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Exposing the Gaps: How the 3Rs Fail to Protect Animals in Research

Written by Kati Bertrand
November 2024

White mouse in laboratory© iStock.com/D-Keine

A lot has changed since Russell and Burch defined the 3Rs—Replacement, Reduction, and Refinement in 1959,1 after which they became the central ethical framework for the use of nonhuman animals in biomedical research worldwide.

“Replacement means the substitution for conscious living higher animals of insentient material.  

Reduction means reduction in the numbers of animals used to obtain information of a given amount and precision.  

Refinement means any decrease in the incidence or severity of inhumane procedures applied to those animals which still have to be used.” 1 

From modern human-relevant technologies to research on animal sentience and cognition, the ethical landscape of research using animals has evolved.2 The rise of organ-on-chip technologies, artificial intelligence, and high-throughput in vitro systems presents opportunities to replace animals in research comprehensively. Created over half a century ago, the 3Rs framework is now out of date. Rather than advocating for a rapid transition to these new technologies, the 3Rs’ emphasis on incremental Refinement and Reduction continues to validate the status quo, providing a distorted ethical justification that allows experimenters to continue business as usual.3

Recently, the 3Rs have faced significant criticism for their failure to prevent harm to animals. This is due to the framework’s narrow focus on procedural ethics rather than addressing broader systemic and moral questions surrounding animal experimentation.

The 3Rs operate on the notion that animals are instruments for human benefit rather than individuals with inherent moral value.3,4 While the 3Rs call for reducing suffering, they do not challenge the fundamental practice of using animals as tools for experimentation, instead assuming that animal research is both necessary and unavoidable. This paradigm seeks to mitigate harm but does not engage with more comprehensive critiques that call for ending the use of animals in favor of newer technologies.5,6

Bioethicists have argued that the 3Rs do not go far enough in respecting animal autonomy and rights.7 Others have pointed out that the principles fail to encompass the full complexity of animal welfare and ethical considerations in research8–10. Some theorize that the 3Rs may have been appropriate during their inception but now require a modern update.11–13

The principle of Replacement is often interpreted to mean substituting sentient animals with simple or cutting-edge in vitro methods and computer modeling. However, “legislators often do not necessarily mean replacement in an absolute sense when they call for replacement measures; instead, the use of seemingly less sentient animals, like rodents or fish, are readily accepted as a form of replacement.” 14 This ambiguous definition gives researchers and those in oversight ample room to avoid true Replacement, which may explain why many institutions continue to use animal models, even when viable alternatives exist.15 The reluctance to adopt new technologies is also driven by scientific conservatism and a lack of incentives to shift away from long-standing practices.16

The combination of an equivocal definition for Replacement, comfort in the familiar, and insufficient incentives may all contribute to why “in the European Union (and elsewhere), the overall use of animals in laboratories has failed to undergo any significant decline.”17 The rise in total animal experimentation provides strong evidence that the 3Rs have been unsuccessful.6  With the increase in the use of animals worldwide, including around 200,000 primates and 160,000 dogs,18 it is clear that experimenting on animals remains a first choice, not a last resort.19

Replacement is said to be a priority within the 3Rs framework. Still, it does not advocate for eliminating the use of animals in research altogether and allows for the continued use of animals when experimenters claim that they perceive alternatives as insufficient. This creates an ethical loophole where researchers’ failure to exercise due diligence in exploring nonanimal models—capable of producing equally valid or superior data to animal models—or their bias toward animal-based research allows them to justify their previously held contentions.5

“The Three Rs may, in reality, have been used to justify and to perpetuate the continued use of animals, due to some researchers focusing more closely on refinement or reduction, instead of replacement.“11

Reduction calls for minimizing the number of animals used in research by improving experimental designs, statistical methods, and study replication.20 In some cases, small-scale studies designed under the banner of Reduction fail to provide statistically significant results, resulting in the use of even more animals in subsequent experiments.21 The number of animals used can also be a dimension of harm. Brønstad et al. wrote: “The reduction principle, or limiting the harm to a few, can sometimes be at odds with a refinement effort which results in little harm but involves a greater number of animals.”22 Rodriguez Perez calls this one of the “3R dilemmas.”23

Refinement aims to minimize the suffering of animals used in experiments by improving their living conditions and using less invasive techniques.20 While progress has been made, such as better housing standards and analgesic use, the scope of Refinement remains limited by the primary goal of obtaining data. Animal suffering in experiments is often seen as a necessary trade-off. The success of Refinement hinges on the expertise and ethical commitment of the researchers and oversight bodies like Institutional Animal Care and Use Committees (IACUCs), whose review processes have often been criticized for being inconsistent and their makeup underqualified to assess animal welfare in highly specialized research areas.24

“The hierarchy of the 3Rs envisaged by Russell and Burch—with Replacement as the main goal, Reduction as an option when there are no nonanimal alternatives, and Refinement as the last principle to be applied—appears to have been inverted…”25

Systemic Issues and Barriers

Several systemic issues have contributed to the failure of the 3Rs framework. There is a lack of regulatory enforcement and uniformity in the application of the 3Rs across regions and research institutions. While the principles are designed to guide researchers in minimizing animal suffering, studies have shown that compliance with the 3Rs varies significantly, often due to inadequate training, ambiguity, and a lack of harmonization in regulatory frameworks.4,20 A 2021 review highlighted that discrepancies between legislative demands and application processes lead to IACUCs receiving incomplete submissions and undermine the effectiveness of harm-benefit analyses where they are required.26 Even where regulations exist, oversight bodies like IACUCs mainly comprise members who conduct experiments on animals27 or who lack the expertise or resources to properly evaluate either the ethical implications of the research proposals or the availability of nonanimal methods to answer the research question, representing a possible animal method bias.28

Training is another critical issue. While most federal laws worldwide require animal care personnel to be trained in welfare practices, Russell and Burch envision additional ethical training. A 2014 survey of laboratory animal science students and animal experimenters observed that “58% of respondents admitted to be completely unaware of the 3Rs, 21% claimed to know but failed to name the 3Rs correctly, and 20% properly named these principles.”29 This survey included career researchers who had been conducting experiments on animals for over 10 years.

Considering the shortcomings of the 3Rs, some researchers and ethicists have proposed adding a fourth “R”—Rejection.24 This principle would permit the outright Rejection of certain experiments when the harm to animals outweighs the potential benefits. Rather than simply refining or reducing harm, Rejection calls for re-evaluating whether some studies should proceed at all. By considering not just the method of animal use but the ethical justification for the research itself, Rejection could shift the conversation toward a more transformative change in how science views and uses nonhuman animals.

The failure of the 3Rs to significantly reduce animal suffering or challenge the underlying necessity of animal experimentation points to the need to update the ethical landscape. Modernizing animal ethical statutes, implementing roadmaps to phase out experiments on animals,30 and embracing emerging animal-free technologies could finally move biomedical research beyond the 3Rs and toward a future where animal suffering is no longer a part of the scientific ecosphere.

  1. Russell WMS, Burch RL. The Principles of Humane Experimental Technique. Methuen; 1959.
  2. Locke P, Romanchik R, Kincaid B, Golden E. The 3Rs and Non-Human Animals in Biomedical Research: The Next 65 Years. Animal Law Rev. 2024;30(2):165.
  3. Landi MS, Shriver AJ, Mueller A. Consideration and Checkboxes: Incorporating Ethics and Science into the 3Rs. JAALAS. 2015;54(2):224.
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  6. Müller ND. The 3Rs Alone Will Not Reduce Total Animal Experimentation Numbers: A Fundamental Misunderstanding in Need of Correction. J Appl Anim Ethics Res. 2023:1-16. doi:10.1163/25889567-bja10042
  7. Walker RL. Virtue Ethics and Laboratory Animal Research. ILAR. 2019;60(3):415-423. doi:10.1093/ilar/ilaa015
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  11. Bailey J. It’s Time to Review the Three Rs, to Make them More Fit for Purpose in the 21st Century. Altern Lab Anim. 2024;52(3):155-165. doi:10.1177/02611929241241187
  12. Schuppli CA, Fraser D, McDonald M. Expanding the three Rs to meet new challenges in humane animal experimentation. Altern Lab Anim. 2004;32(5):525-532. doi:10.1177/026119290403200507
  13. Müller ND. Beyond Anthropocentrism: The Moral and Strategic Philosophy behind Russell and Burch’s 3Rs in Animal Experimentation. Sci Eng Ethics. 2024;30(5):44. doi:10.1007/s11948-024-00504-1
  14. Blattner CE. Rethinking the 3Rs: From Whitewashing to Rights. In: Herrmann K, Jayne K, eds. Animal Experimentation: Working Towards a Paradigm Change. BRILL; 2019:168-193. doi:10.1163/9789004391192_007
  15. Taylor K, Gericke C, Alvarez LR. Botulinum toxin testing on animals is still a Europe-wide issue. ALTEX. 2019;36(1):81-90. doi:10.14573/altex.1807101
  16. Fenwick N, Danielson P, Griffin G. Survey of Canadian Animal-Based Researchers’ Views on the Three Rs: Replacement, Reduction and Refinement. PLOS ONE. 2011;6(8):e22478. doi:10.1371/journal.pone.0022478
  17. Marshall LJ, Constantino H, Seidle T. Phase-In to Phase-Out—Targeted, Inclusive Strategies Are Needed to Enable Full Replacement of Animal Use in the European Union. Animals. 2022;12(7):863. doi:10.3390/ani12070863
  18. Taylor K, Alvarez LR. An Estimate of the Number of Animals Used for Scientific Purposes Worldwide in 2015. Altern Lab Anim. 2019;47(5-6):196-213. doi:10.1177/0261192919899853
  19. Balls M. It’s Time to Reconsider The Principles of Humane Experimental Technique. Altern Lab Anim. 2020;48(1):40-46. doi:10.1177/0261192920911339
  20. Graham ML, Prescott MJ. The multifactorial role of the 3Rs in shifting the harm-benefit analysis in animal models of disease. Eur J Pharmacol. 2015;759:19-29. doi:10.1016/j.ejphar.2015.03.040
  21. Schneider B. [Justification of repeated animal experiments and determination of the required number of animals according to the German Animal Protection Act]. Arzneimittelforschung. 2009;59(6):318-325.
  22. Brønstad A, Newcomer CE, Decelle T, Everitt JI, Guillen J, Laber K. Current concepts of Harm-Benefit Analysis of Animal Experiments – Report from the AALAS-FELASA Working Group on Harm-Benefit Analysis – Part 1. Lab Anim. 2016;50(1 Suppl):1-20. doi:10.1177/0023677216642398
  23. Rodriguez Perez C, Shaw DM, Earp BD, Elger BS, Persson K. One R or the other – an experimental bioethics approach to 3R dilemmas in animal research. Med Health Care and Philos. 2024;27(4):497-512. doi:10.1007/s11019-024-10221-y
  24. Curzer HJ, Perry G, Wallace MC, Perry D. The Three Rs of Animal Research: What they Mean for the Institutional Animal Care and Use Committee and Why. Sci Eng Ethics. 2016;22(2):549-565. doi:10.1007/s11948-015-9659-8
  25. Franco NH, Olsson IAS. Scientists and the 3Rs: attitudes to animal use in biomedical research and the effect of mandatory training in animals imprisoned in laboratories science. Lab Anim. 2014;48(1):50-60. doi:10.1177/0023677213498717
  26. Jörgensen S, Lindsjö J, Weber EM, Röcklinsberg H. Reviewing the Review: A Pilot Study of the Ethical Review Process of Animal Research in Sweden. Animals (Basel). 2021;11(3):708. doi:10.3390/ani11030708
  27. Hansen LA, Goodman JR, Chandna A. Analysis of Animal Research Ethics Committee Membership at American Institutions. Animals. 2012;2(1):68. doi:10.3390/ani2010068
  28. Krebs CE, Herrmann K. Confronting the bias towards animal experimentation (animal methods bias). Front Drug Discov. 2024;4. doi:10.3389/fddsv.2024.1347798
  29. Franco NH, Olsson I a. S. Scientists and the 3Rs: attitudes to animal use in biomedical research and the effect of mandatory training in laboratory animal science. Lab Anim. 2014;48(1):50-60. doi:10.1177/0023677213498717
  30. People for the Ethical Treatment of Animals. The Research Modernization Deal. 2023. https://www.peta.org/wp-content/uploads/2023/01/peta-research-modernization-deal.pdf

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