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OCR for page 4
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
OCR for page 6
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
OCR for page 8
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
OCR for page 9
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.
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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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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.
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Zool. 1:255-268.
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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.
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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
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Animals, D. Gotze, ed. Berlin: Springer-Verlag.
Representative terms from entire chapter:
animal models
