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5-1987

The Scientific Disadvantages of Using Random Source Animals for Research and Testing

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THE SCIENTIFIC DISADVANTAGES OF USING

RANDOM SOURCE ANIMALS FOR RESEARCH AND TESTING

THE HUMANE SOCIETY OF THE UNITED STATES 2100 L STREET, N.W., WASHINGTON, DC 20037 May, 1987

THE SCIENTIFIC DISADVANTAGES OF USING

RANDOM SOURCE ANIMALS FOR RESEARCH AND TESTING

There should be no apology for the length of this document, for its sheer size is one reason for its importance. Consisting principally of refer­ enced excerpts from the published scientific literature, this documentation authoritatively refutes the assertion that unclaimed pet animals from shelters are needed for biomedical research and are scientifically appro­ priate for that purpose. This is the most extensive collection of such information currently available.

The term "random source" refers to animals used in laboratory work which were not bred specifically for that purpose._ The use of such animals (in­ cluding unclaimed pet animals from pounds and shelters) for research and testing is a longstanding tradition, a practice still strongly defended by many scientists. In the preparation of this paper, several of these indi­ viduals at the National Institutes of Health and other research facilities were invited in writing to provide published evidence supporting this pos­ ition. Many op~niono were offered, but no empirical ~v~d~nQ~. Not one research study was forthcoming to support the claim that random source animals are good "animal models" as C:.Jmpared to purpose-bred animals or that certain studies h~quin~ the use of random source animals. Evidently, no .6 u.Qh do Qu.m~nta:Uo n ~wt.6 .

As can be readily seen in the pages to follow, substantial opposition by credible scientists to the use of random source animals has a long and dis­ tinguished tradition of its own. In essence, the critique states that the genetic, medical and environmental histories of laboratory animals are extremely important factors in how they will respond to experimental or testing procedures. Thus, unnecessary and often costly problems are created when animals of unknown, uncontrollable, and highly variable random source backgrounds are used in the laboratory.

The documentation is arranged in chronological order (1958-1986). For pur­ poses of saving space, the paragraph formatting of the original articles was not retained. Original emphases remain in italics while emphases added are underlined throughout.

For those who advocate the continued utilization of unclaimed pets from animal shelters (and other random source animals) for research and testing, arguing that such use is both necessary and high quality science, the chal­ lenge posed by this scientific literature review is clear.

Ironically, the weight of scientific autho~y continues to support the use of random source animals while the weight of scientific ~v~d~nQ~ clearly does not. 1

THE SCIENTIFIC DISADVANTAGES OF USING

RANDOM SOURCE ANIMALS FOR RESEARCH AND TESTING

"First. in order to obtain uniform and consistent results in experimental research. it is only logical to use animals in as uniform a state of health as possible .... From a practical standpoint, 100 percent of the pound dogs must be considered infested by intestinal worms and fleas. If the infestations are pronounced, the animals are apt to be ane:""lic, and even if their general appearance is not bad these animals are not good subjects for experimentation .... lf the results of the experiment are to be evaluated under the light of, first, the death or survival of the animal, second, the changes on its biologic processes, and third, the resulting pathology in its organs, one must try to avoid by all possible means strange mechanisms being added to the experiment proper .... lt may be argued that all this is expensive. Yes. progress is expensive but necessary. and in the final analysis jt is cheaper to do a thing right once than to do many things wrong many times."

Dr. J .J. Perez-Alvarez. 1958. Some elements of error in experimental surgery. Surgery (Editorial) 43 (2): p. 310-312.

"Are we to have standards of normalcy for the dog used in physiologic experimentation? Any diseased animals could well be delivered to the laboratory by a disinterested and untrained attendant in response to a telephone call for a normal dog .... The investigator, without further concern, proceeds to conduct an elaborate day-long experiment involving two or more assistants, several technicians, much expensive apparatus, numerous chemicals, glassware, recording paper, and many hours or days in the analysis of data. Results and conclusions are published which influence the opinions of others and establish physiologic phenomena for the 'normal' dog. Much of the data is often recognized years later as indicating that the dog was probably 'different' or 'not normal.' The 'normal' dog could be severely anemic. infested with fleas. lice. ticks. and intestinal parasites such as amoebae. He could have struggled to survive in a state of malnutrition in a poor neighborhood, without the care and attention necessary for normal growth and development. He may be influenced by an extreme sense of insecurity and anxiety .... Even more, consider the possible psychologic trauma produced by his captivity, transportation to the laboratory, neglect, and nonsympathetic care during his imprisonment .... Surely, a normal dog, accurately established as such by the necessary measures, is not too great a requirement for any investigation. Too often the requisites of performance of investigators. apparatus. and methods far exceed the requirements for the state of the health of the experimental animal. No matter how good the method or the performance of the apparatus, an abnormal animal is not suitable for obtaining results intended to define the normal state of health. True. science is concerned with the unknown. but the conditions of the study should be maximally known .... Normalcy should be supported by criteria of care and health in dogs as well as in man regardless of the demands on effort and funds. Treat not the dog like a dog but more like a man, or the experimental results will 'go to the dogs'."

Dr. George E. Burch. 1959. Of the normal dog. Amer. Heart J. (Editorial) 58: p. 805-806.

"As the cost of the experiments in which dogs are used tends to be very high in terms of apparatus and manpower, it is important to ensure that every possible care be exercised in the provision of healthy, disease-free dogs." 2

Dr. James A. Baker. 1961. Symposium: Production and management of dogs for research (Introduction). Proceed. of the Animal Care Panel 11 (4): p. 207.

"Confusing clinical and histopathological data. with the resultant loss of valuable time and expense from the use of dogs with unknown histories and residue of previous infections, has led to the establishment of a controlled dog breeding kennel .... ln pharmaceutical research the reliability and significance of data from animal experimentation depend not only on the keenness of the individual or research team, but also on the uniformity of the laboratory animals which are employed .... A dog breeding program was initiated in 1955, when it became apparent that the quality of available dogs was not suitable, especially for toxicological purposes. Previous to this time, all dogs were purchased and were invariably in a poor state of health. To bring the dogs to a condition suitable for experimental study required a great deal of time in diagnosis, proper treatment, and in the improvement in their nutritional state. All of this, however, gave no assurance against erroneous results when the dogs were examined, grossly and histologically, for pathological changes. Because the history was unknown in any of the dogs. effects of previous infections could cause a confusing patholoaical picture."

Dr. John E. Gilmartin. 1961. The establishment of a dog breeding kennel for pharmaceutical research. Proceed. of the Animal Care Panel 11 (4): p. 222-229.

"Because of the high susceptibility of dogs to enzootic diseases during experimental procedures, it became apparent that such studies were impossible without disease-free animals .... Even healthy young animals, free from parasites and well immunized beforehand, are apt to succumb to distemper, hepatitis, or other enzootic diseases in the two or three months that immediately follow their exposure to radiation .... ln order to study the basic immunologic problems of marrow transplantations, free from the complications of intercurrent disease, we were obliged to set up facilities for dog care that permitted study of essentially disease-free animals .... lt is apparent that animals procured and studied in the manner outlined above is appreciably more expensive in initial cost than is the usual dog obtained from the city pound. However, long-term studies of dogs soon involve animals that represent a large investment in terms of the time of the professional personnel conducting the investigation, room and board for the dog, drugs, laboratory tests and so forth. The inadvertent death from disease of even a few such dogs not only represents a verv large financial loss but may invalidate an entire experiment. This accumulative cost is not usually considered in calculations of the cost of studies involving dogs. When the accumulative investment in time and overhead is taken into account. the relative insignificance of initial cost and relative economy of the units and animals described above becomes evident."

Drs. E. Donnall Thomas & Joseph W. Ferrebee. 1961. Disease-free dogs for medical research. Proceed. of the Animal Care Panel 11 (4): p. 230-233.

"The panel concludes that.. .. 3) Disease-free dogs are essential for research because: a) Uncontrolled infections in experimental dogs can be ruinous to nutritional experiments that depend on growth records; b) Uncontrolled infections, by causing death of puppies, can be disastrous to genetic studies; c) Residual lesions found in dogs after recovery from some infectious diseases can cause confused experimental results in all instances that depend upon histological examination for conclusions; ... .4) For acute experiments, such as those conducted by physiologists or surgeons, requirements for disease-free or immunized dogs may not be essential but, even for such work, 3 uniformity of results might warrant the increased expenditures."

Animal Health Care Panel. 1961. Conclusions. Proceed. of the Animal Care Panel 11 (4): p. 244.

"Germ-free techniques can now be applied to answer many previously insoluble problems .... Large germ-free animals will be valuable, if not necessary, to answer provocative and fundamental immunological questions .... A great deal will be learned from elucidation of factors necessary for organisms to be invasive and pathogenic .... The dog has been the traditional animal used in many surgical and physiological experiments. Although pups were obtained free of bacteria, they were found to harbor the parasite Toxocara canis .... Essentially, the main reason to use the germ-free dog in the study of intestinal obstruction is to eliminate the Clostridia and their toxins which are found in the muscles and viscera of this animal. We believe that these factors have negated many experiments .... By starting with the germ-free animal, one can study the effects of single microorganisms and the relationship of multiple microorganisms .... lt can be said that the potential use of germ-free animals is universai. ... Experience with the germ-free animals repeatedly has emphasized one point of extreme importance. That is the total inadequacy of conventional laboratory animals .... Such factors as the genetics, breeding, and nutrition of these animals have been creditably assessed and controlled; however, their microbiological status has been woefully ignored. Laboratory animals are infested with myriads of external and internal parasites. bacteria. and viruses. Many of these are pathogenic. It is impossible to control their effects on the animal. either before or during the experiment. Thus, although such things as the constituents of diets and the amount of drugs injected usually are very accurately measured, these are given to animals whose response may vary tremendously due to different and uncontrollable microbiological contaminations. Many results chalked up as 'biological variations' may be due to apparent, latent, and subclinical infections. This must be eliminated to give meaning to many of these experiments .... Certified animals known to be free of parasites and pathogenic bacteria and viruses are the only ones that should be used experimentally .... Only when this is done for all species of laboratory animals can biological experimentation reach its full potential."

Drs. Jerome J. Landy, James H. Growden & Russell L. Sandberg. 1961. Use of large, germ-free animals in medical research. J. A mer. Med. Assoc. 178 (11): p. 1 06-109.

"Purebred dogs have a real place in research, especially where long-term experimental work is to be performed, surgical techniques are being studied, or where the experimental differences being measured are small. Genetically and phenotypically purebred dogs are much more uniform than the general run of dogs from the pound. They are usually in good physical condition and relatively free o( parasites since most producers of purebred dogs take pride in the production of superior dogs. Purebred dogs of the same breed are more nearly constant in their anatomy and physiology than their brothers from the street: the overall results obtained from the use of uniform purebred dogs are more consistent and reliable: this permits the use of fewer dogs in order to produce statistical significance .... lt is imperative that the experiment is designed in such a manner that maximum data can be obtained by the use of the dogs and equipment available in a reasonable length of time. This means that experiments must be planned in such a way that the data obtained will be relatively free of bias, with the minimum amount of influence by uncontrolled but related factors .... Experimental variation can be minimized by the use of homogeneous animals of similar genetic origin handled under similar management. Purebred dogs of the same breed, same strain and same sex usually respond in a similar manner. Dogs from the street or pounds are not generally very useful in nutrition experiments since they tend to be strongly heterogeneous and their offspring show similar lack of uniformity. The response of street dogs in nutrition experiments is so unpredictable that 4 most nutrition experiments, and almost all those connected with growth and reproduction, are with dogs from purebred parentage .... lf one resorts to this amount of planning. then the expense of using purebred dogs is verv little more than the expense connected with non-purebred dogs .... The real key to the success of an experiment is repeatability. With purebred dogs of a related strain within a breed, individual dog responses to variables are likely to be similar. The odds of repetition to specific variables in additional experiments is enhanced. One of the most frequently asked questions relating to purebred versus crossbred or mongrel tests is, 'Is the purebred dog typical of the dog on the street in this response?' Any group of dogs from the street would not necessarily be typical of another group of street dogs. The advantages of the purebred dogs are emphasized. The purebred dog will at least enable experiments to be conducted under controlled conditions with a minimum of uncontrolled factors."

Drs. J.E. Corbin, R.K. Mohrman & H.L. Wilcke. 1962. Purebred dogs in nutrition research. Proceed. of the Animal Care Panel 12 (4): p. 163-168.

"A major problem in this research is that no two experimental animals are identical. The variations in the microbiological flora of the integumentary, respiratory, and digestive systems makes it difficult to determine which of the organisms are pathogenic and for what portion of a disease process they are responsible. In order to determine the effects of a virus alone or together with other selected microorganisms or environmental variables, it became necessary to obtain gnotobiotic [germ-free] dogs as research tools."

Drs. Richard A. Griesemer & John P. Gibson. 1963. The gnotobiotic dog. Lab. Animal Care 13 (4), Part 2: p. 643-649.

"The demands of present day research have changed greatly. not only in more precise methods and instrumentation but in the quality of animals used as well. This particularly applies to dogs used for experimentation. Compare the dog used in research today with the unwanted foundlings or half-starved specimens gathered from the streets of large cities a few years ago. The use of such animals jn research programs often resulted jn a succession of questionable symptoms and pathological manifestations. resulting in a mass of unintelligible data when an experiment was terminated. Out of these early disappointments in experimental results came the recognition for the need of animals in which a high degree of dependable data could be expected .... The uniformity of results observed following the use of such animals in experimental work has been most gratifying."

Drs. P.C. Underwood & C.G. Durbin. 1963. Beagles for pharmacological studies. Lab. Animal Care 13 (4): p. 525-529.

"The germ-free animal is an invaluable tool for studies in which microbial flora might have a modifying influence, beneficial or harmful, on the physiological status of the host.. .. Before an animal can be successfully used as an instrument of research. its parameters of physiological 'normalcy' should be known .... ln all such respects, the germ-free animal compares favorably with, or is superior to, its conventional counterpart. In addition, these animals are not subject to intercurrent infection, which can interrupt or alter critical experiments with conventional animals .... For studying certain problems, utilization of the germ-free animal has practical advantages. Since these animals live in a controlled environment, they may be used as monitors of the microflora in an environment of unknown character. They may be used in certain kinds of experimental surgery, especially in tissue transplantation, since germ-free animals are not subject to infection when 5 given drugs which reduce antibody production ... The use of germ-free animals may be of help in solving many biological problems .... Further use of germ-free animals in research programs will increase the need for such animals. They do provide unique experimental advantages which should be exploited."

Dr. Moris Pollard. 1964. Germ-free animals and biological research. Science 145: p. 247-251.

"This study defines a population of mongrel dogs obtained from pounds in eastern North Carolina from a clinicopathologic standpoint...The 'normal' mongrel dog is an often used but poorly defined laboratory animal. This study was undertaken to define, clinicopathologically, a given population of mongrel dogs and to compare the data collected with that obtained from a more homogeneous population .... The data used for comparative purposes was obtained from a colony of purebred beagles .... A wider variety of pathologic alterations were seen in the mongrel population, a number of which are associated with the increased parasitism common in free ranging dogs .... The laboratory reared animals showed less clinicaL gross and microscopic evidence of disease."

Drs. James R. Pick & James W. Eubanks. 1965. A clinicopathologic study of heterogeneous and homogeneous dog populations in North Carolina. Lab. Animal Care 15 (1): p. 11-17.

"Eighty-seven percent of 100 stray dogs obtained from various areas of eastern and southeastern United States were found to harbor either heartworms and/or intestinal helminths upon autopsy. Dual or multiple infections were common .... ln view of the present findings, animals to be used for cardiac and other surgical experiments should be thoroughly screened for microfilaria and intestinal helminths."

Drs. Phillip H. Mann & George Bjotvedt. 1965. The incidence of heartworms and intestinal helminths in stray dogs. Lab. Animal Care 15 (1 ): p. 102. ·

"The hemograms of 56 newly purchased pound dogs were compared with those of 44 dogs that had been housed in the laboratory for over 4 months .... The most significant findings were that newly received (nonconditioned) dogs demonstrated statistically significant lower values with respect to hemoglobin levels and packed cell volumes. These observed changes are believed to be related to environmental stress or diseases not apparent at the time of examination ..... Many diseases, both infectious and metabolic, as well as changes in an animal's environment, will result in an abnormality in some of the blood values. Such alterations in the normal blood picture indicate that the animal involved is not in a state of equilibrium and should not be used for long term studies .... Routine hemograms performed on laboratory dogs may have the added value of impressing upon investigators that the general appearance of an animal alone is not a satisfactory criteria for selecting dogs for medical research. Many of the dogs that were apparently healthy presented blood values outside of the normal ranges. therefore clinical examination can be misleading as evidenced by this study."

Drs. Orland A. Soave & Colden C. Boyle. 1965. A comparison of the hemograms of conditioned and non-conditioned laboratory dogs. Lab. Animal Care 15 (5): p. 359-362. ------

"The Departmental Committee on Experiments on Animals under the chairmanship of Sir Sydney Littlewood recommends that the Secretary of State should be empowered .... to prohibit the use of 6 laboratory animals (other than monkeys and animals of farm species) not bred for the purpose in registered laboratories or breeding units outside laboratories .. ..lt is a common experience that the supply of laboratory animals. especially cats. is extremely erratic and unreliable.... This is based on seasonal breeding peaks and also on the high demand for cats by university departments during term-time. A proper planning of experiments is thus made quite impossible .... The condition of cats supplied for experimental purposes is generally extremely poor and it is not uncommon to lose more than 50 percent of the intake within one week before the start of experimentation since most laboratories will quarantine animals supplied from outside sources. This leads obviously to a considerable wastage of already very scarce and expensive laboratory animals .... The poor condition and low resistance of these animals prejudice the performance of lengthy and elaborate experiments under anesthesia and reduce considerably the success rate. On account of the condition of the animals. experiments have to be repeated unnecessarily. thus again leading to wastage of valuable animals. The scientific value. if any. of experiments carried out on such animals must consequently be very limited. Apart from this wastage of animals, the scientist undertaking the experiment also loses still more of the already limited time available for experimentation. Experiments on animals in poor general condition are thus a highly uneconomic procedure from the point of view not only of the cost of the animals but also of the high cost of the time wasted .... There is, of course, the risk that. .. the laboratory may be receiving stolen property with all its subsequent legal implications .... For these organizational, economic, scientific and legal reasons it was decided to start at first a small holding colony .... Our 40 percent loss, in rearing the cats to 6 months of age .... must reflect the unlikelihood of obtaining at any time well-nourished, parasite-free and reasonably healthy cats in quantity from any source other than from recognized colonies."

Dr. H. Reinert & G.K.A. Smith. 1966. Establishment of an experimental cat breeding colony. Nature 209 (5027): p. 1005-1008.

"So long as there is a market for stray cats and dogs. there is always the possibility of abuse. One way of undercutting the market is via the public pound. But the pound still leaves the chance that someone bereaved by the loss of a beloved pet will resent the possibility of its turning up as an experimental animai. ... Medical research would benefit in precision and in the reproducibility of experiments if it used only selected types of felines and canines especially bred for the purpose .... lf carefully selected, inbred lines of canines and felines were developed, we could expect much greater reliability in the results of the work on drug safety, developmental anomalies, behavior and surgical transplantation. These genetically pure lines should not be confused with the cat and dog breeds now valued as house pets, and even less with the strays which besides their dubious heredity may have had cruel handling (to influence their behavior in psychological tests) and infectious diseases (to confound their response to drugs and vaccinations) .... Scaven0in0 animals with unknown histories from the streets -- animals with the possible sti0ma of having been stolen -- seems an incon0ruous way to get experimental material which must later be subject to the most scrupulous observation and. for the most useful findings. ideal care .... Medical research can only benefit from the use of animals of well defined strains. bred under controlled conditions of nutrition and custody .... Research will also benefit by being uncoupled from anxieties about pets."

Dr. Joshua Lederberg. 1966 (August 21 ). Animals for research: If cats and dogs were bred for laboratory, medicine would benefit and pets would be safe. The Wash. Post. Science and Man.

"Nearly every species of laboratory animal has been raised under germ-free condition .... Our interest in germ-free cats stemmed from the difficulties encountered in using laboratory cats in research. Infectious diseases of the respiratory and gastrointestional tracts were frequently present 7 in cats raised in a conventional laboratory environment.. .. The germ-free cats were well-developed, playful, and resembled kittens raised in a conventional laboratory environment except that their growth was not interrupted by spontaneous disease .... The best source of pregnant cats to obtain germ-free kittens was our caesarean-derived, disease-free breeding colony .... The germ-free cat will serve as the ideal research tool with which to determine the dietary requirements of cats and to evaluate the nutritional role of the microbial flora."

Drs. M.W. Rohovsky, R.A. Griesemer & L.G. Wolfe. 1966. The germ-free cat. Lab. Animal Care 16 (1): p. 52-59.

"The need for a large. standard laboratory dog for studies such as transplantation and open heart suroery is increasinoly apparent. The 'ideal' large laboratory dog should have the following characteristics: 1) Genetic uniformity; 2) Large litters; 3) Early maturity; 4) Stress resistance; 5) Size, 50-70 pounds; 6) Easy keeping; 7) Gentleness; 8) Trainability; 9) Short hair; 10) Short or curly tail; 11) Quietness; 12) Cage tolerance. Work done in this laboratory indicates that the Labrador retriever meets most of these specifications .... Despite this remarkable progress, projects requiring the use of large animals are forced to use pound dogs of completely unknown oenetic background. age, and health. All these variables result in the costly use of many animals to obtain questionable data .... Researchers have been slow to grasp the advantages in using purebred healthy dogs to reduce animal variables. cost. and criticism in their investigations .... Reduction of Costs: The production and use of healthy standard dogs may at first appear to be an extravagance that few investigators can afford. Analysis. however. indicates that for many projects the use of such an animal would actually make possible a considerable economy. First. by a reduction of animal variables a smaller number of animals would be required to obtain sionificant data. Second. fewer animals will be found unsuitable durino the course of an experiment. and fewer animals will become ill or die durinQ the course of a particular study .... Figure 1 depicts the relative costs of a long term research dog. It can be readily seen that the initial purchase cost is a small percentage of the total expense .... Dogs usually reach a pound for some good reason: e.g .. bad disposition. lack of trainability. advanced age. poor health. or physical defects. These factors make them unsatisfactory for many investigations .... Public Relations: Not the least of the advantages to be gained from maintaining a laboratory dog breeding center is the expected improvement in public relations. Many people, both within and without the scientific community, look askance at the nebulous way in which dogs are currently procured for research. Basically, they are afraid that someone's family pet may accidently become impounded and find his way to the research laboratory ....

Miscellaneous Advantages of a Laboratory Dog Breeding Colony: .... A vast pool of normal data can be obtained to serve as a normal base line for animals from that population. This would save a considerable amount of time and money for any oiven study .... ln order to reduce variables as much as possible, one would like to start with a breed of relatively constant phenotype. As uniform genotype as possible is also important.. .. lndividuals who invested considerable amounts of time and money in their experimental animals soon became aware of the advantages of standard laboratory dogs .... ln general, investioators who have once used standard doos from the breedino colony are reluctant to return to the use of pound doos. and it is felt that the demand will continue to orow as the program advances and more investigators become aware of the advantages of paying sliohtly more for better research animals."

Drs. William S. Fletcher, Allan L. Rogers & Leroy F. Erickson. 1966. The need for a large standard laboratory dog. Lab. Animal Care 16 (1): p. 1-8. 8

"The vast reservoir of comparative data available from many earlier surgical experiments, and the variety and complexity of surgical experiments that could be performed, prompted our interest in the use of germ-free dogs .... Even the techniques are constantly being refined, they are sufficient to rear healthy gnotobiotic dogs .... The establishment of reliable techniques for rearing germ-free dogs to sufficient size for surgical experiments presents the surgeon with a new tool that can be used to further knowledge of the role of bacteria in surgical problems."

Drs. James B. Heneghan, C. Edward Floyd & Isidore Cohn. 1966. Gnotobiotic dogs for surgical research. J. Sura. Research 6 (1): p. 24-31.

"During the past five years members of this laboratory have been investigating the histotoxic effects of drugs of different chemical constitution by means of conventional light microscopy and electron microscopy. A number of ultrastructural changes have been observed which could not be explained on the basis of drug toxicity ... To determine whether these findings were the result of intraspecies difference or were due to some other unknown factors, a study was undertaken to establish a base line of canine liver ultrastructure and to determine if any alteration could be noted between common street dogs and purebred beagles .... A general physical examination and a battery of clinical-laboratory tests were conducted after the dogs arrived at the laboratory .... These laboratory tests revealed no significant differences between the street dogs and the beagles; all were within normal limits .... ln contrast to the beagles .. the street dogs were not a uniform group of animals with respect to hepatic ultrastructure. Variation within normal limits was far greater than that observed in the beagles, and distinctly abnormal structures were also found ... Of far more significance was the presence of ultrastructural abnormalities or lesions in the street dog liver. ...

Before one can state with certainty that a given subcellular change reflects a reaction of injury. be it chemical or physical. a detailed study of the organelles under 'normal' conditions is imperative. Numerous publications stressing submicroscopic cellular change under different physiochemical stress situations have been reviewed .... Few of them emphasize the possible adverse effect of variations in the exRerimental animal on interRretation. The existence of similar lesions in pre-experimental animals as a result of previous stress situations is a definite possibility, especially in species such as the dog where animal sources are not as standardized as in the rat. In our studies nontreated purebred beagles showed no hepatic ultrastructural lesions. The livers of the untreated street dogs, however, exhibited changes which have been associated with various diseases as reported in the literature .... ln the evaluation of drug toxicity by the use of electron microscopy one must have rigid controls to be able to come to a logical decision. These rigid controls must consist of a population of experimental animals in which the tissue ultrastructure is well established and which has a uniform and known history. Purebred beagles from a single, well-managed kennel can provide such a population. Street dogs. even though well kept and clinically normal. do not provide a sufficiently uniform population. Kennel-raised dogs from many sources may not be satisfactory because they also could have a varied environmental or genetic background. It is important, therefore, that the investigator establish the base line ultrastructure for his population of animals .... Street dog liver was not uniform or 'normal' when studied by electron microscopy. This would eliminate this source of dogs as an adequate animal for ultrastructural chronic toxicity work."

Drs. Robert J. Stein, Ward R. Richter & Gissur Brynjolfsson. 1966. Ultrastructural pharmacopathology: I. Comparative morphology of the livers of the normal street dog and purebred beagles: A base line study. ExRer. and Molecular Pathology 5: p. 195-224. 9

"In the past the supply of cats to laboratories has been in the hands of dealers. some of whom have rearettably been unscrupulous persons who have acquired them by dishonest methods. This has often placed genuine users of cats in an invidious and embarassing position. Apart from this, cats from dealers have other severe disadvantages. e.g .. disease. which is mostly in the incubating stage and endo- and ecto-parasites. both of which can and do destroy research programs. Another difficulty is getting from dealers cats of the required weight, sex and type at the time they are wanted. In order to avoid such hazards it was decided in 1955 to start a pilot closed cat colony .... The object was to supply the research divisions in the National Institute for Medical Research with all the cats they needed and, despite the increasing demands, this object has been achieved .... ln our paper of 1958 we ex~ressed the hope that in time we would be able to produce all the cats needed by our research divisions. We have been in that pleasant position for the last five years and with the right technical help and veterinary advice we see no reason why cat breeding units should not be a feature of every breeding establishment. Because of their cost. a cat unit poses an economic question. but in our opinion it solves the much areater one: the moral question -- 'Where and how do we get our cats?"'

Drs. Joan H.L. Lamotte & D. J. Short. 1966. The breeding and management of cats under laboratory conditions. J. of the lnst. of Animal Tech.? 17 (3): p. 85-96.

"Science requires uniformity in its experimental tools so that variables may be reduced and experiments made reliable. accurate. precise and reproducible. The two variables in living things are genetic makeup and environmental history. Pound animals are arguably poor tools for scientific work because all of them are to some extent physically. temperamentally, and genetically unknown quantities .... One alternative is to use in all chronic experiments, animals bred for laboratory use. The scientific benefits of using these animals arise from the reduction of variables and the consequent increase in precision and reliability of results. The economic benefits of usina these animals are associated with the scientific benefits: improvement in scientific results lowers the cost of experimentation .... Finally. since the variables are reduced. fewer animals are required .... Apparently without dissent. the scientific community accepts the wisdom of this alternative .... Even though the disadvantages of using pound animals applies most strongly to their use in chronic experiments, some scientists have concluded that, to some extent, the disadvantages apply to animals used in acute experiments as well."

California Senate Fact Finding Committee on Public Health and Safety. 1967 (January). The supply of dogs and cats used in laboratories for teaching and research. California Senate. p. 28-30.

"An animal suitable for experimental cardiac operations should have certain characteristics that are not commonly required in other fields of surgical research. Ideally, the animal should resemble man as to the size of the heart and its anatomy, the major parameters of circulatory hemodynamics, and the blood coagulation mechanisms. The animal used most extensively for cardiovascular surgical research. the dog. fulfills few of the above criteria."

Drs. Lawrence I. Bonchek, Constantine J. Tatooles & Nina S. Braunwald. 1967. Experimental cardiac surgery in the calf. Annals of Thoracic Surg. 3 (3): p. 211-216.

"We are going to talk about a small facet of research work -- the production of the research beagle .... which can be fully guaranteed and are standard animals with known source and history. l.o. this way fewer animals are required for a aiven study. losses from natural causes during the study 1 0 should become a thino of the past. and the risk of buyino stolen animals or those from doubtful sources is avoided .... The most desirable situation would arise if all do0s used for research were bred specifically for this pumose."

Drs. Douglas Appleton & Carol Appleton. 1967. The production of the research beagle. J. of the lnst. of Animal Tech. 18 (3): p. 124-130.

"Respiratory disease with high morbidity and mortality has occurred repeatedly in newly acquired mongrel dogs at this institute. The disease occurred notwithstanding canine infectious hepatitis (ICH) and canine distemper virus (CDV) prophylaxis with attenuated vaccines .... Seventy-five mature dogs of mixed breeds were purchased from a commercial vendor. At time of arrival, each dog was examined by a veterinarian and only those which appeared to be free of overt disease signs were accepted .... During a 6-week period of observation, 53 of 75 dogs developed significant signs of respiratory disease .... Ten of the 53 sick dogs died with histopathologic evidence of respiratory disease .... Most of the dogs had 4 or more signs of disease and 79% of the dogs had lower respiratory disease signs .... The dogs in this study have been derived from multiple environments and maintained in a common facility under conditions that would favor the transmission of respiratory agents. Therefore, the recovery of multiple agents from dogs with respiratory disease is not surprising .... Viruses were recovered from throat specimens of 21 of 53 dogs with respiratory disease and from the post-mortem tissues of 7 Of I 0 dogs. Many of these dogs were infected with more than one agent."

Drs. L.N. Binn, G.A. Eddy, E.C. Lazar, J. Helms & T. Murnane. 1967. Viruses recovered from laboratory dogs with respiratory disease. Proceed. of the Society of Exper. Biolo0y and Med. 126: p. 140-145.

"In keeping with the more critical role of the animal in research, the biologist can ill afford to treat animal experimentation in the same naive manner as is currently the fashion. It is all too common to find multimillion dollar research projects. consuming the time of hiohly talented scientists. based upon studies on animals obtained from city pounds. with little thou0ht 0iven to their suitability for the research being conducted. Animals used for significant research should be selected on the basis of possessing specific characteristics needed for an experiment just as the scientists, experimental methods, reagents, and instruments. The greatest obstacle that we as biologists must overcome is our patent lack of appreciation in the design of animal studies for the criticality of the selection of the experimental animal to the outcome of our research. Countless studies are misleadino or completely useless because the wrong animal was selected. 0enetic variations were not taken into account. diseased or stressed animals were employed. animals had specific concurrent infections that altered the results of the study, or animals were improperly housed and managed during the study. The development of adequate experimental animals must be given high national priority, and adequate resources must be made available to the program .... The objective of the entire program must be to develop for biomedical science animal systems that approach the refinement of the chemically pure reagents and complex instruments we demand for our research."

Dr. W. R. Pritchard. 1968. Animal research in the new biology. Lab. Animal Care 18 (2): p. 230-234.

"The dog most commonly used in biomedical research is variously described. Though seldom used in print, the simplest description of the majority of research dogs would be 'available dogs.' Such I I frankness would tell us that study subjects are most frequently selected on the basis of their availability rather than on the basis of their suitability. Various euphemisms are employed to describe the available dog. We frequently read mongrel. street. gound. random source. aggarently healthy, conditioned .... Such descriptions do not touch upon inherent differences of great magnitude. within the species Canis familiaris. nor do they adequately characterize the health status of animals. The basis genetic and health differences are somehow thought to be removed by applying the terms mongrel, street, pound or random source. The continuing acceptability in the research laboratory of the ill-defined and chronically diseased dog is one of the enigmas of modern-day biomedical research. If one ponders the advances in research methodology and instrumentation which have occurred in this century. it seems strange indeed that a research subject of such poor definition continues to be acceptable to modern day research workers .... We may be unwittingly assisting in the perpetuation of less th.an satisfactory dogs for research by virtue of the roles we play in helping to assure a continuing supply of such animals to the research laboratory ....

Describing the commonly used research dog. and the events which surround its procurement and use does not make a particularly inspiring story .... The term random source, however, does not confer either uniformity or normalcy upon the animals so designated. Random source dogs include almost the whole spectrum of the species, in varying states of disease and health. They range from mongrels to purebred dogs of almost any breed. Probably the most uniform characteristic of random source dogs is the opportunity which they have had for becoming exposed to common canine diseases .... So, on the one hand, we have the grossly variable and chronically diseased random source dog and, on the other, the exacting requirements of sophisticated biomedical research .... Our observations lead us to believe that we cannot further improve the physical condition of the random source dog by further extension of the conditioning period. Still. we are not satisfied with the random source dog as a research subject.. .. We have examined the research requirements and uses of dogs within our setting and have developed and initiated programs which will eventually permit us to discontinue the traditional reliance upon random source dogs as research subjects .... Even the normal healthy dog may not necessarily be the preferred subject in all procedures for which the dog is presently used. This brings up another consideration regarding the rather universal availability of the random source dog. It would seem that dogs are sometimes used simply because they are available. Other species, though inherently more satisfactory for a given study, may not be readily available and, are, therefore, not used ....

Within our setting. large numbers of dogs have traditionally been used in cardiovascular surgical research. even though the dog is not an ideal subject for such studies .... lt is our intention and program goal to eliminate the need for random source dogs. The usual response to any proposal for replacing the random source dog with a more suitable and normal subject is that laboratory or specifically reared research dogs cost too much. A simple comparison between the initial purchase price of a random source dog and a laboratory reared dog is a meaningless exercise. Such comparisons fail to get at the heart of the matter. for the really significant costs are the costs associated with utilizing dogs in biomedical research. If we consider the cost of scientific manpower, laboratory space, and instrumentation which is involved in research studies requiring dogs, then the initial purchase price of the animal becomes a less significant matter. To me. the truly expensive dog is the dog that is less than satisfactory for the intended research: for an unsatisfactory research subject is unduly wasteful of laboratory space. instrumentation. and scientific manpower .... ln my judgment, we will contribute little to biomedical research if we limit our role to helping to perpetuate the use of random source dogs .... lt seems to me that we could make a more meaningful contribution by using our knowledge and energies to assure the availability of laboratory reared dogs. It is my contention that if normal laboratory reared do0s were employed in place of random source dogs. significantly fewer do0s would be required for research. The use of uniform dogs. specifically reared for research. would seem mandatory if the exactino requirements of 12 sophisticated biomedical research are to be met."

Dr. Raymond D. Zinn. 1968 (Dec. 15). The research dog. J. Amer. Vet. Med. Assoc. 153 (12): p. 1883-1886.

"This is the fifth procurement specification in a series prepared by the Institute of Laboratory Animal Resources. The purpose of the procurement specification is to help research facilities obtain animals of desired uniformity and quality from suppliers .... Adherence to these specifications by research facilities and breeders will assure superior animals .... This specification applies to kennel-bred and kennel-produced dogs that are purchased by research facilities. The subcommittee believes animals must be held in a stable environment, and given an adequate diet, appropriate immunization, and proper treatment to be considered suitable for laboratory use."

Institute of Laboratory Animal Resources, National Academy of Sciences/National Research Council. 1969. A report of the subcommittee on dog and cat procurement standards. Procurement specification V.: Kennel-produced dogs. Preface.

"This is the sixth procurement specification in a series produced by the Institute of Laboratory Animal Resources. The purposes of the procurement specification is to help research facilities obtain animals of desired uniformity and quality from suppliers .... Adherence to these specifications by research facilities and breeders will assure superior animals .... This specification applies to colony-bred and colony-produced cats that are purchased by research facilities. The subcommittee believes animals must be held in a stable environment, and given an adequate diet, appropriate immunization, and proper treatment to be considered suitable for laboratory use."

Institute of Laboratory Animal Resources, National Academy of Sciences/National Research Council. 1969. A report of the subcommittee on dog and cat procurement standards. Procurement specification VI.: Colony- produced cats. Preface.

"The survival of purebred Labrador retrievers undergoing prosthetic heart valve replacement is 93%. while that of conditioned. healthy pound dogs of similar size is 73%. The use of purebred. healthy animals in research reduces variables in the experiment. decreases the overall cost of the experiment. and assures the availability of appropriate experimental animals when needed. In the face of increasingly restrictive animal care legislation, as well as increasing cost and decreasing availability of pound dogs, the maintenance of a breeding colony of large standard laboratory dogs is a feasible answer to the problem. During the initial testing of heart valve prostheses in dogs, it was observed that of the dogs being used, the Labrador retriever consistently withstood the procedure better than mongrels or other breeds of dogs .... Survival in each category of valve replacement was better among the Labrador retrievers than pound dogs .... The cost of an experimental heart valve replacement by a competent cardiovascular team is considerable. even by modern fiscal standards. The costs. documented in Table 2. would be higher in many metropolitan areas. The table does not include the time of the surgeons. overhead. autopsy costs. tissue blocks. or photoaraphy. but only the actual operative and postoperative care expense. In terms of the experimental operative cost. the price of the dog is insignificant. and in the presence of an experienced team with a standard procedure. the dog is by far the most important variable in the experiment.. .. The increased survival would more than offset the initial cost of the do0. There are many other benefits from using purebred, healthy dogs for research. First, the variables are fewer. The animals are of known genetic background, age, weight, and state of health, and extensive base line physiological and 13 biochemical data are available. Accordingly, fewer animals are needed for critical experiments. Second. doos of a size, aoe and state of health suitable for experiments of this type may frequently not be available. resultino in the waste of time of valuable research personnel and facilities. Third, the maintenance of exemplary breeding and research facilities which are open to the public precludes allegations concerning the origin and care of animals used in research."

Drs. William S. Fletcher, Rodney H. Herr & Allan Rogers. 1969. Survival of purebred Labrador retrievers versus pound dogs undergoing experimental heart valve replacement. Lab. Animal Care 19 (4): p. 506-508.

"Although cats are widely used in research .... difficulties are continually encountered in obtaining animals of acceptable quality. A recent survey of disease in Laboratory Animals .... revealed an average loss of 28% in home bred animals before use .... The principles and practical methods needed to establish an 'SPF' [Specific Pathogen Free] colony of animals are now well known .... Cats are notoriously difficult animals to breed in large colonies, and under conventional conditions high levels of pre-weaning mortality can be expected to occur. Even if the mortality can be kept in check by low density housing and routine vaccination, very high standards of management are required if vigorous and healthy animals are to be produced to order. ... The information given in this paper reinforces their contention that breeding cats under SPF conditions is a successful way of eliminating many of the problems which plague conventional cat colonies .... ln addition to the benefits already outlined, there are other important advantages to be obtained from maintaining a cat colony under SPF conditions. Firstly. the stocking density in an SPF colony can almost certainly be higher than under conventional conditions. and this factor alone may make it more economical to breed cats under SPF conditions, than under conventional ones. Secondly. a considerable amount of labour is saved as there are virtually no sick animals to nurse. or routine injections to be administered. and finally. there is a considerable saving on the costs of medication. In conclusion, the benefits of breeding and maintaining cats under Specific Pathogen Free conditions would seem to indicate that it is likely that the majority of cats bred for research in the future will be bred under these conditions."

Drs. Michael F. W. Festing & John Bleby. 1970. Breeding performance and growth of SPF cats. J... Small Animal Practice 11: p. 533-542.

"Serologic tests were carried out to determine the occurrence of viral infections in 169 [randomly procured] dogs during a 3-week conditioning period after their arrival at a laboratory. One hundred twenty-three (72.8%) of the dogs developed respiratory disease and 22 (13.0%) died .... The occurrence of multiple viral infections in dogs can be inferred from the observation that more than 71 .6% of the dogs had serologic evidence of infection by 4 viruses .... Parainfluenza SV-5 virus was also highly communicable in dogs, since 71.6% of the sick and apparently healthy dogs had serologic evidence of infection .... The frequent occurrence of multiple viral infection in the dogs added to the difficulty of assessing the etiologic significance of each agent."

Dr. L.N. Binn, Mr. E.C. Lazar & Drs. J. Helms & R.E. Cross. 1970. Viral antibody patterns in laboratory dogs with respiratory disease. Amer. J. Vet. Research 32 (4): p. 697-702.

"The genetic composition of experimental animals has a profound effect on the results and interpretations of biological studies. Thus a working knowledge of the principles of genetics and their application to the beagle is indispensable for the proper selection of individuals for study as 1 4 well as for the design of experiments .... Genetic variation enters the picture in two ways: (1) differences between related individuals will tend to be smaller than differences between unrelated individuals in a population; and, (2) the response in the measured traits possessed by the animals in question .... The first question in selecting genetic material for an experiment concerns the ultimate application of the interpretation of the results. If the experiment is to be a basis for extrapolation to other species, or to other breeds, or even to other populations within the breed, a wide range of genotypes is indicated. However, it should be remembered that the laroer the oenetic variance. the oreater will be the number of animals required to demonstrate a particular maonitude of difference with a certain statistical significance. On the other hand, if information is desired on the mechanism responsible for a particular reaction, rather than the occurrence of the reaction, animals should be as genetically alike as possible .... Genotype-treatment interactions are critical when extrapolating from experiments performed on one population to the breed as a whole. or to other species .... The primary function of a breeding colony producing dogs for experiments is to provide healthy dogs having specified phenotypic characteristics, a defined genetic structure, and an average genotype constant over the years .... A most promising development for the future is the breeding of lines of dogs having characteristics especially useful for particular areas of research .... Lines differing significantly in various physiological characteristics would be invaluable for basic physiological anq biochemical experiments on the mechanisms controlling such traits. The potential is virtually unlimited. and the breedino of doos for specialized laboratory uses will oreatly increase the value of the doo for laboratory experiments."

Dr. Fred T. Shultz. 1970. Chapter 21: Genetics. In: The beagle as an experimental dog. Dr. Allen C. Anderson (Editor). Ames Iowa: The Iowa State Univ. Press. p. 489-509.

"In fact we have been actively tryino to educate the biomedical research scientist that the animal used should be equal or of better quality than the instrument used to measure the results. Sometimes we find an unfortunate lack of appreciation of the need to maintain a quality animal and have the proper animal available for his proposed research. The investigator may be making measurements to the fourth decimal point with a sophisticated instrument but using an animal with an unknown disease history and unknown genetic stock. So the emphasis of our prooram both jn fundino and in education is to upgrade the thinkino of researchers that proper research animals are necessary and the quality of these animals is vital to their project. Hopefully. this may at least help allay some fears that the house pet is a good animal for research purposes. It is not a good or desirable research animal."

Dr. Thomas Bowery, Director of Research Resources, National Institutes of Health. 1972. Hearinos before a subcommittee of the committee on appropriations. House of Representatives. ninety-second Conoress. second session. Departs. of Labor and Health, Education, and Welfare Appropriations for 1973. Part 4. p. 4.

"The need for a nomenclature for outbred stocks of laboratory animals has been widely recognized .... The main consideration of the present rules is therefore to minimize genetic changes in the course of propagating the stocks .... The main function of a system of nomenclature is to assist the biomedical investigator in choosing adequate research stocks and in communicating with breeders of such stocks .... Lists of outbred stocks should enable investigators to trace alternative sources of supply of any one stock, if such sources are available .... ln order to minimize changes due to inbreeding and genetic drift, the population should be maintained in such numbers as to give less than 1% inbreeding per generation .... The primary objective in the maintenance of an outbred stock is to ensure that the stock remains constant in all characteristics for as many generations as 15 possible."

International Committee on Laboratory Animals (ICLA). 1972. International standardized nomenclature for outbred stocks of laboratory animals. In: ICLA Bulletin No. 30. Wash., D.C.: U.S. Dept. of Health, Education, and Welfare; National Institutes of Health. p. 5-14.

"Most animal models are not, in fact, an accurate representation of the larger object, which in most cases is man. I can put it another way and more bluntly, that a staggering amount of medical research is accomplished on inappropriate models. This has been responsible for an enormous duplication of effort. confusion of results and often plain misunderstandings. For example. in cardiovascular research .... there has been an amazingly small effort to determine the validity of the dog's cardiovascular system as a model for that of man. The dog came to occupy its present prominent position due to largely nonscientific reasons. The mongrel dog is available, cheap, convenient, and tractable, and I suppose that it continues to be used for all of these reasons. But tractability, cheapness, availability and convenience are not really bona fide criteria for selection of a model. Other, more appropriate models do exist, but many investigators have been unwilling to look beyond the dog .... The laboratory pig, for example, offers researchers an excellent experimental model of the human skin and cardiovascular system .... ! think it is possible that at one point in the history of research there was some justification for the use of the semi-starved and anemic. worm-laden pound animal or random rabbit. I think it is also likely that many experiments of the past were conducted on animals which were too sickly or rundown to serve as adequate laboratory tools. The recently enacted Animal Research and Animal Welfare legislation provides no real assurance that our animal subjects will, in fact, be healthy or uniform. I think the need for standardization in our animal stocks is all too obvious. This implies that there is a need for genetically controlled sources .... so the investigator can have some real insight into the validy of both his model and his results."

Dr. Robert Van Citters. 1973. The role of animal research in clinical medicine. In: Research animals in medicine. Dr. L.T. Harmison (Editor). Wash., D.C.: U.S. Dept. of Health, Education, and Welfare; Public Health Service; National Institutes of Health. Publication No (NIH) 72-333. p. 3-8.

"The animal subject.. .. is a subject from which we derive all of our initial data, all of our initial observations, all of our initial biological materials. And yet what investigator among us would be willing to accept funds to do a research program that did not have instrumentation that was sensitive and reliable enough to yield the answers to our questions or the analytical method that was sensitive enough? We would refuse to do that study. But we don't refuse with a fully compromised animal subject from which we derive that data initially. I don't care how good the instrument is that follows that initial piece of material you obtain. you will not correct the variability with good instrumentation."

Dr. Julius Cass. 1973. The use of implantable telemetry systems for animal monitoring. In: Research animals in medicine. Dr. L.T. Harmison (Editor). Wash., D.C.: U.S. Dept. of Health, Education, and Welfare; Public Health Service; National Institutes of Health. Publication No. (NIH) 72-333. p. 1271-1293.

"It is the basic premise of the authors that one of the primary problems of medical research performed on doas is the dog itself. Although scientific institutions have been meticulous about the 1 6 quality of other animals used in research, they have been content for the most part to use dogs of unknown age. health, temperament genetic and nutritional backgrounds. The result has been the use of large numbers of dogs for the production of much questionable data.'".The documentation of the superiority of dogs bred for research to random source dogs is scarce, but it is generally known that there is a high mortality rate of dogs in research for reasons other than the experimental procedures. There is a report from Colorado that a group of random source dogs undergoing renal autotransplants and a routine immunosuppressive schedule suffered a 50% mortality rate for a variety of reasons. The superiority of the Labrador retrievers from the University of Oregon Medical School Canine Breeding Colony to random source pound dogs for experimental heart valve replacement was tested .... ln addition to altering experimental results the use of pound dogs may also increase research costs in spite of the initial low cost of the dog .. '"There is no doubt that these costs have increased so that it is apparent that the cost of the dogs is a minor part of the total expense. yet the untimely death of each subject dog escalates the overall cost of experimentation. It seems conclusive that care must be exercised in selecting dogs used in research and efforts to improve the quality of research dogs should be continued and intensified .... AII of these research projects are designed to define the dog, in order to provide a better research model."

Drs. J.W. Templeton, A.L. Rogers & W.S. Fletcher. 1973. Progress in the development of a histocompatible dog. In: Research animals jn medicine. Dr. L.T. Harmison (Editor). Wash., D.C.: U.S. Dept. of Health, Education, and Welfare; Public Health Service; National Institutes of Health. Document No. (NIH) 72-333. p. 1073-1079.

"Although unparalleled advances have been made in research laboratory instrumentation and methodology durina this century. the standard research dog of today is essentially the same as its counterpart of 50 or 100 years ago. As an alternative to the continued use of dogs of unknown genetic background. age. temperament and disease experience. the National Institutes of Health and various other facilities have undertaken to breed dogs selected to meet specific investigational requirements. Although such animals are generally more expensive on an individual basis than those obtained from vendors. it has been shown that overall needs for dogs can be reduced by their use. This presentation will summarize the experiences of the NIH Animal Center in breeding and rearing American foxhounds for research as compared with quarantining and conditioning random source dogs .... These data also indicate a growing tendency for dealers and research institutions to breed dogs specifically for research .... Random source dogs, for the most part, consist of unowned 'wild' dogs, rejected hunting dogs and strays or unwanted pets. They may be mongrel or purebred, and are in various states of health. The various steps required to bring the random source dog from its original setting into the laboratory .... average .. ,probably about 30 days. Exposure of the dogs to a variety of pathogens at each facility involved and stress stemming from frequent transportation and changes in social grouping, diet, husbandry and environment are considered principal factors responsible for the morbidity and mortality observed among random source dogs at the research facility .... During the fiscal year 1965 through 1967, dogs accepted for quarantine and conditioning suffered a combined mortality/morbidity rate of about 65% .... From fiscal year 1971 to the present, we have been purchasing 30-day preconditioned random source dogs and quarantining them for an additional 15 days. Reduction of the conditioning period at the NIH was undertaken to reduce space requirements for random source dogs and thus permit increased production of colony bred dogs. The benefits accruing to the conditioning facility and the NIH researcher by this arrangement are shown ....

Dissatisfaction with the quality of random source dogs led to establishing a production colony of purebred foxhounds to provide standard dogs for the NIH researcher. Some of the advantages of the colony bred research dog include: known age and genetic background and acceptable temperament In 17 addition. morbidity and mortality associated with common canine diseases .... can largely be eliminated. Production of uniform, purebred dogs also lends itself to ease in assembling base line reference data pertaining to anatomy, physiology, hematology and biochemistry for specific sex, age or other groups .... The argument generally employed against the use of dogs specifically bred for research is that their initial purchase cost is more than that for random source dogs. While this is true. it is an oversimplification of the situation. for it fails to take into consideration all of the expenses associated with utilizing dogs in research .... The cost of the dog becomes an even less significant factor. Another important consideration is the stamina and viability of the research dog. Reported observations that the survival rate of Labrador retrievers was substantially higher than that of healthy, conditioned random source dogs undergoing open heart surgery [Fletcher et al., 1969] are similar to opinions expressed by NIH researchers using purebred foxhounds and random source dogs. In this regard, arguments against using purebred dogs become even less tenable .... The firm establishment and continued enlargement of the breeding colony is expected to further reduce the need to quarantine and condition random source dogs. Research institutions concerned with reducing the numbers of dogs required to meet their program needs and with increasing the quality of the dogs used might consider adapting either or both of the alternatives described above. "

Drs. S. Potkay & J.D. Bacher. 1973. The research dog: Random source or colony reared? In: Research animals in medicine. Dr. L.T. Harmison (Editor). Wash., D.C.: U.S. Dept. of Health, Education, and Welfare; Public Health Service; National Institutes of Health; publication No. (NIH) 72-333. p.1061-1065.

"In conjunction with the regular experimental work in this laboratory, clinical laboratory values of general interest were determined on 150 conditioned mongrel dogs and 89 purebred Labrador retrievers. Significant, but not large, differences were found between the two groups .... The differences appear to reflect the greater homogeneity, less stress, prior experience, and some metabolic characteristics of the Labrador retrievers. This report presents the only data available comparing conditioned mongrel dogs as used widely in biomedical research with comparable purebred dogs .... The differences [in leukocyte va1ues] clearly reflect the more highly stressed history of the mongrel dogs .... The mongrel dogs had much higher sodium concentrations and rower chlorides than the Labrador retrievers. We have no explanation for this .... The Labrador retrievers have higher lactate and lower pyruvate levels than mongrel dogs .... The data suggest that the Labrador retriever and beagle do not differ widely in blood values. Conditioned dogs are also similar but do have significant signs of their previous history of stress .... As might be expected, our results suggest that significant differences between breeds or colonies of animals will occur in constituents directly related to metabolism. It is in these areas that care must be used in comparing work done on different breeds or groups of animals."

Drs. David C. Secord & J. C. Russell. 1973. A clinical laboratory study of conditioned mongrel dogs and Labrador retrievers. Lab. Animal Science 23 (4): p. 567-571.

"Random source dogs and cats are used extensively in biomedical research. They originate from a wide variety of sources and represent surplus products of uncontrolled breeding. Frequently they have undesirable conformation or temperament and are afflicted with diseases. Between the time of the purchase by the dealer and delivery to the research laboratory. random source animals are subjected to several environmental and food changes. contact with sick animals. and exposure to numerous pathogenic agents .... AII random source dogs undergo 45 days of quarantine and conditioning prior to their release to NIH laboratories. Before January 1970 this was done entirely at NIH facilities. Since then, dogs which are purchased have been preconditioned by the vendor for 30 days. 18

This program change reduced the size of the random source dog colony by about 65%, releasing space to permit expansion of the canine breeding program .... Cats are purchased in an unconditioned state and undergo a 45-day quarantine in NIH facilities .... The purchase of 30-day conditioned dogs has shifted the period of high mortality and morbidity to the vendor's facilities, resulting in a marked reduction in the illness and death of dogs within the NIH colony. Of 2,242 dogs received since January 1, 1970, 252 (11.2%) became ill and 17 (0.76%) died .... Respiratory disease causes an estimated 95% of all illness and death seen among random source dogs .... Dogs are exposed to a variety of agents between the time that they are acquired by the animal dealer and their delivery to the research laboratory. The combination of factors, including the exposure to pathogens, stress, and the immunological status of the individual dogs is believed to be related to the incidence and severity of the diseases seen during the conditioning period ....

While several of the organisms listed above have been isolated by others from the lungs of the dogs which died from bronchopneumonia, their roles were considered secondary to predisposing factors, such as primary viral disease, malnutrition, and exposure .... More than 75% of unconditioned random source dogs accepted for quarantine harbor one or more species of hookworms, roundworms, whipworms or tapeworms .... Since the majority of the dogs quarantined are used in cardiovascular research, the elimination of microfilaria-infected dogs is of major concern in the quarantine program .... During fiscal year 1971, 35.1% of the 2,510 cats became ill and 14% died .... Respiratory disease is the major cause of morbidity among random source cats .... Ocular lesions compatible with feline rhinotracheitis virus infection are frequently seen. Endoparasites are found frequently, but cause no obvious clinical signs. About 75% of fecal flotation examinations are positive for hookworms, and 45% for roundworms. Fifty-five percent of the cats are found to harbor tapeworms. Morbidity and mortality rates among random source dogs and cats are hiah during their 45-day quarantine and conditioning period .... Most infectious diseases are attributable to the exposure of the animals to a wide variety of pathogens while they are stressed during holding and transport by pounds and vendors before and during delivery to the research institutions. [Discussion post-article]: Very honestly. we would love to be out of the business of supplying random source dogs. We would like to supply colony-reared dogs and we hope that eventually we'll get there (Palmer) .... Oogs, especially random source dogs used in the laboratory without examination of the right ventricle and pulmonary artery, can never be said to be free of heart worms. They are asymptomatic and do exist as a problem in the laboratory. There are many occasions of accidental findings of the worms: there's negative blood, but the adults are there; they're just not producing microfilaria at that stage [Chairman, not named]."

Dr. A.E. Palmer. 1973. Diseases encountered during the conditioning of random source dogs and cats. In: Research animals in medicine. Dr. L.T. Harmison (Editor). Wash., D.C.: U.S. Dept. of Health, Education, and Welfare; Public Health Service; National Institutes of Health. Publication No. (NIH) 72-333. p. 981-989.

"Greater emphasis is being placed on the use of kennel-produced animals in research. Limited exposure to disease. good conditioning. and genetic uniformity are some of the reasons for their greater value. In many instances. reductions in the number of dogs required to obtain significant results offset their greater cost.. .. lt should be recognized that the term random source does not mean that animals are uniform or normal. They range from mongrel to all the recognized breeds and exhibit varying stages of health. The most uniform characteristic of random source dogs is that they have had the opportunity to become exposed to the common canine diseases. Many of these animals are stray animals and have been exposed to the rigors of weather as well as a variety of diseases. Often they are malnourished and must be held for some time before they can be used for research. Shipment from collection points to pounds, dealers, and research facilities represents an additional 1 9 stress to already weakened animals. The exactino requirements of sophisticated biomedical research are incompatible with the use of malnourished and diseased random source doos .... There is increased activity in genetically defining the dog because of its wide use as an experimental animal. The presence of hereditary defects in stocks of dogs that are presumed to be free of these conditions can be devastating .... The choice of dogs for a specific physiologic study depends on the genetic background of the animai. .. Behavioral factors are receiving greater attention since they might affect the outcome of an investigation .... The astute investigator can minimize these factors by use of animals whose behavior is known and by careful selection .... Conditioning random source animals after initial selection is necessary since many harbor infectious agents or for other reasons are unsuitable for studies on arrivai. ... Procurement of more uniform animals that have been raised specifically for research and are free of infectious diseases reduces the time necessarv for conditioning and produces more reliable results."

National Academy of Sciences. 1973. Doos: Standards and ouidelines for the breeding. care. and manaoement of laboratory animals. Wash., D.C.: N.A.S. p. 1-15.

"Monarel dogs are useful for certain. very elementary. short-term studies but are totally unsuitable for the hioh quality of research needed for predictino human effects from chemicals. Monorels are usually infested with parasites and often diseased and in poor health. Purebred dogs, especially beagles specifically developed and bred for research purposes, do not have these problems and are less likely to die of extraneous causes during the experiments. Thus, an. experiment with purebred beagles requires many fewer animals -- perhaps only one-tenth as many n to get statistically significant results."

National Academy of Sciences. 1974 (June 24). Beagles held vital to poison tests. In: Los Anoeles Times. Part 1, p. 5.

"It has been brought to my attention that the [Everett] City Council is reviewing the possibility to issue dogs from your city animal control center to federally licensed vendors for resale to institutions for research. My experience as a veterinarian with twenty-five years experience as the Director of the Animal Care Facilities at the University of Wash. enables me to be in a position of critical judgment in this matter .... To release animals to vendors to sell to research institutions for research is extremely inhumane .... lt is the common practice of research institutions to accept a dog or cat as a healthy animal providing that animal can stand and eat. Generally no preoperative procedures are performed as jn human medicine, .. Postoperative care js lackino in most institutions. These animals are usually left alone to roll around in cages during the recovery stage. more often than not are not aiven suppportjve fluid therapy and follow-up of the postoperative care by the surgeon is. in general. lacking. These statements will be contrary to those statements made by investigators both here and elsewhere. but research veterinarians will substantiate the above statements .... At present, institutions will tell you that they have staff veterinarians. More or less these appointments are only to 'paper' satisfy the United States Department of Agriculture when in reality, they may observe the animals weekly and in some cases monthly."

Dr. Tommy W. Penfold, Director, Vivarium, Univ. of Wash.. 1974 (Dec. 10). Letter to the Mayor, City Council and County Commissioners of the City of Everett, Wash ..

"Mortality rates were followed for 5 years in cats purchased from random sources and used for 20 medical research. The mean annual mortality was 31 % .... The handlino and care of random source cats for medical investioation presents difficult health problems for the research institution. The animals are usually collected from different locations, are in various states of health, are housed together, and are shipped under crowded conditions to arrive at the research facility in poor condition. Many laboratories using cats under these circumstances report high mortality rates .... Mortality of cats originating from pounds or suppliers collecting animals from pounds represents a loss of valuable investigative material as well as economic. These losses can be expected to continue for as long as cats of unknown origin are purchased for research programs."

Dr. Orland A. Soave. 1974. Mortality of cats in a research institution: A five-year study. Lab. Animal Science 24 (1 ): p. 99-100.

"The symposium on Environmental and Genetic Factors Affecting Laboratory Anjmals ... was organized to emphasize the significant effect that even slight environmental or genetic chanaes can have on experimental results .... A common error in basic science research is the assumption that the animals used in different laboratories or under varying environmental conditions in the same laboratory are all similar. This assumption. based on the absence of moss signs of disease. overlooks the possibility of equally important altered or abnormal biologic responses .... The biologic processes that are modified by these environmental factors include behavioral, physiological, endocrinological, pharmacological and biochemical responses .... ln addition, many genetic factors have been identified that can alter the way an animal responds under a wide variety of experimental conditions. Unfortunately, the majority of articles reporting scientific research on animals fail to give adequate information about these important factors~~ .. This discrepancy implies that investigators generally ionore the impact on their experimental results of the numerous variables affecting their animals .... The omissions discussed in the preceding paragraph suggest that many investioators do not fully recognize the influence of environmental and genetic factors on experimental results or the fact that failure to give an adequate description of these variables makes it difficult. if not impossible. to duplicate an experiment in other laboratories""lnability to duplicate these conditions in a similar experiment could result in significant variations in the values measured. thereby producino ·confusion and discrepancies in the literature~~ .. Subclinical infections can alter. unbeknownst to the investioator. the response of animals used in many different experiments .... This lack of standards makes it even more important for investigators to be aware of the role that slight variations in the environment or genetic constitution may play in the interpretation of data .... lt is our hope that the papers in this symposium will stimulate investigators to give more consideration to the effect of environmental variables on the animals used in research projects."

Drs. C. Max Lang & Elliot S. Vesel!. 1976. Environmental and genetic factors affecting laboratory animals: Impact on biomedical research. Federation Proceedinos 35 (5): p.1123-1124. Symposium at the 59th annual meeting of the Federation of American Societies for Experimental Biology.

"Only some of the diverse factors that can affect drug disposition and response in laboratory animals have been identified at the present time. These numerous factors contribute to large day-to-day variations that have become a major problem impeding the investigation of drug disposition and response in laboratory animals. Although these variations render many experiments difficult to interpret and produce large discrepancies in the literature, few published investigations using laboratory animals provide sufficient details to permit replication of the studies under similar conditions with respect to these variables. Thus, the importance of these variables in affecting results is apparently insufficiently recognized at present.. .. Laboratorv animals have frequently been 21 used in biomedical research as though they were rigid instruments of unvarying character. rather than plastic biological systems responding in diverse ways to alterations in their internal or external environment. Fortunately. in recent years there has been increasing recognition that laboratory animals must be respected as sensitive biological systems. Nevertheless. in many laboratories little. if any. attention is currently paid to aspects of the environment of the animal which can influence experimental results!!0.As experiments become more sophisticated, depending on small biological changes and complex instrumentation for recording these changes, the mythical nature of many so-called 'normal' or 'average' values in laboratory animals becomes apparent. Pursuit of numerous variables that can alter the so-called 'normal' values in laboratory animals has ceased to be simply an annoying exercise preceding a successful experiment.. .. From the point of view of this symposium, the variables listed in Table 1 contribute significantly to the wide range of many so-called 'normal' values that appear in the literature as a result of experiments done on animals in different laboratories under diverse conditions and environments. While scientists generally adhere scrupulously to the injunction to control all variables in their experiments, the factors listed in Table 11 are insufficiently appreciated as constituting significant variables capable of markedly affecting experimental results in laboratory animals .... Once it is more generally appreciated that discrepancies among results of different laboratories may arise from one or several of these variables. it becomes possible to discover by a systematic approach which variables or combination of variables are responsible for the discordance in any particular situation. Ease in manipulating these environmental variables. trivial as they may seem. could facilitate not only increased concordance in the literature but also new discoveries of a basic nature."

Drs. Elliot S. Vesel!, C. Max Lang, William J. White, G. Thomas Passananti, Richard N. Hill, Thomas L. Clemens, Dai Kee Liu & W. Dean Johnson. 1976. Environmental and genetic factors affecting the response of laboratory animals to drugs. Federation Proceed. 35 (5): p.1125-1132. Symposium at the 59th annual meeting or the Federation of American Societies for Experimental Biology.

"Subclinical disease may have effects too .... But again, few of these studies have been done in animals not obviously infected or sick, or in animals with subclinical infections or chronic infections and illnesses .... We do indeed recognize that the environment affects our experimental results and that effects of the environment in our animals can be both dramatic and subtle. What we acknowledge is not. however. translated often into practice: and many of our data are confounded by environmental effects that we do not control. are unaware of. or for which we make no provision ....Thus. this field of environmental and genetic factors affecting the response of laboratory animals represents an exciting area of biological research for future generations. Its appeal lies in the following: 1) Small chances in environmental conditions and oenetic constitution can produce Iaroe alterations in the responses of the animal; 2) Only a portion of the environmental and genetic conditions that cause such changes in laboratory animals have been identified, or once identified, adequately quantified; and 3) Systematic investigations of such variables can result not only in closer correlation between animal models and physiological or diseased states existing in man but also in discovery of new biological principles."

Dr. J. R. Fouts. 1976. Overview of the field: Environmental factors affecting chemical or drug effects in animals. Federation Proceed. 35 (5): p. 1162-1165. Symposium at the 59th annual meeting of the Federation of American Societies for Experimental Biology.

"By usino better quality animals in laboratory experiments, the number of animals suffering pain or discomfort could be reduced. At the same time, experimental results would be less confused by the effects of disease among animals""Unfortunately. few research workers have access to any 22 formal training in the use of laboratory animals. As a result. many work with 'cheap' animals of undefined quality. This can cause considerable confusion. Results may not be repeatable. and in the long run more animals and money may well be required than with high quality animals .... Animal experimentation is full of pitfalls for the unwary. One of the most important is the presence of disease-causing organisms iri many colonies. Outbreaks of disease cause substantial financial losses each year .... However, the effects of subclinical disease can be much more insidious. leading in some cases to the wrong interpretation of experimental results .... Unfortunately. some research workers continue to obtain animals from non-accredited breeders. presumably in the mistaken belief that by buying cheap animals they can cut the costs of their research proqram .... The financial value of using laboratory-bred dogs in experimental surgery is illustrated in some recently published American figures. They compared the five-day survival of 85 laboratory-bred, healthy Labradors with that of 75 healthy, conditioned 'pound' dogs .... 93% of the laboratory-bred dogs survived the operation, compared with only 73% survival rate of the pound dogs .... Thus the use of 'cheap' dogs would increase the cost of the experiment .... Extra dogs would have to undergo the inevitable pain and discomfort associated with this type of experiment. The observation that cheap animals equal expensive. and often bad. research is an almost universal law of animal experimentation .... lt is now time for biomedical research workers to .... take urgent steps to upgrade all animal research to the level of the best."

Dr. Michael F.W. Festing. 1977 (July 20). Bad animals mean bad science. New Scientist. p. 130-131.

"Animals are highly variable and difficult to measure .... Biologic considerations require dealing with methodological error but also with normal variation, multiple genetic and environmental influences, and intraindividual and interindividual differences still within the normal range. Biologic scatter can be reduced if systematic components of jntraindividual variation are defined .... lnapparent laboratory infections represented a constant hazard to research quality control and standardization. The choice of a mouse or a rat for research necessitates that factors be defined and controlled .... Genetic history here [transplantation research] is crucial to the research progress .... lf genetic factors are of minor importance, then it will not matter which strain is used; while if genetic factors are of major importance, non-inbred strains would be inefficient and would not indicate that the character in question was strongly inherited. The best experimental material is a mixture of genotypes arranged to be representative of several genotypes giving high precision information on important genetic factors."

Dr. George J. Race. 1977. Biological variability: Precision in biomedical research. In: The future of animals. cells. models. and systems in research. development. education. and testing Wash., D.C.: National Academy of Sciences/ National Research Council. p. 34-57.

"Even the most carefully designed experiment can be vitiated by an animal model lacking in inteqrity .... Species have been utilized with little or no discrimination. Sometimes an investigator has used the species before and is familiar with it; or, it is too much trouble to learn about alternate but superior animals; or, one species bites and another does not. Frequently, experimental animals are altered by exogenous materials or by surgical intervention, not because these are the best ways to approach the problem, but because they are the easiest ways .... Some of the critical cost factors are intangible. such as credibility of the data and the number of 'bits' of data obtainable from each animal. The animal's life span is an important factor, particularly in studying cumulative effects of low doses of an agent. The experiment is abortive if the animal dies before the effect is apparent.. .. ln general, animals are more revealing since they are specially selected for certain traits and/or are 23 often inbred which itself leads to interesting observations .... This controlled environment enhances the chances of disease expression and makes it possible to recognize the disease state and follow its development."

Drs. Leo K. Bustad, Gerald A. Hegreberg & George A. Padgett. 1977. Animal models. In: The future of animals. cells. models. and systems in research. development. education. and testing. Wash., D.C.: National Academy of Sciences/ National Research Council. p. 130-151.

"In his third question, Dr. Benirschke recognized the lack of standardization of such variables as nutritional or environmental status as possibly alfecting the reliability of intact animal experimentation. Today we are fairly in the vineyard of the Institute for Laboratory Animal Resources and the mission that organization embarked upon a long time ago. As Dr. Benirschke remarked, 'At least for the common laboratory animals, standards of care and housing, management, and diet have been set to minimize these variables,' and I think I will be permitted to add that in recent years we have seen a quantum jump in the improved definition and control of these important variables in biomedical research, and, although it has not been mentioned, I think the scientific community can take pride in the fact that it pioneered the whole development of a system of gnotobiosis, in which animals, after caesarean, were taken into barrier-sustained quarters and had a package of known microorganisms given them. One long-troubling variable, the animal's microflora, was under control to a degree theretofore nonexistent."

Dr. Howard A. Schneider. 1977. Summary. In: The future of animals. cells. models. and systems in research. development. education. and testing. Wash., D.C.: National Academy of Sciences/ National Research Council. p. 318-327.

"Genetic characteristics are among the most important factors to be considered in selecting animals for use in biomedical research. Experimental results reported by previous investigators may be impossible to reproduce where the experiment is repeated on animals obtained from different sources, even though they are of the same strain or stock name .... Some of the genetic changes produce visible differences .... and others influence more subtle characteristics, such as metabolism, longevity, disease resistance, and immune response .... Accurate identification and recording of the strain or genetic background of animals used in a research project are important. Failure to document such information and publish it in research reports makes it difficult. if not impossible. to duplicate an experiment in other laboratories."

National Institutes of Health. 1978. Guide for the care and use of laboratory animals. Wash., D.C.: U.S. Dept. of Health, Education, and Welfare; Public Health Service; National Institutes of Health. Publication No. (NIH) 80-23. p. 15.

"Cats used in research must be as uniform as possible and maintained under standardized conditions. if experimental results are to be reproducible .... Colony-reared cats are bred and raised for research purposes. They are superior to random source cats, in that their diet and growth rate are known and they are accustomed to handling and restricted activity .... Although the genetic background of colony-reared cats can be controlled, it usually is not. Unless inbred cats are wanted, efforts should be made to maintain a large gene pool through scheduled outbreeding .... The ultimate in freedom from disease is obtained through the use of 'germ-free' cats obtained by caesarean section and raised in a sterile environment. Because germ-free cats are never exposed to microorganisms, they are free of infectious and parasitic diseases. Because their diet, external environment, and genetic background 24 can also be controlled, germ-free cats serve as a base line for comparison with other kinds of cats. They also serve as a source of disease-free breeding stock for the initiation of specific-pathogen-free or other colonies .... Cats from pounds (generally county or city facilities for holding captured stray animals) resemble those procured from animal dealers as unconditioned random source cats .... There is no nationwide minimal standard for pound facilities. Purebred animals acquired from pounds may have been there because of abandonment, old age, difficult disposition, escape from home, culling from breeding programs, or production of offspring by mismating. The present five-day holding period required by federal law does not specify vaccination and allows only a minimal period for stabilization and acclimation. Under these conditions. mortality rates in cats arriving at research facilities often reach 30%. As one might exgect. many of the survivors are unsuitable for exgerimental gumoses ....

Colony-reared animals are superior for research. Not only can diseases be prevented. but oenetic. nutritional. behavioral. and environmental variables can be controlled: this results in healthy. standardized laboratory animals .... The proper selection of cats as appropriate animals for a specific research objective requires an understanding of their strains or breeds; their structural, functional, and behavioral attributes; spontaneous diseases that they may acquire; and other models of human disease. Formerly. most cats used in research were random source animals and were used in experiments that required no information as to the cats' history. However. a orowino number of investioators prefer a more defined subject than that available throuoh random source systems and they are seeking cats with known medical. husbandry. and genetic histories; this is causing an increased demand for cats from breeding colonies .... Most studies using laboratory animals rely on the selection and maintenance of healthy subjects to grovide the most valid and useful results and to prevent wasted time. effort and exgense. Dependable data cannot be derived from sick animals. and mortality losses can ruin an experiment."

National Academy of Sciences. 1978. Laboratory animal management :Cats. Wash., D.C.: N.A.S. , p. C3-C8.

"The response of laboratory animals to a oiven reoimen of treatment can be influenced by many factors. Diet is one of the more important variables; yet, it is usually given little consideration in the design of experiments. Subtle changes in enzyme systems, microbial flora, and organ and tissue composition occasioned by unrecognized dietary modifications can result in biased data and errors in interpretation. This is particularly the case with long-term chronic studies where major losses in time, effort and resources may be sustained. Variable factors of diet, affecting either nutrient or contaminant content, make it impossible to compare data accurately within one or among different laboratories .... Consistent. reproducible results require control over as many variables as possible .... "

National Academy of Sciences. 1978. Control of diets in laboratory animal exgerimentation. Wash., D.C.: N.A.S., p. A3-A11.

"A prospective study was conducted to identify the viruses causing respiratory diseases in unconditioned, random source dogs .... Severe and often fatal respiratory disease continues as the most important problem in the preparation of unconditioned, random source dogs for laboratory use. Canine distemper virus is the major pathogen, although several other viruses have been recovered from sick laboratory dogs .... During the quarantine period, severe respiratory disease occurred in some dogs of each group. Signs of respiratory disease were evident in 86 of 164 (52%) dogs. and 34 died .... ln each shipment of doos. evidence of canine distemper was associated with prolonoed fatal 25 disease. despite the immediate vaccination of the dogs upon arrival. Vaccination failure could be attributed to canine distemper exposure prior to arrivai. ... Based on these and previous studies of respiratory disease in random source dogs, canine distemper SV 5 and canine adeno virus type II were consistently associated with epizootic respiratory disease. As these dogs were often infected before arrival at our facility, immunization against these viruses after arrival usually was unsuccessful. Accordingly, the only practical alternative would be to select immune or seropositive dogs .... Procurement of dogs immune to canine distemper virus should result in a major reduction in non-fatal and fatal respiratory disease."

Drs. L.N. Sinn, J.P. Alford, R.H. Marchwicki, T.J Keefe, R.J. Beattie & H.G. Wall. 1979. Studies of respiratory disease in random source laboratory dogs: Viral infections in unconditioned dogs. Lab. Animal Science 29 (1 ): p. 48-52.

"for biomedical research involving laboratory animals to be effective in the sense that results from different laboratories can be compared and evaluated. there must be recognized criteria for animal care. including definitions of animal health. status and genetic constitution. Genetic uniformity. which facilitates reproducibility of experiments. is highly desirable in experimentation with animals and should be used wherever practicable. Comparisons among results derived from work with different genetically defined types within the same species may add to the significance of those findings .... Other species, in which genetically completely homogeneous animals are not available, are also essential for research. For these species, clear recognition of the genetic status of each stock, provision of as much genetic information as feasible, and colony management designed to avoid genetic differentiations within a single colony are all desirable goals."

National Academy of Sciences. 1979. Laboratory animal management: Genetics. Wash., D.C.: N.A.S., p. A4.

"Many of the cats accepted by institutions for research use are from rural areas where they may be exposed to a variety of sources of antibiotic-resistant salmonella .... Because of the increased use of cats in biomedical research, concern arises that cats shedding antibiotic-resistant salmonella will serve as reservoirs of salmonella for infection of animal clinicians, investigators, and healthy animals. A recent study was undertaken to monitor the carrier rate of salmonella in random source cats designed for use in research at the Massachusetts Institute of Technology (MIT). A high incidence (1 0.6%) of salmonella-infected cats was documented .... ln the present study, 80% of the salmonella isolates were resistant to one or more of the antibiotics tested .... A widespread use of antibiotics therapeutically and as feed supplements for animals increases the risk of transmission of R factors from normal enteric bacteria in animals to other animals and to persons .... As a result of contact with cats shedding enteric salmonella. other animals. investigators. and animal technicians may become infected with antibiotic-resistant salmonella."

Ms. Celia M. Beaucage & Dr. James G. Fox. 1979. Transmissible antibiotic resistance in salmonella isolated from random source cats purchased for use in research. Amer. J. Vet. Research 40 (6): p. 849-851.

"Yet, in spite of these major contributions, there are many areas of biomedical research in which inbred strains are hardly used at aii .... Unfortunately there is some suspicion about the value of inbred strains jn research on the grounds of cost. and because they are often considered to be 'unnatural.' and therefore are bad models of the more 'naturally' outbred human 26 population .... However. in most research work involving laboratory animals the animal only represents a small fraction (usually on the order of 10%) of the total cost of the research project if all costs (including salaries and overheads) are taken into account. If the use of inbred strains improves the quality of the research. this is likely to more than pay for the extra cost of the animals. The charge that inbred strains are 'unnatural.' and are therefore bad models of 'natural' human populations. involves a misunderstanding of the methodology of scientific research .... The great advantage of using the inbred mouse (or other species) lies in the fact that individuals of the same inbred strain are genetically identical, and thus one important variable in any experimental situation is under the control of the experimenter. Generality can always be increased by basing any study on a range of different inbred strains .... lt is precisely because in such animals many of the variables that can influence the results of an experiment are controlled that such animals are so valuable in research. Finally, it should be pointed out that the use of inbred strains is. in fact. increasing very rapidly at present. ... The value of inbred strains of laboratory animals in cancer research has been appreciated by geneticists for many years .... Their value in other disciplines was recognized by Dr. W.L. Russell (1941), who also noted that. .. .'Any geneticist who samples the recent literature in such fields as physiology. biochemistry. bacteriology. pathology. cancer research and experimental medicine in general is struck by [the fact thatl most of the workers who are still using animals of uncertain origin could profit by the use of inbred strains.' .... lt is a sad reflection on biomedical science that these words are still true thirty-seven years after they were written .... ~ becoming clear that genetically defined strains should now become the standard tool jn biomedical research."

Dr. Michael F.W. Fasting. 1979. Inbred strains in biomedical research. New York: Oxford University Press. Preface - p. 4.

"The University of California, San Diego (UCSD) is interested in establishing a list of persons or kennels in California and bordering states that would consider breeding dogs for medical research. Animals raised for the University would be used for biomedical teaching and research. Because of the importance of the research it is imperative that the animals supplied have traceable backgrounds and are accustomed to confinement to minimize behavioral problems and to facilitate handling."

Mr. Gilbert A. James, UCSD Senior Buyer, Dept. of Materiel Management. 1979 (Feb. 15). Memorandum.

"The appropriate strain of laboratory animal to use in biomedical research is one which will provide the most useful information without introducing extraneous genetic and environmental variation .... Thus, laboratory animals that have been produced in micobiologically defined environments. fed standardized diets. and are genetically defined are the research animals of choice .... Genetically defined laboratory strains are those that are identifiable by known developmental, biochemical, immunological, or other heritable characteristics. In cases where the choice of an experimental animal is determined by the type of animal used in onooing research or in the corroboration of completed work. the use of oenetically and microbiolooically defined animals becomes more important."

Drs. H.A. Hoffman, K.T. Smith, J.S. Crowell, T. Nomura & T. Tomita. 1980. Genetic quality control of laboratory animals with emphasis on genetic monitoring. In: 7th international council for laboratory animal science symposium. New York: Gustav Fischer Verlag. p. 307-317. 27

"The science of genetics furnished the means of standardizing animals through intensive inbreeding. The adaptation of gnotobiotic techniques to large-scale production was one of the important factors contributing to the development of a biomedical genetic resource .... Laboratorv animals reared under these conditions have become superior research tools since experimental results are not compromised by the effects of subclinical or acute infections .... As biomedical research becomes increasingly more sophisticated, the challenge of assuring a good supply of healthy, well-defined, and characterized laboratory animals also becomes more complex .... We now realize that environmental factors are crucial experimental variables; and if they are not recognized and controlled, the validity of research results may be questioned .... The microbiological status of animals also can determine the outcome of an experiment. Agents that do not normally produce disease may create problems in experimental situations when the animals are subjected to stress .... Because of these intricate relationships. it is desirable to use laboratorv animals that are as 'clean' as possible and to define completely the microbial agents present.. .. As both our animal models and our research techniques become more sophisticated and sensitive, it is increasingly important that the development of new strains is a combined effort between geneticist and medical investigator .... Cats, dogs, poultry, swine, goats, sheep and nonhuman primates are all being bred for use as laboratory models .... The use of these animals will benefit research just as the use of laboratory-reared rodents increased the sophistication of our current projects. The genetic background of laboratory animals can be a critical factor in the success of an experiment. Any institution which provides research animals to other organizations must be particularly concerned about the genetic integrity of these animals .... Currently our geneticists are developing profiles for a breeding colony of dogs .... For example, dogs with higher frequencies of lipoproteins may be artificially selected for development of a model for atherosclerosis. The chances for success in this type of project are increased greatly if profiles are available for the animals involved."

Dr. Joe R. Held. 1980. Considerations in the provision and characterization of animal models. In: 7th international council for laboratory animal science symposium. New York: Gustav Fischer Verlag. p. 9-16.

"The principles of experimental design dictate that batches of animals used in toxicological screening should be as uniform as possible. in order to avoid experimental 'noise.' which leads to false positive and negative results. Therefore. animals should as far as possible be of uniform weight and age. they should be free of disease and should be maintained in uniform environmental conditions. on a standard diet. Genetic variation should be eliminated .... The principles of good experimental design estabished many decades ago have been widely accepted by most research workers in both the biological and physical sciences. Basically. these principles state that all variables influencing an experimental unit should be controlled as far as possible. but one variable. 'the treatment.' should be deliberately and systematically varied. However, most toxicological screening experiments ignore these principles by using genetically variable outbred stocks in the belief that such stocks will improve the quality of their experiments. In fact, the use of such heterogeneous or 'noisy' experimental material reduces the precision of an experiment.. .. The case for using inbred strains of laboratory animals in toxicity testing was summarized very concisely by Heston [1968] as follows: 'Yet the question is sometimes asked, why not use genetically heterogeneous stock mice so the results will be more applicable to the genetically heterogeneous human population? The answer is that we are not trying to set up a model with mice exactly comparable with human beings. This would be impossible because mice and men are different animals. What we are trying to do is to establish certain facts with experimental animals and this can be done, or done more easily, when the genetic factors are controlled. Once the facts are established, we then, with much common sense, see how these facts can be applied to man. When genetic variability is desired. this can be obtained in the highest degree by using animals of a number of inbred strains. This variation between strains is 28 usually much areater than is found in animals of a non-inbred stock which actually may be rather uniform although more variable than an inbred strain.' .... Thus, animals are in a sense useful models of man not because they are like man, but because in many ways they differ from man. The fact that inbred strains are available enhances their value as it leads to within-strain uniformity and between-strain variability.''

Dr. Michael F.W. Festing. 1980. Inbred strains and the factorial experimental design in toxicological screening. In: 7th international council for laboratory animal science symposium. New York: Gustav Fischer Verlag. p. 59-66.

"Since the major focus of this conference is on the use of animal models for human disease, a word is in order on how one can select an animal model to best 'approximate a human population.' Conventional wisdom suggests that 'a randomly breeding' group of animals would be the best choice, since humans are 'a randomly breeding' population. However, closer examination of this proposition shows that it is not completely tenable. Human populations do not breed randomly in a strict sense, since they are segregated by geographical. ethnic and sociological factors that limit mating behavior and tend to concentrate certain genes in specific populations. The randomly bred animal populations that are often used to approximate human populations show some degree of genetic restriction also .... Hence. comparing the human and the randomly breeding animal may have the dual disadvantage of a variable level of selection in each species and the possibility of the selection's being in directions that would affect the characteristic being studied in an opposite manner. This situation would be particularly deleterious if quantitative variables were being studied because the variance in the measurements would most likely render the comparisons meaningless."

Dr. Thomas J. Gill, Ill. 1980. The use of randomly bred and genetically defined animals in biomedical research. Amer. J. of Pathology 101 (3S): p. S21-S32.

"Thus research requiring beagles or malamutes could hardly be performed on a mix-breed population of pound dogs. Cardiovascular surgical procedures are developed on dogs of a uniform size because of the need for standardized sizes of valves, tubing, and blood volume. These dogs are most readily available from purpose-bred colonies of a uniform type .... Long. chronic studies in which many hours or years of study are invested in the animals require that they be uniform and unvarying. Slight changes due to stress or hardly noticeable changes jn blood cell values often add sufficient variability when analyzing data. making interpretation difficult or impossible. Additional animals may have to be added to the study sample or additional studies performed to account for the uncontrolled variability produced by the variable backgrounds of exposure and handling of the pound animals.''

The American Association for Laboratory Animal Science. 1981. Legislative handbook (Draft). p. 14-16.

"We recognize the long-term benefits of laboratory reared primates for biomedical research. By the turn of the 21st century, most primates used in research will be laboratory reared. The use of these animals will revolutionize research just as the use of laboratory reared rodents increased the sophistication of our current projects.,.First. laboratory reared animals will be of better quality since they are basically disease-free. The use of these animals will increase the validity of the research and eliminate a variety of hazards to personnel. Second. the supply of uniform groups of 29 genetically characterized animals will result in better standardization. more accurate work and lead to a reduction in the number of primates needed for a particular study. In addition, once animals are genetically characterized, we can measure the impact of other factors such as nutrition. Third, the problem of availability would be obviated by insuring continuity of supply, which would save research time and money. In addition, domestic breeding of animals would eliminate the mortality loss we experience .... "

Dr. Joe R. Held. 1981. Breeding and use of nonhuman primates in the U.S.A. Inter. J. Study Animal Problems 2(1): p. 27-37.

"One reason, sometimes advanced, for the use of random-bred mice in research is that random-bred mice more closely approximate the random-bred features of the human population and, thus, provide a better basis for judging the effects of toxic agents, for example, than do inbred mice. I regard this argument as specious. An investigator's first obligation is to design interpretable experiments. The task of extrapolating from experiments with animals to inferences about mankind is difficult. at best. It is not helped by shoddy experimentation."

Dr. Earl E. Green. 1981. Genetics and probability in animal breeding experiments. New York: Oxford University Press. p. 271.

"The Laboratory Animal Science Association believes that for scientific. economic and ethical reasons all dogs and cats. in common with other animals used for research. should be bred for this puroose. The Association therefore urges that every effort should be made, both in the U.K. and overseas, initially to regulate and later to prohibit the purchase of dogs and cats for research purposes except from recognized breeders."

Laboratory Animal Science Association. 1981. L.A.S.A. policy statement on dogs and cats. Lab. Animals 15: p. 405.

"The aim of the chapter is to outline the current status of laboratory animal science, and to consider some of the ways in which the scientific validity of the work may be improved, and the suffering minimized, by the use of high quality, defined animals. Although it is possible for a research worker to pay little attention to the health and quality of the animals used in research. the best results are undoubtedly obtained by those research workers who use only microbiologically and genetically 'defined' animals .... Behavior, response to drugs, sex, weight, and shape of many organs, numbers, and types of spontaneous tumors, and response to antigens depends not only on the species but also on the strain of animai .... The microbiologically and genetically defined laboratory animal. maintained in a controlled environment. fed on a defined diet and cared for by trained animal technicians under the supervision of a scientifically qualified animal curator is clearly a very superior anjmai.,,.Unfortunately, many scientists are not making full use of such animals ....

The animal tests are usually carried out on genetically variable outbred stocks. Two arguments are used to justify the use of such stocks. These are firstly that the animal is used as a 'model' of man, and man is 'outbred,' therefore outbred laboratory animals should be used. Secondly, it is argued that the tests should include animals of a wide range of different genotypes in order to get a broad genetic base for extrapolation to man. Unfortunately, neither of these arguments will withstand critical evaluation .... and they result in the use of genetically variable material which violates one of the first laws of experimentation. namely that the experimenter should control all relevant 30 variables. An outbred stock is one in which there is an unknown. and uncontrollable. deoree of genetic variation or 'noise' which in critical situations may well obscure any treatment effect. The argument that outbred animals should be used because man is outbred fails to recoonize the two step nature of experimental inference. In any experiment, the first step is to decide whether the experimental treatment has affected these particular experimental animals .... Only after this question has been answered is it possible to interpret the importance of the results in human terms .... Use of an animal incapable. because of 'noise.' of distinouishino between two treatments is of no value at aii .... Even the use of disease-free animals has been resisted with arouments based more on an emotional resistance to change rather than a rational assessment of the benefits of such animals .... Expensive. but good quality animals are justified on the grounds that such animals give substantially better results than poorer quality ones. and the additional cost is insignificant with the total cost of research .... ln the universities. on the other hand. the higher cost of good quality animals means that fewer can be purchased from a fixed research budget which does not take account of all of the costs involved in animal experimentation. Thus. the research worker is tempted to stretch his research funds by buying cheap animals from non-accredited sources. even though in strict accounting terms this could be totally uneconomicai. ... Had the full cost of the operation, including the surgeon's time, also been taken into account, the value of the laboratory-bred dog would have been ever more overwhelming. Yet. research workers both in the U.S.A. and the U.K. continue to use these 'cheap' animals in the hope that it will preserve their research budgets .... High quality, genetically and microbiologically defined animals may easily be produced with current technology. The more widespread use of such animals would give more valid scientific results and would reduce the number of laboratory animals that become sick from disease unrelated to the experimental treatment. Thus. on humanitarian and economic grounds it is highly desirable."

Dr. Michael F.W. Festing. 1981. The "defined" animal and the reduction of animal use. In: Animals in research. Dr. David Sperlinger (Editor): New York: John Wiley & Sons. p. 285-306.

"Scientific criteria related to anatomy. physiology. and pathology are more important than the practical considerations of availability. cost. and size. although these must be taken into account.. .. The dog has been widely used because of factors such as availability, size, and relative tractability. Once used in a scientist's training, a species has tended to be selected for the remainder of that scientist's career .... lt appears that size, availability, and relative ease of handling remain the principal reasons for the selection of the dog in splanchnic blood flow work .... As will be seen below, other species than the dog may be proven to be more appropriate in the future .... Dogs may be so unique in their splanchnic circulations that one must 'question the suitability of dogs as models for experiments whose ultimate design presumably culminates in a better understanding of the pathophysiological events accompanying septic shock in man' [Swan et al., 1977] .... 1n a recent shock study the authors chose rats in preference to dogs because of their low cost, availability, and because controlled breeding can make them less subject to individual variation .... Cost is often cited as a major factor in the selection of the animal model system. By this is usually meant the initial cost of the animal. Unfortunately. the greater cost is usually the daily maintenance (food. medical care. sanitation. cage or enclosure acauisition. record-keeping. etc.) of each animal and as a result. scientists are frequently 'penny-wjse and pound-foolish.' It is far better to purchase the most appropriate species and quality of animal. even at a higher cost. than to obtain a less costly but less healthy individual .... !! can be seen that even 7 or 14 days (or more) multiplied by the per diem rate soon render differences in initial cost very slight. For too long the choice of an animal model system has been a function of factors other than scientific appropriateness in terms of anatomy, physiology, or pathology. While availability, size, temperament, and cost are necessary realities in the decision making process, more reliance on the truly relevant scientific factors involved would seem required." 31

Dr. Franklin M. Loew. 1981. Selection of experimental animal models (Chapter 3). In: Measurement of blood flow: Applications to splanchnic circulation. Drs. D. Neil Granger & Gregory B. Bulkley (Editors). Baltimore, MD.: Williams & Wilkins. p. 48-55.

"For many years investigators concerned with research animals have focused on the physical needs of the animals and have given little consideration to the animals' emotional needs. However, when a dog or cat has an abnormal behavior pattern, there is something wrong with that animal. Abnormal behavior patterns may reflect internal or environmental changes that can affect experimental results .... lndividual dogs or cats are influenced by genetic and environmental factors, both of which can hinder the satisfactory development of the animal. Laboratory rearing produces more uniform individuals: random source animals are subject to extremes and thus there are more differences among them."

Dr. Bonnie V. Beaver. 1981. Behavioral considerations for laboratory dogs and cats. The Compend. on Cont. Educ. for the Animal Health Tech. 2 (4): p. 212-215.

"The use of disease free cats is necessary in order to evaluate physiologically normal animals .... All of this is required in order to eliminate as many variables as possible, to exclude any extraneous data from influencing the research results and to maximize the probability of obtaining usable data from each experimental animal. If less well controlled populations are used. the loss of data and the decreased survival due to complicating factors ultimately results in a requirement for more animals. more time and greater expense."

John L. Naler, Chief, Investigations and Legislative Div., Dept. of the Army. 1982 (Feb. 12). Letter to Mr. L. A. Sprotte.

"Next. I believe that the general use of pound animals in research is a penny-wise and pound­ foolish situation in many cases. Cleanjng up and 'sizing' the typical group of pound dogs is often more expensive than buying laboratory raised animals to start with. And even then there are still variables which must be taken into consideration in the final analysis or judgment. The cost of laboratory raised animals. which are the very vehicle upon which a significant decision is being made. is a very minor portion of the total cost of most studies. Thus to use the research model as an area to economize is often false economy. Over the years we have been involved with many 'reruns' because the initial study, using pound dogs, could not be interpreted to the satisfaction of the FDA. Therefore, the argument of cost of animals, as far as research is concerned, is not valid. Last, in response to the question, could registered, commercial breeders provide both dogs and cats in sufficient quantity to meet the needs of the research industry in California, my answer is a resounding yes."

Mr. Robert W. Denison, President, Laboratory Research Enterprises, Inc. (Kalamazoo, Mi.). 1982 (March 18). Letter to California Senate President David Roberti.

"The Scientists Group for Reform of Animal Experimentation, an organization including physicians, veterinarians and research scientists, is opposed to the use of pound animals for research and experimentation on both scientific and ethical grounds .... The scientific community is realizing increasingly. that the use of random source animals introduces many unsuspected variables. which 32 can seriously affect the outcome of an experiment. and lead to false conclusions. Further work based on these conclusions leads to more and more waste of time and money, and delays progress."

Scientists Group for Reform of Animal Experimentation (Whitestone, N.Y.). 1982. Position statement on the use of random source animals.

"I am Dr. Moneim Fadali, a surgeon in private practice and also on the clinical staff of UCLA. I have been involved with surgical research including animal research for several years at university institutions. I can comfortably state the following: stray animals and animals obtained from animal shelters are not good subjects for precise scientific research. There are so many important pieces of information that are missing. such as genetic background of the animal. environmental conditions. past history of diseases. vaccinations and medications that the animal could have received. The age of the animal is important also. All these factors, in my judgment, can alter the response of animals to the experimental procedure performed and, therefore, can lead to mixed results with unreliable conclusions obtained. For reproducibility and precise animal research, animals are bred for the purpose of research under controlled conditions. When this is done, many variables that can interfere with scientific accuracy are eliminated. This. too. could be economical and cost effective since eliminating variables and unknowns from any experimental setting will undoubtedly result in decreases in the number of experimental observations required to reach a certain scientific conclusion."

Dr. Moneim A. Fadali. 1983 (May 31 ). Los Angeles. Letter to Dr. Michael A. Giannelli.

"In anticipiation of legislation being passed in the State of Calitornia (the Roberti bill) which would prohibit the use of random source dogs in research, the University of California, San Diego, School of Medicine established a breeding colony using random source animals in order to provide dogs for research in the futu-re .... [Wel believed it would be possible to establish a dog breeding colony that co'Uid produce top quality research animals on a minimum budget. ... We found this technique very cost effective, requiring very little increase in time and labor while resulting in a 93% conception rate ... Cost information -- including start-up costs for the dog breeding colony: preliminary cost accounting indicates that the cost for a 4 1/2 month old pup, 40 to 50 pounds in weight, to be approximately $280 to $300. The quality of these animals is far superior in health and conformation to any that might be obtained from the animal shelters for approximately $61, and the birth date and health histories of the animals are known and recorded. Finally, should legislation pass in the State of California prohibiting the release of random source dogs to research institutions, the University of California San Diego School of Medicine will be prepared to continue to meet their animal resource needs with its own closed colony of healthy stock that has been raised in a research environment."

Drs. Jack E. Vanderlip and Sharon L. Vanderlip. 1983 (May-June). Establishing a breeding colony using random source dogs. Lab. Animal 12 (4): p. 35-43.

"As a physician it is my opinion as I expressed to you that there is little if any need to utilize household type pets in the area of medical research. Certainly there has been extensive data derived on utilization of inbred animals .... specifically for the purpose of controlled research studies and thus there seems little need to use pets for these purposes. Thus I concur entirely with you that there is no true documented need for the current utilization and I feel that it is unkind and cruel utilization of pets for these purposes." 33

Dr. William S. Cryan. 1983 (Aug. 22). Long Beach Medical Group. Letter.

"The use of stray or ownerless domestic animals for experimental purposes is not recommended. Such animals may be in poor physical condition and thus unsuitable as experimental subjects, or may have been stolen from their owners. These risks are avoided by obtaining animals from reliable sources."

Council for International Organizations of Medical Sciences. 1983. Proposed international guiding principles for biomedical research involving animals. Geneva, Switzerland: World Health Organization and U.N.E.S.C.O., C.I.O.M.S./83/AE.2/REV.2. Special Provisions 2.1 (Acquisition). p. 7.

"In Great Britain it has been illegal since 1876 for veterinary students to sacrifice live animals for teaching purooses. Dr. T.E. Gibson, current President of the British Veterinary Association, recently wrote, 'Live animals are not used in survival surgery in this country as they are in the U.S.A .... The B.V.A. and the Royal College of Veterinary Surgeons were all against it.. .. The idea of making healthy animals sick for purposes of training is totally repugnant to the profession in this country' .... The variable and unknown genetic. medical. and environmental backgrounds of random source pound animals creates scientific disadvantages and necessitates using many more animals .... Pound animals lack a standardized health status and constitute higher risks for illness and premature mortality. Former pets suffer psychologically more in a research environment. an important ·humane consideration. as well as posing a danger of stress-precipitated responses confounding the interpretation of data .... Pound animals are unquestionably cheaper in initial purchase price, but they are false economy. In addition to the scientific disadvantages discussed earlier, for most purposes pound animals must undergo extensive conditioning before being ready for research. When these conditioning costs are considered, the initial savings in purchase price shrinks dramatically .... As long as dogs and cats are used for research. the following principles should be adhered to: a) conduct the highest quality research: b) use the fewest animals necessary: c) reduce the suffering to the minimum possible. and: d) lessen the associated social/political problems to the lowest achievable leyel. On all four counts. the perpetuation of pound seizure cannot be justified."

Dr. Michael A. Giannelli. 1983. Pound seizure: Retrospective and outlook. Calif. Veterinarian I (Jan.): p. 69-71, p. 101.

"The requirements for breeding and supplying establishments should be specified in greater detail and should be no less stringent than those for user establishments. The restriction of the use of dogs and cats should not be limited to those 'straying.' The restriction should apply to dogs and cats 'lost, stolen or strayed.' The use for experimental purposes of dogs or cats taken from the streets should never be permitted."

The British Veterinary Association. 1983 (Sept.). Scientific procedures on living animals (CMND 883). Comments submitted to the Home Secretary.

"Pound seizure is an ill-conceived practice dama0ing to the good name of science and to its quality. The use of animals from shelters for experimentation is not only unnecessary and unethical. but it is detrimental to sound research. Strays are of undetermined genetic, environmental and medical 34 background. They react unpredictably and inconsistently, making questionable the reliability of most research in which they are used. Pound seizure perpetuates inferior research. The use of shelter animals for experimentation creates a schism between pet owners and research scientists. The interests and needs of science can be served without the use of unclaimed pets in research. Pound seizure is an unsound practice."

Statement (1983-84) signed by California physicians (21 0), veterinarians (157), Ph.D.'s (199) and others (170) with doctoral degrees. (List of names available from the Fund for Animals.)

"It is often argued that, because humans constitute a random source gene pool, random source dogs would not only be adequate but would be even more appropriate than purpose-bred animals. However, Festing (1981 ), a geneticist with the U.K. Medical Research Council, contends that this is invalid reasoning. If it were not. then there would be no reason for the growing use of defined strains of rodents with known genetic and microbiological backmound: random source rats and mice (e.g.. from the city dump) would be perfectly adequate. More than three-quarters of the respondents to a recent survey (T. Wolfle, reported at the 1981 AALAS annual meeting) stated that purpose-bred animals would be more reliable, but few gave detailed reasons for their opinion. "

Dr. Andrew N. Rowan. 1984. Of mice. models. and men. Albany, New York: State University of New York Press. p. 157.

"Commercially produced swine were successfully used to replace dogs in several surgical research J;~rojects at The Johns HoJ;~kins University School of Medicine. They were especially successful as replacements for dogs in the basic operative surgery course offered as an elective to medical students. Advantages of swine over dogs included anatomic and J;!hysiologic differences shared with man. better health. and economic considerations .... Traditionally. the dog has been the most commonly used laboratory animal in surgical research and teaching. This tradition has been changing over the last decade. and a survey showed that the use of swine increased by almost 100% between 1968 and 1978. while traditional laboratory animals such as the dog decreased substantially. Reasons for the decline in the use of dogs in surgical research include decreasing availability of dogs in areas where the use of pound dogs in research and teaching has been restricted by legislation, increasing costs of available dogs, and public sentiment against the use of dogs in research .... Commerical swine may be readily procured in a healthy status with a known vaccination and worming schedule from commercial swine producers more cheaply than dogs in many areas of the United States. The better health of the swine made them better candidates for surgery than ROund dogs that may be incubating diseases when mocured,,The Rig has some unique Rhysiologic and anatomic characteristics of the heart and cardiovascular system that has rendered it an effective animal model in exJ;)erimental cardiovascular surgery. Humans and pigs have a similar distribution of the coronary arteries and effective collateralization of the blood supply of the myocardium when a coronary artery is blocked; this is unlike the dog. For these and other reasons, in our laboratory the pig has replaced the dog as a model to study methods of myocardial protection during open heart surgery .... The choice of the dog as an animal model of human surgery has been based on tradition rather than J;!hysiologic considerations in many instances. Investigators and physiologists will have to reassess their choice of the dog as an animal model in coming years .... lnvestigators in our laboratory have found that conventional swine tend to be more healthy and yield more consistent results than pound dogs. In addition. in our area. swine are more available and more economical.''

Dr. M. Michael Swindle. 1984. Swine as replacements for dogs in the surgical teaching and research laboratory. Lab. Animal Science 34 (4): p. 383-385. 35

"The use of specific pathogen free (SPF) cats, bred specifically for research purposes and therefore of known pedigree, quality, age, etc., is becoming increasingly common. This trend has much to commend it, even though the animals are more expensive and sources of supply are still somewhat limited .... Most research dogs are acquired from random sources. usually municipal pounds. Such doas have completely unknown genotypes. behavioral experiences and disease exposure profiles ... Dogs from random sources (pounds) have often been discarded by their owners and turned lose to fend for themselves: thus. nutritional and disease problems will be frequently encountered in these animals. Some few of the random source (pound) dogs that are legally acquired by a research institution will. nonetheless. inevitably be 'lost' pets .... Dogs specifically bred for research should be the models of choice for those types of studies in which defined genetic, environmental and health statuses are necessary .... The pathophysiological changes that may be associated with the chronic low grade infections and poor nutritional status frequently encountered in the unconditioned dog, constitute a totally uncontrolled variable. This may be expected, in many situations, to distort the results obtained and affect the repeatability and interpretation."

Canadian Council on Animal Care. 1984. Guide to the care and use of experimental animals (Vol. 2). Ottawa, Ontario, Canada: C.C.A.C. p. 65-82.

"Straying animals of a domesticated species shall not be used in procedures. A general exemption made under the conditions of Paragraph I of this Article may not extend to stray dogs and cats."

Ad Hoc Committee of Experts for the Protection of Animals. 1985 (May 31 ). European convention for the protection of vertebrate animals used for experimental and other scientific purposes. Article 21. p. 1 0.

"A basic principal of experimental science is reproducility. If a particular procedure, test or result is not reproducible, then its validity is questionable. Use of random source animals. such as those acquired from pounds. causes problems in this area. There is a need for standardization of animals for any type of research involving physiology. experimental pathology. immunology. pharmacology and related areas. The researcher must be able to differentiate between the effects of the experimental procedure and any pre-experiment conditions of the animal subjects utilized. Colony-bred animals are the appropriate subjects in such areas of research. They are characterized by: a) precise genetic history; thus eliminating inherited disorders that might produce abnormal physiological or morphological variability; b) pathology free; c) parasite free; d) a proper history of gestation, weaning and subsequent postnatal development (especially with regard to nutrition); e) have established, predictable, stable physiological parameters, and; f) are raised under conditions of humane treatment and minimized psychological stress; are accustomed to the procedures and environments found in laboratories .... The pharmaceutical industry has long recognized the need for standardization through purpose-bred animals in order to control variability in their tests ....

There are several areas that are often mentioned as arguments in favor of using these [random source] animals. One is the genetic diversity argument. The reasoning here is fallacious. ~ want genetic diversity. you can produce it through purpose breeding where you will have some idea of what genetic stock you are starting with. There is a great deal of difference between genetic diversity and genetic ignorance .... Researchers often confuse the differences between 'mongrel' dogs (which may be necessary for some experiments) and 'random source' dogs. Mongrel dogs have a known, mixed genetic background. Random source dogs, however, are not equivalent, since they have 36 a totally unknown genetic background."

Dr. John McArdle. i 985. Why you should be concerned about the practice of pound seizure: Remarks deli~red to a meeting of the National Society for Medical Research.

"Alternatives to random source animals exist. In medical research there are several in vivo techniques, computer modeling and diagnostic imaging, to mention only a few available alternatives. In medical and veterinary school, teaching alternatives include cadavers, dummies, computer­ simulated laboratories and audio-visual techniques .... lt is basically inhumane to place a trusting domesticated animal in a laboratory cage, apart from the issue of subjecting any animal to pain and suffering. Studies using animals with unknown histories are not scientifically valid because there are too many variables. In addition, random source animals all too frequently have contagious diseases which spread rapidly. Because of this, many laboratories stopped requisitioning animals from shelters. Pound seizure undermines the confidence of the public in pounds and shelters. Consequently, where pound seizure is the law, a great number of people abandon animals in the streets rather than turn them in to shelters, creating a public hazard as well as prolonged suffering for the traumatized former pet."

Dr. Richmond C. Hubbard, Chairman, Medical Research Modernization Committee (New York, N.Y.). i 985. Policy statement in opposition to pound seizure.

"The sale of shelter animals is strongly opposed by PsyETA for civic. scientific. economic. and ethical reasons .... A former pet that finds him or herself in a small cage and strange surroundings at a research facility is highly fearful and stressed. This type of negative emotional conditioning introduces an extraneous variable which can confound research findings. In addition, because these animals are of unknown origin and history, and often have injuries, diseases and genetic abnormalities, they are unacceptable as subjects for research. The pharmaceutical industry avoids using animals of unknown source because preexisting physiological conditions make them unsuitable for drug testing .... On ethical grounds it is indefensible to betray former pets by subjecting them to experimentation and laboratory conditions that are stressful and painfui. ... From an economic point of view the use of pound animals is an unsound practice .... Data on dogs and cats supplied by shelters to medical, dental and veterinarian schools as well as other research institutions show a high death rate, requiring the purchase of more animals."

Psychologists for the Ethical Treatment of Animals (Lewiston, Me.). 1985. Position papers by the dozen. p. 9-i 0.

"lntramurally. NIH does not use any animal from a pound or shelter but rather acquires any purchased dogs or cats and primates from USDA registered and approved dealers. None of these dealers acquire animals from pounds or shelters; they come from both purpose-bred colonies and from a few dealers who buy animals from rural areas (farm dogs and cats). As has been the case for over a decade, NIH supplies the majorities of its intramural requirements for dogs through the inhouse breeding program in Poolesville [Maryland]."

Dr. Thomas L. Wolfle, Executive Director, Interagency Research Animal Committee. 1985 (Aug.26). Dept. of Health and Human Services, National Institutes of Health. Letter to Dr. John McArdle. 37

"The domestic dog has a status akin to the holy cows of India, and a very large number of people regard dogs as quasi-human in character. In part because of this special standing of the dog and its widespread use in biomedical research, there is a renewed discussion of the use of animals in research .... We have come to the conclusion that the status of the dog in Western society is such that it is desirable to minimize its use in the laboratory .... Thus, it will probably be necessarv to phase out the significant use of dogs if a major battle over the use of animals for research is to be avoided. Our faculty has begun to move toward the replacement of the dog by the Yucatan miniature pig. These animals are in many ways superior to the dog for pumoses of research. They are small (20 kg.). good tempered. genetically quite uniform. and disease free. We plan at this university to move rapidly toward a breeding unit to supply our large animal needs and feel that this can be done for a third of the cost of breeding dogs .... ln fact. a high standard of animal care and phasing out of the use of dogs should result in a much higher standard of research."

Drs. J.C. Russell & D.C. Secord. 1985. Holy dogs and the laboratory: Some Canadian experiences with animal research. Perspectives in Bioi. & Med. 28 (3): p. 374-381.

"I'm not in favor of using pets for experiments. I don't have the stomach for it and I don't believe it produces good data. It

Dr. Richard Olsen, Director, Feline Leukemia Virus Task Force, School of Veterinary Medicine, Ohio State University. 1985 (Sept. 22). AIDS-like virus deadly to cats. Dayton Daily News. p. 2H.

"By definition. 'randomly outbred' means that nothing is known about the genetic constitution of the individual animal except that jt falls within the normal range of genetic variation of members of the species. To make experimental results obtained with animals as relevant to man as possible. the animals used should be as similar as possible in critical physiological and metabolic characteristics to a specific human population at risk, for example people with increased susceptibility to heart disease. If such animals are not available, it may be possible to produce them by using appropriate parental lines with defined characteristics .... The overwhelming genetic rationale for not using randomly outbred animals for biomedical research is that each such animal has a unique and unknown genotype. Thus. the variance of any parameter obtained with a small population of such animals includes unknown degrees of undefined genetic and environmental variation. Therefore. the population will not be reproducible. This problem can be alleviated by using large populations of experimental animals but the cost would be prohibitive. Scientific data obtained from well-designed experiments must be reproducible. Since the genetic constitution determines the constitutive metabolic and physiologic characteristics of each organism, reproducibility of scientific data is made difficult unless organisms with the same genotype are used as the experimental subjects .... Environmental variation can be controlled to almost any desired degree by the investigator: however genetic variation can only be controlled by the use of pedigreed breeding stocks."

Dr. George L. Wolff, National Center for Toxicological Research. 1985 (Aug. 20). Letter to Dr. Michael A. Giannelli.

"One of the fundamental principles of experimental design is that all variables should be controlled as far as js practicable. Failure to control relevant variables introduces 'noise.' which obscures treatment effects. making it necessary to use lamer numbers of animals .... There seem to be no 38 biochemical or biological reasons for using outbred stocks. The use of inbred strains offers many advantages. such as fewer false positive or false negative results for a given size of experiment. new ways of interpreting the results. and experiments which are repeatable .... Toxicologists should stop deluding themselves that the use of outbred stocks is scientifically justified .... The use of inbred strains would provide a statistically and biologically more powerful experiment. needing fewer animals as well as having a number of other distinct qualitative advantages ... .'When genetic variability is desired this can be obtained in the highest degree by using animals of a number of inbred strains. This variation between strains is usually much greater than is found in animals of a non-inbred stock which actually may be rather uniform although more variable than an inbred strain [Heston, 1968].' .... There is absolutely no evidence that the predictive value of the experiment would be enhanced by using outbred animals. However, the use of an outbred stock may mean that the experiment is incapable of detecting a toxic effect because it is obscured by experimental noise .... The argument that outbred animals should be used because they more closely resemble human populations is not logically valid,. .. The main effect of deliberately choosing heterogeneous material. such as an outbred stock is to lower the efficiency of the experiment, and no benefit is derived from such heterogeneity .... Probably the most important initial step is to convince toxicologists that the use of outbred stocks does indeed violate the principles of good experimental design .... lt is vital that the experimenter understands exactly what he is doing. and does not attempt to put forward spurious scientific arguments to justify his actions. There is no place for self-deception in science."

Dr. Michael F .W. Festing. 1985. The use of inbred strains in toxicological screening as a means of reducing the number of animals used. Animal Experimentation. Proceedings of a F.R.A.M.E. symposium: Alternatives to Laboratory Animals. I.S.B.N. No. 0950170038. p. 69-78.

"Genetic characteristics are among the most important factors to be considered in selecting animals for use in biomedical research .... Outbred animals are also used in biomedical research (Gill. 1980). To facilitate direct comparison of research data derived from outbred stocks. these animals must be maintained by breeding schemes designed to maximize genetic heterogeneity .... Accurate identification, using standardized nomenclature where it is available and recording both the strain and substrain or genetic background of all animals used in a research project are important (I.L.A.R., 1979).''

National Institutes of Health. 1985. Guide for the care and use of laboratorv animals. Chapter 5, Special Considerations. U.S. Dept. of Health and Human Services, Public Health Service, National Institutes of Health. Publication No. (NIH) 85-23. p. 49.

"Cats commonly used in biomedical research are also recognized as a reservoir of Salmonella .... Over a period of 28 months, 159 random source cats for use in research were received in 50 shipments from licensed USDA dealers .... Of 159 cats studied, 17 (1 0. 7%) shed C. jejeuni and 3 (2.0%) had Salmonella typhimurium isolated from their feces .... The high prevalence of C. jejeuni in cats designated for use in biomedical research clearly establishes these animals as a reservoir for these bacteria. Contact with cats shedding enteric C. jejeuni-C. coli may inadvertently expose research personnel to Campylobacter infection. As a result, we recommend that cats received from commercial vendors for research purposes be screened for enteric Campylobacter as well as Salmonella before being released to investigators for use in research.''

Drs. J. G. Fox, J. A. Ackerman, & C. E. Newcomer. 1985. The prevalence of Campylobacter jejeuni in random source cats used in biomedical research. J. of Infect. Diseases 151 (4): p. 743. 39

"Laboratory research on animals offers a greater opportunity to control variables such as genetic background, prior experience, and environmental conditions, all of which affect behavior and can obscure the influence of the factor under study .... After the discrimination or predictibility of a model, certain other criteria stand out as being necessary for a good biological model. A model should .... be available to multiple investiaators: be exportable from one laboratorv to another .... be of defined genetic homogeneity or heterogeneity; possess unique anatomical, physiological, or behavioral attributes; be accompanied by readily available background data .... Fewer animals may be used in an experiment by sharing a control group with other investigators or by not using a concurrent control group. In both cases, all the physical and genetic characteristics of the treatment group(s) must be matched to those of the control group, and the conditions under which the data are collected must be as precisely duplicated as possible .... One of the principal reasons for the increased use of rodents in all areas of biomedical research has been the availability of genetically homogeneous or pathogen-free strains. For some studies, however, a further degree of genetic definition is needed. These studies require that the research animal carry some specific genetic traits that are suited to the objectives of the research .... lndividual animals vary in their behavior both between subjects and. in the case of one subject. over time. The goal of a behavioral experiment is to identify patterns that remain when these two sources of variability have been eliminated or taken jato account. An investigator attempts to conclude that observed effects are due to the conditions being manipulated in the experiment and not to extraneous factors,,Greater precision in the conduct of an experiment may reduce variability and increase power. For example, highly precise behavioral measurements coupled with the elimination or control of extraneous variables would reduce the need for large numbers of subjects .... One way of reducing variability !and hence increasing power) is to use highly homogeneous populations of subjects .... ln most inbred strains all subjects are highly identical genetically and genetically stable .... ln contrast, outbred stocks of animals are genetically variable. They contain an unknown and uncontrollable degree of genetic variation that may obscure or mask experimental treatment effects. Inbred strains not only increase statistical power. they also reduce variability between experiments conducted in different laboratories or in the same laboratory at different times ....

It can be argued that experiments should rely on animals drawn from heterogeneous. outbred populations jn order to get a broad genetic basis for results that can be extrapolated. for example. to heterogeneous human populations. Yet the differences between different inbred strajns are usually greater than the differences between individuals of an outbred stock. Greater generality. then. may be obtained by conducting experiments with two or more inbred strains .... ln either research or testing, the principal cost associated with animal use is that of human labor. Animals must be fed, watered, and have their cages cleaned. They require attendant veterinary care and are housed in facilities needing labor-intensive sanitation. Such labor costs are the major component of both the expense of producing animals in breeding facilities and the cost of maintaining them in laboratory facilities prior to and during research and testing .... lt is important to note that maintenance expenses can quickly exceed and even dwarf acquisition costs ....

"[Denmark] A recent ordinance requires that as of January 1, 1986, all dogs, cats, and rabbits be purpose-bred .... [Netherlands] A law governing trade in livestock confines trade in dogs and cats to licensed dealers, thus protecting pets, and an ordinance taking effect in 1986 requires that dogs, cats, and rabbits be purpose-bred .... [Sweden] Animals used in laboratories now must be bred for that purpose .... [England] Source of animals: All animals [must be] purpose-bred in registered establishments (except for farm animals and animals taken from the wild) .... [Draft Convention of the Council of Europe] The Ad Hoc Committee of Experts for the Protection of Animals [recommends that member states] use only mice, rats, guinea pigs, golden hamsters, rabbits, dogs, cats or quail originating in or acquired directly from registered breeding establishments, subject to national 40 exemptions .... Straying domestic animals cannot be used and exemptions are not permitted (Article 22)."

United States Office of Technology Assessment. 1986. Alternatives to animal use in research. testing. and education. Wash., D.C.: U.S. Congress.

"I am Dr. Neal D. Barnard. M.D, Chairman of the Physicians Committee for Responsible Medicine in Washington. D.C. and faculty member of the Georae Washington Universitv Medical Center. I speak as a practicing physician, a teacher of residents and medical students, and one who has worked in research funded by the National Institutes of Health. I also want to convey what I have been hearing from physicians across the United States .... ! hear from many doctors who are convinced that in the emerging discussion on animal research, we lose all credibility if we will not even oppose sending pets and strays to laboratories. Anyone who tells you that research would not continue if they are denied the supply of former pets is simply being dishonest about the grants process. The cost of animals is very small compared to salaries and overhead costs .... lf any laboratory is consuming such a massive number of animals that the supply from animal shelters will make a significant accounting difference, we should consider whether we really want to send so many pets to such a facility .... Biocking the conduit of animals from pounds to labs is a mild economic incentive for rethinking research needs. It will not change the course of research, but at most, could be an incentive for marginal programs which have not received wholehearted backing from their institution to consider whether animals are necessary. This is a healthy process, long overdue. Our absurdly generous subsidy of animal supply simply promotes their use. and is a disincentive for looking to other means of inquirv."

Dr. Neal D. Barnard, Chairman, Physicians Committee for Responsible Medicine (Wash., D.C.). 1986. Policy statement opposing the use of shelter animals in research.

"Some researchers point out that the 'randomness' of pound source animals is actually a desirable trait for some types of research. The claim is that the genetic heterogeneity of these animals more closely approximates that of the human population. Therefore, the argument continues, these animals are better research subjects than genetically homogeneous animals. There are several serious flaws in this line of reasoning. First, the heterogeneity of pound source animals is only conjecture. an unproven assumption. Because most of the animals in the pound are from human homes, it is just as likely that human whims and desires, as to who will breed with whom, had a major effect on the genetic makeup of the animals. Therefore, the animals' genetic makeup may reflect human influence rather than being truly random. Second, even if pound source animals really did have a heterogeneous makeup. how would one ever know? I would agree that heterogeneity is important under some circumstances but one must be able to determine the subjects' makeup at the end of the experiment so that one can compare the results with the variables. With pound source animals it cannot be determined if variations in the results might be related to prior medical history. genetic factors. or degree of socialization. As I am sure you are aware. there is increasing published evidence that these factors can have profound effects on the outcome of almost all types of research or testing. Third, no one has done an exhaustive immunologic survey of dogs and cats from the pound to see what type of tissue-related immune factors they have. These factors also can have a major influence on almost any type of research or testing being done."

Dr. Nedim C. Buyukmihci, Univ. of Calif., Davis, School of Veterinary Medicine. 1986 (Jan. 3). Letter to Dr. Michael A. Giannelli. 41

"Among more than 470 research grants currently supported by the March of Dimes Birth Defects Foundation, fewer than 10 percent involve animals, mostly mice or rats of genetically pure strains that are specially bred for scientific study. Domestic animals are typically of uncertain and diverse health histories. and so are not appropriate for most birth defects research."

Mr. Dave Younkin & Mr. Jerome J. Radwin. 1986 (April 10). March of dimes research involvino animals. Memorandum to the March of Dimes headquarters and field staff.

"While most laboratory animals, which are bred and reared in controlled environments, pose no direct threat to laboratory workers, labs usino wild-caught animals and random source dogs and cats could have problems. Even if the animals are thorouohly examined and quarantined for a reasonable period of time. they can still spread rabies in the laboratory. for the incubation period of animal rabies can be as long as four years."

Newsfronts. 1986 (Sept.). Lab Animal 15 (6): p. 9.

"The laboratory hound is emerging as an especially useful purpose-bred dog for biomedical research and testinQ. The need for a better genetic background. a defined health status. and reduced variables in research animal models has resulted in increasing numbers of investigators who require puroose-bred dogs such as laboratory hounds. The term laboratory hound is used in this paper .... to identify a mixed-breed hound that is a reliable and consistent animal with adequate genetic diversification to avoid the problems caused by inbreeding .... The colony mixed-breed hound has become, for a number of reasons, a valuable tool in pharmacological research. Its increased popularity and acceptance are due to its calm, gentle disposition, ease of handling, uniformity of body size and conformation, and its long legs and short hair. It can be obtained with an excellent health status, free from communicable diseases, heartworms, and internal and external parasites. This improved health status has helped support a consistent finding that base line clinical laboratory results and physiological parameters are jn the normal ranoe and correlate well amono individual laboratory hounds. Pata generated jn a variety of research protocols usjng this animal have generally been consistent and reproducible. The laboratory hound is suitable for both acute and chronic research in either anesthetized or conscious preparations. These dogs adapt well to the laboratory environment, have docile temperaments, and rarely become excitable .... lnvestigators have achieved success with the laboratory hound in cardiovascular studies .... The laboratory hound has also been used in acute cardiorespiratory research, where it has gained widespread acceptance. Supporting this acceptance are correlation and reproducibility of generated data from animal to animal and the ease with which the hound can be used with respect to its disposition and as a candidate for surgical preparations."

Drs. David K. Johnson, R. Alan Bonner & Mr. Conrad A. Knutsen. 1986 (Sept.). The laboratory hound. Lab Animal 15 (6): p. 33-36.

"A program for the development of a large canine model .... for preclinical pharmacokinetic and toxicological studies using novel drug delivery systems was recently initiated at the Upjohn Center for Clinical Pharmacology located at the University of Michigan Medical School. As a model for these studies, the laboratory hound proved useful, reliable, and readily available .... A major impediment in the development of new drugs had been the lack of a suitable animal modei. ... Before an animal can be used for preclinical pharmacokinetic studies, a number of criteria must be met. The animal should 42 be vigorous enough to tolerate surgical hepatic artery catheterization and pump implantation surgery. It should be able to withstand some potential toxicity which may result from long-term infusion of investigational drugs .... The laboratory hound meets all of these requirements. It is a purpose-bred mixed-breed hound with a known genetic background and health status. and it is readily available. We have not observed that hounds of a mixed genetic background exhibit any apparent increase in variability of the arterial system used for catheter emplacement. ... The purpose-bred hound offers a number of advantages for these drug infusion studies .... Because these animals are purpose-bred their health history can be evaluated before they are purchased. Using this model, it is now possible to perform comprehensive preclinical pharmacokinetic and toxicological studies of new and previously existing chemotherapeutic agents in the same device that would be used for administration of these agents in human patients."

Mr. Conrad A. Knutsen. 1986 (Sept.). The laboratory hound in the development of drug delivery systems. Lab Animal 15 (6): p. 41-46. 43

THE SCIENTIFIC DISADVANTAGES OF USING

RANDOM SOURCE ANIMALS FOR RESEARCH AND TESTING

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