Animal testing on rodents

{{short description|Overview article}} {{Main article|Animal testing}} {{Animal testing}} Rodents have been employed in biomedical experimentation from the 1650s.<ref name="a1">{{cite journal |vauthors=d'Isa R, Fasano S, Brambilla R |title=Editorial: Animal-friendly methods for rodent behavioral testing in neuroscience research |journal= Frontiers in Behavioral Neuroscience|volume=18 |article-number=1431310 |year=2024 |pmid=38983871 |doi=10.3389/fnbeh.2024.1431310|doi-access=free |pmc=11232432 }}</ref> Rodent studies up to the early 19th century were mainly physiological or toxicological. The first rodent behavioral study was carried out in 1822, a purely observational study,<ref name="a2">{{cite journal |vauthors=d'Isa |title=The first rodent behavioral study (1822) and the diffusion of human-bred albino rats and mice in the 19th century |journal= Frontiers in Psychology|volume=15 |article-number=1532975 |year=2025 |pmid=39963185 |doi=10.3389/fpsyg.2024.1532975 |doi-access=free |pmc=11831927 }}</ref> while quantitative rodent behavioral testing began in the late 19th century.<ref name="a1" /><ref name="a2" /> Currently, rodents are commonly used in animal testing for physiological, pathological and behavioral scientific studies, particularly mice and rats, but also guinea pigs, hamsters, gerbils and others. Mice are the most commonly used vertebrate species, due to their availability, size, low cost, ease of handling, and fast reproduction rate.

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==Statistics== In the UK in 2015, there were 3.33 million procedures on rodents (80% of total procedures that year). The most common species used were mice (3.03 million procedures, or 73% of the total) and rats (268,522, or 6.5%). Other rodents species included guinea pigs (21,831 / 0.7%), hamsters (1,500 / 0.04%), and gerbils (278 / 0.01%).<ref>[https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/537708/scientific-procedures-living-animals-2015.pdf "Annual Statistics of Scientific Procedures on Living Animals, Great Britain, 2015] Home Office</ref>

In the U.S., the numbers of rats and mice used are not reported, but estimates range from around 11 million<ref>[http://speakingofresearch.com/facts/statistics/ US Statistics, 2014] - Speaking of Research</ref> to approximately 100 million.<ref>{{cite book|last1=Carbone|first1=L|title=What Animals Want: Expertise and Advocacy in Laboratory Animal Welfare Policy|date=2004|publisher=Oxford University Press|isbn=978-0-19-516196-0}}</ref> In 2000, the Federal Research Division, Library of Congress, published the results of an analysis of its Rats/Mice/and Birds Database: Researchers, Breeders, Transporters, and Exhibitors.

{{Quote|Over 2,000 research organizations are listed in the database, of which approximately 500 were researched and of these, 100 were contacted directly by FRD staff. These organizations include hospitals, government organizations, private companies (pharmaceutical companies, etc.), universities/colleges, a few secondary schools, and research institutes. Of these 2,000, approximately 960 are regulated by USDA; 349 by NIH; and 560 accredited by AALAC. Approximately 50 percent of the organizations contacted revealed a specific or approximated number of animals in their laboratories. The total number of animals for those organizations is: 250,000–1,000,000 rats; 400,000–2,000,000 mice; and 130,000–900,000 birds.}}

==Rodent types==

===Mice=== {{Main article|Laboratory mouse}} Mice are the most commonly used vertebrate species, popular because of their availability, size, low cost, ease of handling, and fast reproduction rate.<ref>{{cite journal |vauthors=Willis-Owen SA, Flint J |title=The genetic basis of emotional behaviour in mice |journal=Eur. J. Hum. Genet. |volume=14 |issue=6 |pages=721–8 |year=2006 |pmid=16721408 |doi=10.1038/sj.ejhg.5201569|doi-access=free }}</ref> Mice are quick to reach sexual maturity, as well as quick to gestate, where labs can have a new generation every three weeks as well as a relatively short lifespan of two years.<ref name="economist.com">{{Cite news|url=https://www.economist.com/news/christmas-specials/21712058-evolution-scientific-mainstay-worlds-favourite-lab-animal-has-been-found|title=The world's favourite lab animal has been found wanting, but there are new twists in the mouse's tale|newspaper=The Economist|access-date=2017-01-10|date=2016-12-24}}</ref>

They are widely considered to be the prime model of inherited human disease and share 99% of their genes with humans.<ref name=Sanger>[http://www.sanger.ac.uk/Info/Press/2002/021205.shtml The Measure Of Man], Sanger Institute Press Release, 5 December 2002</ref> With the advent of genetic engineering technology, genetically modified mice can be generated to order and can cost hundreds of dollars each.<ref name=Taconic>{{cite web|url=http://www.taconic.com/find-your-model/gems/taconic-transgenic-models|title=Transgenic Mouse & Rat Models - Positive Negative Selection & Isogenic DNA Gene Target|first=Taconic|last=Biosciences|website=www.taconic.com}}</ref>

Transgenic animal production consists of injecting each construct into 300–350 eggs, typically representing three days' work. Twenty to fifty mice will normally be born from this number of injected eggs. These animals are screened for the presence of the transgene by a polymerase chain reaction genotyping assay. The number of transgenic animals typically varies from two to eight.<ref name='mgc'>{{cite web|url=http://mgc.wustl.edu/services/ |title=WUSM :: Mouse Genetics Core :: Services |publisher=Washington University in St. Louis |date=2005-07-07 |access-date=2007-10-22 |archive-url=https://web.archive.org/web/20070804081632/http://mgc.wustl.edu/services/ |archive-date=2007-08-04 }}</ref>

Chimeric mouse production consists of injecting embryonic stem cells provided by the investigator into 150–175 blastocysts, representing three days of work. Thirty to fifty live mice are normally born from this number of injected blastocysts. Normally, the skin color of the mice from which the host blastocysts are derived is different from that of the strain used to produce the embryonic stem cells. Typically two to six mice will have skin and hair with greater than seventy percent ES cell contribution, indicating a good chance for embryonic stem cell contribution to the germline.<ref name='mgc'/>

===Syrian hamsters=== {{main article|Animal testing on Syrian hamsters}}

Golden or Syrian hamsters (''Mesocricetus auratus'') are used to model the human medical conditions including various cancers, metabolic diseases, non-cancer respiratory diseases, cardiovascular diseases, infectious diseases, and general health concerns.{{sfn|Valentine|Daugherity|Singh|Maurer|2012|p=875-898}} In 2006–07, Syrian hamsters accounted for 19% of the total animal research participants in the United States.<ref name="2007 USDA">{{Citation |author=United States Department of Agriculture |date=September 2008 |title=Animal Care Annual Report of Activities - Fiscal Year 2007 |publisher=United States Department of Agriculture |url=https://ourcompass.files.wordpress.com/2010/06/2007_ac_report.pdf |access-date=14 January 2016 }}</ref>

===Rats=== {{main article|Laboratory rat}}Rodents such as rats are the most common model in researching effects of cardiovascular disease, as the effects on rodents mimic those in humans.<ref>{{Cite journal |last1=Jia |first1=Tian |last2=Wang |first2=Chen |last3=Han |first3=Zhengxi |last4=Wang |first4=Xiaozhi |last5=Ding |first5=Ming |last6=Wang |first6=Quanyi |date=2020-12-07 |title=Experimental Rodent Models of Cardiovascular Diseases |journal=Frontiers in Cardiovascular Medicine |volume=7 |article-number=588075 |doi=10.3389/fcvm.2020.588075 |issn=2297-055X |pmc=7750387 |pmid=33365329|doi-access=free }}</ref>

Rats have also been used as tools in research to try to find if there is a difference in the effects of cocaine on adults versus adolescents.<ref>{{Cite journal |last1=Kerstetter |first1=Kerry A. |last2=Kantak |first2=Kathleen M. |date=2007-10-01 |title=Differential effects of self-administered cocaine in adolescent and adult rats on stimulus–reward learning |journal=Psychopharmacology |language=en |volume=194 |issue=3 |pages=403–411 |doi=10.1007/s00213-007-0852-6 |pmid=17609932 |s2cid=21293891 |issn=1432-2072}}</ref> {{expand section|date=May 2015}}

==Limitations==

While mice, rats and other rodents are by far the most widely used animals in biomedical research, recent studies have highlighted their limitations.<ref name="nytimes.com">{{cite news|last1=Kolata|first1=Gina|title=Mice Fall Short as Test Subjects for Some of Humans' Deadly Ills|work=The New York Times |url=https://www.nytimes.com/2013/02/12/science/testing-of-some-deadly-diseases-on-mice-mislead-report-says.html?_r=0|access-date=6 August 2015|agency=New York Times|date=11 February 2013}}</ref> For example, the utility of the use of rodents in testing for sepsis,<ref name="Mouse Models of Sepsis and Septic S">{{cite journal |last1=Korneev |first1=K. V. |title=Mouse Models of Sepsis and Septic Shock |journal=Molecular Biology |date=18 October 2019 |volume=53 |issue=5 |pages=704–717 |doi=10.1134/S0026893319050108|pmid=31661479 |doi-access=free }}</ref><ref name="pnas.org">{{cite journal|last1=Seok|title=Genomic responses in mouse models poorly mimic human inflammatory diseases|journal=Proceedings of the National Academy of Sciences|date=7 January 2013|display-authors=etal|doi=10.1073/pnas.1222878110|volume=110|issue=9|pages=3507–3512|pmid=23401516|pmc=3587220|bibcode=2013PNAS..110.3507S|doi-access=free}}</ref> burns,<ref name="pnas.org"/> inflammation,<ref name="pnas.org"/> stroke,<ref>{{cite journal|last1=Bart van der Worp|first1=H|title=Can Animal Models of Disease Reliably Inform Human Studies?|journal=PLOS Medicine|date=30 March 2010|doi=10.1371/journal.pmed.1000245|pmid=1000245|pmc=1690299|volume=2|issue=6048|page=1385|doi-access=free}}</ref><ref name="The Trouble With Animal Models">{{cite news|last1=Gawrylewski|first1=Andrea|title=The Trouble With Animal Models|url=http://www.the-scientist.com/?articles.view/articleNo/25184/title/The-Trouble-with-Animal-Models/|access-date=6 August 2015|agency=The Scientist|date=1 July 2007}}</ref> ALS,<ref>{{cite journal|last1=Benatar|first1=M|title=Lost in translation: Treatment trials in the SOD1 mouse and in human ALS|journal=Neurobiology of Disease|date=April 2007|volume=26|issue=1|pages=1–13|doi=10.1016/j.nbd.2006.12.015|pmid=17300945|s2cid=24174675}}</ref><ref name="nature.com">{{cite news|last1=Check Hayden|first1=Erika|title=Misleading mouse studies waste medical resources|url=http://www.nature.com/news/misleading-mouse-studies-waste-medical-resources-1.14938|access-date=6 August 2015|agency=Nature|date=26 March 2014}}</ref><ref name="ReferenceA">{{cite news|last1=Perrin|first1=Steve|title=Preclinical research: Make mouse studies work|url=http://www.nature.com/news/preclinical-research-make-mouse-studies-work-1.14913|access-date=6 August 2015|agency=Nature|date=26 March 2014}}</ref> Alzheimer's,<ref>{{cite journal|last1=Cavanaugh|first1=Sarah|last2=Pippin|first2=John|last3=Bernard|first3=Neal|title=Animal models of Alzheimer disease: historical pitfalls and a path forward1|journal=ALTEX|date=10 April 2013|volume=31|issue=3|pages=279–302|doi=10.14573/altex.1310071|pmid=24793844|doi-access=free}}</ref> diabetes,<ref>{{cite journal|last1=Roep|first1=Bart|last2=Atkinson|first2=Mark|last3=von Herrath|first3=Matthias|title=Satisfaction (not) guaranteed: re-evaluating the use of animal models in type 1 diabetes|journal=Nature Immunology|date=November 2004|volume=4|issue=12|pages=989–997|doi=10.1038/nri1502|pmid=15573133|s2cid=21204695}}</ref><ref>{{cite journal|last1=Charukeshi Chandrasekera|first1=P|last2=Pippin|first2=John|title=Of Rodents and Men: Species-Specific Glucose Regulation and Type 2 Diabetes Research|journal=ALTEX|date=21 November 2013|volume=31|issue=2|doi=10.14573/altex.1309231|pmid=24270692|pages=157–176|doi-access=free}}</ref> cancer,<ref>{{cite journal|last1=Glenn Begley|first1=C|last2=Ellis|first2=L|title=Drug development: Raise standards for preclinical cancer research|journal=Nature|date=29 March 2012|volume=483|issue=7391|pages=531–533|doi=10.1038/483531a|pmid=22460880|bibcode=2012Natur.483..531B|s2cid=4326966|doi-access=free}}</ref><ref>{{cite journal|last1=Voskoglou-Nomikos|first1=T|last2=Pater|first2=J|last3=Seymour|first3=L|title=Clinical predictive value of the in vitro cell line, human xenograft, and mouse allograft preclinical cancer models|journal=Clinical Cancer Research|date=15 September 2003|volume=9|issue=11|pages=4227–4239|url=http://clincancerres.aacrjournals.org/content/9/11/4227.full.pdf|access-date=6 August 2015|pmid=14519650}}</ref><ref>{{cite journal|last1=Dennis|first1=C|title=Cancer: off by a whisker|journal=Nature|date=17 August 2006|volume=442|issue=7104|pages=739–41|pmid=16915261|doi=10.1038/442739a|bibcode=2006Natur.442..739D|s2cid=4382984|doi-access=free}}</ref><ref>{{cite journal|last1=Garber|first1=K|title=Debate Grows Over New Mouse Models of Cancer|journal=Journal of the National Cancer Institute|date=6 September 2006|volume=98|issue=17|doi=10.1093/jnci/djj381|pmid=16954466|pages=1176–8|doi-access=free}}</ref><ref>{{cite news|last1=Begley|first1=Sharon|title=Rethinking the war on cancer|url=http://www.newsweek.com/rethinking-war-cancer-88941|access-date=6 August 2015|agency=Newsweek|date=5 September 2008}}</ref> multiple sclerosis,<ref name="ReferenceB">{{cite news|last1=Bolker|first1=Jessica|title=There's more to life than rats and flies|url=http://www.nature.com/articles/491031a.epdf?referrer_access_token=mRazf08HTEQ4B01NC1O8VtRgN0jAjWel9jnR3ZoTv0NPVVqscpw1wRD-aOnqVyzRGPDcQ-HwDV4uQqyv5fUDmKSC08AzdlxA1s_WXl6gq0tZY5VUM9YCCgYvGw2RWC8-jkV9J08u2hCNGi5Sq4d_5_XRmZM8_HwQl2s3JHV4-6jRMviooARCY5SLSapB7tNG-k5waCKj4Wy1A5B-OMx5nA%3D%3D&tracking_referrer=www.nature.com|access-date=6 August 2015|agency=Nature|date=1 November 2012}}</ref> Parkinson's disease<ref name="ReferenceB"/> and other illnesses has been called into question by a number of researchers. Regarding experiments on mice in particular, some researchers have complained that "years and billions of dollars have been wasted following false leads" as a result of a preoccupation with the use of these animals in studies.<ref name="nytimes.com"/>

Mice differ from humans in several immune properties: mice are more resistant to some toxins than humans; have a lower total neutrophil fraction in the blood, a lower neutrophil enzymatic capacity, lower activity of the complement system, and a different set of pentraxins involved in the inflammatory process; and lack genes for important components of the immune system, such as IL-8, IL-37, TLR10, ICAM-3, etc.<ref name="Mouse Models of Sepsis and Septic S"/> Laboratory mice reared in specific-pathogen-free (SPF) conditions usually have a rather immature immune system with a deficit of memory T cells. These mice may have limited diversity of the microbiota, which directly affects the immune system and the development of pathological conditions. Moreover, persistent virus infections (for example, herpesviruses) are activated in humans, but not in SPF mice, with septic complications and may change the resistance to bacterial coinfections. "Dirty" mice are possibly better suitable for mimicking human pathologies. In addition, inbred mouse strains are used in the overwhelming majority of studies, while the human population is heterogeneous, pointing to the importance of studies in interstrain hybrid, outbred, and nonlinear mice.<ref name="Mouse Models of Sepsis and Septic S"/> An article in ''The Scientist'' notes, "The difficulties associated with using animal models for human disease result from the metabolic, anatomic, and cellular differences between humans and other creatures, but the problems go even deeper than that" including issues with the design and execution of the tests themselves.<ref name="The Trouble With Animal Models"/>

For example, researchers have found that many rats and mice in laboratories are obese from excess food and minimal exercise which alters their physiology and drug metabolism.<ref>{{cite journal|last1=Cressey|first1=Daniel|title=Fat rats skew research results|journal=Nature|date=2 March 2010|volume=464|issue=19|page=19|doi=10.1038/464019a|pmid=20203576|doi-access=free}}</ref> Many laboratory animals, including mice and rats, are chronically stressed which can also negatively affect research outcomes and the ability to accurately extrapolate findings to humans.<ref>{{cite journal|last1=Balcomb|first1=J|last2=Barnard|first2=N|last3=Sandusky|first3=C|title=Laboratory routines cause animal stress.|journal=Contemporary Topics in Laboratory Animal Science|date=November 2004|volume=43|issue=6|pages=42–51|pmid=15669134}}</ref><ref>{{cite journal|last1=Murgatroyd|first1=C|title=Dynamic DNA methylation programs persistent adverse effects of early-life stress|journal=Nature Neuroscience|date=8 November 2009|volume=12|issue=12|pages=1559–1566|doi=10.1038/nn.2436|display-authors=etal|pmid=19898468|s2cid=3328884}}</ref> Researchers have also noted that many studies involving mice, rats and other rodents are poorly designed, leading to questionable findings.<ref name="The Trouble With Animal Models"/><ref name="nature.com"/><ref name="ReferenceA"/> One explanation for deficiencies in studies of rodents housed in laboratory cages is that they lack access to environmental agency and thus the ongoing freedom to make decisions and experience their consequences. By housing rodents under extreme impoverished conditions, these captive animals bear diminished resemblance to humans or their wild conspecifics.<ref>Lahvis, Garet (June 29, 2017). "Unbridle biomedical research from the laboratory cage". eLife: 1–10. doi:10.7554/eLife.27438.</ref>

Some studies suggests that inadequate published data in animal testing may result in irreproducible research, with missing details about how experiments are done are omitted from published papers or differences in testing that may introduce bias. Examples of hidden bias include a 2014 study from McGill University in Montreal, Canada, which suggests that mice handled by men rather than women showed higher stress levels.<ref name="economist.com"/><ref>{{Cite journal|last=Katsnelson|first=Alla|title=Male researchers stress out rodents|url=http://www.nature.com/news/male-researchers-stress-out-rodents-1.15106|journal=Nature|doi=10.1038/nature.2014.15106|year=2014|s2cid=87534627|doi-access=free}}</ref><ref>{{Cite news|url=https://www.science.org/content/article/male-scent-may-compromise-biomedical-research|title=Male Scent May Compromise Biomedical Research|date=2014-04-28|newspaper=Science {{!}} AAAS|access-date=2017-01-10}}</ref> Another study in 2016 suggested that gut microbiomes in mice may have an impact upon scientific research.<ref>{{Cite news|url=https://www.science.org/content/article/mouse-microbes-may-make-scientific-studies-harder-replicate|title=Mouse microbes may make scientific studies harder to replicate|date=2016-08-15|newspaper=Science {{!}} AAAS|access-date=2017-01-10}}</ref>

==References== {{Reflist}}

===Sources=== *{{cite book |last1=Valentine |first1=Helen |last2=Daugherity |first2=Erin K. |last3=Singh |first3=Bhupinder |last4=Maurer |first4=Kirk J. |editor1-last=Suckow |editor1-first=Mark A. |editor2-last=Stevens |editor2-first=Karla A. |editor3-last=Wilson |editor3-first=Ronald P. |title=The laboratory rabbit, guinea pig, hamster, and other rodents |date=2012 |publisher=Elsevier Academic Press |location=Amsterdam |isbn=978-0-12-380920-9 |pages=875–898 |edition=1st. |chapter=The Experimental Use of Syrian Hamsters}}

==External links== *[https://web.archive.org/web/20090605024919/http://hopes.stanford.edu/rltdsci/studyhd/am00.html Information about mouse models] from HOPES: Huntington's Disease Outreach Project for Education at Stanford *[https://www.creative-animodel.com/Animal-Model-Development/Animal-Models-of-Disease.html Animal Model of Disease] from Animal Research Organization

Category:Animal testing on rodents