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Criteria for Selecting Experimental Animals Scientists who are planning experiments evaluate both animal and nonanimal approaches. If there are no suitable alternatives to the use of live animals, the appropriate species is selected on the basis of various scientific and practical factors, including the following: . Which species will yield the most scientifically accurate and inter- pretable results? According to critical review of the scientific literature, which spe- cies have provided the best, most applicable historical data? . On which species will data from the proposed experiments be most relevant and useful to present and future investigators? Which species have special biologic or behavioral characteristics that make them most suitable for the planned studies? Which species have features that render them inappropriate for the planned studies? Which species present the fewest or least severe biologic hazards to the research team? Which species require the fewest number of animals? Which species that meet the above criteria are most economical to acquire and house? For many scientific experiments, the answer to those questions will be the domestic dog, Canis familiaris. The size, biologic features, and coop 4

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CRITERIA FOR SELECTING EXPERIMENTAL ANIMALS s erative, docile nature of the well-socialized dog make it the model of choice for a variety of scientific inquiries. The contributions of the dog to human health and well-being are numerous (Gay, 1984~. Although research with dogs is often primarily to benefit humans, it has also greatly benefited dogs that are kept as companion animals. Examples of the benefits to dogs are improvements in diagnostic techniques; treat- ments for diabetes and arthritis; surgical procedures for correcting or treat- ing cardiovascular, orthopedic, and necrologic disorders; and therapies for bacterial, neoplastic, and autoimmune diseases. Moreover, dogs have been necessary for the development of vaccines that protect companion animals against viral diseases (e.g., distemper and parvovirus disease) and drugs that prevent parasitic diseases (e.g., dirofilariasis, or heartworm disease). GENETIC FACTORS All domestic dogs, irrespective of breed, are Canis familiaris. Canine genotypes and phenotypes vary among breeds as a result of selective breed- ing, which has created variations in allele frequency between breeds. A1- though "pure" breeds might have a higher frequency of some genes, much genetic variation remains in most breeds. The canine karyotype consists of 78 chromosomes (Minouchi, 1928~. Most of the autosomes are acrocentric or telocentric, and many pairs do not differ markedly in size. Recently, an improved method for staining canine chromosomes has been developed that makes karyotyping with Giemsa banding feasible (Stone et al., 1991~. A number of loci have been identified that code for the antigens of the canine major histocompatibility complex, which has been designated DLA (Vriesendorp et al., 1977~. Initially, several alleles were defined with sero- logic techniques at three class I loci, and several alleles were defined with cellular techniques at a DLA class II locus (Bull et al., 1987; Deeg et al., l986~. Molecular techniques are being used to refine the definition of the DLA class I loci, and at least eight class I genes have been demonstrated in the dog (Sarmiento and Storb, 1989~. Molecular-genetic studies to charac- terize canine class II loci correlate well with earlier work in which tech- niques for cell typing for class II antigens were used (Sarmiento and Storb, 1988a,b). The characterization of canine DLA loci is extremely useful for transplantation studies (Ladiges et al., 1985) and for demonstrating an asso- ciation between the major histocompatibility complex and some inherited canine diseases (Teichner et al., 19901. Attempts are under way to develop maps that identify the location of canine genes that control particular traits (e.g., inherited diseases and such behavioral tendencies as herding and aggression). Two approaches are used. The first relies on the principle that the relative positions of genes in a

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6 DOGS: LABORATORY ANIMAL MANAGEMENT particular region of DNA are comparable in humans, dogs, and other spe- cies. Conserved regions can be identified in DNA samples with restriction- fragment length polymorphisms (usually called RFLPs) that have been identified with probes for human and murine genes whose chromosomal locations are known. To enhance the detection of polymorphisms, investigators some- times produce dog-coyote hybrids, cross-breed two widely divergent dog breeds, or analyze a large, well-defined canine kindred (Joe Templeton, Department of Veterinary Pathobiology, College of Veterinary Medicine, Texas A&M University, College Station, Tex., personal communication, 1993~. The second approach uses simple sequence-repeat polymorphisms (microsatellite probes). Specific simple sequence-repeat markers that are highly polymorphic in dogs have been developed to study the canine ge- nome (Ostrander et al., 1992, 1993~. These and other techniques, such as chromosomal in situ hybridization and somatic cell hybridization, will likely greatly increase our understanding of canine genetics. Inherited defects including lysosomal storage diseases, retinal degen- erations, coagulopathies, complement deficiency, and various musculoskel- etal, hematopoietic, immunologic, and necrologic diseases- are common in purebred dogs, and many specific disorders are found most commonly in particular breeds (Patterson et al., 1989~. This phenomenon might be re- lated, in part, to breeders' inadvertent selection for mutant alleles that are closely linked to loci that determine breed-typical traits or to the chance increase in frequency of particular mutant alleles caused by the founder effect or random genetic drift. The high frequency of inherited canine disorders (compared with murine disorders) was recognized as early as 1969 (Cornelius, 1969~. During the 20-year period 1960-1980, 20 percent of more than 1,200 literature citations on naturally occurring animal models of human diseases involved dogs (Hegreberg and Leathers, 1980~. A compila- tion in 1989 noted that 281 inherited disease entities had been reported in dogs (Patterson et al., 1989~. Many of those constitute the only animal models for investigating the corresponding human diseases (Patterson et al., 1988~. The 19-fascicle Handbook: Animal Models of Human Disease (RCP, 1972-1993) lists 83 canine models of human diseases, many of which are hereditary, and the two-volume Spontaneous Animal Models of Human Dis- ease (Andrews et al., 1979) describes many canine models. In scientific studies in which genetic uniformity is desirable or in long- term studies in which the expected differences between experimental and control subjects are likely to be small, purpose-bred dogs (e.g., beagles) might be a more appropriate choice than dogs of unknown provenance. An advantage of using beagles, as opposed to other purpose-bred dogs, is the potential availability of other members of the kindred. But if the studies are to determine the greatest range of a variable that is likely to occur among the experimental subjects or if the experiments are of short duration, ran

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CRITERIA FOR SELECTING EXPERIMENTAL ANIMALS 7 dom-source dogs might be more useful and less expensive (see "Procure- ment" in Chapter 5~. BIOLOGIC FACTORS Dogs are monogastric carnivores with a short generation time (i.e., the calculated interval between when a pup is born and when its first offspring could be born) and a maximum life span of approximately 20 years; larger breeds appear to have a shorter maximum life span than smaller breeds. The canine mortality rate doubles every 3 years, compared with every 0.3 year for the rat (maximum life span, 5.5 years), every 15 years for the rhesus monkey (maximum life span, more than 35 years', and every 8 years for humans (maximum life span, more than 110 years) (Finch et al., 1990~. Dogs are useful models for studying the lifetime effects of environmental factors, and there is an extensive literature on their use in radiation biology (see Gay, 1984; Shifrine and Wilson, 1980~. Selective breeding has resulted in a spectrum of behaviors and a large range of canine body sizes, from the giant breeds (e.g., Irish wolfhound), which can measure 91 cm (36 in) at the shoulder and weigh more than 56 kg (124 lb), to the toy breeds (e.g., Pomeranian), which can measure less than 31 cm (12 in) in height and weigh less than 4.5 kg (10 lb). Larger dogs, which can include mongrels or dogs of unknown breeding, are par- ticularly well suited to cardiovascular, transplantation, and orthopedic stud- ies, because body weights and blood volumes approximate those of humans (see Gay, 1984; Shifrine and Wilson, 1980; Swindle and Adams, 1988~. The dog's size also lends itself to procedures that cannot be carried out in smaller species, e.g., when the instrumentation essential for collecting sci- entific data is bulky and cannot be miniaturized and when the resolution of imaging equipment requires a larger target field than is available in a small animal. An individual dog often can be studied in great detail or in many ways, which might reduce the number of subjects needed for a study and generate a more definitive data set. For example, it is possible to take multiple blood samples of several milliliters each from a single dog over some period without compromising the dog's well-being, but taking samples of similar size during the same period from a single mouse or rat would be impossible. BEHAVIORAL FACTORS The social unit for dogs is the pack, and most dogs can be socialized to accept humans as the dominant individual in their social hierarchy, espe- cially if the techniques used to socialize them provide rewarding experi- ences (e.g., food treats, petting, and verbal reinforcements) and minimize

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8 TABLE 2.1 Selected Caninea Zoonoses DOGS: LABORATORY ANIMAL MANAGEMENT Disease in Humans Agent Mode of Transmission (Intermediate Host or Vector)b Acariasis Amebiasis American trypanosomiasis (Chagas' disease) Brucellosis Campylobacteriosis Coenurosis C o lib ac i it o s is Cutaneous larva migrans Dipylidiasis Df2 infections Dirofilariasis Giardiasis Hydatidosis Larva currens Leishmaniasis (cutaneous) Leishmaniasis (visceral) Leptospirosis Pasteurellosis Rabies Ringworm (dermatomycoses) Rocky Mountain spotted fever Salmonellosis Scabies Tularemia Visceral larva migrans Yersiniosis Cheyletiella yasguri Entamoeba histolytica Trypanosoma cruzi Brucella cants Direct Campylobacter jejuni Direct Taenia multiceps Direct Enteropathogenic Escherich~a cold Ancylostoma braziliense Ancylostoma caninum Dipylidium caninum Dysgonic fermenter-2 Dirofilaria immitis Dirofilaria repens Giardia intestinalis (canis) Echinococcus granulosus Strongyloides stercoralis Leishmania braziliensis perurlana Leishmania donovani Leptospira spp. (usually L. canicola) Pasteurella multocida Rabies virus Microsporum cants Trich op hyto n men tagrop hytes Rickettsia rickettsii Salmonella spp. Sarcoptes scabiei Francisella tularensis Toxacara cants ~ . ~ 1 oxascarls ceonzna Yersinia enterocolitica Direct Direct Indirect (triatomine insect) Direct Direct Indirect (dog flea) Direct Indirect (mosquito) Direct Direct Direct Indirect (phlebotomine flies) Indirect (phlebotomine flies) Direct Direct Direct Direct Indirect (tick) Direct Direct Indirect (tick) Direct Direct aNorth, Central, and South American dogs. bDirect = transmission by direct contact with the dog, its excretions, or its secretions; no other vector or intermediate host is required. aversive experiences. Different breeds and individual dogs differ in the ease and rapidity with which they can be socialized to humans (Scott and Fuller, 1965~. However, properly socialized dogs can be docile and can be trained to cooperate in procedures that require repeated contacts with re- search personnel. For example, most dogs will allow venipuncture with

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CRITERIA FOR SELECTING EXPERIMENTAL ANIMALS minimal restraint and will cooperate during detailed physical and neuro- logic evaluations. HAZARDS 9 Unvaccinated dogs might harbor rabies virus, and preexposure immuni- zation should be made available to personnel who are at substantial risk of infection (NRC, 1985~. Dogs also have internal and external parasites that can be shared with humans (see "Parasitic Diseases" in Chapter 5~. Table 2.1 lists selected zoonoses, zoonotic agents, and modes of transmission. Detailed discussions of zoonoses have been published (Ache and Szyfres, 1987; August, 1988; Elliot et al., 1985; Fishbein and Robinson, 1993; Hubbert et al., 1975~. Personnel can develop allergies to canine dander and saliva, can be bitten or scratched, might suffer hearing impairment from prolonged exposure to excessive noise generated by barking dogs or mechanical equipment, or can be injured while lifting or transporting large dogs. To deal with these and other animal-related health problems, institutions must provide occupational health programs for personnel who work in animal facilities or have substantial animal contact (NRC, 1985~. REFERENCES Acha, P. N., and B. Szyfres. 1987. Zoonoses and Communicable Diseases Common to Man and Animals, 2d ed. Scientific Pub. No. 503. Washington, D.C.: Pan American Health Organization. 963 pp. Andrews, E. J., B. C. Ward, and N. H. Altman, eds. 1979. Spontaneous Animal Models of Human Disease. New York: Academic Press. Vol. I, 322 pp.; vol. II, 324 pp. August, J. R. 1988. Dygonic fermenter-2 infections. J. Am. Vet. Med. Assoc. 193:1506- 1508. Bull, R. W., H. M. Vriesendorp, R. Cech, H. Grosse-Wilde, A. M. Bijma, W. L. Ladiges, K. Krumbacher, I. Doxiadis, H. Ejima, J. Templeton, E. D. Albert, R. Storb, and H. J. Deeg. 1987. Joint report of the Third International Workshop on Canine Immunogenetics. II. Analysis of the serological typing of cells. Transplantation 43:154-161. Cornelius, C. E. 1969. Animal models A neglected medical resource. N. Engl. J. Med. 28 1 :934-944. Deeg, H. J., R. F. Raff, H. Grosse-Wilde, A. M. Bijma, W. A. Buurman, I. Doxiadis, H. J. Kolb, K. Krumbacher, W. Ladiges, K. L. Losslein, G. Schoch, D. L. Westbroek, R. W. Bull, and R. Storb. 1986. Joint report of the Third International Workshop on Canine Immunogenetics. I. Analysis of homozygous typing cells. Transplantation 41:111 - 117. Elliot, D. L., S. W. Tolle, L. Goldberg, and J. B. Miller. 1985. Pet-associated illness. N. Engl. J. Med. 313:985-995. Finch, C. E., M. C. Pike, and M. Witten. 1990. Slow mortality rate accelerations during aging in some animals approximate that of humans. Science 249:902-905. Fishbein, D. B., and L. E. Robinson. 1993. Rabies. N. Engl. J. Med. 329:1632-1638. Gay, W. I. 1984. The dog as a research subject. The Physiologist 27:133-141. Hegreberg, G., and C. Leathers, eds. 1980. Bibliography of Naturally Occurring Animal Models of Human Disease. Pullman, Washington: Student Book Corp. 146 pp.

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10 DOGS: LABORATORY ANIMAL MANAGEMENT Hubbert, W. T., McCulloch, W. F., and Schnurrenberger, P. R., eds. 1975. Diseases Transmit- ted from Animals to Man, 6th ed. Springfield: Ill: Charles C Thomas. 1,236 pp. Ladiges, W. C., H. J. Deeg, R. F. Raff, and R. Storb. 1985. Immunogenetic aspects of a canine breeding colony. Lab. Anim. Sci. 35(1):58-62. Minouchi, O. 1928. The spermatogenesis of the dog with special reference to meiosis. Jpn. J. Zool. 1:255-268. NRC (National Research Council), Institute of Laboratory Animal Resources, Committee on Care and Use of Laboratory Animals. 1985. Guide for the Care and Use of Laboratory Animals. NIH Pub. No. 86-23. Washington, D.C.: U.S. Department of Health and Human Services. 83 pp. Ostrander, E. A., P. M. Jong, J. Rine, and G. Duyk. 1992. Construction of small-insert genomic DNA libraries highly enriched for microsatellite repeat sequences. Proc. Natl. Acad. Sci. USA 89:3419-3423. Ostrander, E. A., G. F. Sprague, Jr., and J. Rine. 1993. Identification and characterization of dinucleotide repeat (CA)n markers for genetic mapping in dog. Genomics 16:207-213. Patterson, D. F., M. E. Haskins, P. F. Jezyk, U. Giger, V. N. Meyers-Wallen, G. Aguirre, J. C. Fyfe, and J. H. Wolfe. 1988. Research on genetic diseases: Reciprocal benefits to animals and man. J. Am. Vet. Med. Assoc. 193:1131-1144. Patterson, D. F., G. A. Aguirre, J. C. Fyfe, U. Giger, P. L. Green, M. E. Haskins, P. F. Jezyk, and V. N. Meyers-Wallen. 1989. Is this a genetic disease? J. Small Anim. Pract. 30:127-139. RCP (Registry of Comparative Pathology). 1972-1993. Handbook: Animal Models of Human Disease, fascicles 1-19. Washington, D.C.: Registry of Comparative Pathology. Avail- able from RCP, Armed Forces Institute of Pathology, Washington, DC 20306-6000. Sarmiento, U. M., and R. F. Storb. 1988a. Characterization of class II alpha genes and DLA- D region allelic associations in the dog. Tissue Antigens 32:224-234. Sarmiento, U. M., and R. F. Storb. 1988b. Restriction fragment length polymorphism of the major histocompatibility complex of the dog. Immunogenetics 28:117-124. Sarmiento, U. M., and R. F. Storb. 1989. RFLP analysis of DLA class I genes in the dog. Tissue Antigens 34:158- 163. Scott, J. P., and J. L. Fuller. 1965. Genetics and the Social Behavior of the Dog. Chicago: University of Chicago Press. 468 pp. Shifrine, M., and F. D. Wilson, eds. 1980. The Canine as a Biomedical Research Model: Immunological, Hematological, and Oncological Aspects. Washington, D.C.: U.S. De- partment of Energy. 425 pp. Stone, D. M., P. B. Jacky, and D. J. Prieur. 1991. The Giemsa banding pattern of canine chromosomes, using a cell synchronization technique. Genome 34:407-412. Swindle, M. M., and R. J. Adams, eds. 1988. Experimental Surgery and Physiology: Induced Animal Models of Human Disease. Baltimore: Williams & Wilkens. 350 pp. Teichner, M., K. Krumbacher, I. Doxiadis, G. Doxiadis, C. Fournel, D. Rigal, J. C. Monier, and H. Grosse-Wilde. 1990. Systemic lupus erythematosus in dogs: Association to the major histocompatibility complex class I antigen DLA-A7. Clin. Immunol. Immunopathol. 55 :255-262. Vriesendorp, H. M., H. Grosse-Wilde, and M. E. Dorf. 1977. The major histocompatibility system of the dog. Pp. 129-163 in The Major Histocompatibility System in Man and Animals, D. Gotze, ed. Berlin: Springer-Verlag.