. Rodent heart rates (500–700 bpm)
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. Canine myocardial infarct models are widely used for the study of ventricular arrhythmias, where the influence of the spinal cord and autonomic nervous system on arrhythmogenesis and pursuit of new therapeutic approaches have become objects of intense focus (Baburin et al., 2018; Chen et al., 2013, 2016; del Rio et al., 2015; Lopshire et al., 2009; Nasi-Er et al., 2019a,b; Wang et al., 2015; Zhang et al., 2018; Zhou et al., 2019)
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From page 45... ...
VA cardiovascular disease research using laboratory dogs The VA has used dogs since the 1960s to investigate the consequences and treatment of cardiac rhythm disorders and heart failure. Early VA investigations using the dog resulted in the development and routine clinical use of the pacemaker to stabilize heart rate in humans (Chardack, 1964; Chardack et al., 1960, 1962, 1963)
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From page 46... ...
Use of companion dogs to study dog thoracic spinal cord injury There is a growing body of research into the restoration of motor function which employs a variety of interventions in large animals. This research has seen considerable growth in the realm of veterinary medicine, aided by the relatively high incidence of SCI in companion dogs and the willingness of many pet owners to "volunteer" their affected dogs for research that may offer a therapeutic benefit for the dog.
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From page 47... ...
. Current use of dogs in spinal cord injury research A search of the PubMed database for SCI studies involving dogs published in 2017–2019 revealed that almost all of these used companion dogs with thoracic injury, including one study that harvested cells from oral mucosa to generate stem cells for transplantation into the spinal cord (Ito et al., 2019)
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From page 48... ...
. VA spinal cord injury research using laboratory dogs Recent advances in the development of new devices to stimulate breathing in humans with cervical SCI, described above, represent the culmination of more than two decades of research and rely on a dog model that was developed by the same group of VA investigators (Walter et al., 2007)
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From page 49... ...
Nonetheless, given the great diversity of response to imaging compounds among laboratory species, the possibility that dogs may be required for specific imaging needs in the future cannot be ruled out. Research Areas with Recent Laboratory Dog Use at the VA This section describes the state of research in four areas of recent laboratory dog use at the VA -- diabetes, narcolepsy, OA and chronic pain, and experimental pharmacology and toxicology.
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. VA diabetes research using laboratory dogs Research performed in the century since the discovery of insulin has elucidated the role played by pancreatic islet cells in the control of blood glucose and tissue glucose use.
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. VA narcolepsy research using laboratory dogs Narcolepsy affects an estimated 10,000–20,000 veterans (VA, 2018b [protocol no.
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. Investigators are increasingly using companion dogs to assess novel pain management techniques for both arthritis and cancer pain, including the implantation of mesenchymal stem cells; the intra-articular injection of micro-fragmented adipose tissue, hyaluronic acid, or resiniferatoxin; and the intrathecal delivery of substance P-saporin; and they have seen improved outcomes with some of these novel techniques as compared with standard-of-care analgesic treatment (Brown and Agnello, 2013; Carapeba et al., 2016; Iadarola et al., 2018; Shah et al., 2018; Zeira et al., 2018)
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. VA osteoarthritis and chronic pain research using laboratory dogs Medications required for effective pain relief or surgical anesthesia can have the side effect of slowing breathing, sometimes to a dangerous degree.
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Summary The laboratory dog is not currently used as the model of choice for primary pharmacological research unrelated to product development. Research Areas with Potential Future Companion Dog Use at the VA This section describes three areas for possible future VA biomedical research involving companion dogs -- cancer, infectious disease, and Alzheimer's disease.
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In the area of cancer research, the pursuit of this goal may involve the use of animal models. Dogs as models in cancer research Historically the laboratory dog played a very limited role in advancing the understanding of cancer biology, particularly when compared to rodents.
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. In recent years, researchers have demonstrated the utility of companion dogs for infectious disease research.
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. Summary Recent investigations have begun to demonstrate the utility of studying infectious disease in companion dogs, which can benefit both dogs and humans.
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Given recent developments in Alzheimer's disease research, companion and possibly laboratory dogs may play a role in future studies aimed at testing Alzheimer's disease interventions. Research Areas Previously Investigated by the VA Using Laboratory Dogs In addition to the research areas described above, the VA submitted to the committee information on six additional research areas in which laboratory dogs had been used.
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. This method has subsequently been used in humans to maximize weight loss, and there is evidence that it may be useful for treating bowel dysfunction after a spinal cord injury.
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Based on the request from the VA to review areas of research from 2016 onward, the committee concludes that laboratory dogs currently remain scientifically necessary in these areas of active biomedical research at the VA: • mechanistic insights of premature ventricular contraction-induced cardio myopathy; • autonomic nerve activity and cardiac arrhythmias; • cardiovascular disease requiring functional modeling of the human Purkinje system; and • development and testing of implantable devices to stimulate respiration and cough in spinal cord injury. Laboratory dogs are no longer the preferred model for studies of diabetes or narcolepsy, for most imaging studies, or for primary pharmacological research.
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From page 61... ...
While companion dog clinical trials can be challenging to conduct due, in part, to the financial and time costs of collecting an appropriate population of companion animals for a particular trial, these studies are possible and deserve priority consideration by VA researchers and leaders. THE VA'S BIOMEDICAL RESEARCH REVIEW PROCESS VA-funded biomedical research using laboratory dogs takes place either in VA medical centers or through partnerships with local academic centers (e.g., the St.
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intramural canine research review process. NOTE: CRADO = Chief Research and Development Officer; CVMO = Chief Veterinary Medical Officer; eRA= electronic Research Administration; IACUC = institutional animal care and use committee; IRB = institutional review board; ORD = Office of Research and Development; SECVA = Secretary of Veterans Affairs; VA-SF424 Guide = guide for preparing and submitting VA-ORD applications.
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From page 63... ...
As concluded in Chapter 2, based on documentation provided by the VA and other organizations as well as on two site visits by subgroups of the committee, the committee finds that the VA's biomedical research programs involving laboratory dogs appear to satisfy applicable laws and regulations surrounding animal research. The primary form of documentation provided to the committee was the ACORP associated with VA protocols using laboratory dogs.
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The ACORP analysis also revealed instances where the investigators did not adequately explain the relevance of the study to veterans' health. Conclusion 3-5: Principal investigators frequently cited previous experience with and historical data in dog models as primary justifications for using laboratory dogs.
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In March 2018, prior to the VA's request that the National Academies of Sciences, Engineering, and Medicine undertake this study, the federal government enacted new restrictions on the VA's use of laboratory dogs, mandating that no federal funds "may be used to conduct research using canines unless: the scientific objectives of the study can only be met by research with canines."7 Section 254 of the Consolidated Appropriations Act of 2018 further required the Secretary of the VA to "directly approve" any such studies, and to submit to the U.S. Congress within 180 days "a detailed report outlining under what circumstances canine research may be needed if there are no other alternatives."8 In December 2019, as the committee neared the end of its deliberative process, the Further Consolidated Appropriations Act of 20209 was enacted into law.
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From page 66... ...
The five committee members in the minority assert that it is indeed sufficient, and they believe that the inquiry should end there. Referring to the definition of "necessary" from the Oxford English Dictionary -- "required to be achieved" or "essential" -- they assert that determining the use of dogs to be necessary in a line of VA research is equivalent to finding that the laboratory dog is the only animal model that can satisfy an important study objective.
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Many institutions, including the VA, are legally obligated to follow PHS Policy and therefore the recommendations in the Guide. In light of such ethical considerations, the majority believes that where multiple species, including the laboratory dog, can be adequately used to answer the scientific question, the species that will incur the fewest burdens should be selected and that such considerations must play a role in determining when a proposed protocol is "necessary." The committee majority recognizes that this ethical consideration may at times be in conflict with the current law.
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From page 68... ...
biomedical research when the dog is not scientifically necessary.14,15 In order to conduct biomedical research that will lead to meaningful outcomes to support improved health of veterans, the following criteria should be met before approving the use of laboratory dogs when other animal models are also scientifically appropriate: 1. The scientific question and the knowledge expected to be gained will advance understanding or medical practices related to veterans' health; 2.
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From page 69... ...
Beyond that Recommendation 2 contradicts accepted policies of various other federal agencies, such as NIH, many of which treat some animals, such as the chimpanzee, differently from others, and the Animal Welfare Act privileges any "dog, cat, monkey (nonhuman primate mammal) , guinea pig, hamster, rabbit, or such other warm-blooded animal" over every other type of sentient species, including rats and mice, birds used for research, and farmed animals, such as horses, livestock, and poultry.17 Thus, the minority members believe that while it is certainly important to grapple with the broad ethical issues surrounding animal research, this report is not the proper venue, as it was intended to address scientific questions and ethical and regulatory positions taken by the VA and the federal government specific to the laboratory dog.
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A few ACORPs also seemed to misapply the Three Rs by prioritizing reduction in the number of dogs used over refinement. Tracking Impact of Laboratory Dog Research Through Prospective Registration: A Strategy for Improving Quality and Reducing Animal Use In recent years, many commentators have encouraged the prospective registration of preclinical studies, particularly those designed to test disease interventions and toxicology in animals (Anderson and Kimmelman, 2012; Heinl et al., 2020)
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should enhance its scientific and ethical review process so that it better integrates the assessment of harm and burden with assessments of value and impact associated with biomedical research using laboratory dogs. There should be an explicit and strong connection between scientific review and institutional animal care and use committee (IACUC)
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From page 72... ...
and the relative harm that the proposed study would bring to the candidate subjects. Scientific review committees and IACUCs would be conducting simultaneous reviews of the analysis of harm and benefit, such that all three parties -- principal investigator, scientific review committee, and IACUC -- would develop an agreed-upon understanding of "scientific necessity," reconcile any differences of perspective related to the proposed study, and generally pool accountability for decisions related to the use of laboratory dogs.
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2014. Chronic spinal cord stimulation modifies intrinsic cardiac synaptic efficacy in the suppression of atrial fibrillation.
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2004. Percutaneous endoscopic cellular transplantation into the lower lumbar spinal cord.
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1985. High-frequency spinal cord stimulation in a subacute animal model of spinal cord injury.
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2017. A review of stem cell therapy for spinal cord injury: Large animal models and the frontier in humans.
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2017. An injectable hydrogel enhances tissue repair after spinal cord injury by promoting extracellular matrix remodeling.
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2017. Animal models of cerebral amyloid angiopathy.
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2010. Implantation of polymer scaffolds seeded with neural stem cells in a canine spinal cord injury model.
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2009. Spinal cord stimulation improves ventricular function and reduces ventricular arrhythmias in a canine postinfarction heart failure model.
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2018. Development of an International Canine Spinal Cord Injury observational registry: A collaborative data-sharing network to optimize translational studies of SCI.
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Washington, DC: The National Academies Press. NSCISC (National Spinal Cord Injury Statistical Center)
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2012. Xanthine oxidase inhibition prevents atrial fibrillation in a canine model of atrial pacing-induced left ventricular dysfunction.
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2017. Animal models of spinal cord injury: A systematic review.
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2018. Targeted neurotechnology restores walking in humans with spinal cord injury.
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2018. The hemisection approach in large animal models of spinal cord injury: Overview of methods and applications.
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1991. Effects of left ventricular volume overload produced by mitral regurgitation on diastolic function.
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