of mice and ethics

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Current Health Sciences Journal Vol. 38, No. 1, 2012 January March

ReviewOf Mice and Ethics

C.T.STREBA,C.C.VERE,CRISTINA MISCU,D.I.GHEONEA,LARISA SANDULESCU,T.CIUREA,I.ROGOVEANU,A.SAFTOIU

Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, Romania

ABSTRACT Using animals in research has always been a subject of debate amongst scientific communitiesworldwide. The decision to perform certain experiments on live animal subjects is always taken after a series ofexperiments were already performed, leaving this as a final requirement before live human testing. It should alwaysbe performed when it is determined that it will provide a significant advancement in the field and will later result in animprovement to the human, social or environmental well-being. Historically, animals have been used in scientificexperiments since ancient times. Their usage has varied greatly, and so did the moral implications. As medicineadvanced through the centuries, using live or dead animals was of crucial importance for physiology or anatomyexperiments. In modern society, animal experiments are a right attributed to competent researchers who can ensurehumane care and use of the animals in controlled environments, with as little discomfort as possible to the livinganimal. Mice were used as prime subjects for medical experiments, especially in pharmacokinetics studies andtreatment.

KEY WORDS Mice; Laboratory animals; Ethics; Animal experiments

Introduction the mouse as an animal model

Text Murine experiments are some of the mostcommonly used small animal models for testingvarious types of treatments and effects, primarilybecause of their convenience in acquiring,breeding, housing and transportation. Micegenomics are well established and a high numberof different strains exist in order to accommodatealmost all experimental needs. They have a

relatively high reproductive performance, newgenerations being produced in a short period oftime. They are easily fed, their daily cycle can beregulated and their housing needs can be met withrelative low costs of operations in a small space.However, their small size poses problems withcertain procedures and the quantity of workingtissue obtained for some types of experiments isrelatively low. Their high numbers do howeverovercome the latter limitation, as several animalsmay be included in the same experimental lot, thusproviding a larger volume of data in a certain

direction.As with all experimental animal models, many

scientific advancements were obtained from theirusage, therefore validating their use in controlledexperiments. The morality of the usage of suchanimals in experiments that require physicaldamage or result in animal death has always beena question of debate, either philosophical or in therealm of humane activism [1].

Short history of animal usage in scientificexperiments

The first live animal experiments date back to500 BC, when in Antic Greece the firstobservations regarding the structure and function

of organs in live animals were recorded.Pythagoras proclaimed that the soul passesthrough animal and human forms, evenembodying plants as well; Hippocrates,considered by many as the father of medicine,related the first aspects of diseased organs in bothhumans and animals. During the first century ofour era, in the Roman Empire, Galenus uses

vivisection in some of the first recordedphysiological studies, thus establishingexperimental medicine as we know it today. Hisresearch was however preceded by a number ofboth Greek and Roman anatomists that usedvivisection to characterize the appearance oforgans and hypothesize on their function.

Vesalius (1514-1564) recreated some ofGalenus experiments and almost a century later,W. Harvey published the first scientificexperiment involving the use of animals, in 1638,stating his theory of reproduction Exercitatio

anatomica de motu cordis et sanguinis inAnimalibus.

During the 1800s, animal experiments werethe only way to study physiological processesnaturally occurring in a living organism. LouisPasteur tested his anti-rabies vaccine on dogs in1885, while the diphtheria anti-toxin wassynthetized by injecting guinea pigs with thetoxin.

The rules for experimenting on live animalswere set as early as in the 19th century, as JeremyBentham (1748-1832) proclaimed utilitarism, the

ethic principle that tried to correlate the benefitobtained with the level of the action required to

C. T. Streba, MD, PhD student, Assist. Prof., Dept. of Gastroenterology, Univ. of Medicine and Pharmacy of Craiova


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obtain it. He also introduced the notion of moralitywhen using animals for experimentation, due totheir capacity to feel pain. In 1824, in England, theSociety for the Preservation of Cruelty to Animalswas established, being the first organized bodythat militated for animal rights, in particular forthat period referring to carriage horses. The

modern embodiment of this society has broadenedits spectrum, and its branches worldwide militatefor the rights of all animals, including the onesinvolved in scientific experiments [2]. ClaudeBernard, considered by many as the father ofmodern physiology, extensively used animals inhis demonstrations; his wife created the firstassociation dedicated to protecting the rights oflaboratory animals, in 1860. The British Crueltyto Animal Act was signed in 1876 in England,effectively being the first law to regulate the usageof animals in laboratory settings; later on, in 1909,its counterpart was adopted in the United States ofAmerica [3]. Efforts intensified in both Europeand the USA towards limiting the use of animalsin laboratory studies, this leading to thefoundation of the National Anti-VivisectionSociety (NAVS) in 1875, and the British Unionfor the Abolition of Vivisection (BUAV) in 1898,both by active militant for animals rights, FrancesPower Cobbe. The English writer Henry StephensSalt was the first to write a piece on animal rights,in his book Animals' Rights: Considered in

Relation to Social Progress published in 1894.He however defended the use of animals injustified medical experiments.

The principle of the 3 Rs

In the 2nd half of the 20th century, zoologistWiliam M.S. Russel and microbiologist Rex I.Burch defined the principle of the three Rs:Refinement, Reduction and Replacement, whichshould govern any scientific procedure andcomplex set of experiments. This practicalstrategy was cited by any major act governing the

ethics of animal research, ever since it waspublished in 1959. They thus became theinternational approach to decision-making whendesigning experiments and the use of animals in ahumane fashion [35].

Replacement refers to finding alternativemethods in experimental models whichcircumvent the use of animals altogether, or theusage of species lower on the phylogenetic scale(for instance, replacing vertebrates withinvertebrates).

Refinement refers to altering experimentalprocedures in order to minimize or eliminatediscomfort or pain for the animals. This

requirement is however hard to accomplish incertain studies which require by designexperiments that should inflict a certain degree ofdistress upon the animal. However, even in thesesettings, all efforts should be made towardsestablishing the cost-benefit ratio for performingthi

were alreadysub

de humane end-points for animal

al regulationsreg

replace animals from suchexp

Romania publishing it as anoff

s part of the experiment.

Reduction refers to performing the experimentsin certain ways designed to minimize the numberof animals, discomfort and pain inflicted, whilemaintaining the level and significance ofinformation obtained. Animal reuse is not a validreduction strategy as their well-being may beseverely compromised when they

jected to medical experiments.Applying any of these principles should always

be performed under the supervision of a trainedveterinary specialized in identifying animaldiscomfort, who can intervene when pain ordistress levels surpass those intended by the studyprotocol. Studies resulting in chronic pain orsevere alteration of physiology of the animalshould inclutermination.

European and internationarding animal rightsUNESCO adopted the Universal Declaration of

Animal Rights in Brussels, 1978, which proclaimsthe equality between animals rights for existenceand the respect humans should show towards them

[3,4]. Through this declaration, it was stipulatedthat laboratory animals have the right to protectionand justified use in experiments. This declarationalso stipulated that medical experiments conceivedto inflict physical or psychic suffering on ananimal should not be performed, while developingmethods to

eriments.On March 18th 1986, in Strasbourg, the

European Council ratified the convention for theprotection of vertebrate animals utilized inexperiments and other scientific purposes. Itsstipulated goals were the reduction of the numberof animals used in research, while using them onlyfor diagnostic, prophylactic and treatmentpurposes, under general anesthesia or any othermethods employed to reduce pain and discomfort.All European countries adopted this convention inthe next two decades,

icial act in 2006.The United Nations also regulated the use of

animals in laboratory settings through the86/609/EEC directive, given on the 24th of

October 1986. It re-stated the use of the 3 Rs asan active governing principle of medical research,further enforcing that no experiment should


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Current Health Sciences Journal Vol. 38, No. 1, 2012 January March

involve animals if a safe alternative exists,yielding similar results, and, whenever possible,alternative techniques should be employedtow

ative Methods (ZEBET), aren

used in research; in present, its resultsare

y techniques and methods andespecially the training of personnel involved in

Ed

d during theres

ite

for humane approaches whenexperimenting on animals, remains to be

ichrial policies to ensure that

-PCCA-2011-3.1-0252:

ards reducing the number of specimens usedand decreasing the pain derived from procedures.

In following years, several bodies emergedwith a common goal of restricting the use of

animals in medical experiments to the requiredminimum while maintaining the quality of thescientific results. Their methods involvedalternative financing and resourcing options,cooperation with research centers towardsvalidating results and creating open fora foralternative methods. Such bodies were theEuropean Centre for Validation of AlternativeMethods (ECVAM), founded in 1991 or theGerman Centre for the Documentation andEvaluation of Altern

owned database for alternative methods toanimal experiments.

In 1990, the International Conference onHarmonization (ICH) attempted to unifyguidelines for animal testing, thus greatly reducingthe numbers

the main accepted rules for reporting testresults.

The 86/609/EEC directive was replaced on the22nd of September 2010 by the Directive2010/63/EU which regulated the protection ofanimals used for experimental and other scientific

purposes. This new directive took the issue onestep further, taking it in line with recentadvancements and updating the legislationaccordingly. It also set minimal standards forhousing, laborator

animal handling.

itorial policies regarding reportinganimal experiments

The accepted method of disseminatingscientific knowledge is through publication inpeer-reviewed journals. Therefore, all results ofscientific experiments pass the filter set by thesepublications, and their ethical standards should inturn influence the methods use

earch period, by actively enforcing theinternationally adopted directives.

For the purpose of standardization, theARRIVE (Animal Research: Reporting In VivoExperiments) guidelines were developed by theNational Centre for the Replacement, Refinementand Reduction of Animals in Research (NC3Rs).

This came as a necessity after the installment ofthe high standards of quality required for reportingtrials involving human subjects [68]. Another

example of regulations is the Gold StandardPublication Checklist (GSPC), effectively a list of

ms designed to increase the level ofstandardization in animal experimentation [9, 10].

A number of studies were concerned with thequality of the editorial policies of scientificpublications in regards to animal usage [1015].

One study found that, out of a sample of 138 in-print journals, 85 contained on-line instructionstowards the authors clearly stating the need forwritten adhesion to ethical requirements foranimal studies [12]. Most studies concluded thatno relationship between how long a journal hasexisted, its open-access policy or boardcomposition influences the ethical standardsrequired for publication of animal studies.Biomedical journals are however more prone toinclude clear ethical requirements for animalstudies, of all journals in the general field ofbiology [1214]. Standardized regulations such asARRIVE and GSPC are standard requirements tobe fulfilled for submission to most journals.However, one recent study has shown that ethicalissues related to how accurate procedures arerelated and even suspicion of altering protocols tofit within standardized guidelines, still plagues arather high number of studies [10]. The rejectionrate of many journals on ethical grounds isrelatively low, proving that most studies doconform to ethical regulations stipulated. Whether

this is an attempt to fraudulently bend protocols inorder to comply to editorial policies, or itrepresents a real effort to ensure the optimumconditions

determined.

Conclusions

Mice are one of the most commonly usedspecies in animal model, making for almost 90%of all species involved in medical experiments.

The usage of animals for scientific research

contribute towards scientific progress in all areas.It is however imperative to establish standardizedwelfare conditions in order to ensure the humanetreatment of laboratory animals. For this,fundamental principles were established and thewhole academic and scientific communities havetaken important steps towards providing aframework for experiments. An important helpshould come from scientific journals, whshould refine their editoall studies conform to basic ethical principles.

AcknowledgementsDocumentation for this article was performed as part of theresearch project PN-II-PT


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Hyperthermic magnetic nanoparticle ablation of liver and

egrate the threeRs, and to make systematic reviews more feasibAltern Lab Anim 2010;38:167182.

pancreatic tumors.

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Correspondence Adress:Cristin Constantin Vere MD, PhD, Assoc Professor, University of Medicine andPharmacy of Craiova, Petru Rares Street, no 2 Craiova, Dolj, Romania. E-mail: [email protected]

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