Animal testing on rodents

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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

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

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

Rats

Rodents such as rats are the most common model in researching effects of cardiovascular disease, as the effects on rodents mimic those in humans. [11] 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. [12]

Limitations

While mice, rats and other rodents are by far the most widely used animals in biomedical research, recent studies have highlighted their limitations. [13] For example, the utility of the use of rodents in testing for sepsis, [14] [15] burns, [15] inflammation, [15] stroke, [16] [17] ALS, [18] [19] [20] Alzheimer's, [21] diabetes, [22] [23] cancer, [24] [25] [26] [27] [28] multiple sclerosis, [29] Parkinson's disease [29] 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. [13]

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. [14] 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. [14]

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. [17]

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. [17] [19] [20] 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]

See also

Related Research Articles

<span class="mw-page-title-main">Mouse</span> Small long-tailed rodent

A mouse is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse. Mice are also popular as pets. In some places, certain kinds of field mice are locally common. They are known to invade homes for food and shelter.

<span class="mw-page-title-main">Model organism</span> Organisms used to study biology across species

A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workings of other organisms. Model organisms are widely used to research human disease when human experimentation would be unfeasible or unethical. This strategy is made possible by the common descent of all living organisms, and the conservation of metabolic and developmental pathways and genetic material over the course of evolution.

<span class="mw-page-title-main">Animal testing</span> Use of nonhuman animals in experiments

Animal testing, also known as animal experimentation, animal research, and in vivo testing, is the use of non-human animals in experiments that seek to control the variables that affect the behavior or biological system under study. This approach can be contrasted with field studies in which animals are observed in their natural environments or habitats. Experimental research with animals is usually conducted in universities, medical schools, pharmaceutical companies, defense establishments, and commercial facilities that provide animal-testing services to the industry. The focus of animal testing varies on a continuum from pure research, focusing on developing fundamental knowledge of an organism, to applied research, which may focus on answering some questions of great practical importance, such as finding a cure for a disease. Examples of applied research include testing disease treatments, breeding, defense research, and toxicology, including cosmetics testing. In education, animal testing is sometimes a component of biology or psychology courses. The practice is regulated to varying degrees in different countries.

<span class="mw-page-title-main">MPTP</span> Chemical compound

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is an organic compound. It is classified as a tetrahydropyridine. It is of interest as a precursor to the neurotoxin MPP+, which causes permanent symptoms of Parkinson's disease by destroying dopaminergic neurons in the substantia nigra of the brain. It has been used to study disease models in various animals.

<span class="mw-page-title-main">Laboratory mouse</span> Mouse used for scientific research

The laboratory mouse or lab mouse is a small mammal of the order Rodentia which is bred and used for scientific research or feeders for certain pets. Laboratory mice are usually of the species Mus musculus. They are the most commonly used mammalian research model and are used for research in genetics, physiology, psychology, medicine and other scientific disciplines. Mice belong to the Euarchontoglires clade, which includes humans. This close relationship, the associated high homology with humans, their ease of maintenance and handling, and their high reproduction rate, make mice particularly suitable models for human-oriented research. The laboratory mouse genome has been sequenced and many mouse genes have human homologues. Lab mice sold at pet stores for snake food can also be kept as pets.

An animal model is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of harming a human. Although biological activity in an animal model does not ensure an effect in humans, many drugs, treatments and cures for human diseases are developed in part with the guidance of animal models. Animal models representing specific taxonomic groups in the research and study of developmental processes are also referred to as model organisms. There are three main types of animal models: Homologous, Isomorphic and Predictive. Homologous animals have the same causes, symptoms and treatment options as would humans who have the same disease. Isomorphic animals share the same symptoms and treatments, only. Predictive models are similar to a particular human disease in only a couple of aspects. However, these are useful in isolating and making predictions about mechanisms of a set of disease features.

Lymphocytic choriomeningitis (LCM) is a rodent-borne viral infectious disease that presents as aseptic meningitis, encephalitis or meningoencephalitis. Its causative agent is lymphocytic choriomeningitis mammarenavirus (LCMV), a member of the family Arenaviridae. The name was coined by Charles Armstrong in 1934.

<span class="mw-page-title-main">Laboratory rat</span> Rat used for scientific research

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<i>Plasmodium berghei</i> Single celled parasite, rodent malaria

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<span class="mw-page-title-main">Genetically modified mouse</span>

A genetically modified mouse or genetically engineered mouse model (GEMM) is a mouse that has had its genome altered through the use of genetic engineering techniques. Genetically modified mice are commonly used for research or as animal models of human diseases, and are also used for research on genes. Together with patient-derived xenografts (PDXs), GEMMs are the most common in vivo models in cancer research. Both approaches are considered complementary and may be used to recapitulate different aspects of disease. GEMMs are also of great interest for drug development, as they facilitate target validation and the study of response, resistance, toxicity and pharmacodynamics.

The diet-induced obesity model is an animal model used to study obesity using animals that have obesity caused by being fed high-fat or high-density diets. It is intended to mimic the most common cause of obesity in humans. Typically mice, rats, dogs, or non-human primates are used in these models. These animals can then be used to study in vivo obesity, obesity's comorbidities, and other related diseases. Users of such models must take into account the duration and type of diet as well as the environmental conditions and age of the animals, as each may promote different bodyweights, fat percentages, or behaviors.

<span class="mw-page-title-main">Rodent</span> Order of mammals

Rodents are mammals of the order Rodentia, which are characterized by a single pair of continuously growing incisors in each of the upper and lower jaws. About 40% of all mammal species are rodents. They are native to all major land masses except for New Zealand, Antarctica, and several oceanic islands, though they have subsequently been introduced to most of these land masses by human activity.

<span class="mw-page-title-main">Genetically modified mammal</span>

Genetically modified mammals are mammals that have been genetically engineered. They are an important category of genetically modified organisms. The majority of research involving genetically modified mammals involves mice with attempts to produce knockout animals in other mammalian species limited by the inability to derive and stably culture embryonic stem cells.

A knockout mouse, or knock-out mouse, is a genetically modified mouse in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are important animal models for studying the role of genes which have been sequenced but whose functions have not been determined. By causing a specific gene to be inactive in the mouse, and observing any differences from normal behaviour or physiology, researchers can infer its probable function.

<span class="mw-page-title-main">Three Rs (animal research)</span> Principles for ethical use of animals in science

The Three Rs (3Rs) are guiding principles for more ethical use of animals in product testing and scientific research. They were first described by W. M. S. Russell and R. L. Burch in 1959. The 3Rs are:

  1. Replacement:methods which avoid or replace the use of animals in research
  2. Reduction: use of methods that enable researchers to obtain comparable levels of information from fewer animals, or to obtain more information from the same number of animals.
  3. Refinement: use of methods that alleviate or minimize potential pain, suffering or distress, and enhance animal welfare for the animals used.

Patient derived xenografts (PDX) are models of cancer where the tissue or cells from a patient's tumor are implanted into an immunodeficient or humanized mouse. It is a form of xenotransplantation. PDX models are used to create an environment that allows for the continued growth of cancer after its removal from a patient. In this way, tumor growth can be monitored in the laboratory, including in response to potential therapeutic options. Cohorts of PDX models can be used to determine the therapeutic efficiency of a therapy against particular types of cancer, or a PDX model from a specific patient can be tested against a range of therapies in a 'personalized oncology' approach.

Syrian hamsters are one of several rodents used in animal testing. Syrian hamsters are used to model human medical conditions including various cancers, metabolic diseases, non-cancer respiratory diseases, cardiovascular diseases, infectious diseases, and general health concerns. In 2014, Syrian hamsters accounted for 14.6% of the total animal research participants in the United States covered by the Animal Welfare Act.

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. 1 2 "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. 1 2 "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 et al. 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. ↑ Jia, Tian; Wang, Chen; Han, Zhengxi; Wang, Xiaozhi; Ding, Ming; Wang, Quanyi (2020-12-07). "Experimental Rodent Models of Cardiovascular Diseases". Frontiers in Cardiovascular Medicine. 7: 588075. doi: 10.3389/fcvm.2020.588075 . ISSN   2297-055X. PMC   7750387 . PMID   33365329.
  12. ↑ Kerstetter, Kerry A.; Kantak, Kathleen M. (2007-10-01). "Differential effects of self-administered cocaine in adolescent and adult rats on stimulus–reward learning". Psychopharmacology. 194 (3): 403–411. doi:10.1007/s00213-007-0852-6. ISSN   1432-2072. PMID   17609932. S2CID   21293891.
  13. 1 2 Kolata, Gina (11 February 2013). "Mice Fall Short as Test Subjects for Some of Humans' Deadly Ills". The New York Times. New York Times. Retrieved 6 August 2015.
  14. 1 2 3 Korneev, K. V. (18 October 2019). "Mouse Models of Sepsis and Septic Shock". Molecular Biology. 53 (5): 704–717. doi: 10.1134/S0026893319050108 . PMID   31661479.
  15. 1 2 3 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.
  16. ↑ 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.
  17. 1 2 3 Gawrylewski, Andrea (1 July 2007). "The Trouble With Animal Models". The Scientist. Retrieved 6 August 2015.
  18. ↑ 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. S2CID   24174675.
  19. 1 2 Check Hayden, Erika (26 March 2014). "Misleading mouse studies waste medical resources". Nature. Retrieved 6 August 2015.
  20. 1 2 Perrin, Steve (26 March 2014). "Preclinical research: Make mouse studies work". Nature. Retrieved 6 August 2015.
  21. ↑ 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.
  22. ↑ 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. S2CID   21204695.
  23. ↑ 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.
  24. ↑ 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. S2CID   4326966.
  25. ↑ 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.
  26. ↑ 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. S2CID   4382984.
  27. ↑ 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.
  28. ↑ Begley, Sharon (5 September 2008). "Rethinking the war on cancer". Newsweek. Retrieved 6 August 2015.
  29. 1 2 Bolker, Jessica (1 November 2012). "There's more to life than rats and flies". Nature. Retrieved 6 August 2015.
  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. S2CID   3328884.
  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 . S2CID   87534627.
  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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