3
Use of Random Source Dogs and Cats for Research

The statement of task given to this Committee by NIH was specific to the use of animals from Class B dealers in scientific research, but this report addresses the use of random source dogs and cats in particular, per the intent of Congress (as discussed in the Summary and Chapter 1). The two types of animals, random source and Class B, are inextricably linked but also differ; Class B dealers acquire both random source and non–random source animals, as defined in Chapter 1. As detailed in Chapter 4, only 20 percent of dogs from Class B dealers are clearly identified as random source animals from pounds and shelters. Thus, most dogs from Class B dealers are non–random source and similar to those available through other sources. Because random source animals and specifically random source animals from pounds and shelters are the driving force for Congressional and public concern, and are the animals of interest to NIH, the Committee was compelled to discuss the specific attributes, both desirable and undesirable, of random source animals in this report.

Dogs and cats, regardless of source, have been used in American biomedical research for over a century, and random source dogs and cats have contributed to advances in both human and animal health. But the American public is divided in its opinions about the use of dogs and cats from shelters and pounds in research. Public attitudes are difficult to measure accurately, however, since opinion polls are often biased to serve the needs or perspective of the polling agency. For example, in a 1990s public opinion poll conducted by the Survey Research Center of the University of Michigan Institute for Social Research, 61 percent of respondents favored the use of unwanted animals from the pound for medical research and only



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3 Use of Random Source Dogs and Cats for Research The statement of task given to this Committee by NIH was specific to the use of animals from Class B dealers in scientific research, but this report addresses the use of random source dogs and cats in particular, per the intent of Congress (as discussed in the Summary and Chapter 1). The two types of animals, random source and Class B, are inextricably linked but also differ; Class B dealers acquire both random source and non–random source animals, as defined in Chapter 1. As detailed in Chapter 4, only 20 percent of dogs from Class B dealers are clearly identified as random source animals from pounds and shelters. Thus, most dogs from Class B dealers are non–random source and similar to those available through other sources. Because random source animals and specifically random source animals from pounds and shelters are the driving force for Congressional and public concern, and are the animals of interest to NIH, the Committee was compelled to discuss the specific attributes, both desirable and undesir- able, of random source animals in this report. Dogs and cats, regardless of source, have been used in American biomedical research for over a century, and random source dogs and cats have contributed to advances in both human and animal health. But the American public is divided in its opinions about the use of dogs and cats from shelters and pounds in research. Public attitudes are difficult to mea- sure accurately, however, since opinion polls are often biased to serve the needs or perspective of the polling agency. For example, in a 1990s public opinion poll conducted by the Survey Research Center of the University of Michigan Institute for Social Research, 61 percent of respondents favored the use of unwanted animals from the pound for medical research and only 4

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46 ISSUES IN THE USE OF RANDOM SOURCE DOGS AND CATS IN RESEARCH 23 percent were against such use. Similarly, 75 percent would oppose a law to prevent unclaimed pound animals from being used in medical research for the public benefit (Michigan Society for Medical Research [MISMR]).1 But the results of the Michigan poll must be balanced with the knowledge that it is a regional poll, limited in scope (see Box 2-1). At the other end of the spectrum, the results of a national poll con- ducted by the American Humane Association in 1988 showed that many members of the public opposed pound seizure (discussed further in Chapter 4) because they viewed shelters as havens for homeless animals and not a resource for biomedical research (American Humane Shoptalk 1988). This perspective is shared by some academic institutions, exem- plified by the Colorado State University College of Veterinary Medicine and Biological Sciences (CVMBS) policy on animal use: “College policy prohibits the acquisition of live animals from shelters, either directly or indirectly through third party vendors, for use in research or teaching. The College recognizes that many individuals in our society are opposed, on ethical and scientific grounds, to the release of animals from shelters (pound seizure) for use in research or teaching. This objection is founded in the understanding that pounds or animal shelters were not designed as facilities to supply animals for such activities. Rather, they were developed to be places where people may bring unwanted or stray animals in the hope of a new home being found. If not successfully adopted, the animals may be euthanized. The release of these animals for research or teaching may be interpreted as a breach of the public trust that could lead to loss of public support” (CVMBS 2006a). In addition to concern about the use of pound animals in research, the CVMBS policy also addresses the quality of care provided to the animals used by the College: “In selecting sources from which to purchase animals to be used in research and teaching, the CVMBS strives to patronize only those suppliers who maintain the highest standards of animal care. Examples of preferred animal sources for teaching and research include: Animals typically available through well-established, federally licensed and regulated sources of purpose-bred and raised ani- mals for teaching and research are used exclusively for species such as dogs and cats” (CVMBS 2006b). The tendency to view dogs and cats as family members has become stronger in the past 20 years, as evidenced not only by polls (according to a 2007 Harris poll, 88 percent of pet owners view their pets as family members) but also by increased spending on veterinary care, food, toys, clothing, and day care, and by the PETS Act passed by Congress in 2006 (Harris Poll 2007). After Hurricane Katrina, when scores of people either refused to evacuate and/or returned home early out of concern for their pets, 1 http://www.mismr.org/educational/pound.html

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4 USE OF RANDOM SOURCE DOGS AND CATS FOR RESEARCH the PETS Act mandated that disaster plans include provisions for companion animals (The White House 2006). The public has also become increasingly vocal in support of improved care for pound animals and in opposition to the euthanasia of adoptable shelter animals, as evidenced by the rise in the number of “no kill” pounds and shelters and by veterinary specialization in shelter medicine (Zawistowski 2008). It is unlikely that public opinion has shifted dramatically to now favor pound seizure. The professional and scientific communities view the issue somewhat differently. The American Veterinary Medical Association, in its November 2007 official policy position statement, “believes there is ample justification for prudent and humane use of random source dogs and cats in research, testing and education.”2 The American Physiological Society (APS) supports the continued use of random source animals, recognizing that they have attributes that are important in the fields of study relevant to its members: “The American Physiological Society recognizes the importance of research that depends upon animals of large size, advanced age, and diverse genetic background. These are known as ‘random source animals’. . .”3 THE “3RS” PRINCIPLE The universal principle that guides biomedical research on animals is the “3Rs” doctrine of Russell and Burch (1959; see also NRC 2003) that promotes reduction, refinement, and replacement of research animals whenever scientifically feasible. As discussed in Chapter 2, the number of dogs and cats used in research has been dwindling for the past 20 years, and random source dogs and cats make up a very small percentage of those animals. Although many animals in shelters and pounds are elderly or terminally ill and brought to shelters by their owners for immediate euthanasia (Kass et al. 2001), substantial numbers are otherwise healthy and could in theory be used for biomedical research studies. In addition, if these animals are not accessible for research, additional purpose-bred animals must be generated to fill the need. Therefore, some might argue that failure to use unwanted pound and shelter animals for research runs counter to the “reduction” component of the 3Rs principle. In contrast, others would argue that use of random source animals does not address the “refinement” or “replacement” components, or the “reduction” of the overall number of animals used. Thus, even this issue is not straightforward. 2 http://www.avma.org 3 http://www.the-aps.org

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48 ISSUES IN THE USE OF RANDOM SOURCE DOGS AND CATS IN RESEARCH DESIRABILITy OF RANDOM SOuRCE DOgS AND CATS FOR RESEARCH One of the challenges of animal-based research is identification of an optimal model for biomedical research endeavors. Well-chosen animal models provide reproducible insight into normal function, disease states, and effectiveness of drugs and devices for treatment. Animal models that are less than optimal decrease the quality of knowledge and increase the chance for adverse drug and device events. As a result, the search for the best animal model is essential for understanding diseases and developing treatments for them. Random source dogs and cats represent a potentially important source of animals with unique anatomic and physiologic attributes as well as naturally occurring diseases such as cancer, genetic diseases, age-related diseases, and infectious diseases. The Committee emphasizes that its task was to identify “common research topics” for which these animals are “desirable” and to describe “specific characteristics” that make them “par- ticularly well suited” for these studies. The Committee was not tasked with comparing attributes of random source animals to those of purpose-bred animals nor with identifying attributes unique to random source or Class B dogs and cats. The supposedly greater tractability of random source dogs and cats is sometimes cited as an advantage for their use. For example, opinion provided to the Committee by some investigators through the APS (per- sonal communication to the Committee from David Kass, October 2008) indicated that random source animals were often behaviorally more pre- disposed than purpose-bred animals to training such as resting quietly for conscious animal studies or running on a treadmill. While tractability is certainly an important trait for studies requiring measurement of blood pres- sure, heart rate, and circulating hormones in conscious animal models, it is important to emphasize that this trait is largely a function of prior socializa- tion with humans and therefore not confined to random source animals. Poorly socialized dogs and cats, regardless of source, can be expected to be more fearful of, and resistant to, interactions with unfamiliar people includ- ing laboratory personnel (Serpell and Jagoe 1995; Turner 2000). Conversely, properly socialized purpose-bred animals can be as tractable as former pets. Therefore, generalizations regarding tractability cannot be made, and depend on individual animals and their socialization and history. Furthermore, according to the AWA, PHS Policy, and the Guide, justifi- cation for the use of a particular species is required for approval of a scien- tific protocol, but justification of the source of such animals is not. Because there is no regulatory requirement to maintain records of the source(s) of research animals, documentation and justification for the use of dogs and

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4 USE OF RANDOM SOURCE DOGS AND CATS FOR RESEARCH cats from random sources (such as Class B dealers, pounds, and shelters) are not available. Given this lack of information, the “necessity” of the use of these animals is nearly impossible to determine. Nonetheless, the Commit- tee was able to identify fields (described in the next section) and “common research topics” where the potential exists to use random source animals, including in NIH-funded research, and describe the particular characteris- tics that may make these animals well suited for research in these areas. It is important to emphasize that these characteristics may not be unique to random source animals and that in many cases other animals, including Class A animals, may also have these particular characteristics. RANDOM SOuRCE DOgS: ANATOMIC AND PHySIOLOgIC ATTRIBuTES Scientific investigation may require the use of older, larger, or geneti- cally diverse dogs, or dogs with naturally occurring disease, any of which may be available as random source animals. In contrast, purpose-bred dogs, such as those supplied by Class A dealers, tend to be young and healthy; they include beagles, “mini-mongrels,” and hounds weighing 23-27 kg (50-60 pounds) with a defined genetic background and disease-free status suitable for many types of biomedical research. A common argument for the use of random source dogs is the need for larger (27-37 kg, or 60-80 pounds) and older animals that are physically and physiologically similar to humans (Parsons et al. 1996; Sasajima et al. 1999). But demand for these larger and older animals is usually not great and maintaining even small numbers of larger animals for long periods may not be cost effective for vendors of purpose-bred dogs. Cardiovascular Large mixed-breed random source dogs have been used in the study of cardiac diseases, and in the development of procedures and devices to alleviate them, because of their size, depth of the chest cavity, and large heart and great vessels (aorta and pulmonary arteries). These features allow adequate working space to perform complex cardiac procedures and accommodate human commercially produced devices for testing. The dog’s cardiovascular system is similar to that of humans in both size and function. Anatomically, the dog’s coronary artery system mimics chronic remodeling in humans following myocardial ischemia with exten- sive subepicardial collateral vessels and can serve as a model for regional and global myocardial ischemia (Swindle and Adams 1988). But there are differences in coronary artery anatomy and cardiac physiology between random source dogs and purpose-bred dogs, and these differences (or “con-

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0 ISSUES IN THE USE OF RANDOM SOURCE DOGS AND CATS IN RESEARCH ditioning”) can affect the animal’s physiological status. Data presented on behalf of the American Physiological Society indicated that random source animals exhibited a greater increase in coronary blood flow and myocardial oxygen consumption (Tune et al. 2000; personal communication, Bill Yates, to Committee, October 2008). Furthermore, the incidence of idiopathic extramural coronary arteritis occurred less often in purpose-bred animals than in random source animals (Hartman 1989). The dog’s coronary sinus, or venous drainage of the heart, is also similar to human anatomy, allowing for investigation of chronic resynchronization therapy and development of devices and procedures to treat severe conges- tive heart failure (Reising et al. 1998; Williams et al. 1994). Physiologically, the cardiac electrical conduction system in the dog mimics that of humans, so dogs are used for studies of normal and abnormal cardiac conduction, including atrial fibrillation and other dysrhythmias (Lee et al. 2006). Random source animals have also been used to study dilatative cardio- myopathy using an induced rapid pacing model. These dogs had cardiac myosin isoform shifts (myosin heavy chain (MHC)-b and ventricular light chain (VLC)-2) in the heart chambers similar to those observed in end-stage human heart failure (Fuller et al. 2007). Conditions have been identified in random source animals that specifically contributed to identification and treatment of mechanisms associated with cardiac arrhythmias—including Long QT syndrome, Brugada syndrome, and Timothy’s syndrome—that are not present in purpose-bred dogs. For example, when purpose-bred beagles were used for research associated with Brugada syndrome, they were found to be unsuitable due to the lack of certain ion channel muta- tions, whereas random source dogs developed the characteristics of this arrhythmia (Antzelevitch 2008). Pulmonary Scientists investigating diseases in pulmonary medicine and using thoracic surgical procedures seek barrel-chested large breed dogs for several reasons. Pulmonary function studies use dog models because of physio- logic aspects such as increasing microvascular pressure creating pulmonary edema (Swindle and Adams 1988), which has been used as a model for acute respiratory distress syndrome (Reising et al. 1998) and acute lung injury (Kaczka et al. 2005) in humans. Large dogs have a readily accessible single pulmonary artery and vein of the left lower lung lobes, allowing for ease of cannulation and analysis of pulmonary metabolism. Historically, lung transplant procedures were developed using large random source dogs because of the deep chest cavity, again allowing access for complex anas- tomoses of vascular and airway structures (Blumenstock et al. 1981).

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1 USE OF RANDOM SOURCE DOGS AND CATS FOR RESEARCH Orthopedic Random source dogs have been and continue to be integral to the development of prosthetic devices for hip and knee replacements and of fixation devices and techniques, as well as vertebral fusion models, tendon and ligament repair, and assessment of biomaterials for orthopedic pro- cedures (Arnoczky et al. 1982; Greis 2001). In some circumstances, the larger animal’s size accommodates human prosthetic devices, but many of these materials and devices eventually are designed for veterinary use in smaller animals. Thus medical advances with research dogs now afford companion dogs many of the same benefits as for humans, such as hip and knee replacement, arthroscopic ligament repair, meniscectomy, and other procedures associated with degenerative joint disease. Older dogs have been used to study osteoarthritis, cervical disc degen- eration, and vertebral fusion because the pathophysiology of the mature articular surfaces and vertebral disc is similar to that of aged humans (An and Friedman 1999; Hunter et al. 2004; Smith et al. 1998). Cervical disc degeneration occurs naturally in older large breed dogs and the cervical and lumbar disc spaces are large enough to support artificial disc prosthet- ics and materials used for fusion or replacement of this structure (Cook et al. 1994). Many orthopedic studies use older, skeletally mature animals to reflect an adult human population rather than younger (less than 1-year-old) dogs (Frick et al. 1994). In humans, intervertebral disc disease is preceded by the disappearance of notochordal cells in the nucleus pulposus (inner portion of the disc). Similarly, older (5-year-old) mixed-breed dogs have few notochordal cells in the nucleus pulposus and are considered to be an adequate model of the human clinical condition (Hunter et al. 2004). Therefore, older large breed random source dogs have been used and are desirable for these studies (Hasegawa et al. 1995; Katsuura and Hukuda 1994; Nguyen-minh et al. 1997). Age-Related Disease Rodent and primate studies indicate that older animals are physiologi- cally different from younger animals (Ferrari et al. 2003). Advanced age is an attribute commonly found in random source animals and may make them desirable for research. Random source dogs may have age-related chronic or persistent dis- ease conditions such as congestive heart failure, arthritis, allergy, dementia, and neoplastic conditions that may make them desirable for investigations into similar human conditions. For example, canine osteosarcoma has a predictable metastatic rate and pattern that make it attractive for studies of antimetastatic approaches. Canine and feline malignant mammary tumors

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2 ISSUES IN THE USE OF RANDOM SOURCE DOGS AND CATS IN RESEARCH have a similar metastatic pattern to that of mammary tumors in women, namely metastasis to the regional lymph nodes and lung (MacEwen 1990). More recently, random source animals have been used in NIH-funded stud- ies of the ocular system, dementia, and cardiac function (Anyukhovsky et al. 2005; Dun et al. 2003; Goralska et al. 2007, 2009; Studzinski et al. 2006; Taylor et al. 2004). Advanced age itself, independent of disease conditions, may be desir- able for some studies. Several studies investigating veterinary and human pharmaceuticals have revealed varying efficacies and toxicological side effects related to the age of the animal subjects. For example, a COX-2 inhibitor intended to treat older, arthritic animals was recently developed and toxicologically tested using only young beagle dogs. Once on the market, it was discovered that older dogs metabolized the drug very differ- ently, resulting in severe side effects that included gastric ulcers, liver and kidney damage, and death.4,5 Acquisition of aged dogs poses a logistical and financial challenge that can be addressed with random source animals. Representatives of one purpose-bred vendor testified that they could provide older animals (retired breeders) on a limited basis but that they are unavailable in substantial numbers; purpose-bred animals generally are sold as young as possible (usually 6-9 months) to minimize the expense of housing (personal com- munication with Class A vendors). In addition, the average duration of NIH grants usually prohibits an investigator from requesting animals years before they are required given the lack of certainty of funding beyond a single grant cycle. It would be reasonable to assume that the cost of maintaining dogs and cats for several years would be passed on to the users (personal communication with Class A vendors), as vendors of purpose-bred animals would be unlikely to sustain the costs of maintaining the animals for a long time unless they knew a customer base was available to purchase them at or beyond a certain age. The challenge of funding is illustrated by an example of recent work on a canine model of dementia in the aged beagle. Approximately 20 ani- mals from a single colony were used for these studies over a 2- to 3-year period. The multicenter investigative team was supported by up to four NIH individual investigator grants and by several other significant non-NIH sources, all of which represent a level of combined extramural support far beyond that typically attained by individual NIH-funded investigators (Opii et al. 2008; Siwak-Tapp et al. 2007, 2008). On the other hand, this work also exemplifies an alternative for access to aged animals through existing purpose-bred research colonies. 4 http://www.the-aps.org/pa/policy/animals/ pethealth.htm 5 http://www.fda.gov/ohrms/DOCKETS/dockets/04n0559/04N-0559_emc-000003-01.pdf

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3 USE OF RANDOM SOURCE DOGS AND CATS FOR RESEARCH genetic Diversity Genetic diversity may be an attribute necessary for some aspects of cur- rent and future biomedical research, and the genetic diversity represented among the many breeds in the general dog population cannot be reproduced in purpose-bred colonies. Furthermore, maintenance of maximal genetic diversity in a single colony of dogs would require more than 200 breeding pairs (personal communication from Stephen O’Brien to the Committee, Janu- ary 2009). Nobel laureate Dr. E. Donnall Thomas, who received the award for his work in bone marrow transplantation, stated that “marrow grafting could not have reached a clinical application” (Thomas 1990, pp. 581-582) without the use of outbred dogs. Non-purpose-bred dogs have also been critical in the development of hematopoietic cell transplantation or bone marrow trans- plantation because of their genetic diversity, large size, long life, and the fact that, other than humans, they are the only mammals to possess these qualities (Ostrander and Wayne 2005). In addition, genetically diverse animals have also been instrumental in studies of total body irradiation, chemical and radioimmunological myeloablation, in vivo and in vitro graft manipulation, and graft-versus-host disease studies (Lupo and Storb 2007). Naturally Occurring Infectious Diseases Random source dogs exposed to outdoor environments and vari- ous vectors that may carry disease can be effective models of naturally occurring infectious diseases. Vector-borne diseases such as heartworm (Dirofilaria immitus), Lyme disease (Borrelia burgdorferi), Rocky Mountain spotted fever (Rickettsia rickettsii), babesiosis (Babesia microti), ehrlichiosis (Ehrlichia canis), and/or the antibodies to these organisms can be identified in random source dogs that have been exposed to outdoor environments (Scorpio et al. 2008). Random source animals may also have Sarcoptic mange (Sarcoptes scabiei), Demodectic mange (Demodex canis), or coccid- iosis from natural exposure to parasites. To maintain the naturally occurring infection, standard conditioning or treatments for these parasitic diseases may be withheld from some random source animals so that they are avail- able for studies involving these infections. Research on naturally occurring infectious diseases of dogs is generally not supported by the NIH, but some members of the Committee believed that it was important to point out that the U.S. Department of Health and Human Services Food and Drug Administration (FDA) Center for Veterinary Medicine’s (CVM) Guidance Document for New Animal Drug Applications6 6 http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/ ucm123821.htm

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4 ISSUES IN THE USE OF RANDOM SOURCE DOGS AND CATS IN RESEARCH (Guidance 61) states that for dose determination studies natural infections are ideal, whereas induced infections are acceptable. In addition, Guid- ance 90 “Guidance for Industry – Effectiveness of Anthelminthics: General Recommendations, Final Guidance” states that the use of natural or induced infections in effectiveness studies should be determined by the type of parasite and the claim proposed by the sponsor. Finally, according to the International Harmonization of Anthelminthic Efficacy Guidelines7 (VICH GL#19, FDA/CVM Guidance #111), “Dose confirmation studies should be conducted using naturally or artificially infected animals; however, at least one study should be conducted in naturally infected animals for each para- site claimed on the label.” Therefore, although studies on naturally infected dogs do not typically apply to NIH-funded research, random source animals may be important for other types of research. Spontaneously Occurring Animal Models of Human Disease The genetically diverse pet population has been the source of unique animal models that are not available from vendors of purpose-bred animals; for example, diseases have been identified in a mixed population of pet animals in Germany (Neumann and Bilzer 2005), and random source ani- mals have served as controls for studies in comparison to purebred animals (Basso et al. 2004; Smucker et al. 1990). Most often, spontaneously occurring diseases have been identified in a particular breed and a colony established using non-purpose-bred animals. For example, spontaneous genetic animal models for sleep apnea, mus- cular dystrophy, progressive retinal atrophy, hereditary nephropathy, and hemophilia A and B have been identified in non-purpose-bred dogs (Canine Inherited Disorders Database;8 Wolfe 2009). There are no other large animal models for these diseases. In some circumstances, individual investigators have established breeding colonies to study these diseases. Examples of dog colonies maintained at research facilities as models of genetic disease include hemophilia A dogs derived from Irish setters, hemophilia B dogs derived from Lhasa Apsos, von Willebrand disease dogs derived from Scottish terriers, and Duchenne muscular dystrophy dogs derived from golden retrievers (Nichols et al. 2009; Wang et al. 2009). In addition, other genetic diseases have been identified in breeds of dogs used for gene-based therapy. The Swedish Briard (RPE65) is the only dog 7 http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TD7-42G0KJG-1&_user=10&_ rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_searchStrId=951858672&_ rerunOrigin=google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5= cfaefa728a34a1786eb1f1b3d6ffbf66 8 http://www.upei.ca/~cidd/intro.htm

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 USE OF RANDOM SOURCE DOGS AND CATS FOR RESEARCH breed that has responded successfully to gene therapy for retinal degenera- tion, opening the door for several human clinical trials. Alaskan Malamutes and German shorthaired pointers may also provide similar success in gene therapy for achromatopsia (Stieger et al. 2009). Finally, naturally occurring dog and cat models for human genetic heart diseases exist and are criti- cal for the development of gene-based therapy; for example, Portuguese water dogs are maintained at the University of Pennsylvania as a model for dilatative cardiomyopathy (Sleeper et al. 2009). These valuable models are examples of the desirability or necessity of access to random source animals as genetically diverse control animals, and of as yet undetermined animal models that may result from naturally occurring single nucleotide polymorphisms, epigenetic occurrences, or other genetic alterations (personal communication, Stephen O’Brien to the Committee, January 2009). Discovery of new models of human disease has not typically arisen through large-scale random screening of random source dogs from shelters, pounds, or Class B dealers. Instead, these animals are usually sought out as naturally occurring disease models based on knowl- edge of their availability from random sources. The development of novel dog models of human disease relies on a sophisticated process of referral by breeders or veterinarians aware of nuances in a certain breed, veterinary medical workup, scientific characterization, and validation as an animal model. Such programs are ongoing with NIH support for the discovery of novel models in dogs and cats (see Chapter 4). RANDOM SOuRCE CATS: ANATOMIC AND PHySIOLOgIC ATTRIBuTES Cats have long been a mainstay of NIH-funded studies of neurologi- cal, cardiovascular, and respiratory diseases and the immune system. The similarity of these physiological systems to those of humans as well as the size and tractability of cats make them ideal for many experimental models. As such, a large database exists based on studies using cats as models of human disease. As with dogs, the genetic diversity of the general cat population (and of some purpose-bred cats) has provided several valuable genetically based models of human disease. For example, a colony of hypertrophic cardio- myopathy Maine Coon cats is maintained at the University of California, Davis, and cats with mucopolysaccharidosis are maintained and studied at the University of Pennsylvania (Haskin 2009). There are over 200 hereditary human diseases with correlates in cats (O’Brien et al. 2008). Following are a few illustrative examples.

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60 ISSUES IN THE USE OF RANDOM SOURCE DOGS AND CATS IN RESEARCH eases (e.g., canine distemper, canine parvovirus, canine parainfluenza virus, feline panleukopenia, feline calicivirus, and feline herpes virus). In addition, respiratory and intestinal diseases caused by viruses, bacteria, protozoa, and helminths are among the most common ailments that cause considerable morbidity and suffering for shelter animals. The quality of care for shelter animals varies widely across the coun- try. Shelters are not required to isolate, vaccinate, deworm, or provide treatment for illnesses in the animals (Miller and Zawistowski 2004) and, based on discussions with shelter experts (there is no published literature), the Committee found that many shelters do not have veterinarians on staff or even serving as advisors. Although some animals are very well cared for, they may be behaviorally abnormal, and they are almost certainly stressed. Furthermore, dogs and cats in shelters and pounds often have undocumented vaccination histories and frequently arrive at the shelter with compromised health—they may have heartworms, fleas, ticks, mites, lice, ringworm, or intestinal parasites, and/or a variety of disease agents that spread more readily than would normally be expected because the animals are mixed together. They may be placed into different types of group or communal housing, where unreliable sanitation practices contribute to dis- ease spread. Research has shown that the longer animals stay in shelters and pounds, the more likely they are to develop respiratory disease (Edinboro et al. 2004). Even if vaccinated immediately upon entry, a stay of several days at a shelter puts animals at higher risk for respiratory disease because respiratory vaccines are not always effective in preventing infection. An additional consideration is that it is often not possible to detect animals that are incubating some infectious diseases because they appear clinically normal and diagnostic evaluation may be unavailable, incomplete, or mis- leading (as in instances of false negatives or positives). To address these problems, the research institution or the Class B dealer (or both) conditions random source dogs and cats that enter research insti- tutions (whether from shelters and pounds, Class B dealers, or other legal sources). The conditioning generally includes a period of quarantine, treat- ment for parasites, vaccination, deworming, and other health-related pro- cedures that make the animal more suitable for research. Even so, the animals may still have health problems since not all infectious agents can be eliminated by antibiotics or deworming or prevented through vaccination. In contrast, purpose-bred animals are more likely to be microbiologically defined. ZOONOTIC DISEASE HAZARDS AMONg RANDOM SOuRCE ANIMALS Some infectious disease agents associated with dogs and cats in the general pet population, and therefore among some random source animals,

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61 USE OF RANDOM SOURCE DOGS AND CATS FOR RESEARCH pose a potential threat to humans. In the 2008 Compendium of Veterinary Standard Precautions for Zoonotic Disease Preention in Veterinary Personnel (Appendix 1), the National Association of State Public Health Veterinarians lists 54 “zoonotic diseases of importance” in the United States; of these, 26 are associated with dogs and/or cats as the “most common species associ- ated with transmission to humans” (2008). An earlier NRC report (1994, Table 2.1, p. 8) lists 27 “Selected Canine Zoonoses Causing Disease in Humans,” beginning with “acariasis” (mange) and ending with “yersiniosis” (see also NRC 1997, p. 95). And the World Health Organization Collaborat- ing Center for New and Emerging Zoonoses lists numerous zoonotic agents, both common and rare, in domestic dogs and cats.9 Some common agents, such as Pasteurella spp., are present in the oral and nasal cavities of 12-92% of dogs and 52-99% of cats and are associated with infections from animal bites (Greene and Goldstein 2006). Other agents of concern include Bar- tonella henselae, the agent of “cat scratch disease” that is commonly carried by young cats; Salmonella and Campylobacter spp., which cause enteric disease; Sarcoptes spp., which causes scabies (in humans; called mange in animals); and Microsporidium (Microsporum) canis, which causes ringworm. Rabies represents a particularly serious zoonotic hazard among animals with unknown exposure and vaccination histories but is rare. Incidents of zoono- ses in the research laboratory are fortunately rare, but recognition, control, and prevention of canine and feline zoonotic hazards are important aspects of institutional occupational safety programs (NRC 1997). ADVERSE EFFECTS OF INFECTIOuS DISEASE ON RESEARCH Exposure to infectious disease is a risk the research community can avoid. As discussed earlier, the use of random source animals for the study of naturally occurring infectious disease may be desirable, but in the other situations intercurrent infections may be deleterious to research. These considerations are generally taken into account by the individual inves- tigator in concert with veterinary professionals at the research institution. Nonetheless, undetected (subclinical) infections can still compromise or confound research results. A recent study that documented canine expo- sure to three frequently reported tick-borne bacterial pathogens reported the results of molecular analysis and serology on 21 random source dogs from Class B dealers (Scorpio et al. 2008): the test results were positive in 17 dogs, but none showed any signs of clinical disease. The authors concluded that “Exposure to and potential for infection with these bacteria and other pathogens may contribute to blood and tissue alteration that 9 http://faculty.vetmed.ucdavis.edu/Faculty/bbchomel/WHO_Zoonoses/zoonoses_species.htm

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62 ISSUES IN THE USE OF RANDOM SOURCE DOGS AND CATS IN RESEARCH could confound experiments and lead to misinterpretation of data in canine models” (p. 23). Heartworms (Dirofilaria immitus) are generally associated with dogs, but the incidence of infection in cats can be quite high in endemic areas—one study reported 76% prevalence in outdoor-housed cats in North Carolina (Atkins et al. 2005). Overt infection makes the animals unsuitable for most research, but even Dirofilaria-seropositive cats that lack adult worms in the heart and lung may have significant pulmonary disease, making them potentially unsuitable for cardiopulmonary studies (Browne et al. 2005). ANIMAL WELFARE ISSuES A basic understanding of the terms animal welfare, stress, and distress is essential to the discussion of humane issues and animal welfare in the context of this report and the Committee’s statement of task. “Animal welfare” generally refers to the state of an animal and the extent to which it is faring well or ill in a particular situation or at a par- ticular point in its life. Different experts give priority to different aspects of an animal’s state when assessing its welfare: some emphasize unpleasant or pleasant subjective feelings (Boissy et al. 2007; Dawkins 1980; Duncan 1993), while others focus on the animal’s ability to express “natural” or species-typical behavior (Rollin 1995) or its capacity to adapt to, or cope with, the demands of its environment (Broom and Fraser 2007). One thing all agree on is that there is no single, reliable measure of an animal’s wel- fare (Appleby 1999; Mason and Mendl 1993). Most animal welfare experts therefore advocate multiple measures of aspects that are likely to reflect an animal’s welfare (e.g., behavioral responses, physiological indicators, immune function) while at the same time recognizing that the final deter- mination inevitably involves a degree of subjectivity (Dawkins 1980; Fraser 1995; Mason and Mendl 1993). A recent NRC report (2008, p. 2) defines “stress” as a “real or per- ceived perturbation to an organism’s physiological homeostasis or psycho- logical well-being.” Animals respond to such perturbations by displaying a “stress response,” characterized by behavioral and physiological efforts to restore homeostasis. Potential stressors may be physical or emotional and include overcrowding; changes in routine, diet, environment, temperature, or humidity; perceived threats to safety; sources of pain or discomfort; and malnutrition, illness, or physical restraint, among others. A certain amount of stress is a normal part of any animal’s life and should not necessarily be considered detrimental to welfare. Stress should be regarded as a welfare problem only when the degree of perturbation is sufficiently acute or prolonged, and an animal’s capacity to restore homeo- stasis is exceeded. Many authorities now use the term “distress” to describe

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63 USE OF RANDOM SOURCE DOGS AND CATS FOR RESEARCH the aversive negative state that arises when an animal is pushed to the limit of its ability to cope with, or adapt to, environmental stressors (NRC 2008), while the term “suffering” generally applies only to the conscious experi- ence of highly aversive or unpleasant mental and emotional states, such as pain or fear (Dawkins 1998). The question of whether random source dogs and cats experience a greater degree of stress and distress in the research laboratory setting than do purpose-bred animals cannot be answered directly as no published studies have addressed this question. Indirect evidence that the transition to life in laboratory housing may be stressful and distressing for former pets can, however, be derived from studies that have examined how pet dogs and cats respond to, and cope with, comparable transitions—for example, among pets relinquished to animal shelters, or those confined temporar- ily in boarding kennels, catteries, or veterinary hospital cages. Most such studies have found behavioral and physiological changes (e.g., elevated heart rate and glucocorticoid levels, reduced heart rate variability and white blood cell counts) consistent with the effects of moderate to severe stress. These responses may take 2 to 5 weeks to return to “normal” baseline levels, although some animals may remain in a distressed state for several months (Beerda et al. 1999a, b; Hennessy et al. 2001; Kessler and Turner 1997, 1999; McCobb et al. 2005; Rochlitz et al. 1998; Siracusa et al. 2008; Stephen and Ledger 2006; Väisänen et al. 2005). Chronic stress is immunosuppressive and reduces both cell-mediated and humoral immunity, thus increasing susceptibility to infectious disease, vasodepressive syncope, blood clots, coronary vasoconstriction, and other effects (Gregory 2004). A variety of factors may contribute to these out- comes, including the stressful effects of physical confinement and lack of stimulation, loss of social companions, exposure to unfamiliar people or conspecifics, and lack of control over environmental stressors (Beerda et al. 1999a, b; Carlstead et al. 1993; Hubrecht 1995; McCrave 1991). Because some random source dogs and cats are former pets or strays and therefore not used to prolonged cage confinement, it is reasonable to infer that they may have more difficulty adjusting to laboratory conditions than purpose- bred animals (see British Veterinary Association Animal Welfare Foundation et al. 2004). In summary, based on the limited available evidence, random source dogs and cats used for research probably endure greater degrees of stress and distress compared to purpose-bred animals. This conclusion has implications both for the welfare of random source animals and for their reliability as research models. Stress and distress are known to significantly alter animals’ physiological and behavioral responses to experimental manipulations, and will therefore affect the quality of the scientific results obtained from such animals (NRC 2008; Reinhardt 2004).

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