Animal testing on rodents

Rodents are commonly used in animal testing, 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 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%).[1]

In the U.S., the numbers of rats and mice used are not reported, but estimates range from around 11 million[2] to approximately 100 million.[3] 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.

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.[4] 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.[5]

They are widely considered to be the prime model of inherited human disease and share 99% of their genes with humans.[6] With the advent of genetic engineering technology, genetically modified mice can be generated to order and can cost hundreds of dollars each.[7]

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.[8]

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.[8]

Syrian hamsters

Syrian hamsters 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.[9] In 2006-07, Syrian hamsters accounted for 19% of the total animal research participants in the United States.[10]

Rats
Main article: Laboratory rat

Limitations

While mice, rats and other rodents are by far the most widely used animals in biomedical research, recent studies have highlighted their limitations.[11] For example, the utility of the use of rodents in testing for sepsis,[12][13] burns,[13] inflammation,[13] stroke,[14][15] ALS,[16][17][18] Alzheimer’s,[19] diabetes,[20][21] cancer,[22][23][24][25][26] multiple sclerosis,[27] Parkinson’s disease[27] 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.[11]

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.[28] 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.[29]

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.[15]

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.[30] 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.[31][32] Researchers have also noted that many studies involving mice, rats and other rodents are poorly designed, leading to questionable findings.[15][17][18] 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 [33].

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.[5][34][35] Another study in 2016 suggested that gut microbiomes in mice may have an impact upon scientific research.[36]

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See also

References
  1. "Annual Statistics of Scientific Procedures on Living Animals, Great Britain, 2015 Home Office
  2. US Statistics, 2014 - Speaking of Research
  3. Carbone, L (2004). What Animals Want: Expertise and Advocacy in Laboratory Animal Welfare Policy. Oxford University Press. ISBN 9780195161960.
  4. Willis-Owen SA, Flint J (2006). "The genetic basis of emotional behaviour in mice". Eur. J. Hum. Genet. 14 (6): 721–8. doi:10.1038/sj.ejhg.5201569. PMID 16721408.
  5. "The world's favourite lab animal has been found wanting, but there are new twists in the mouse's tale". The Economist. 2016-12-24. Retrieved 2017-01-10.
  6. The Measure Of Man, Sanger Institute Press Release, 5 December 2002
  7. Biosciences, Taconic. "Transgenic Mouse & Rat Models - Positive Negative Selection & Isogenic DNA Gene Target". www.taconic.com.
  8. "WUSM :: Mouse Genetics Core :: Services". Washington University in St. Louis. 2005-07-07. Archived from the original on 2007-08-04. Retrieved 2007-10-22.
  9. Valentine 2012, p. 875-898.
  10. United States Department of Agriculture (September 2008), Animal Care Annual Report of Activities - Fiscal Year 2007 (PDF), United States Department of Agriculture, retrieved 14 January 2016
  11. Kolata, Gina (11 February 2013). "Mice Fall Short as Test Subjects for Some of Humans' Deadly Ills". New York Times. Retrieved 6 August 2015.
  12. Korneev, K. V. (18 October 2019). "Mouse Models of Sepsis and Septic Shock". Molecular Biology. 53 (5): 704–717. doi:10.1134/S0026893319050108.
  13. Seok; et al. (7 January 2013). "Genomic responses in mouse models poorly mimic human inflammatory diseases". Proceedings of the National Academy of Sciences. 110 (9): 3507–3512. Bibcode:2013PNAS..110.3507S. doi:10.1073/pnas.1222878110. PMC 3587220. PMID 23401516.
  14. Bart van der Worp, H (30 March 2010). "Can Animal Models of Disease Reliably Inform Human Studies?". PLOS Medicine. 2 (6048): 1385. doi:10.1371/journal.pmed.1000245. PMC 1690299. PMID 1000245.
  15. Gawrylewski, Andrea (1 July 2007). "The Trouble With Animal Models". The Scientist. Retrieved 6 August 2015.
  16. Benatar, M (April 2007). "Lost in translation: Treatment trials in the SOD1 mouse and in human ALS". Neurobiology of Disease. 26 (1): 1–13. doi:10.1016/j.nbd.2006.12.015. PMID 17300945.
  17. Check Hayden, Erika (26 March 2014). "Misleading mouse studies waste medical resources". Nature. Retrieved 6 August 2015.
  18. Perrin, Steve (26 March 2014). "Preclinical research: Make mouse studies work". Nature. Retrieved 6 August 2015.
  19. Cavanaugh, Sarah; Pippin, John; Bernard, Neal (10 April 2013). "Animal models of Alzheimer disease: historical pitfalls and a path forward1". ALTEX. 31 (3): 279–302. doi:10.14573/altex.1310071. PMID 24793844.
  20. Roep, Bart; Atkinson, Mark; von Herrath, Matthias (November 2004). "Satisfaction (not) guaranteed: re-evaluating the use of animal models in type 1 diabetes". Nature Immunology. 4 (12): 989–997. doi:10.1038/nri1502. PMID 15573133.
  21. Charukeshi Chandrasekera, P; Pippin, John (21 November 2013). "Of Rodents and Men: Species-Specific Glucose Regulation and Type 2 Diabetes Research". ALTEX. 31 (2): 157–176. doi:10.14573/altex.1309231. PMID 24270692.
  22. Glenn Begley, C; Ellis, L (29 March 2012). "Drug development: Raise standards for preclinical cancer research". Nature. 483 (7391): 531–533. Bibcode:2012Natur.483..531B. doi:10.1038/483531a. PMID 22460880.
  23. Voskoglou-Nomikos, T; Pater, J; Seymour, L (15 September 2003). "Clinical predictive value of the in vitro cell line, human xenograft, and mouse allograft preclinical cancer models" (PDF). Clinical Cancer Research. 9 (11): 4227–4239. PMID 14519650. Retrieved 6 August 2015.
  24. Dennis, C (17 August 2006). "Cancer: off by a whisker". Nature. 442 (7104): 739–41. Bibcode:2006Natur.442..739D. doi:10.1038/442739a. PMID 16915261.
  25. Garber, K (6 September 2006). "Debate Grows Over New Mouse Models of Cancer". Journal of the National Cancer Institute. 98 (17): 1176–8. doi:10.1093/jnci/djj381. PMID 16954466.
  26. Begley, Sharon (5 September 2008). "Rethinking the war on cancer". Newsweek. Retrieved 6 August 2015.
  27. Bolker, Jessica (1 November 2012). "There's more to life than rats and flies". Nature. Retrieved 6 August 2015.
  28. Korneev, K. V. (18 October 2019). "Mouse Models of Sepsis and Septic Shock". Molecular Biology. 53 (5): 704–717. doi:10.1134/S0026893319050108.
  29. Korneev, K. V. (18 October 2019). "Mouse Models of Sepsis and Septic Shock". Molecular Biology. 53 (5): 704–717. doi:10.1134/S0026893319050108.
  30. Cressey, Daniel (2 March 2010). "Fat rats skew research results". Nature. 464 (19): 19. doi:10.1038/464019a. PMID 20203576.
  31. Balcomb, J; Barnard, N; Sandusky, C (November 2004). "Laboratory routines cause animal stress". Contemporary Topics in Laboratory Animal Science. 43 (6): 42–51. PMID 15669134.
  32. Murgatroyd, C; et al. (8 November 2009). "Dynamic DNA methylation programs persistent adverse effects of early-life stress". Nature Neuroscience. 12 (12): 1559–1566. doi:10.1038/nn.2436. PMID 19898468.
  33. Lahvis, Garet (June 29, 2017). "Unbridle biomedical research from the laboratory cage". eLife: 1–10. doi:10.7554/eLife.27438.
  34. Katsnelson, Alla (2014). "Male researchers stress out rodents". Nature. doi:10.1038/nature.2014.15106.
  35. "Male Scent May Compromise Biomedical Research". Science | AAAS. 2014-04-28. Retrieved 2017-01-10.
  36. "Mouse microbes may make scientific studies harder to replicate". Science | AAAS. 2016-08-15. Retrieved 2017-01-10.
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