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Anesthesia protocols in laboratory animals used for scientific purposes
Cicero luca, fazzotta salvatore, davide palumbo vincenzo, cassata giovanni, ignazio lo monte attilio.
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Correspondence: Dr. Salvatore Fazzotta Università degli studi di Palermo, Via del Vespro, 129 - Palermo, Italia Tel. 091 6552666-3312902679 Fax 0916552666 E-mail: [email protected]
Received 2016 Oct 13; Accepted 2016 Oct 19.
This work is licensed under a Creative Commons Attribution 4.0 International License
Background: A suitable, effective and free of complications anesthetic protocol is very important in experimental studies on animal models since it could bias the outcome of a trial. To date there is no universally accepted protocol for induction, maintenance and recovery from anesthesia. The endotracheal intubation with the use of inhalation anesthesia is used very especially in the from of large size laboratory animals, because it is a secure and easy control mode. However, it is not common for small laboratory animals because of the high technical skills required. Aim: The aim of this paper is a review of the main methods of induction of anesthesia in laboratory animals. Materials and methods: We performed an electronic search of MEDLINE (PubMed interface), ISI Web of Science and Scopus using the keywords “anesthesia” and “animal (s)” or “protocol (s)” or “surgery”, without the data or the language restriction. We consider only the most common laboratory animals (rats, mice, rabbits, pigs). We identify all the scientific articles that refer to the use of anesthetics for studies on laboratory animals in all areas: experimental surgery, CT, MRI, PET. All documents identified the search criteria are subject to review only by identifying relevant studies. Conclusions: There is a strong need for application of existing guidelines for research on experimental animals; specific guidelines for anesthesia and euthanasia should be considered and reported in future studies to ensure comparability and quality of animal experiments. ( www.actabiomedica.it )
Keywords: experimental surgery, laboratory animals, induction and maintenance of anesthesia, inhalation anesthetic, anesthetical drugs
Introduction
Laboratory animals are sometimes used in experimental clinical studies such as pre-marketing of a drug or a medical-surgical device or in regenerative medicine and surgery. The anesthesia protocols influence the survival of laboratory animals and can also greatly affect the experimental data results. To date, there is no anesthetic protocol widely used for single laboratory animal species. The murine species (rats and mice) is the most used model in various research fields, such as for organ transplantation, regenerative medicine and imaging. The pigs are animals that are used for the search, since their cardiorespiratory physiology is very similar to humans ( 1 ). The pig animal model, however, is extremely sensitive, so the primary objective is therefore to provide a quiet environment without causing anguish and stress and it should be also adequately sedated for transport also ensuring normothermia ( 2 ). The lagomorphs model is instead an animal model of medium size useful, for example, in studies in which the murine model is too small and pig model too big. Four aspects are of paramount importance for a correct management of the trial: a correct inhalation anesthetic, effective anesthesia, the duration of the entire experimental procedure and a correct protocol of endotracheal intubation ( 3 ).
In general, anesthesia can affect some physiological parameters, such as pressure, blood oxygen saturation, cerebral blood flow and many other factors that may affect the postoperative follow-up. The majority of anesthetic agents decrease the cerebral metabolism and they often affect the neurotransmission of nerve impulses, for which, the body temperature and other physiological parameters, should be monitored during anesthesia ( 4 ).
Search strategy
We performed an electronic search of MEDLINE (PubMed interface), ISI Web of Science and Scopus using the keywords “anesthesia” and “animal (s)” or “protocol (s)” or “surgery” in
“Title/Abstract/Keywords”, without the data or the language restriction, to identify all the scientific articles that refer to the use of anesthetics for studies on laboratory animals in all areas: experimental surgery, CT, MRI, PET. All documents identified the search criteria are subject to review only by identifying relevant studies.
Overall, 27 publications were identified, 8 of them have been excluded according to our study criteria. Each experimental study on animal model we tested was approved by the “Organismo Preposto al Benessere Animale” (OPBA), as required by current regulations. In total they have been taken into account and analyzed 19 scientific studies regarding the use of anesthesia in laboratory animals for different surgical procedures and not.
Premedications
The anesthesia is commonly used in laboratory animals, and can be induced by different methods depending on the type of study and the type of animal taken into account.
Konno et al., for the sedation in rats, used a closed glass chamber, where inside is fed a mixture of isoflurane (Escain®) at a concentration of 5% with airflow used as a carrier gas for 1 min ( 5 ).
After sedation and intubation of the subject, it is used by Konno et al. a mixture, called «M / M / B: 0.3 / 5.4» described by Kawai et al ( 6 ) e Kirihara et al. ( 7 ) as an anesthetic injected intraperitoneally at a dose of 0,3 mg/kg b.w. of medetomidine (Domitor®), 4,0 mg/kg b.w. of midazolam (Dormicum®) e 5.0 mg/kg b.w. of butorphanol (Vetorphale®) as premedication ( 5 ).
Hedenqvist et al. suggest to use sufentanil-midazolam combination as premedication in rabbits ( 8 ) and medetomidine like anesthesia protocols in small laboratory animals. Parenteral anesthetic combinations such as ketamine and xylazine are suggest like the agents of choice for anesthesia in the rabbit, because they are effective, easily administered and inexpensive ( 9 ). The ketamine/xylazine/acepromazine combination is also a useful regimen for normovolemic animals when anesthetic duration greater than that produced by ketamine/xylazine alone is required ( 9 ).
Re et al. creating a mixture of lidocaine, ketamine ( 10 ) and an opioid (0.6 mg ketamine /kg/h and lidocaine 3 mg/kg/h combined with morphine 0.24 mg/kg/ or fentanyl 0.0045 mg/kg/h) administered during premedication, they have noticed no significant decrease in the minimum alveolar concentration of volatile anesthetics administered in pig models ( 11 ). However, the effectiveness of this combination shows marked variations and opioids are likely to be less effective in pigs than in other species ( 11 ).
Induction and maintenance of anesthesia
The induction of anesthesia in small animals is carried out, in most cases, using anesthetic gas.
According Risling et al. the open-drop delivery of isoflurane or sevoflurane is an effective tool to anesthetize mice and small animals. The volatile concentration needed to induce anesthesia in mice following the application of 0.5 ml of anesthetic in an induction chamber volumes of 725 mL to 87.6 kPa and 20°C, measured by a gas analyzer of precision. Anesthesia was induced with isoflurane at concentrations of 6,80±0,57% after 35.70±6.95 s while using sevoflurane induction is significantly longer (45.50±9,96 s) and requires concentrations of gas greater than (7.41±00:57%). Animals taken into the study had a rapid recovery both by using isoflurane than with sevoflurane ( 12 ).
The twelve Wistar rats studied by Konno et al., after premedication and induction of anesthesia intraperitoneally, were intubated with endotracheal tube and connected to the circuit for inhalation anesthesia with isoflurane maintained at a concentration 3.0% for males and 2.5% for females for a period of 5 min. Subsequently, the concentration of isoflurane is reduced to 2.5% for males and 2.0% for females up to the interruption of anesthesia ( 13 ).
During anesthesia, all rats should be heated on a hot plate. All intubations have ended successfully within 1 minute, and the values of vital signs measured up to 30 minutes after the monitoring were normal and stable. Moreover, the histopathological observation of the trachea and the lungs carried by Konno et al. showed no trauma despite endotracheal intubation is not easy in small animals and requires technical skill and special equipment ( 13 ). These results suggest that endotracheal intubation is a reliable, safe and environment with regard to the welfare of rats ( 14 ).
On a study reported by Imai et al. of 8 experimental models lagomorphs (white New Zealand rabbits), it was used an anesthetic gas line that provides for the administration of halothane or isofluorane. In this study it is seen that it is preferable to use the halothane as it gives a less respiratory depression during anesthesia than using isofluorane ( 15 , 16 ).
Hedenqvist et al. have evaluated the possibility of finding an alternative to using isoflurane to maintain anesthesia in rabbits ( 8 ). In the study published in 2015 they have made 18 compared Himalaya rabbits divided into two groups of equal number: they were premedicated with 0.1 mg kg (-1) medetomidine and 5 mg/kg of carprofen subcutaneously, followed by the induction of intravenous sufentanil (2.3 mg mL) and midazolam (0.45 mg mL). After endotracheal intubation, anesthesia was maintained with sufentanil-midazolam in 9 subjects and Sevoflurane in the remaining 9. There were no significant differences between the two groups. In rabbits treated with sevoflurane, however, mean arterial pressure decreased in the pre-surgical phase, the heart rate increased by 25% during and after surgery, and body weight decreased by 4% after surgery ( 8 ).
For bigger animal models such as the pig, Pehböck et al. recommend starting the anesthesia by injection of ketamine and propofol followed by endotracheal intubation during spontaneous breathing ( 3 ). It is therefore necessary the presence of a specialist in anesthesia for a correct management of the airway of the animal in order to avoid dangerous complications such as death. The vascular access can be provided by a cut-down (skin incision for insertion needle-venous cannula) or ultrasound-guided techniques in the groin or in the neck region ( 17 ).
Jalde et al. of nine pigs premedicated with a bolus intramuscular injection of ketamine 10 mg/kg intravenous dose of propofol 2mg/kg injected prior to intubation have noted that very high doses of propofol caused sudden arrhythmias and refractory with circulatory collapse in some animals in the studio. Therefore, it is recommended, according to the authors, infusing low doses of ketamine intravenously in order to reduce the total amount of propofol. Anesthesia was maintained with sevoflurane which promotes a low Vt (Tidal volume) and less influence of propofol the neuro-ventilatory efficiency ( 18 ).
After intubation, maintenance anesthesia is performed by Pehböck et al. on the pig model with morphine or piritramide, propofol and rocuronium ( 3 ). Normothermia (38.5°C) must be guaranteed ( 19 ).
Mikkelsen et al. use propofol and remifentanil infusion but have noticed, especially after a single bolus of remifentanil, a lowering of cerebral oxygenation levels although within normal limits ( 20 ).
There are few centers that perform a check of the subject during the study procedures in laboratory animals. According to the study carried out by Uhlig et al. no control during anesthesia were described in 439 cases out of 732 (60.0%) of interventions involving the use of anesthesia. In the remaining procedures 293/732 (40.0%) involving anesthesia, the use of monitoring techniques have been described during the only anesthesia 114/293 (38.9%), the experimental procedures 26/293 (8,9%) or in both cases in 113/293 (38.6%) of the interventions. In 40/293 interventions (13.7%) is no monitoring was specified ( 21 ).
Post-anaesthesia monitoring
Post-anesthetic monitoring is very important in the recovery phase of the laboratory animals. It is important to control the side effects that might be from general data, such as heart rate, body temperature and the concentration of gases and electrolytes in the blood, as well as it is important to assess the reflex responses. According Fleischmann et al. mice should be awakened in their cages and evaluate the heart rate, body temperature and the degree of pain for at least 24 hours ( 22 ).
There are many methods tried to assess pain in rats that holds the account or vital signs and can rely on an accurate animal inspected ( 23 ). Arterial blood gases exam, recommended postoperatively, can reveal acidosis, hypoxia, hypercapnia and an increased concentration of glucose ( 22 ). To induce waking in rats, as well as set a pain relief, it is appropriate to use anesthetic antagonists to ensure a faster awakening. Fleischmann, using naloxone-flumazenil-atipamezole, noted that rats regained consciousness after 110±18 s and are quickly returned to the physiological basal values. Without antagonist instead mice showed marked hypothermia (22±1.9°C) and bradycardia (119±69 beats/min) to several hours ( 22 ). The effect of anesthesia induced in rabbits is antagonizzabile in 25-25 min with rapid animal’s recovery time. Fundamental becomes the monitoring of body temperature, heart rate and oxygen saturation in the blood according to Flecknell studies ( 24 ).
In bigger animals models, such as pigs, it is good to have an adequate observation center for a few days in the frame of reference so that you can transfer the animal immediately after surgery and avoid a second sedation for transportation. The recovery phase in the large animals is slower and requires support and continuous monitoring in the later stages upon awakening ( 25 ).
Anesthetic agents which are most frequently used (ketamine, propofol, isoflurane/halothane) to induce and maintain anesthesia in laboratory animals influence the carbon dioxide tension in arterial blood (PaCO2) or exhaled (as ETCO2 ) and can cause respiratory acidosis. They must therefore be carefully monitored all the vital parameters of the animal and restoring fluid and electrolyte balance in the event that it were altered.
Ketamine typically increases cerebral blood flow and indirect sympathetic mimetic effects on the metabolism of the brain ( 26 ) increasing the plasma concentration of norepinephrine and, being an antagonist of NMDA receptors, it can also determine neuronal damage known as Olney lesions ( 27 ). All these combination of drugs used in rabbits xylazine-ethyl-(1-methyl-propyl) malonyl-thio-urea salt (EMTU), ketamine-EMTU, xylazine-pentobarbital, xylazine-acepromazine-ketamine (XAK), ketamine-chloral hydrate and ketamine-xylazine can induce a depression of respiratory rate. Although rectal temperature values were reduced to some degree in each group, the most profound hypothermia was induced by XAK ( 28 ). Propofol is a short-act anesthetic drug that readily crosses the blood-brain barrier; its effect starts after a minute. It is rapidly cleared from plasma, and the consciousness returns more quickly with propofol that with other anesthetic drugs. Propofol allows a better cerebral autoregulation most other anesthetic agents ( 29 ). Isoflurane and halothane allow ga ood control of anesthesia duration and deepness ( 30 ). The anesthesia can also affect the blood glucose levels and lipid concentration that may indirectly affect brain metabolism ( 31 ).
The cerebral metabolism may also be affected by changes in body temperature, and in particular that hypothermia is common during prolonged anesthesia in small animals. Hyperglycemia, for example, can greatly increase the risk of global cerebral ischemia ( 32 ) since the fluctuations in blood glucose levels can greatly affect brain function by modulating the mechanisms and neuroprotective properties of the blood-brain barrier. Blood glucose levels should be monitored carefully during maintenance of anesthesia in order to avoid both hyper- and hypoglycemia ( 4 ). Medetomidine commonly used to sedate laboratory animals can cause hypotension and respiratory depression, especially at low doses, while not reduce cerebral blood flow ( 33 ). The drugs mainly used in different anesthesia protocols in the literature can cause numerous side effects that could change the success of a clinical trial and damages the animal model “quod vitam”. Monitoring of vital signs and animal welfare must be safeguarded during all study procedures ( 34 ).
Conclusions
This systematic review revealed insufficient reporting of methods of anesthesia in experimental studies. The studies are always with a low number of laboratory animals. In addition, this review shows that there is a strong need for guidelines in research on experimental animals; specific guidelines for anesthesia and euthanasia should be considered and reported in future studies to ensure comparability and quality of animal experiments. This is very important to translate experimental results in (future) clinical applications.
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Guinea pigs (400-600g) are the commonly used experimental animals. they are very docile and easy to raise and maintain they are highly sensitive to histamine. They are used in experimental asthma to study bronchodilators . they are also used to local anaesthetics and as a model in amoebiasis and cholera as they are sensitive to this micro organism.
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National Research Council (US) Committee on Dogs. Laboratory Animal Management: Dogs. Washington (DC): National Academies Press (US); 1994.
Laboratory Animal Management: Dogs.
- Hardcopy Version at National Academies Press
2 Criteria for Selecting Experimental Animals
Scientists who are planning experiments evaluate both animal and nonanimal approaches. If there are no suitable alternatives to the use of live animals, the appropriate species is selected on the basis of various scientific and practical factors, including the following:
- Which species will yield the most scientifically accurate and interpretable results?
- According to critical review of the scientific literature, which species have provided the best, most applicable historical data?
- On which species will data from the proposed experiments be most relevant and useful to present and future investigators?
- Which species have special biologic or behavioral characteristics that make them most suitable for the planned studies?
- Which species have features that render them inappropriate for the planned studies?
- Which species present the fewest or least severe biologic hazards to the research team?
- Which species require the fewest number of animals?
- Which species that meet the above criteria are most economical to acquire and house?
For many scientific experiments, the answer to those questions will be the domestic dog, Canis familiaris . The size, biologic features, and cooperative, docile nature of the well-socialized dog make it the model of choice for a variety of scientific inquiries. The contributions of the dog to human health and well-being are numerous (Gay, 1984).
Although research with dogs is often primarily to benefit humans, it has also greatly benefited dogs that are kept as companion animals. Examples of the benefits to dogs are improvements in diagnostic techniques; treatments for diabetes and arthritis; surgical procedures for correcting or treating cardiovascular, orthopedic, and neurologic disorders; and therapies for bacterial, neoplastic, and autoimmune diseases. Moreover, dogs have been necessary for the development of vaccines that protect companion animals against viral diseases (e.g., distemper and parvovirus disease) and drugs that prevent parasitic diseases (e.g., dirofilariasis, or heartworm disease).
- Genetic Factors
All domestic dogs, irrespective of breed, are Canis familiaris . Canine genotypes and phenotypes vary among breeds as a result of selective breeding, which has created variations in allele frequency between breeds. Although ''pure" breeds might have a higher frequency of some genes, much genetic variation remains in most breeds.
The canine karyotype consists of 78 chromosomes (Minouchi, 1928). Most of the autosomes are acrocentric or telocentric, and many pairs do not differ markedly in size. Recently, an improved method for staining canine chromosomes has been developed that makes karyotyping with Giemsa banding feasible (Stone et al., 1991).
A number of loci have been identified that code for the antigens of the canine major histocompatibility complex, which has been designated DLA (Vriesendorp et al., 1977). Initially, several alleles were defined with serologic techniques at three class I loci, and several alleles were defined with cellular techniques at a DLA class II locus (Bull et al., 1987; Deeg et al., 1986). Molecular techniques are being used to refine the definition of the DLA class I loci, and at least eight class I genes have been demonstrated in the dog (Sarmiento and Storb, 1989). Molecular-genetic studies to characterize canine class II loci correlate well with earlier work in which techniques for cell typing for class II antigens were used (Sarmiento and Storb, 1988a,b). The characterization of canine DLA loci is extremely useful for transplantation studies (Ladiges et al., 1985) and for demonstrating an association between the major histocompatibility complex and some inherited canine diseases (Teichner et al., 1990).
Attempts are under way to develop maps that identify the location of canine genes that control particular traits (e.g., inherited diseases and such behavioral tendencies as herding and aggression). Two approaches are used. The first relies on the principle that the relative positions of genes in a particular region of DNA are comparable in humans, dogs, and other species. Conserved regions can be identified in DNA samples with restriction-fragment length polymorphisms (usually called RFLPs) that have been identified with probes for human and murine genes whose chromosomal locations are known. To enhance the detection of polymorphisms, investigators sometimes produce dog-coyote hybrids, cross-breed two widely divergent dog breeds, or analyze a large, well-defined canine kindred (Joe Templeton, Department of Veterinary Pathobiology, College of Veterinary Medicine, Texas A&M University, College Station, Tex., personal communication, 1993). The second approach uses simple sequence-repeat polymorphisms (microsatellite probes). Specific simple sequence-repeat markers that are highly polymorphic in dogs have been developed to study the canine genome (Ostrander et al., 1992, 1993). These and other techniques, such as chromosomal in situ hybridization and somatic cell hybridization, will likely greatly increase our understanding of canine genetics.
Inherited defects—including lysosomal storage diseases, retinal degenerations, coagulopathies, complement deficiency, and various musculoskeletal, hematopoietic, immunologic, and neurologic diseases—are common in purebred dogs, and many specific disorders are found most commonly in particular breeds (Patterson et al., 1989). This phenomenon might be related, in part, to breeders' inadvertent selection for mutant alleles that are closely linked to loci that determine breed-typical traits or to the chance increase in frequency of particular mutant alleles caused by the founder effect or random genetic drift. The high frequency of inherited canine disorders (compared with murine disorders) was recognized as early as 1969 (Cornelius, 1969). During the 20-year period 1960–1980, 20 percent of more than 1,200 literature citations on naturally occurring animal models of human diseases involved dogs (Hegreberg and Leathers, 1980). A compilation in 1989 noted that 281 inherited disease entities had been reported in dogs (Patterson et al., 1989). Many of those constitute the only animal models for investigating the corresponding human diseases (Patterson et al., 1988). The 19-fascicle Handbook: Animal Models of Human Disease (RCP, 1972–1993) lists 83 canine models of human diseases, many of which are hereditary, and the two-volume Spontaneous Animal Models of Human Disease (Andrews et al., 1979) describes many canine models.
In scientific studies in which genetic uniformity is desirable or in long-term studies in which the expected differences between experimental and control subjects are likely to be small, purpose-bred dogs (e.g., beagles) might be a more appropriate choice than dogs of unknown provenance. An advantage of using beagles, as opposed to other purpose-bred dogs, is the potential availability of other members of the kindred. But if the studies are to determine the greatest range of a variable that is likely to occur among the experimental subjects or if the experiments are of short duration, random-source dogs might be more useful and less expensive (see "Procurement" in Chapter 5 ).
- Biologic Factors
Dogs are monogastric carnivores with a short generation time (i.e., the calculated interval between when a pup is born and when its first offspring could be born) and a maximum life span of approximately 20 years; larger breeds appear to have a shorter maximum life span than smaller breeds. The canine mortality rate doubles every 3 years, compared with every 0.3 year for the rat (maximum life span, 5.5 years), every 15 years for the rhesus monkey (maximum life span, more than 35 years), and every 8 years for humans (maximum life span, more than 110 years) (Finch et al., 1990). Dogs are useful models for studying the lifetime effects of environmental factors, and there is an extensive literature on their use in radiation biology (see Gay, 1984; Shifrine and Wilson, 1980).
Selective breeding has resulted in a spectrum of behaviors and a large range of canine body sizes, from the giant breeds (e.g., Irish wolfhound), which can measure 91 cm (36 in) at the shoulder and weigh more than 56 kg (124 lb), to the toy breeds (e.g., Pomeranian), which can measure less than 31 cm (12 in) in height and weigh less than 4.5 kg (10 lb). Larger dogs, which can include mongrels or dogs of unknown breeding, are particularly well suited to cardiovascular, transplantation, and orthopedic studies, because body weights and blood volumes approximate those of humans (see Gay, 1984; Shifrine and Wilson, 1980; Swindle and Adams, 1988). The dog's size also lends itself to procedures that cannot be carried out in smaller species, e.g., when the instrumentation essential for collecting scientific data is bulky and cannot be miniaturized and when the resolution of imaging equipment requires a larger target field than is available in a small animal.
An individual dog often can be studied in great detail or in many ways, which might reduce the number of subjects needed for a study and generate a more definitive data set. For example, it is possible to take multiple blood samples of several milliliters each from a single dog over some period without compromising the dog's well-being, but taking samples of similar size during the same period from a single mouse or rat would be impossible.
- Behavioral Factors
The social unit for dogs is the pack, and most dogs can be socialized to accept humans as the dominant individual in their social hierarchy, especially if the techniques used to socialize them provide rewarding experiences (e.g., food treats, petting, and verbal reinforcements) and minimize aversive experiences. Different breeds and individual dogs differ in the ease and rapidity with which they can be socialized to humans (Scott and Fuller, 1965). However, properly socialized dogs can be docile and can be trained to cooperate in procedures that require repeated contacts with research personnel. For example, most dogs will allow venipuncture with minimal restraint and will cooperate during detailed physical and neurologic evaluations.
Unvaccinated dogs might harbor rabies virus, and preexposure immunization should be made available to personnel who are at substantial risk of infection (NRC, 1985). Dogs also have internal and external parasites that can be shared with humans (see "Parasitic Diseases" in Chapter 5 ). Table 2.1 lists selected zoonoses, zoonotic agents, and modes of transmission. Detailed discussions of zoonoses have been published (Acha and Szyfres, 1987; August, 1988; Elliot et al., 1985; Fishbein and Robinson, 1993; Hubbert et al., 1975). Personnel can develop allergies to canine dander and saliva, can be bitten or scratched, might suffer hearing impairment from prolonged exposure to excessive noise generated by barking dogs or mechanical equipment, or can be injured while lifting or transporting large dogs. To deal with these and other animal-related health problems, institutions must provide occupational health programs for personnel who work in animal facilities or have substantial animal contact (NRC, 1985).
Selected Canine Zoonoses.
- Acha, P. N., and B. Szyfres. 1987. Zoonoses and Communicable Diseases Common to Man and Animals, 2d ed. Scientific Pub. No. 503. Washington, D.C.: Pan American Health Organization. 963 pp.
- Andrews, E. J., B. C. Ward, and N. H. Altman, eds. 1979. Spontaneous Animal Models of Human Disease. New York: Academic Press. Vol. I, 322 pp.; vol. II, 324 pp.
- August, J. R.1988. Dygonic fermenter-2 infections. J. Am. Vet. Med. Assoc.193:1506–1508. [ PubMed : 3215808 ]
- Bull, R. W., H. M. Vriesendorp, R. Cech, H. Grosse-Wilde, A. M. Bijma, W. L. Ladiges, K. Krumbacher, I. Doxiadis, H. Ejima, J. Templeton, E. D. Albert, R. Storb, and H. J. Deeg. 1987. Joint report of the Third International Workshop on Canine Immunogenetics. II. Analysis of the seralogical typing of cells. Transplantation43:154–161. [ PubMed : 3798556 ]
- Cornelius, C. E.1969. Animal models—A neglected medical resource. N. Engl. J. Med.281:934–944. [ PubMed : 4897690 ]
- Deeg, H. J., R. F. Raff, H. Grosse-Wilde, A. M. Bijma, W. A. Buurman, I. Doxiadis, H. J. Kolb, K. Krumbacher, W. Ladiges, K. L. Losslein, G. Schoch, D. L. Westbroek, R. W. Bull, and R. Storb. 1986. Joint report of the Third International Workshop on Canine Immunogenetics. I. Analysis of homozygous typing cells. Transplantation41:111–117. [ PubMed : 2934876 ]
- Elliot, D. L., S. W. Tolle, L. Goldberg, and J. B. Miller. 1985. Pet-associated illness. N. Engl. J. Med.313:985–995. [ PubMed : 3900726 ]
- Finch, C. E., M. C. Pike, and M. Witten. 1990. Slow mortality rate accelerations during aging in some animals approximate that of humans. Science249:902–905. [ PubMed : 2392680 ]
- Fishbein, D. B., and L. E. Robinson. 1993. Rabies. N. Engl. J. Med.329:1632–1638. [ PubMed : 8232433 ]
- Gay, W. I.1984. The dog as a research subject. The Physiologist27:133–141. [ PubMed : 6463120 ]
- Hegreberg, G., and C. Leathers, eds. 1980. Bibliography of Naturally Occurring Animal Models of Human Disease. Pullman, Washington: Student Book Corp. 146 pp.
- Hubbert, W. T., McCulloch, W. F., and Schnurrenberger, P. R., eds. 1975. Diseases Transmitted from Animals to Man, 6th ed.Springfield: Ill: Charles C Thomas. 1,236 pp.
- Ladiges, W. C., H. J. Deeg, R. F. Raff, and R. Storb. 1985. Immunogenetic aspects of a canine breeding colony. Lab. Anim. Sci.35(1):58–62. [ PubMed : 2580117 ]
- Minouchi, O.1928. The spermatogenesis of the dog with special reference to meiosis. Jpn. J. Zool.1:255–268.
- NRC (National Research Council), Institute of Laboratory Animal Resources, Committee on Care and Use of Laboratory Animals. 1985. Guide for the Care and Use of Laboratory Animals. NIH Pub. No. 86-23. Washington, D.C.: U.S. Department of Health and Human Services. 83 pp.
- Ostrander, E. A., P. M. Jong, J. Rine, and G. Duyk. 1992. Construction of small-insert genomic DNA libraries highly enriched for microsatellite repeat sequences. Proc. Natl. Acad. Sci.USA89:3419–3423. [ PMC free article : PMC48879 ] [ PubMed : 1314388 ]
- Ostrander, E. A., G. F. Sprague, Jr., and J. Rine. 1993. Identification and characterization of dinucleotide repeat (CA)n markers for genetic mapping in dog. Genomics16:207–213. [ PubMed : 8486359 ]
- Patterson, D. F., M. E. Haskins, P. F. Jezyk, U. Giger, V. N. Meyers-Wallen, G. Aguirre, J. C. Fyfe, and J. H. Wolfe. 1988. Research on genetic diseases: Reciprocal benefits to animals and man. J. Am. Vet. Med. Assoc.193:1131–1144. [ PubMed : 3058665 ]
- Patterson, D. F., G. A. Aguirre, J. C. Fyfe, U. Giger, P. L. Green, M. E. Haskins, P. F. Jezyk, and V. N. Meyers-Wallen. 1989. Is this a genetic disease?J. Small Anim. Pract.30:127–139.
- RCP (Registry of Comparative Pathology). 1972–1993. Handbook: Animal Models of Human Disease, fascicles 1–19. Washington, D.C.: Registry of Comparative Pathology. Available from RCP, Armed Forces Institute of Pathology, Washington, DC 20306-6000.
- Sarmiento, U. M., and R. F. Storb. 1988a. Characterization of class II alpha genes and DLAD region allelic associations in the dog. Tissue Antigens32:224–234. [ PubMed : 2905843 ]
- Sarmiento, U. M., and R. F. Storb. 1988b. Restriction fragment length polymorphism of the major histocompatibility complex of the dog. Immunogenetics28:117–124. [ PubMed : 2899546 ]
- Sarmiento, U. M., and R. F. Storb. 1989. RFLP analysis of DLA class I genes in the dog. Tissue Antigens34:158–163. [ PubMed : 2574506 ]
- Scott, J. P., and J. L. Fuller. 1965. Genetics and the Social Behavior of the Dog. Chicago: University of Chicago Press. 468 pp.
- Shifrine, M., and F. D. Wilson, eds. 1980. The Canine as a Biomedical Research Model: Immunological, Hematological, and Oncological Aspects. Washington, D.C.: U.S. Department of Energy. 425 pp.
- Stone, D. M., P. B. Jacky, and D. J. Prieur. 1991. The Giemsa banding pattern of canine chromosomes, using a cell synchronization technique. Genome34:407–412. [ PubMed : 1889737 ]
- Swindle, M. M., and R. J. Adams, eds. 1988. Experimental Surgery and Physiology: Induced Animal Models of Human Disease. Baltimore: Williams & Wilkens. 350 pp.
- Teichner, M., K. Krumbacher, I. Doxiadis, G. Doxiadis, C. Fournel, D. Rigal, J. C. Monier, and H. Grosse-Wilde. 1990. Systemic lupus erythematosus in dogs: Association to the major histocompatibility complex class I antigen DLA-A7. Clin. Immunol. Immunopathol.55:255–262. [ PubMed : 1691064 ]
- Vriesendorp, H. M., H. Grosse-Wilde, and M. E. Dorf. 1977. The major histocompatibility system of the dog. Pp. 129–163 in The Major Histocompatibility System in Man and Animals, D. Götze, ed. Berlin: Springer-Verlag.
- Cite this Page National Research Council (US) Committee on Dogs. Laboratory Animal Management: Dogs. Washington (DC): National Academies Press (US); 1994. 2, Criteria for Selecting Experimental Animals.
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Techniques of Blood Collection in Laboratory Animals
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Blood is collected from laboratory animals for various scientific purposes, for example, to study the effects of a test drug on various constituents, such as hormones, substrates, or blood cells. In the field of pharmacokinetics and drug metabolism, blood samples are necessary for analytical determination of the drug and its metabolites. Blood is also needed for some in vitro assays using blood cells or defined plasma protein fractions.
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Biological Sample Collection from Experimental Animals
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Article Contents
Introduction, experimental design: initial steps, design of the animal experiment, experimental design: final considerations.
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Practical Aspects of Experimental Design in Animal Research
Paula D. Johnson, D.V.M., M.S., is Executive Director, Southwest Association for Education in Biomedical Research, University of Arizona, Tucson; David G. Besselsen, D.V.M., Ph.D., is Veterinary Specialist and Chief, Pathology Services, University Animal Care, University of Arizona, Tucson.
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Paula D. Johnson, David G. Besselsen, Practical Aspects of Experimental Design in Animal Research, ILAR Journal , Volume 43, Issue 4, 2002, Pages 202–206, https://doi.org/10.1093/ilar.43.4.202
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A brief overview is presented of the key steps involved in designing a research animal experiment, with reference to resources that specifically address each topic of discussion in more detail. After an idea for a research project is conceived, a thorough review of the literature and consultation with experts in that field are pursued to refine the problem statement and to assimilate background information that is necessary for the experimental design phase. A null and an alternate hypothesis that address the problem statement are then formulated, and only then is the specific design of the experiment developed. Likely the most critical step in designing animal experiments is the identification of the most appropriate animal model to address the experimental question being asked. Other practical considerations include defining the necessary control groups, randomly assigning animals to control/treatment groups, determining the number of animals needed per group, evaluating the logistics of the actual performance of the animal experiments, and identifying the most appropriate statistical analyses and potential collaborators experienced in the area of study. All of these factors are critical to designing an experiment that will generate scientifically valid and reproducible data, which should be considered the ultimate goal of any scientific investigation.
Experimental design is obviously a critical component of the success of any research project. If all aspects of experimental design are not thoroughly addressed, scientists may reach false conclusions and pursue avenues of research that waste considerable time and resources. It is therefore critical to design scientifically sound experiments and to follow standard laboratory practices while performing these experiments to generate valid reproducible data ( Bennett et al. 1990 ; Diamond 2001 ; Holmberg 1996 ; Larsson 2001 ; Sproull 1995 ; Weber and Skillings 2000 ; Webster 1985 ; Whitcom 2000 ). Data generated by this approach should be of sufficient quality for publication in well-respected peer-reviewed journals, the major form of widespread communication and archiving experimental data in research. This article provides a brief overview of the steps involved in the design of animal experiments and some practical information that should also be considered during this process.
Literature Search
A thorough search of the scientific literature must be performed to determine what is known about the focus of the study. The search should include current and past journal articles and textbooks, as well as information available via the internet. Journal searches can be performed in any number of appropriate journal databases or indexes (e.g., MEDLINE, TOXLINE, PUBMED, NCBI, AGRICOLA). The goals of the literature search are to learn of pertinent studies and methods, identify appropriate animal models, and eliminate unnecessary duplication of research. The “3Rs” of animal research ( Russell and Burch 1959 ) should also be considered at this stage: reduction of animal numbers, refinement of methods, and replacement of animals by viable nonanimal alternatives when these exist. The literature search is also an important component of an institutional animal care and use committee (IACUC 1 ) protocol submission to provide evidence that the project is not duplicative, that alternatives to the use of animals are not available, and that potentially painful procedures are justified.
Scientific Method
The core aspect of experimental design is the scientific method ( Barrow 1991 ; Kuhn 1962 ; Lawson 2002 ; Wilson 1952 ). The scientific method consists of four basic steps: (1) observation and description of a scientific phenomena, (2) formulation of the problem statement and hypothesis, (3) use of the hypothesis to predict the results of new observations, and (4) the performance of methods or procedures to test the hypothesis.
Problem Statement, Objectives, and Hypotheses
It is critical to define the problem statement, objectives, and hypotheses clearly. The problem statement should include the issue that will be addressed experimentally and its significance (e.g., potential application to human or animal health, improved understanding of biological processes). Objectives should be stated in a general description of the overall goals for the proposed experiments and the specific questions being addressed. Hypotheses should include two distinct and clearly defined outcomes for each proposed experiment (e.g., a null and an alternate hypothesis). These outcomes may be thought of as the two experimental answers to the specific question being investigated: The null hypothesis is defined as no difference between experimental groups, and the alternate hypothesis is defined as a real difference between experimental groups. Development of a clearly stated problem statement and the hypotheses are necessary to proceed to the next stage of the experimental design process, although they obviously can (and likely will) be modified as the process continues. Examples of a problem statement and various types of hypotheses follow:
Problem statement: Which diet causes more weight gain in rats: diet A or diet B?
Null hypothesis: Groups are expected to show the same results (e.g., rats on diet A will gain the same amount of weight as rats on diet B).
Alternate hypothesis: Experimental groups are expected to show different results (e.g., rats will gain more weight on diet A than diet B, or vice versa).
Nontestable hypothesis: A result cannot be easily defined or interpreted (e.g., rats on diet A will look better than rats on diet B). What does “better” mean? Its definition must be clearly stated to create a testable hypothesis.
Identification of Animal Model
In choosing the most appropriate animal models for proposed experiments, we offer the following recommendations: (1) Use the lowest animal on the phylogenic scale (in accordance with replacement, one of the 3Rs). (2) Use animals that have the species- and/or strain-specific characteristics desirable or required for the specific study proposed. (3) Consider the costs associated with acquiring and maintaining the animal model during the period of experimentation. (4) Perform a thorough literature search, network with colleagues within the selected field of study, and/or contact commercial vendors or government-supported repositories of animal models to identify a potential source of the animal model. (5) Consult with laboratory animal veterinarians before final determination of the animal model.
Identification of Potential Collaborators
The procedures required to carry out the experiments will determine what, if any, additional expertise is needed. It is important to identify and consult with potential collaborators at the beginning of project development to determine who will be working on the project and in what capacity (e.g., as coinvestigators, consultants, or technical support staff). Collaborator input into the logistics and design of the experiments and proper sample acquisition are critical to ensure the validity of the data generated. Core facilities at larger research institutions provide many services that involve highly technical procedures or require expensive equipment. Identification of existing core facilities can often lead to the development of a list of potential intramural collaborators.
Research Plan
A description of the experimental manipulations required to address the problem statement, objectives, and hypotheses should be carefully devised and documented ( Keppel 1991 ). This description should specify the experimental variables that are to be manipulated, suitable test parameters that accurately assess the effects of experimental variable manipulation, and the most appropriate methods for sample acquisition and generation of the test data. The overall practicality of the project as well as the time frame for data collection and evaluation are determined at this stage in the development process.
Practical issues that may need to be addressed include the lifespan of the animal model (for chronic studies), the anticipated progression of disease in that model (to determine appropriate time points for evaluation), the amount of personnel time available for the project, and the costs associated with performing the experiments ( De Boer et al. 1975 ). If the animals are to receive chemical or biological treatments, an appropriate method for administration must be identified (e.g., per os via the diet or in drinking water [soluble substances only], by osmotic pump, or by injection). Known or potential hazards must also be identified, and appropriate precautions to minimize risk from these hazards must be incorporated into the plan. All experimental procedures should be detailed through standard operating procedures, a requirement of good laboratory practice standards ( EPA 1989 ; FDA 1987 ).
Finally, the methods to be used for data analysis should be determined. If statistical analysis is required to document a difference between experimental groups, the appropriate statistical tests should be identified during the design stage. A conclusion will be drawn subsequently from the analysis of the data with the initial question answered and/or the hypotheses accepted or rejected. This process will ultimately lead to new questions and hypotheses being formulated, or ideas as to how to improve the experimental design.
Experimental Unit
The entity under study is the experimental unit, which could be an individual animal or a group. For example, an individual rat is considered the experimental unit when a drug therapy or surgical procedure is being tested, but an entire litter of rats is the experimental unit when an environmental teratogen is being tested. For purposes of estimating error of variance, or standard error for statistical analysis, it is necessary to consider the experimental unit ( Weber and Skillings 2000 ). Many excellent sources provide discussions of the types of experimental units and their appropriateness ( Dean and Voss 1999 ; Festing and Altman 2002 ; Keppel 1991 ; Wu and Hamada 2000 ).
N Factor: Experimental Group Size
The assignment of an appropriate number of animals to each group is critical. Although formulas to determine the proper number of animals can be found in standard statistical texts, we recommend consulting a statistician to ensure appropriate experimental design for the generation of statistically significant results ( Zolman 1993 ). Indeed, the number of animals assigned to each experimental group is often determined by the particular statistical test on the basis of the anticipated magnitude of difference between the expected outcomes for each group. The number of animals that can be grouped in standard cages is a practical consideration for determining experimental group size. For example, standard 71 sq in (460 sq cm) polycarbonate shoebox cages can house up to four adult mice, so group sizes that are divisible by four will maximize group size and minimize per diem costs.
A plethora of variables (e.g., genetic, environmental, infectious agents) can potentially affect the outcome of studies performed with animals. It is therefore critical to use control animals to minimize the impact of these extraneous variables or to recognize the possible presence of unwanted variables. In general, each individual experiment should use control groups of animals that are contrasted directly to the experimental groups of animals. Multiple types of controls include positive, negative, sham, vehicle, and comparative.
Positive Controls
In positive control groups, changes are expected. The positive control acts as a standard against which to measure difference in severity among experimental groups. An example of a positive control is a toxin administered to an animal, which results in reproducible physiological alterations or lesions. New treatments can then be used in experimental groups to determine whether these alterations may be prevented or cured. Positive controls are also used to demonstrate that a response can be detected, thereby providing some quality control on the experimental methods.
Negative Controls
Negative controls are expected to produce no change from the normal state. In the example above, the negative control would consist of animals not treated with the toxin. The purpose of the negative control is to ensure that an unknown variable is not adversely affecting the animals in the experiment, which might result in a false-positive conclusion.
Sham Controls
A sham control is used to mimic a procedure or treatment without the actual use of the procedure or test substance. A placebo is an example of a sham control used in pharmaceutical studies ( Spector 2002 ). Another example is the surgical implantation of “X” into the abdominal cavity. The treated animals would have X implanted, whereas the sham control animals would have the same surgical procedure with the abdominal cavity opened, as with the treated animals, but without having the X implanted.
Vehicle Controls
A vehicle control is used in studies in which a substance (e.g., saline or mineral oil) is used as a vehicle for a solution of the experimental compound. In a vehicle control, the supposedly innocuous substance is used alone, administered in the same manner in which it will be used with the experimental compound. When compared with the untreated control, the vehicle control will determine whether the vehicle alone causes any effects.
Comparative Controls
A comparative control is often a positive control with a known treatment that is used for a direct comparison to a different treatment. For example, when evaluating a new chemopreventive drug regime in an animal model of cancer, one would want to compare this regime to the chemopreventive drug regime currently considered “accepted practice” to determine whether the new regime improves cancer prevention in that model.
Randomization
Randomization of the animals assigned to different experimental groups must be achieved to ensure that underlying variables do not result in skewed data for each experimental group. To achieve randomization, it is necessary to begin by defining the population. A homogeneous population consists of animals that are considered to share some characteristics (e.g., age, sex, weight, breed, strain). A heterogeneous population consists of animals that may not be the same but may have some common feature. Generally, the better the definition of the group, the less variable the experimental data, although the results may be less pertinent to large broad populations. Methods commonly used to achieve randomization include the following ( Zolman 1993 ):
Identifying each animal with a unique identification number, then drawing numbers “out of a hat” and randomly assigning them in a logical fashion to different groups. For example, the first drawn number is assigned to group 1, the second to group 2, the third to group 1, the fourth to group 2, and so forth. Dice or cards may also be used to randomly assign animals to experimental groups.
Using random number tables or computer-generated numbers/sampling to achieve randomization.
Experimental Protocol Approval
Animal experimentation requires IACUC approval of an animal care and use protocol if the species used are covered under the Animal Welfare Act (regardless of funding source), the research is supported by the National Institutes of Health and involves the use of vertebrate species, or the animal care program is accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care International ( Silverman et al. 2000 ). In practice, virtually all animal experiments require IACUC approval, which entails full and accurate completion of appropriate protocol forms for submission to the IACUC, followed by clarification or necessary modification of any procedures the IACUC requires. Approval must be obtained before the animal purchase or experimentation and is required before submission of a grant proposal by some funding agencies. If the research involves hazardous materials, then protocol approval from other intramural oversight committees or departments may also be required (e.g., a Biosafety Committee if infectious agents or recombinant DNA are to be used, or a Radiation Safety Committee if radioisotopes or irradiation are to be used).
Animal welfare regulations and Public Health Service policy mandate that individuals caring for or using research animals must be appropriately trained. Specifically, all personnel involved in a research project must be appropriately qualified and/or trained in the methods they will be performing for that project. The institution where the research is being performed is responsible for ensuring this training, although the actual training may occur elsewhere.
Pilot Studies
Pilot studies use a small number of animals to generate preliminary data and/or allow the procedures and techniques to be solidified and “perfected” before large-scale experimentation. These studies are commonly used with new procedures or when new compounds are tested. Preliminary data are essential to show evidence supporting the rationale of a proposal to a funding agency, thereby increasing the probability of funding for the proposal. All pilot projects must have IACUC approval, as for any animal experiment. As soon as the pilot study is completed, the IACUC representative will either give the indication to proceed to a full study or will indicate that the experimental manipulations and/or hypotheses need to be modified and evaluated by additional pilot studies.
Data Entry and Analysis
The researcher has the ultimate responsibility for collecting, entering, and analyzing the data correctly. When dealing with large volumes of data, it is especially easy for data entry errors to occur (e.g., group identifications switched, animal identifications transposed). Quality assurance procedures to identify data entry errors should be developed and incorporated into the experimental design before data analysis. This process can be accomplished by directly comparing raw (original) data for individual animals with the data entered into the computer or with compiled data for the group as a whole (to identify potential “outliers,” or data that deviates significantly from the rest of the members of a group). The analysis of the data varies depending on the type of project and the statistics required to evaluate it. Because this topic is beyond the scope of this article, we refer the reader to the many outstanding books and articles on statistical analysis ( Cobb 1998 ; Cox and Reid 2000 ; Dean and Voss 1999 ; Festing and Altman 2002 ; Lemons et al. 1997 ; Pickvance 2001 ; Wasserman and Kutner 1985 ; Wilson and Natale 2001 ; Wu and Hamada 2000 ).
Detection of flaws, in the developing or final experimental design is often achieved by several levels of review that are applicable to animal experimentation. For example, grant funding agencies and the IACUC provide input into the content and design of animal experiments during their review processes and may also serve as advisory consultants before submission of the grant proposal or animal care and use protocol. Scientific peers and the scientific literature also provide invaluable information applicable to experimental design, and these resources should be consulted throughout the experimental design process. Finally, scientific peer-reviewed journals provide a final critical evaluation of the soundness of the experimental design. The overall quality of the experimental data is evaluated and a determination is made as to whether it is worthy of publication. Obviously, discovering major experimental design deficiencies during manuscript peer review is not desirable. Therefore, pursuit of scientific peer review throughout the experimental design process should be exercised routinely to ensure the generation of valid, reproducible, and publishable data.
The steps listed below comprise a practical sequence for designing and conducting scientific studies. We recommend that investigators
Conduct a complete literature review and consult experts who have experience with the techniques proposed in an effort to become thoroughly familiar with the topic before beginning the experimental design process.
Ask a specific question and/or formulate an appropriate hypothesis. Then design the experiments to specifically address that problem/question.
Consult a biostatistician during the design phase of the project, not after performing the experiments.
Choose proper controls to ensure that only the variable of interest is evaluated. More than one control is frequently required.
Start with a small pilot project to generate preliminary data and work out procedures and techniques. Then proceed to larger scale experiments to generate statistical significance.
Modify original question and procedures, ask new questions, and begin again.
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Abbreviation used in this article: IACUC, institutional animal care and use committee.
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The Ethics of Animal Research
Jan 03, 2020
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The Ethics of Animal Research. Animal Testing. Previously we looked at the use of animals in spaceflight to further our understanding of the space environment. The use of animals in scientific testing has always been, and will continue to be a controversial subject. Animal Testing.
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Presentation Transcript
Animal Testing • Previously we looked at the use of animals in spaceflight to further our understanding of the space environment. • The use of animals in scientific testing has always been, and will continue to be a controversial subject.
Animal Testing • While controversial, it is an unavoidable fact that animal research has allowed the development of medicines and vaccines, surgical techniques and advanced scientific understanding in many areas.
Animal Testing • It is estimated that between 50 and 100 million animals are used in research each year. • Some are purpose bred for testing but many are still caught in the wild.
Measuring Pain and Suffering in Animal Testing • The U.S. Department of Agriculture defines a painful procedure as one that would “reasonably be expected to cause more than slight or momentary pain or distress in a human being to which the procedure was applied” • Do you think this is a valid way to measure suffering in animal tests?
Measuring Pain and Suffering in Animal Testing • In the UK experiments are classified as mild, moderate or substantial in the amount of suffering they cause an animal. • A fourth category of unclassified is used when the animal is anaesthetized but killed before regaining consciousness.
Measuring Pain and Suffering in Animal Testing • In December 2001 the breakdown of experimental licenses was: • 39% mild • 55% moderate • 2% substantial • 4% unclassified • Does this seem a reasonable breakdown to you?
Is Animal Testing Morally Right? • The argument between pro-animal testing parties and opponents to animal testing hinges on whether it is ethical.
Is Animal Testing Morally Right? • Advocates for animal testing say: • Human life has greater intrinsic value than animal life • Legislation protects all lab animals from cruelty or mistreatment • Millions of animals are killed every year for food, is medical research not a more worthy death • Few animals feel pain and are killed before they suffer
Is Animal Testing Morally Right? • Opponents to animal testing say: • Animals have as much right to live as humans • Strict controls have not prevented some animals being abused, though such instances are rare • Deaths for research are unnecessary • Animals suffer while they are locked up and how do we know when they do and don’t feel pain
The Three R’s • The guiding principles for the use of animals in research are the three R’s: • Replacement: Use alternative, non-animal methods to achieve the same scientific aim • Reduction: Use statistical methods so that a smaller number of animals are required • Refinement: Improve the experiments so that animals do not suffer
Ethical Dilemmas • British law requires that any new medicinal drug to be used on humans must undergo a substantial testing program including testing on at least two different species of live mammal. • One of which must be a large non-rodent. • This of course means that any company wanting to release a medical drug must, by law, undertake animal testing regardless of how they fell about it ethically.
Ethical Dilemmas • Animal researchers say it will be impossible to eliminate all animal tests but scientists are always working on ways to minimise the suffering of animals and to ensure as few animals as possible will be required.
Case Study: Laika • Laika, a mixed bred dog ‘recruited’ into the Soviet space program after being found on the streets of Moscow. • Laika’s mission would make her the first creature to orbit the Earth in an attempt to study the prolonged effect of weightlessness on a living being.
Case Study: Laika • Laika was 3 years old when she was launched on the Sputnik 2 spacecraft on November 3rd, 1957. • She was secured in a special pressurised capsule 3 days before launch and provided with a high nutrition gel for food and water.
Case Study: Laika • Laika experienced minimal ill effects during launch but her heart rate did rise to three times its resting rate and she appeared to be quite agitated, eventually calming down. • It appeared that weightlessness alone did not cause major changes to the vital physiological functions of a living creature. • This was good news for human spaceflight.
Case Study: Laika • Cabin temperature begun rapidly climbing to unacceptably high levels. • Temperature control inside the capsule was failing. • Between 5 and 7 hours into the flight telemetry showed that there were no signs of life within the capsule. • Laika had died from stress and overheating, undoubtedly a painful and distressing death.
Case Study: Laika • As the world began to learn of the second Sputnik, no word of Laika’s death was released. • The Sputnik 2 capsule that carried Laika into orbit was not retrievable and it had been intended that Laika would die in orbit. • But at the time the world believed that Laika may be recovered.
Case Study: Laika • Protests from animal protection groups began around the world. • On November 5th a newspaper article in the New York Times included a report from an unnamed Russian scientists that the dog could not live much longer. • Other articles talked about the importance of the information being learned by sending an animal into space.
Case Study: Laika • On November 7th Soviet scientists were still claiming that Laika was in good health when she had in fact been dead for four days. • Eventually the truth of the dog’s fate emerged and on November 11th the Soviets confirmed that Laika was dead. • The exact cause of Laika’s death remained a mystery for decades.
Case Study: Laika • The truth was not confirmed until 2002 when Russian scientists confirmed that Laika had died between 5 and 7 hours after launch due to heat and stress. • Russian scientist Oleg Gazenko who worked on the Soviet Space Program stated that “the more time passes, the more I’m sorry about it. We did not learn enough to justify the death of dog.”
Case Study: Laika • Laika became a hero to the Soviet people and captured the imagination of the world. • Her flight immediately proved the near term capability for human spaceflight.
Case Study: Laika • The question of whether the sacrifice of Laika was justified for the progress of space technology is still debateable in the context of ethics of animal research. • Could the flight have been postponed until recovery of the capsule was possible? • The political climate and the tensions between the United States and the Soviet Union during the “Space Race” meant that the ethical considerations of the mission were not properly considered.
Case Study Discussion • Do you think the mission was justified? • How could the experiment have been improved? • Was the outcome of putting the first man in space a valid aim for sacrificing Laika? • Did the fact that the Russian scientists covered up Laika’s death make the experiment more unethical?
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Presentation Transcript. Laboratory animals • Laboratory animals are those animals that can be bred and reared in laboratory under suitable conditions. • Most common- rat, mice, hamster, guinea pig, rabbit • Large animals- dog, cat, monkey, frog, pigeon, etc. • Depending upon the special characteristics of animal and the study to be ...
The anesthesia protocols influence the survival of laboratory animals and can also greatly affect the experimental data results. To date, there is no anesthetic protocol widely used for single laboratory animal species. The murine species (rats and mice) is the most used model in various research fields, such as for organ transplantation ...
The most important species of laboratory animals Mouse – most frequently used. Pharmacology, genetics of mammals, virology, models of human diseases (mutant strains, transgenic and knock-out mice) Rat – physiology of cognitive processes, behaviour, models of diabetes Rabbit – serology, insulin quantification, pyrogens quantification, tests of irritable effect of chemical substances on ...
White rat (200-250g) is the commonest laboratory animal used in experimental pharmacology. Rats are easy to breed and maintain. Resemble man in several organ function and nutrition and sensitive to most of the drugs; make them very useful experimental animals. However they do not have vomiting centre. The various rat tissue used are colon ...
Sterile syringes and suitable needle size should be used. • Skin of the animals must be wiped with 70% alcohol before injection to avoid any microbial contamination. • After filling syringes with inoculums it is extremely important to get rid of any air bubbles before injection to avoid air embolism.
For many scientific experiments, the answer to those questions will be the domestic dog, Canis familiaris. The size, biologic features, and cooperative, docile nature of the well-socialized dog make it the model of choice for a variety of scientific inquiries. The contributions of the dog to human health and well-being are numerous (Gay, 1984).
1.3 Aim. The aim of these Guidelines is to ensure humane and ethical treatment of animals, while facilitating legitimate scientific research involving experiments on animals. 2. Statutory provisions regarding scientific experiments on animals. Persons engaged in conducting scientific experiments on animals must act in conformity with the ...
Abstract. Blood is collected from laboratory animals for various scientific purposes, for example, to study the effects of a test drug on various constituents, such as hormones, substrates, or blood cells. In the field of pharmacokinetics and drug metabolism, blood samples are necessary for analytical determination of the drug and its metabolites.
Experimental Protocol Approval. Animal experimentation requires IACUC approval of an animal care and use protocol if the species used are covered under the Animal Welfare Act (regardless of funding source), the research is supported by the National Institutes of Health and involves the use of vertebrate species, or the animal care program is ...
The Three R’s • The guiding principles for the use of animals in research are the three R’s: • Replacement: Use alternative, non-animal methods to achieve the same scientific aim • Reduction: Use statistical methods so that a smaller number of animals are required • Refinement: Improve the experiments so that animals do not suffer.