medical research and testing on animals

Ethical care for research animals

WHY ANIMAL RESEARCH?

The use of animals in some forms of biomedical research remains essential to the discovery of the causes, diagnoses, and treatment of disease and suffering in humans and in animals., stanford shares the public's concern for laboratory research animals..

Many people have questions about animal testing ethics and the animal testing debate. We take our responsibility for the ethical treatment of animals in medical research very seriously. At Stanford, we emphasize that the humane care of laboratory animals is essential, both ethically and scientifically.  Poor animal care is not good science. If animals are not well-treated, the science and knowledge they produce is not trustworthy and cannot be replicated, an important hallmark of the scientific method .

There are several reasons why the use of animals is critical for biomedical research: 

••  Animals are biologically very similar to humans. In fact, mice share more than 98% DNA with us!

••  Animals are susceptible to many of the same health problems as humans – cancer, diabetes, heart disease, etc.

••  With a shorter life cycle than humans, animal models can be studied throughout their whole life span and across several generations, a critical element in understanding how a disease processes and how it interacts with a whole, living biological system.

The ethics of animal experimentation

Nothing so far has been discovered that can be a substitute for the complex functions of a living, breathing, whole-organ system with pulmonary and circulatory structures like those in humans. Until such a discovery, animals must continue to play a critical role in helping researchers test potential new drugs and medical treatments for effectiveness and safety, and in identifying any undesired or dangerous side effects, such as infertility, birth defects, liver damage, toxicity, or cancer-causing potential.

U.S. federal laws require that non-human animal research occur to show the safety and efficacy of new treatments before any human research will be allowed to be conducted.  Not only do we humans benefit from this research and testing, but hundreds of drugs and treatments developed for human use are now routinely used in veterinary clinics as well, helping animals live longer, healthier lives.

It is important to stress that 95% of all animals necessary for biomedical research in the United States are rodents – rats and mice especially bred for laboratory use – and that animals are only one part of the larger process of biomedical research.

Our researchers are strong supporters of animal welfare and view their work with animals in biomedical research as a privilege.

Stanford researchers are obligated to ensure the well-being of all animals in their care..

Stanford researchers are obligated to ensure the well-being of animals in their care, in strict adherence to the highest standards, and in accordance with federal and state laws, regulatory guidelines, and humane principles. They are also obligated to continuously update their animal-care practices based on the newest information and findings in the fields of laboratory animal care and husbandry.  

Researchers requesting use of animal models at Stanford must have their research proposals reviewed by a federally mandated committee that includes two independent community members.  It is only with this committee’s approval that research can begin. We at Stanford are dedicated to refining, reducing, and replacing animals in research whenever possible, and to using alternative methods (cell and tissue cultures, computer simulations, etc.) instead of or before animal studies are ever conducted.

Organizations and Resources

There are many outreach and advocacy organizations in the field of biomedical research.

• Learn more about outreach and advocacy organizations

Stanford Discoveries

What are the benefits of using animals in research? Stanford researchers have made many important human and animal life-saving discoveries through their work. 

• Learn more about research discoveries at Stanford

Research using animals: an overview

Around half the diseases in the world have no treatment. Understanding how the body works and how diseases progress, and finding cures, vaccines or treatments, can take many years of painstaking work using a wide range of research techniques. There is overwhelming scientific consensus worldwide that some research using animals is still essential for medical progress.

Animal research in the UK is strictly regulated. For more details on the regulations governing research using animals, go to the UK regulations page .

Why is animal research necessary?

There is overwhelming scientific consensus worldwide that some animals are still needed in order to make medical progress.

Where animals are used in research projects, they are used as part of a range of scientific techniques. These might include human trials, computer modelling, cell culture, statistical techniques, and others. Animals are only used for parts of research where no other techniques can deliver the answer.

A living body is an extraordinarily complex system. You cannot reproduce a beating heart in a test tube or a stroke on a computer. While we know a lot about how a living body works, there is an enormous amount we simply don’t know: the interaction between all the different parts of a living system, from molecules to cells to systems like respiration and circulation, is incredibly complex. Even if we knew how every element worked and interacted with every other element, which we are a long way from understanding, a computer hasn’t been invented that has the power to reproduce all of those complex interactions - while clearly you cannot reproduce them all in a test tube.

While humans are used extensively in Oxford research, there are some things which it is ethically unacceptable to use humans for. There are also variables which you can control in a mouse (like diet, housing, clean air, humidity, temperature, and genetic makeup) that you could not control in human subjects.

Is it morally right to use animals for research?

Most people believe that in order to achieve medical progress that will save and improve lives, perhaps millions of lives, limited and very strictly regulated animal use is justified. That belief is reflected in the law, which allows for animal research only under specific circumstances, and which sets out strict regulations on the use and care of animals. It is right that this continues to be something society discusses and debates, but there has to be an understanding that without animals we can only make very limited progress against diseases like cancer, heart attack, stroke, diabetes, and HIV.

It’s worth noting that animal research benefits animals too: more than half the drugs used by vets were developed originally for human medicine. 

Aren’t animals too different from humans to tell us anything useful?

No. Just by being very complex living, moving organisms they share a huge amount of similarities with humans. Humans and other animals have much more in common than they have differences. Mice share over 90% of their genes with humans. A mouse has the same organs as a human, in the same places, doing the same things. Most of their basic chemistry, cell structure and bodily organisation are the same as ours. Fish and tadpoles share enough characteristics with humans to make them very useful in research. Even flies and worms are used in research extensively and have led to research breakthroughs (though these species are not regulated by the Home Office and are not in the Biomedical Sciences Building).

What does research using animals actually involve?

The sorts of procedures research animals undergo vary, depending on the research. Breeding a genetically modified mouse counts as a procedure and this represents a large proportion of all procedures carried out. So does having an MRI (magnetic resonance imaging) scan, something which is painless and which humans undergo for health checks. In some circumstances, being trained to go through a maze or being trained at a computer game also counts as a procedure. Taking blood or receiving medication are minor procedures that many species of animal can be trained to do voluntarily for a food reward. Surgery accounts for only a small minority of procedures. All of these are examples of procedures that go on in Oxford's Biomedical Sciences Building. 

How many animals are used?

Figures for 2023 show numbers of animals that completed procedures, as declared to the Home Office using their five categories for the severity of the procedure.

# NHPs - Non Human Primates

Oxford also maintains breeding colonies to provide animals for use in experiments, reducing the need for unnecessary transportation of animals.

Figures for 2017 show numbers of animals bred for procedures that were killed or died without being used in procedures:

Why must primates be used?

Primates account for under half of one per cent (0.5%) of all animals housed in the Biomedical Sciences Building. They are only used where no other species can deliver the research answer, and we continually seek ways to replace primates with lower orders of animal, to reduce numbers used, and to refine their housing conditions and research procedures to maximise welfare.

However, there are elements of research that can only be carried out using primates because their brains are closer to human brains than mice or rats. They are used at Oxford in vital research into brain diseases like Alzheimer’s and Parkinson’s. Some are used in studies to develop vaccines for HIV and other major infections.

What is done to primates?

The primates at Oxford spend most of their time in their housing. They are housed in groups with access to play areas where they can groom, forage for food, climb and swing.

Primates at Oxford involved in neuroscience studies would typically spend a couple of hours a day doing behavioural work. This is sitting in front of a computer screen doing learning and memory games for food rewards. No suffering is involved and indeed many of the primates appear to find the games stimulating. They come into the transport cage that takes them to the computer room entirely voluntarily.

After some time (a period of months) demonstrating normal learning and memory through the games, a primate would have surgery to remove a very small amount of brain tissue under anaesthetic. A full course of painkillers is given under veterinary guidance in the same way as any human surgical procedure, and the animals are up and about again within hours, and back with their group within a day. The brain damage is minor and unnoticeable in normal behaviour: the animal interacts normally with its group and exhibits the usual natural behaviours. In order to find out about how a disease affects the brain it is not necessary to induce the equivalent of full-blown disease. Indeed, the more specific and minor the brain area affected, the more focussed and valuable the research findings are.

The primate goes back to behavioural testing with the computers and differences in performance, which become apparent through these carefully designed games, are monitored.

At the end of its life the animal is humanely killed and its brain is studied and compared directly with the brains of deceased human patients. 

Primates at Oxford involved in vaccine studies would simply have a vaccination and then have monthly blood samples taken.

How many primates does Oxford hold?

* From 2014 the Home Office changed the way in which animals/ procedures were counted. Figures up to and including 2013 were recorded when procedures began. Figures from 2014 are recorded when procedures end.

What’s the difference between ‘total held’ and ‘on procedure’?

Primates (macaques) at Oxford would typically spend a couple of hours a day doing behavioural work, sitting in front of a computer screen doing learning and memory games for food rewards. This is non-invasive and done voluntarily for food rewards and does not count as a procedure. After some time (a period of months) demonstrating normal learning and memory through the games, a primate would have surgery under anaesthetic to remove a very small amount of brain tissue. The primate quickly returns to behavioural testing with the computers, and differences in performance, which become apparent through these carefully designed puzzles, are monitored. A primate which has had this surgery is counted as ‘on procedure’. Both stages are essential for research into understanding brain function which is necessary to develop treatments for conditions including Alzheimer’s, Parkinson’s and schizophrenia.

Why has the overall number held gone down?

Numbers vary year on year depending on the research that is currently undertaken. In general, the University is committed to reducing, replacing and refining animal research.

You say primates account for under 0.5% of animals, so that means you have at least 16,000 animals in the Biomedical Sciences Building in total - is that right?

Numbers change daily so we cannot give a fixed figure, but it is in that order.

Aren’t there alternative research methods?

There are very many non-animal research methods, all of which are used at the University of Oxford and many of which were pioneered here. These include research using humans; computer models and simulations; cell cultures and other in vitro work; statistical modelling; and large-scale epidemiology. Every research project which uses animals will also use other research methods in addition. Wherever possible non-animal research methods are used. For many projects, of course, this will mean no animals are needed at all. For others, there will be an element of the research which is essential for medical progress and for which there is no alternative means of getting the relevant information.

How have humans benefited from research using animals?

As the Department of Health states, research on animals has contributed to almost every medical advance of the last century.

Without animal research, medicine as we know it today wouldn't exist. It has enabled us to find treatments for cancer, antibiotics for infections (which were developed in Oxford laboratories), vaccines to prevent some of the most deadly and debilitating viruses, and surgery for injuries, illnesses and deformities.

Life expectancy in this country has increased, on average, by almost three months for every year of the past century. Within the living memory of many people diseases such as polio, tuberculosis, leukaemia and diphtheria killed or crippled thousands every year. But now, doctors are able to prevent or treat many more diseases or carry out life-saving operations - all thanks to research which at some stage involved animals.

Each year, millions of people in the UK benefit from treatments that have been developed and tested on animals. Animals have been used for the development of blood transfusions, insulin for diabetes, anaesthetics, anticoagulants, antibiotics, heart and lung machines for open heart surgery, hip replacement surgery, transplantation, high blood pressure medication, replacement heart valves, chemotherapy for leukaemia and life support systems for premature babies. More than 50 million prescriptions are written annually for antibiotics. 

We may have used animals in the past to develop medical treatments, but are they really needed in the 21st century?

Yes. While we are committed to reducing, replacing and refining animal research as new techniques make it possible to reduce the number of animals needed, there is overwhelming scientific consensus worldwide that some research using animals is still essential for medical progress. It only forms one element of a whole research programme which will use a range of other techniques to find out whatever possible without animals. Animals would be used for a specific element of the research that cannot be conducted in any alternative way.

How will humans benefit in future?

The development of drugs and medical technologies that help to reduce suffering among humans and animals depends on the carefully regulated use of animals for research. In the 21st century scientists are continuing to work on treatments for cancer, stroke, heart disease, HIV, malaria, tuberculosis, diabetes, neurodegenerative diseases like Alzheimer's and Parkinson’s, and very many more diseases that cause suffering and death. Genetically modified mice play a crucial role in future medical progress as understanding of how genes are involved in illness is constantly increasing. 

Animal Use in Research

The AAMC recognizes the extraordinary contribution that high-quality, ethical research using animal models has made to our understanding of biological systems and advancement of treatments that improve both human and animal life.

We also join the broader scientific community in our support of the robust oversight of animal research, including the laws, regulations, and institutional policies that ensure the humane treatment, welfare, and safety of animals utilized in scientific research.

As stated in a 2022 joint letter to Congress, “Animal research remains vital to our mission to understand diseases, discover targeted therapies, alleviate suffering, and improve our quality of life. ... Indeed, the success of the biomedical research community to deliver safe and effective COVID-19 vaccines, was only possible because of research using animal models including non-human primates. To remain at the forefront of pandemic preparedness and discovery for other diseases in search of a cure, animal research remains critical.”

The AAMC strongly condemns harassment and threats against scientists, educators, and institutions that use animals in research. AAMC-member institutions are encouraged to work closely with local, state, and federal law officials to protect students, faculty, staff, animals, and facilities.

Related Organizations

Association for Assessment and Accreditation of Laboratory Animal Care

NIH Animals in Research

NIH Office of Laboratory Animal Welfare

USDA Animal Welfare

NASEM Board on Animal Health Sciences, Conservation, and Research

Foundation for Biomedical Research

National Association for Biomedical Research

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Open Access

Ethical and Scientific Considerations Regarding Animal Testing and Research

* E-mail: [email protected]

Affiliations Physicians Committee for Responsible Medicine, Washington, D.C., United States of America, Department of Medicine, The George Washington University, Washington, D.C., United States of America

Affiliation Physicians Committee for Responsible Medicine, Washington, D.C., United States of America

• Hope R. Ferdowsian, 

Published: September 7, 2011

• https://doi.org/10.1371/journal.pone.0024059
• Reader Comments

Citation: Ferdowsian HR, Beck N (2011) Ethical and Scientific Considerations Regarding Animal Testing and Research. PLoS ONE 6(9): e24059. https://doi.org/10.1371/journal.pone.0024059

Editor: Catriona J. MacCallum, Public Library of Science, United Kingdom

Copyright: © 2011 Ferdowsian, Beck. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The authors are grateful to the National Science Foundation (grant SES-0957163) and the Arcus Foundation (grant 0902-34) for the financial support for the corresponding conference, Animals, Research, and Alternatives: Measuring Progress 50 Years Later. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: HRF and NB are employed by Physicians Committee for Responsible Medicine, which is a non-governmental organization which promotes higher ethical standards in research and alternatives to the use of animals in research, education, and training. Physicians Committee for Responsible Medicine is a nonprofit organization, and the authors adhered to PLoS ONE policies on sharing data and materials.

In 1959, William Russell and Rex Burch published the seminal book, The Principles of Humane Experimental Technique, which emphasized r eduction, r efinement, and r eplacement of animal use, principles which have since been referred to as the “3 Rs”. These principles encouraged researchers to work to reduce the number of animals used in experiments to the minimum considered necessary, refine or limit the pain and distress to which animals are exposed, and replace the use of animals with non-animal alternatives when possible. Despite the attention brought to this issue by Russell and Burch and since, the number of animals used in research and testing has continued to increase, raising serious ethical and scientific issues. Further, while the “3 Rs” capture crucially important concepts, they do not adequately reflect the substantial developments in our new knowledge about the cognitive and emotional capabilities of animals, the individual interests of animals, or an updated understanding of potential harms associated with animal research. This Overview provides a brief summary of the ethical and scientific considerations regarding the use of animals in research and testing, and accompanies a Collection entitled Animals, Research, and Alternatives: Measuring Progress 50 Years Later , which aims to spur ethical and scientific advancement.

Introduction

One of the most influential attempts to examine and affect the use of animals in research can be traced back to1959, with the publication of The Principles of Humane Experimental Technique [1] . William Russell and Rex Burch published this seminal book in response to marked growth in medical and veterinary research and the concomitant increase in the numbers of animals used. Russell and Burch's text emphasized r eduction, r efinement, and r eplacement of animal use, principles which have since been referred to as the “3 Rs”. These principles encouraged researchers to work to reduce the number of animals used in experiments to the minimum considered necessary, refine or limit the pain and distress to which animals are exposed, and replace the use of animals with non-animal alternatives when possible.

Despite the attention brought to this issue by Russell and Burch, the number of animals used in research and testing has continued to increase. Recent estimates suggest that at least 100 million animals are used each year worldwide [2] . However, this is likely an underestimate, and it is impossible to accurately quantify the number of animals used in or for experimentation. Full reporting of all animal use is not required or made public in most countries. Nevertheless, based on available information, it is clear that the number of animals used in research has not significantly declined over the past several decades.

The “3 Rs” serve as the cornerstone for current animal research guidelines, but questions remain about the adequacy of existing guidelines and whether researchers, review boards, and funders have fully and adequately implemented the “3 Rs”. Further, while the “3 Rs” capture crucially important concepts, they do not adequately reflect the substantial developments in our new knowledge about the cognitive and emotional capabilities of animals; an updated understanding of the harms inherent in animal research; and the changing cultural perspectives about the place of animals in society [3] , [4] . In addition, serious questions have been raised about the effectiveness of animal testing and research in predicting anticipated outcomes [5] – [13] .

In August 2010, the Georgetown University Kennedy Institute of Ethics, the Johns Hopkins University Center for Alternatives to Animal Testing, the Institute for In Vitro Sciences, The George Washington University, and the Physicians Committee for Responsible Medicine jointly held a two day multi-disciplinary, international conference in Washington, DC, to address the scientific, legal, and political opportunities and challenges to implementing alternatives to animal research. This two-day symposium aimed to advance the study of the ethical and scientific issues surrounding the use of animals in testing and research, with particular emphasis on the adequacy of current protections and the promise and challenges of developing alternatives to the use of animals in basic research, pharmaceutical research and development, and regulatory toxicology. Speakers who contributed to the conference reviewed and contributed new knowledge regarding the cognitive and affective capabilities of animals, revealed through ethology, cognitive psychology, neuroscience, and related disciplines. Speakers also explored the dimensions of harm associated with animal research, touching on the ethical implications regarding the use of animals in research. Finally, several contributors presented the latest scientific advances in developing alternatives to the use of animals in pharmaceutical research and development and regulatory toxicity testing.

This Collection combines some papers that were written following this conference with an aim to highlight relevant progress and research. This Overview provides a brief summary of the ethical and scientific considerations regarding the use of animals in research and testing, some of which are highlighted in the accompanying Collection.

Analysis and Discussion

Ethical considerations and advances in the understanding of animal cognition.

Apprehension around burgeoning medical research in the late 1800s and the first half of the 20 th century sparked concerns over the use of humans and animals in research [14] , [15] . Suspicions around the use of humans were deepened with the revelation of several exploitive research projects, including a series of medical experiments on large numbers of prisoners by the Nazi German regime during World War II and the Tuskegee syphilis study. These abuses served as the impetus for the establishment of the Nuremberg Code, Declaration of Helsinki, and the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1974) and the resulting Belmont Report [16] – [18] . Today, these guidelines provide a platform for the protection of human research subjects, including the principles of respect, beneficence, and justice, as well as special protections for vulnerable populations.

Laws to protect animals in research have also been established. The British Parliament passed the first set of protections for animals in 1876, with the Cruelty to Animals Act [19] . Approximately ninety years later, the U.S. adopted regulations for animals used in research, with the passage of the Laboratory Animal Welfare Act of 1966 [20] . Subsequent national and international laws and guidelines have provided basic protections, but there are some significant inconsistencies among current regulations [21] . For example, the U.S. Animal Welfare Act excludes purpose-bred birds, rats, or mice, which comprise more than 90% of animals used in research [20] . In contrast, certain dogs and cats have received special attention and protections. Whereas the U.S. Animal Welfare Act excludes birds, rats and mice, the U.S. guidelines overseeing research conducted with federal funding includes protections for all vertebrates [22] , [23] . The lack of consistency is further illustrated by the “U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research and Training” which stress compliance with the U.S. Animal Welfare Act and “other applicable Federal laws, guidelines, and policies” [24] .

While strides have been made in the protection of both human and animal research subjects, the nature of these protections is markedly different. Human research protections emphasize specific principles aimed at protecting the interests of individuals and populations, sometimes to the detriment of the scientific question. This differs significantly from animal research guidelines, where the importance of the scientific question being researched commonly takes precedence over the interests of individual animals. Although scientists and ethicists have published numerous articles relevant to the ethics of animal research, current animal research guidelines do not articulate the rationale for the central differences between human and animal research guidelines. Currently, the majority of guidelines operate on the presumption that animal research should proceed based on broad, perceived benefits to humans. These guidelines are generally permissive of animal research independent of the costs to the individual animal as long as benefits seem achievable.

The concept of costs to individual animals can be further examined through the growing body of research on animal emotion and cognition. Studies published in the last few decades have dramatically increased our understanding of animal sentience, suggesting that animals' potential for experiencing harm is greater than has been appreciated and that current protections need to be reconsidered. It is now widely acknowledged by scientists and ethicists that animals can experience pain and distress [25] – [29] . Potential causes of harm include invasive procedures, disease, and deprivation of basic physiological needs. Other sources of harm for many animals include social deprivation and loss of the ability to fulfill natural behaviors, among other factors. Numerous studies have demonstrated that, even in response to gentle handling, animals can show marked changes in physiological and hormonal markers of stress [30] .

Although pain and suffering are subjective experiences, studies from multiple disciplines provide objective evidence of animals' abilities to experience pain. Animals demonstrate coordinated responses to pain and many emotional states that are similar to those exhibited by humans [25] , [26] . Animals share genetic, neuroanatomical, and physiological similarities with humans, and many animals express pain in ways similar to humans. Animals also share similarities with humans in genetic, developmental, and environmental risk factors for psychopathology [25] , [26] . For example, fear operates in a less organized subcortical neural circuit than pain, and it has been described in a wide variety of species [31] . More complex markers of psychological distress have also been described in animals. Varying forms of depression have been repeatedly reported in animals, including nonhuman primates, dogs, pigs, cats, birds and rodents, among others [32] – [34] . Anxiety disorders, such as post-traumatic stress disorder, have been described in animals including chimpanzees and elephants [35] , [36] , [37] .

In addition to the capacity to experience physical and psychological pain or distress, animals also display many language-like abilities, complex problem-solving skills, tool related cognition and pleasure-seeking, with empathy and self-awareness also suggested by some research. [38] – [44] . Play behavior, an indicator of pleasure, is widespread in mammals, and has also been described in birds [45] , [46] . Behavior suggestive of play has been observed in other taxa, including reptiles, fishes and cephalopods [43] . Self-awareness, assessed through mirror self-recognition, has been reported for chimpanzees and other great apes, magpies, and some cetaceans. More recent studies have shown that crows are capable of creating and using tools that require access to episodic-like memory formation and retrieval [47] . These findings suggest that crows and related species display evidence of causal reasoning, flexible learning strategies, imagination and prospection, similar to findings in great apes. These findings also challenge our assumptions about species similarities and differences and their relevance in solving ethical dilemmas regarding the use of animals in research.

Predictive Value of Animal Data and the Impact of Technical Innovations on Animal Use

In the last decade, concerns have mounted about how relevant animal experiments are to human health outcomes. Several papers have examined the concordance between animal and human data, demonstrating that findings in animals were not reliably replicated in human clinical research [5] – [13] . Recent systematic reviews of treatments for various clinical conditions demonstrated that animal studies have been poorly predictive of human outcomes in the fields of neurology and vascular disease, among others [7] , [48] . These reviews have raised questions about whether human diseases inflicted upon animals sufficiently mimic the disease processes and treatment responses seen in humans.

The value of animal use for predicting human outcomes has also been questioned in the regulatory toxicology field, which relies on a codified set of highly standardized animal experiments for assessing various types of toxicity. Despite serious shortcomings for many of these assays, most of which are 50 to 60 years old, the field has been slow to adopt newer methods. The year 2007 marked a turning point in the toxicology field, with publication of a landmark report by the U.S. National Research Council (NRC), highlighting the need to embrace in vitro and computational methods in order to obtain data that more accurately predicts toxic effects in humans. The report, “Toxicity Testing in the 21 st Century: A Vision and a Strategy,” was commissioned by the U.S. Environmental Protection Agency, partially due to the recognition of weaknesses in existing approaches to toxicity testing [49] . The NRC vision calls for a shift away from animal use in chemical testing toward computational models and high-throughput and high-content in vitro methods. The report emphasized that these methods can provide more predictive data, more quickly and affordably than traditional in vivo methods. Subsequently published articles address the implementation of this vision for improving the current system of chemical testing and assessment [50] , [51] .

While a sea change is underway in regulatory toxicology, there has been much less dialogue surrounding the replacement of animals in research, despite the fact that far more animals are used in basic and applied research than in regulatory toxicology. The use of animals in research is inherently more difficult to approach systematically because research questions are much more diverse and less proscribed than in regulatory toxicology [52] . Because researchers often use very specialized assays and systems to address their hypotheses, replacement of animals in this area is a more individualized endeavour. Researchers and oversight boards have to evaluate the relevance of the research question and whether the tools of modern molecular and cell biology, genetics, biochemistry, and computational biology can be used in lieu of animals. While none of these tools on their own are capable of replicating a whole organism, they do provide a mechanistic understanding of molecular events. It is important for researchers and reviewers to assess differences in the clinical presentation and manifestation of diseases among species, as well as anatomical, physiological, and genetic differences that could impact the transferability of findings. Another relevant consideration is how well animal data can mirror relevant epigenetic effects and human genetic variability.

Examples of existing and promising non-animal methods have been reviewed recently by Langley and colleagues, who highlighted advances in fields including orthodontics, neurology, immunology, infectious diseases, pulmonology, endocrine and metabolism, cardiology, and obstetrics [52] .

Many researchers have also begun to rely solely on human data and cell and tissue assays to address large areas of therapeutic research and development. In the area of vaccine testing and development, a surrogate in-vitro human immune system has been developed to help predict an individual's immune response to a particular drug or vaccine [53] , [54] . This system includes a blood-donor base of hundreds of individuals from diverse populations and offers many benefits, including predictive high-throughput in vitro immunology to assess novel drug and vaccine candidates, measurement of immune responses in diverse human populations, faster cycle time for discovery, better selection of drug candidates for clinical evaluation, and reductions in the time and costs to bring drugs and vaccines to the market. In the case of vaccines, this system can be used at every stage, including in vitro disease models, antigen selection and adjuvant effects, safety testing, clinical trials, manufacturing, and potency assays. When compared with data from animal experiments, this system has produced more accurate pre-clinical data.

The examples above illustrate how innovative applications of technology can generate data more meaningful to humans, and reduce or replace animal use, but advances in medicine may also require novel approaches to setting research priorities. The Dr. Susan Love Research Foundation, which focuses on eradicating breast cancer, has challenged research scientists to move from animal research to breast cancer prevention research involving women. If researchers could better understand the factors that increase the risk for breast cancer, as well as methods for effective prevention, fewer women would require treatment for breast cancer. Whereas animal research is largely investigator-initiated, this model tries to address the questions that are central to the care of women at risk for or affected by breast cancer. This approach has facilitated the recruitment of women for studies including a national project funded by the National Institutes of Health and the National Institute of Environmental Health to examine how environment and genes affect breast cancer risk. This study, which began in 2002, could not have been accomplished with animal research [55] .

Similarly, any approach that emphasizes evidence-based prevention would provide benefits to both animals and humans. Resource limitations might require a strategic approach that emphasizes diseases with the greatest public health threats, which increasingly fall within the scope of preventable diseases.

It is clear that there have been many scientific and ethical advances since the first publication of Russell and Burch's book. However, some in the scientific community are beginning to question how well data from animals translates into germane knowledge and treatment of human conditions. Efforts to objectively evaluate the value of animal research for understanding and treating human disease are particularly relevant in the modern era, considering the availability of increasingly sophisticated technologies to address research questions [9] . Ethical objections to the use of animals have been publically voiced for more than a century, well before there was a firm scientific understanding of animal emotion and cognition [15] . Now, a better understanding of animals' capacity for pain and suffering is prompting many to take a closer look at the human use of animals [56] .

Articles in the accompanying Collection only briefly touch on the many scientific and ethical issues surrounding the use of animals in testing and research. While it is important to acknowledge limitations to non-animal methods remain, recent developments demonstrate that these limitations should be viewed as rousing challenges rather than insurmountable obstacles. Although discussion of these issues can be difficult, progress is most likely to occur through an ethically consistent, evidence-based approach. This collection aims to spur further steps forward toward a more coherent ethical framework for scientific advancement.

Acknowledgments

The authors thank the conference speakers and participants for their participation.

Author Contributions

Conceived and designed the experiments: HRF NB. Contributed reagents/materials/analysis tools: HRF NB. Wrote the paper: HRF NB.

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• 23. Office of Laboratory Animal Welfare (2002) Public Health Service policy on humane care and use of laboratory animals. Available: http://grants.nih.gov/grants/olaw/references/phspol.htm#PublicHealthServicePolicyonHumaneCareandUseofLaboratory . Accessed 2011 Jan 18.
• 24. Office of Laboratory Animal Welfare (2002) U.S. Government principles for the utilization and care of vertebrate animals used in testing, research and training. Available: http://grants.nih.gov/grants/olaw/references/phspol.htm . Accessed 2011 Jan 7.
• 25. Gregory NG (2004) Physiology and behavior of animal suffering. Oxford, U.K.: Blackwell Science. 280 p.
• 26. McMillan FD, editor. (2005) Mental Health and Well-Being in Animals. Oxford, U.K.: Blackwell Publishing Professional. 301 p.
• 27. Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council (2009) Recognition and alleviation of pain and distress in laboratory animals. Washington, D.C.: National Academy Press. 196 p.
• 31. Panksepp J (2004) Affective neuroscience: the foundations of human and animal emotions. Oxford: Oxford University Press. 480 p.
• 32. Koob GF, Ehlers CL, Kupfers DJ, editors. (1989) Animal Models of Depression. Boston, MA: Birkhäuser. 295 p.
• 39. Shettleworth SJ (1998) Cognition, evolution, and behavior. Oxford, U.K.: Oxford University Press. 704 p.
• 40. deWaal F (2009) The age of empathy: nature's lessons for a kinder society. New York, NY: Random House, Inc. 304 p.
• 44. Burghardt GM (2005) The genesis of animal play: testing the limits. Cambridge, U.K.: MIT Press. 501 p.
• 49. Committee on Toxicity Testing and Assessment of Environmental Agents, National Research Council (2007) Toxicity testing in the 21st century: a vision and a strategy. Washington, DC: National Academy Press. 216 p.
• 55. Dr. Susan Love Research Foundation, National Cancer Institute Cancer Biomedical Informatics Grid (2009) Health of Women Study. Available: http://cabig.cancer.gov/action/collaborations/howstudy/ . Accessed 2011 Jan 10.
• 56. Beauchamp TL, Orlans FB, Dresser R, Morton DB, Gluck JP (2008) The Human Use of Animals: Case Studies in Ethical Choice, 2 nd ed. New York, NY: Oxford University Press. 287 p.

Medical breakthroughs underpinned by animal research

The use of animals in biomedical research helps researchers better understand the biological processes that are central to our health. This is essential for developing safe and effective ways of preventing or treating disease.

For over a century, research using animals has advanced the scientific understanding of human health, and the impact of this research is so vast that it can be difficult to measure. However, some key recent examples of lifesaving treatments that were developed thanks to animal research are worth highlighting.

COVID-19 vaccine trials

Professor Sarah Gilbert and her team at the University of Oxford spearheaded a vaccine trial in which they used a safe version of an adenovirus. An adenovirus is a virus that can cause a common cold-like illness.

Previous work funded by the Medical Research Council (MRC) through the UK Vaccine Network used this adenovirus (known as ChAdOx1) by Professor Gilbert in the production of vaccines against the Middle East Respiratory Syndrome coronavirus.

Engineering a spike protein

The team engineered ChAdOx1 to make a specific coronavirus protein, known as the spike protein, from the SARS-CoV-2 virus. As a result, our immune system should in theory be able to recognise the spike protein as ‘foreign’ and form antibodies against it. And then attack the SARS-CoV-2 virus and stop it from causing an infection.

It is hoped that long lasting immunity can be provided through vaccination by ‘bluffing’ the body in this way, and by slipping in parts of the virus that do not harm, but induce the release of antibodies.

The vaccine testing involved animal trials in ferrets and non-human primates at the Public Health England (PHE) laboratories. The team also collaborated with researchers at the BBSRC-funded Pirbright Institute to study the effect of this vaccine in pigs.

Vaccinating millions of people worldwide

Under normal circumstances, animal work must be completed before human trials can start. But because similar vaccines have worked safely in trials for other diseases, the work was accelerated and happened in parallel. It led to the approval by the Medical and Healthcare products Regulatory Agency on 30 December 2020.

This vaccine, commonly known as the Oxford AstraZeneca vaccine, has now been administered to millions of people worldwide.

Professor Alain Townsend’s team at the MRC Human Immunology Unit worked in collaboration with:

• MRC Weatherall Institute of Molecular Medicine
• Radcliffe Department of Medicine
• University of Oxford
• the Biotechnology and Biological Sciences Research Council’s (BBSRC) Pirbright Institute.

Further vaccine development

They have shown that a new potential vaccine against COVID-19, named RBD-SpyVLP, produces a strong antibody response in mice and pigs. It provides vital information for the further development of the vaccine.

Investing in the research and development of the second generation of COVID-19 vaccines is important because they will help fill gaps in efficacy against novel variants. It also addresses issues around production and distribution such as the requirement for cold chain supply logistics.

Find out more about the Oxford-produced RBD-SpyVLP vaccine candidate .

Llama antibody has ‘significant potential’ as COVID-19 treatment

A unique antibody produced by llamas could be developed as a new frontline treatment against COVID-19 and could be taken by patients as a simple nasal spray.

The laboratory research is led by scientists at the Rosalind Franklin Institute. The research was funded by:

• Engineering and Physical Sciences Research Council (EPSRC)
• EPA Cephalosporin Fund

The research has shown that nanobodies (a smaller, simple form of antibody generated by llamas and camels) can effectively target the SARS-CoV-2 virus that causes COVID-19. It is the first step towards developing a new type of treatment against COVID-19.

Preparing for human clinical studies

The scientists are hoping to progress this work from the animal setting to prepare for clinical studies in humans.

Human antibodies have been an important treatment for serious cases during the pandemic, but typically need to be administered by infusion through a needle in hospital.

However, nanobodies have several potential advantages over human antibodies:

• they are cheaper to produce
• it is possible to deliver them directly to the airways through a nebuliser or nasal spray, so they could be self-administered at home rather than needing an injection.

This could have benefits in terms of ease of use by patients, but it also gets the treatment directly to the site of infection in the respiratory tract.

Gene therapy treatment for treating blindness

Inherited eye conditions are currently untreatable because they are caused by mutations in our DNA, which form defective copies of key genes required for normal vision. Gene therapy aims to deliver healthy copies of these defective genes directly to the retina, to correct these genetic mistakes.

MRC has been funding research into gene therapy for inherited eye diseases since 2004. Animal research in mice and dogs has been vital for establishing the necessary proof-of-concept for ocular gene therapy.

Developing a new, efficient technique

In 2011, with MRC funding, a team of scientists at the UCL Institute of Ophthalmology developed a new technique for improving the efficiency of this gene therapy. The results of which were confirmed in mouse models, a special strain of mice to study a particular human disease or condition.

Once the safety and efficacy of this approach was established in mice, the work rapidly progressed to two clinical trials. The first patients receiving this ground-breaking treatment have benefited from significant vision restoration, with more patients now in clinical trials. As well as the benefit to patients, this work is now widely regarded as a landmark for the entire gene therapy field.

Last updated: 17 August 2023

This is the website for UKRI: our seven research councils, Research England and Innovate UK. Let us know if you have feedback or would like to help improve our online products and services .

December 28, 2022

Reevaluating the practice of animal testing in biomedical research, for people, animals, and public health, by casey shook.

Introduction

The phrase “animal testing” refers to the range of experiments performed on living animals for the purpose of studying diseases and biology, the effectiveness of newly developed pharmaceuticals and medications, and the safety of consumer products like cosmetics, cleaners, and food additives.   In the context of biomedical research, animal testing has been mandated by federal law as an initial step in the U.S. Food and Drug Administration’s (FDA) approval process for new drugs, and the results of such testing are often determinative of whether a drug will proceed to clinical trials.

While this practice is touted as reliable, necessary for medical progress, and a source of accurate models of human biology and disease, these claims are often based on opinion and anecdotal evidence.  Scientific literature and systematic review of the effectiveness of animal testing support the view that it is unreliable, lacks predictive value for human health outcomes, can lead to substantial harm to humans, wastes financial resources, and poses ethical issues relating to the use of living animals.  For these reasons, animal testing should be reevaluated under existing federal law and particularly in consideration of the multiple alternative testing methods that have already been developed. This article will evaluate the laws and agencies involved in the oversight of animal testing, the problems associated with this practice, and recommendations to address those problems.

Relevant Federal Laws and Agencies

The Food, Drug, and Cosmetics Act (FD&C Act) and the Animal Welfare Act (AWA) are federal laws that were promulgated to guide the practice of animal testing within the United States.

The FD&C Act was passed in the 1930s in an effort to enhance consumer protection against dangerous and ineffective drugs and deceptive product packaging.  This law mandates the use of animal testing within the FDA’s approval process for new drugs by directing manufacturers to initially assess the toxicology and effectiveness of new products on animal subjects before advancing to human subjects; it does not allow for alternative testing methods.

The AWA establishes the regulation of and standards of care for the transportation, sale, and handling of certain animals, including within research facilities.   The standards of care apply to the handling, housing, feeding, veterinary care, and pain minimization of research animals and requires lab personnel to be trained in humane animal handling.  The animal care unit within the Animal and Plant Health Inspection Service (APHIS) of the U.S. Department of Agriculture (USDA) administers the AWA primarily by conducting pre-licensing inspections and unannounced compliance inspections of facilities engaged in the exhibition of animals, pet sales, animal-based research, and commercial transportation of animals.   The stated purpose of these inspections is to ensure that animals within these facilities are receiving humane, adequate care.

Other regulatory agencies and bodies work in conjunction with the FDA and USDA to oversee the practice of animal testing.

The U.S. Public Health Service (PHS) works to advance public health science and effectuate disease prevention programs across the country.  In regard to animal testing, PHS administers the statutorily mandated Policy on Humane Care and Use of Laboratory Animals  (Humane Care Policy), which works in tandem with the U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training. Both set forth ethical considerations, welfare, and care requirements, while the PHS Humane Care Policy provides additional instruction for implementing these guidelines within institutions and by agencies tasked with oversight.  The Office of Laboratory Animal Welfare (OLAW), within the PHS, is responsible for the administration of this policy.   PHS is also responsible for overseeing two federal agencies closely involved in animal testing for biomedical research purposes, the FDA and the Centers for Disease Control and Prevention (CDC).

The FDA fulfills a duty of preserving public health by overseeing the efficacy and safety of drugs, biological products, medical devices, food, and cosmetic products through its regulatory authority and law enforcement.  Within the FDA, the Center for Drug Evaluation and Research (CDER) is the entity that regulates all prescription and over-the-counter drugs and evaluates data from animal testing. As previously mentioned, the FDA was given its general oversight authority by the FD&C Act and mandates the use of animal testing in biomedical research.

The CDC increases health security by addressing and tracking global disease threats, promoting individual and community healthcare, and advancing health-related technology.  While the CDC does not oversee animal testing in a regulatory sense, the CDC does perform a variety of animal tests and has been reprimanded for repeated violations of the AWA, and even temporarily lost its accreditation by the Association for Assessment and Accreditation of Laboratory Animal Care in 2005.

The U.S. Department of Agriculture (USDA) is composed of 29 agencies and utilizes science and public policy to provide leadership on natural resources, food, nutrition, and rural development.  One agency within the USDA, APHIS, houses the Animal Care Program, which works to ensure humane treatment for animals covered by the AWA, reviews welfare complaints against facilities engaged in animal related activities including animal testing, and performs inspections of such facilities.

In addition to these federal agencies, there are two types of other regulatory bodies involved in the oversight of animal testing: Institutional Animal Care and Use Committees and an accreditation organization, known as the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).   Each institution that engages in animal testing is required to form an animal care and use committee to review protocols involving animal tests and facility inspections and to ensure compliance with federal law.   However, these committees are often subject to insufficient self-regulation.   Any federal lab that is not subject to USDA inspection must be accredited by the AAALAC.  Despite both the AAALAC and FDA’s suggestions that voluntary accreditation through the organization assures compliance with federal animal welfare standards, one study found that labs accredited by the AAALAC received more subsequent AWA citations than non-accredited labs, with demonstrated noncompliance in regard to AWA veterinary care standards and husbandry practices .

Problems Associated with Animal Testing

Animal testing has negative implications for both animals and humans. This practice lacks predictive value for subsequent clinical trials, can result in substantial harm to humans, lacks sufficient oversight and transparency by federal agencies, and is inhumane to animal test subjects, as will be discussed below.

Little Effect on Medical Progress

Animal testing is unnecessary for medical progress because it does not provide accurate models of human disease and lacks predictive value for outcomes of newly developed drugs in clinical trials.   The discrepancies between animal and human health outcomes in biomedical research stem from disparities between models of disease between animals and humans and differences in genetics and physiology between animal species.   Because researchers rely on artificially induced versions of human disease in animals, these studies fail to predict outcomes of new drugs in humans in 50 to 99.7 percent of cases.  Further, while the use of animal testing is defended on the basis of being able to control factors that cannot be controlled with human test subjects, the added stress of the lab environment on animal test subjects often impacts research results and leads to uncontrollable changes such as increased cortisone and blood pressure and changes in neurochemistry and genetic expression.  Without predictive value for the effect of new drugs in humans, animal testing serves very little purpose.

Potential for Human Harm

Harm to humans resulting from animal testing stems from misleading safety studies, abandonment of drugs that would be effective in humans but were ineffective in animals, and subjecting humans to dangerous drugs in clinical trials that appeared to be safe in animals.   Moreover, disregarding effective drugs and testing dangerous drugs wastes the time and financial resources of those involved.   The FDA has found that almost 90 percent of drugs tested in animals are not safe for human use; within the small percentage of drugs that do proceed to clinical trials, nine out of every 10 of those candidate drugs that appear safe and effective in animal studies fail when given to humans.  I n total, only about 12 percent of experimental drugs make it through clinical trials to the market.  While almost all drugs that are deemed not safe for humans in animal testing do not proceed to clinical trials, factors like a delayed reaction to toxicity in the animal test subjects can allow a drug to deviate from the standard approval process.   For example, tamoxifen (one of the most effective drugs for certain breast cancers) and cyclosporine (for organ transplant rejection) both showed toxicity in animals but were found to have substantial therapeutic value for humans.

Lack of Sufficient Federal Laws and Oversight

Both the FD&C Act and the AWA fail to fulfill their intended purposes. First, by exclusively requiring animal testing, the FD&C Act can put humans at risk by advancing dangerous drugs into clinical trials and rejecting effective drugs that fail in animal testing.   Secondly, the AWA is limited in scope, excluding rats, mice, birds, fish, and reptiles from mandatory lab reporting requirements, which equate to roughly 95 percent of animals used in research.   This allows for millions of animals each year to suffer in labs without sufficient oversight or care standards in place to protect them and drastically undermines figures published by the USDA related to animal testing.

In addition, the federal agencies involved with the oversight of animal testing within the United States struggle to fulfill their duties due to insufficient funding, staffing, and loopholes in the applicable federal laws. For example, the USDA’s Animal Care Program last reported that it employs 120 inspectors who are responsible for ensuring compliance across 12,000 facilities annually.   Non-compliant facilities often only receive warning letters, with the USDA failing to pursue civil or criminal penalties, despite an overwhelming number of AWA violations across the country.   A concern for this lack of oversight has been noted by animal welfare groups and members of Congress.

Inhumane Aspects of Animal Testing

Lastly, but of equal importance, is the inhumane nature of animal testing. An estimated 115 million animals are used in lab experiments annually worldwide, with up to 22 million used annually in the United States alone; approximately 85 percent of these are rats and mice.   These millions of animals are subjected to conditions like forced chemical exposure, prolonged physical restraint, food and water deprivation, infliction of injuries and pain, induced diseases such as cancer, neck-breaking, and decapitation.  It has been long established that animals are sentient, complex beings, and many believe that it is cruel to subject such large numbers to experimentation unless these experiments have been definitively proven to further human health and can be conducted in a humane manner.

Recommendations

Despite the complex problems associated with animal testing, there are multiple ways to address them. These include improving general legal protections for animals used in biomedical research by strengthening relevant laws, oversight, and penalty enforcement, further effectuating the principles set forth in the 3Rs alternative (which are discussed in more detail below), and considering existing alternative testing methods in place of animal testing.

Improving Legal Protections

Likely the most effective way to address the problems associated with animal testing is to amend the FD&C Act and AWA to provide stronger protections for animals used in research and to improve oversight and penalty enforcement of welfare standards in labs. H.R. 2565 and S.2952, known as the FDA Modernization Act, were introduced into the House of Representatives and Senate in 2021 and seek to remove the statutory mandate for animal testing within the FD&C Act to allow manufacturers and sponsors of a drug to use alternative testing methods to animal testing to investigate the safety and effectiveness of a drug.  The FDA Modernization Act has the potential to drastically reduce the use of animal testing within biomedical research in favor of more accurate testing methods. Importantly, S.2952 was passed unanimously by the Senate in September of 2022. Similarly, the AWA could be improved by expanding the current definition of “animal” under the law and the USDA’s welfare and care requirements for animals in labs to incorporate all animals, including rats, mice, fish and birds.  In regard to oversight and penalty enforcement, some potential actions that could be taken include increasing transparency into lab reports and experiment design, setting a mandatory reporting requirement for AWA violations, setting stricter guidelines for animal care and use committees within testing facilities, and increasing public awareness efforts of the reality of animal testing.

Designing animal experiments consistent with the 3Rs could significantly reduce the pain and distress suffered by animal test subjects. The concept of the 3Rs—replacement, reduction,  and refinement—was developed by scientists seeking to reduce the use of animals in lab experiments and is first explained in the book Principles of Humane Experimentation .   Emphasis on the 3Rs in biomedical research is consistent with the FDA Modernization Act and places a higher moral and ethical obligation on researchers to their animal test subjects.  While there is currently a lack of reliable metrics to monitor the use of the 3Rs within the context of toxicity testing, the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) has been working since 2000 to increase the effectiveness of U.S. federal agency use of the 3Rs.  ICCVAM, within the National Institute of Environmental Health Sciences (NIEHS), is a conglomerate of seventeen federal regulatory and research agencies that utilize and promote use of the 3Rs through developing new methods, modifying existing regulations, and providing trainings.

Alternative Testing Methods

There are multiple existing alternative testing methods that could decrease the inefficient use of animals in biomedical research and provide more accurate data regarding a new drug’s application to humans prior to clinical trials. Some of these methods include computer simulation, in vitro testing, human-patient simulators, and use of human volunteers.   Computer simulation programs can be used to simulate human biological processes and developing diseases and address the pitfalls of poor experimental design and statistical analysis of an experiment’s results.   In vitro testing refers to the use of biochemical or cell-based systems that mimic the structure and function of human organs and can be used to study the effects of new drugs and other consumer products.   Human-patient simulators provide a better model for certain types of biomedical research because they can breathe, bleed, “die,” and mimic the muscle and tissue layers of human bodies.   Lastly, human volunteers could be used in multiple contexts, such as to test small doses of new drugs through a method known as “micro-dosing” or through brain imaging and recording tests that can replace outdated experiments that are performed directly on the brains of living animals.   All of these methods are consistent with the alternatives provided for in the FDA Modernization Act.

In the context of biomedical research, the use of animal testing is an unreliable, inefficient practice that results in animal and potential human harm while impeding progress in medicine. Though animal testing may never fully be phased out, it should be reevaluated in relation to the changing federal laws that provide for it, the variety of highly accurate alternative testing methods, and ethical principles that underly our society. This would help to protect animals, provide effective drugs to humans faster, and advance public health interests. 

Casey Shook

Hedman family law, portland, or.

Casey Shook is a family law attorney in Portland, OR. She graduated from Willamette University College of Law in 2022, where she helped lead the student chapter of the Animal Legal Defense Fund. Outside of practicing family law, Ms. Shook works with the Defend Them All Foundation to secure a better future for animals and their habitats through community advocacy and legal guidance. She can be reached at [email protected]

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Science, Medicine, and Animals (1991)

Chapter: how have animals contributed to improving human health, how have animals contributed to improving human health.

A hundred years ago, good health was much rarer than it is today. In 1870, the leading cause of death in the United States was tuberculosis. 12 Of all the people born in developed countries like the United States, a quarter were dead by the age of 25, and about half had died by the age of 50. Those fortunate enough to have survived to old age had probably experienced several bouts with diseases like typhoid fever, dysentery, or scarlet fever. 13

Today, the leading causes of death in the United States are heart disease and cancer—diseases of old age rather than infancy and childhood. Fully 97 percent of Americans live past their 25th birthday, and over 90 percent live to be more than 50.

Better nutrition and sanitation did much to reduce the toll from infectious diseases. But these diseases could not have been eliminated as significant causes of death and illness without animal research. Animal research has also made people healthier, since it has contributed to virtually eliminating many infectious diseases like polio or rheumatic fever that can be debilitating without causing death. Animal research has even contributed to better nutrition and sanitation, since it has helped to identify the agents that contribute to good or bad health.

Because of a genetic defect, nude mice such as the one shown here have no thymus and cannot make certain cells essential for various immune responses. This characteristic makes them extremely helpful to scientists working in immunology research.

Methods to combat infectious diseases have not been the only dividends of animal research. Surgical procedures, pain relievers, psychoactive drugs, medications for blood pressure, insulin, pacemakers, nutrition supplements, organ transplants, treatments for shock trauma and blood diseases—all have been developed and tested in animals before being used in humans. 14 In fact, according to the American Medical Association, “Virtually every advance in medical science in the 20th century, from antibiotics and vaccines to antidepressant drugs and organ transplants, has been achieved either directly or indirectly through the use of animals in laboratory experiments.” 15

Animals will continue to be essential in combatting human illness. Though human health has improved greatly over the last 100 years, much remains to be done. Many of today's leading killers, such as cancer, atherosclerosis, diabetes, Alzheimer's disease, and AIDS, remain inadequately understood. Furthermore, debilitating conditions such as traumatic injury, strokes, arthritis, and a variety of mental disorders continue to exact a severe toll on human well-being.

Animal research will be no less important in the future than it has been in the past. Indeed, it may be even more important, because the questions remaining to be answered generally involve complex diseases and injuries that require whole organisms to be studied.

A scientist compares similarities in baboon virus and HIV-1. This is one of the studies being conducted to help discover the proper sequence of the AIDS virus.

The necessity for animal use in biomedical research is a hotly debated topic in classrooms throughout the country. Frequently teachers and students do not have access to balanced, factual material to foster an informed discussion on the topic. This colorful, 50-page booklet is designed to educate teenagers about the role of animal research in combating disease, past and present; the perspective of animal use within the whole spectrum of biomedical research; the regulations and oversight that govern animal research; and the continuing efforts to use animals more efficiently and humanely.

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The 3Rs: What are Medical Scientists Doing about Animal Testing?

The similarities between certain animals and humans mean that animal research can be very useful in understanding how the human body works and in developing and testing new medicines. Many major medical breakthroughs have been made with the help of animal experiments, including the invention of antibiotics, vaccines, and cancer treatments. However, some research can result in pain and suffering for the animals, and although there are laws in place now to protect animals, it would be better if we had alternative ways to move medical science forward. Scientists are working on new approaches that replace, reduce, and refine (improve) animal experiments. This is known as the 3Rs of scientific research. Some of this work focuses on improving the housing for the animals, while other work involves using cells in a test tube or computer models as animal substitutes. The three Rs are a step in the right direction for medical science.

Introduction

It would be risky to try a new medicine out on humans before checking that it is safe and that it works—people could get very sick or even die in the process. Because there are many similarities between animals and humans, and they often get the same illnesses, animal experiments can help us to understand different diseases and to design and test new treatments for diseases. Mammals like mice, rats, and rabbits have the same set of organs including a brain, heart, and lungs that work in the same way they do in humans. That means the animal experiments can give us a reasonable idea of what might happen in a person. Even simple animals like fruit flies and worms can be used to understand how our genes and immune systems work.

Many major medical breakthroughs have been made due to animal experiments. For example, in the 1920s, a surgeon discovered he could relieve the symptoms of diabetes in dogs by injecting them with insulin. Before that, people with diabetes got very sick and did not live for long, but now with the help of insulin, diabetics are able to control the level of sugar in their blood and live normal lives. Animals have been used to develop vaccines to prevent diseases that previously killed billions of people, including polio and meningitis. Animal experiments also allowed us to develop crucial medical practices we now take for granted, like anesthetics to put people to sleep during surgery, cancer treatments, and antibiotics. While a person born 100 years ago would be expected to live for 30 years, people born these days live around 70 years. Discoveries resulting from animal experiments have a lot to do with that increase in lifespan.

However, animal research comes at a cost to the animals, and it is sometimes unavoidable that they will experience pain and suffering. For example, the animals might be given injections, surgery, or an illness like cancer, in order to test new medicines. The procedures carried out on animals are classified as “mild,” “moderate,” or “severe” depending on the level of suffering. About two-thirds of animal experiments are carried out on mice, and 8% of these are considered severe.

In the past, there were no laws in place to control how animal experiments were carried out and some of those experiments caused unacceptable suffering to the animals. Thankfully, in 1876, the UK Parliament passed the “Cruelty to Animals Act,” which meant researchers had to follow a list of rules and would be regularly inspected and would face consequences for cruelty. This act also meant that animal experiments could only be performed if they were absolutely necessary and would help to save human lives, not just because the scientists were curious.

In the 1980s, the law was updated, and there are now very precise instructions on how to care for the animals as well as which experiments can and cannot be done. Scientists have studied animals to work out the best living conditions for them, and this information is used when writing the rules that scientists must follow. All research plans get judged beforehand to make sure the pros outweigh the cons, and these plans must be approved by specialist vets. There are also laws banning the use of great apes like chimpanzees and gorillas in UK research; almost all experiments are done on mice, rats, fish, and birds. Testing of cosmetics (like shower gel and shampoo) and household products (like detergents) is now illegal in many countries, including Europe and India.

In the United States, the Animal Welfare Act was introduced in 1966 and is a federal law that protects mammals used in scientific research.

Although important discoveries have been made and there is much improvement in how laboratory animals are treated, we would all prefer it if we did not have to use animals in experiments at all. So, are scientists doing anything to find alternatives? The answer is a resounding yes! 50 years ago, Bill Russell and Rex Burch wrote a book that introduced the “3Rs” for scientific research [ 1 ]. Rather than reading, writing, and arithmetic (as you may have come across in school), Bill and Rex were referring to replacement, reduction, and refinement. Replacement is about finding different options for experiments, other than animals, and reduction is about developing methods so that fewer animals are needed in each experiment. Refinement is concerned with improving current animal research so that the animals suffer as little as possible.

The 3Rs are now used in deciding the laws around animal research, and these days no experiment can be performed if there is an alternative available that does not use animals. Each experiment has to use the minimum possible number of animals, and the method has to result in the least pain and suffering for the animal. Research using animals in the United States is regulated by the US Department of Agriculture. In the UK, there is a specialized organization called the National Centre for the 3Rs (NC3Rs), 1 which supports work to develop new research methods that replace, reduce, or refine the use of animals.

Replacement

The ultimate replacement for animal experiments would be to use humans or human blood or tissue samples, as the results of human experiments would be the most accurate and relevant to humans. This is not possible in many cases because of the risks involved, but a method called “micro-dosing” is being developed, in which people are given tiny amounts of new medicines to look at how their immune systems respond. Animals like mice and rats can also sometimes be replaced with other living things that are not thought to be able to experience suffering, like fruit flies. Worms have recently been used to discover new antibiotics.

One option for replacing animals is to use in vitro models. “ In vitro ” literally means “in the glass” and refers to studies performed in a test tube in the laboratory, rather than inside a person or animal (which would be called in vivo ). Using in vitro models, complicated systems in the body are simplified so that scientists can concentrate on the one part they are interested in and they can run lots of experiments in a short amount of time. In vitro work has resulted in many important discoveries, including the identification of antibodies, which are a key part of the immune system that recognizes microbes and helps to destroy them.

In our laboratory at the University of Oxford, we are developing an in vitro model to test new vaccines. Normally, to test if a new vaccine works against a certain disease, for example, tuberculosis , scientists would immunize animals with the vaccine and then infect them with tuberculosis to see if they are protected. With our in vitro method, we infect cells (often human cells) in a test tube so that no animals need to get sick. We can compare whether cells from vaccinated animals or people are better at killing the tuberculosis bacteria than are cells from non-vaccinated animals or people [ 2 ]. Other scientists use similar systems to test new medicines and check if they are safe and if they work.

One of the problems with in vitro models is that they may be too simple and therefore might not predict what would happen inside an actual body. For example, a medicine that kills a virus in a test tube might not kill it inside an animal, because the virus can hide away in certain parts of the animal’s body. Or the medicine might appear safe in vitro , but cause side effects in parts of the body that were not represented in the test tube. Scientists are now trying to overcome these problems by building 3D in vitro models. These are more complicated and involve lots of different types of cells that come together to form something similar to a whole organ, like a liver or a heart.

Another way of replacing animal experiments is by using computers or mathematical models. These use calculations based on previous research to predict which medicines might be effective or which side effects might occur if the medicines were given to humans. Recent advances in technology mean that computers can simulate real biological processes in a virtual reality. Such methods have been used to develop vaccines based on information about bacterial genes and have also been used in cancer research to model tumors. One group at the University of Oxford built a computer model to test how drugs might affect the heart [ 3 ]. The different ways of replacing animal experiments are summarized in Figure 1 .

• Summary of the different ways of replacing animal experiments with other types of experiments. * The Nuremberg code - a set of research ethics principles for human experimentation - requires that human experiments are based on the results of animal experiments, in order to protect humans from harm. However, there are some situations in which human volunteers may be used in place of animals - for example we can sometimes study the immune response in people who have been naturally infected with a disease rather than infecting animals experimentally.

To reduce the number of animals used in research, experiments have to be carefully designed and analyzed. If too few animals are used in an experiment, any difference between groups (for example, if an experiment was testing groups of mice receiving different medicines to see which was safest) might be unclear and the experiment would have to be repeated. Repeating the experiment would use even more animals in the long run.

Scientists are also trying to maximize the amount of information they can get from each animal. For example, if they are looking at the progression of a tumor, they might need to sacrifice different animals each week to look inside at the size of the tumors. By scanning the tumors instead, the same animals can be assessed each week and fewer are used overall.

Sharing results between different groups of researchers and organizations, by writing articles and giving presentations, makes it less likely that the same experiments get repeated unnecessarily by different people. Publishers of some scientific journals are helping with this by agreeing to share results that might not otherwise be available. The different ways of reducing the number of animals used in experiments are summarized in Figure 2 .

• Summary of the different ways of reducing the number of animals used in experiments.

Refinement is about minimizing pain and suffering and improving the health and happiness of the animals. Refinement includes making sure the animals have comfortable housing conditions that support their natural needs like socializing, hiding, gnawing, and nest building. There are now rules in place about the size of cages needed and the kinds of toys, hiding places, and bedding material that should be provided. Scientists at the University of Liverpool have been studying the best way to pick up mice to minimize their stress [ 4 ]. Others at the University of British Columbia found that rats prefer to have burrowing materials and the opportunity to climb [ 5 ].

One important refinement in animal experiments is using imaging technologies instead of invasive techniques like surgery or taking blood. Rather than ending an animal’s life to observe how a disease has spread inside the body, pictures can be taken with minimum disturbance while the animal is alive. Imaging can be done with X-rays or scans, or by making parts of the animal’s body “glow in the dark,” using chemicals that occur naturally in algae and jellyfish. Many scientists now monitor cancerous tumor growth and infections with viruses or bacteria in this way. They can even use these methods to look at where medicines travel in the body. Making experiments shorter and using better pain relief are also methods of refinement. The different ways of refining animal experiments are summarized in Figure 3 .

• Summary of the different ways of refining (improving) animal experiments.

Many important medical discoveries have resulted from animal research and countless human lives have been improved or saved by experiments using animals. Animal testing has come a long way since the unregulated experiments of the last century and there are now strict laws in place to protect animals and prevent suffering. However, everyone would prefer it if we could stop using animals in medical research altogether.

Scientists around the world have been working hard to find new methods to replace the use of animals, reduce the numbers of animals used, or improve the experiments to minimize animal suffering. This is in line with the 3Rs principles of scientific research. Most research is now carried out using alternative methods and the number of laboratory animals used in the UK has been reduced by half in the last 30 years, but animals still need to be used in many situations. Bodies are so complicated that we cannot always know how they will react to a disease or medicine just by looking at cells in a test tube, or at a computer program or fruit flies. However, as technology advances in the future and scientists continue to work on the 3Rs, there is hope that one day laboratory animals will only be found in history books.

Genes : ↑ The biological “instructions” passed down from our parents, which determine our characteristics.

Immune System : ↑ Our natural protection against disease-causing organisms like bacteria and viruses.

Diabetes : ↑ A lifelong condition that causes the level of sugar in a person’s blood to become too high. This is because the pancreas does not produce enough of the hormone insulin, or the cells in the body are not responding properly to the insulin that is produced.

Vaccine : ↑ Small amounts of weak or dead bacteria or viruses that help prepare the immune system to fight the disease faster and more effectively, to prevent sickness.

Tuberculosis : ↑ A disease that mainly affects the lungs and is caused by bacteria that can be spread by the coughs and sneezes of an infected person.

Imaging Technologies : ↑ Creating pictures of the inside of a body for analysis. These include techniques such as X-rays and ultrasound.

Conflict of Interest Statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgements

I would like to thank Daniel McShane for his critical reading of this article and the NC3Rs for their support of my research.

[1] ↑ Russell, W., and Burch R. 1959. The Principles of Humane Experimental Technique . Wheathampstead, UK: Universities Federation for Animal Welfare.

[2] ↑ Brennan, M. J., Tanner, R., Morris, S., Scriba, T. J., Achkar, J. M., Zelmer, A., et al. 2017. The cross-species mycobacterial growth inhibition assay (MGIA) project, 2010-2014. Clin. Vaccine Immunol. 24(9):e00142–17. doi:10.1128/CVI.00142-17

[3] ↑ Britton, O. J., Bueno-Orovio, A., Van Ammel, K., Lu, H. R., Towart, R., Gallacher, D. J., et al. 2013. Experimentally calibrated population of models predicts and explains�intersubject variability in cardiac cellular electrophysiology. Proc. Natl. Acad. Sci. U.S.A. 110(23):E2098–105. doi:10.1073/pnas.1304382110

[4] ↑ Gouveia, K., and Hurst, J. L. 2013. Reducing mouse anxiety during handling: effect of experience with handling tunnels. PLoS ONE 8(6):e66401. doi:10.1371/journal.pone.0066401

[5] ↑ Makowska, I. J., and Weary, D. M. 2016. The importance of burrowing, climbing and standing upright for laboratory rats. R. Soc. Open Sci. 3(6):160136. doi:10.1098/rsos.160136

[1] ↑ https://nc3rs.org.uk/ (Accessed: May 22, 2018).

• History of Animal Testing

Animals are used to develop medical treatments, determine the toxicity of medications, check the safety of products destined for human use, and other biomedical , commercial, and health care uses. Research on living animals has been practiced since at least 500 BC. [ 2 ]

Early History

Descriptions of the dissection of live animals have been found in ancient Greek writings from as early as circa 500 BC. Physician-scientists such as Aristotle , Herophilus , and Erasistratus performed the experiments to discover the functions of living organisms. Vivisection (dissection of a living organism) was practiced on human criminals in ancient Rome and Alexandria, but prohibitions against mutilation of the human body in ancient Greece led to a reliance on animal subjects. Aristotle believed that animals lacked intelligence, and so the notions of justice and injustice did not apply to them. Theophrastus , a successor to Aristotle, disagreed, objecting to the vivisection of animals on the grounds that, like humans, they can feel pain, and causing pain to animals was an affront to the gods. [ 79 ] [ 80 ]

Roman physician and philosopher Galen (130-200 AD), whose theories of medicine were influential throughout Europe for fifteen centuries, engaged in the public dissection of animals (including an elephant), which was a popular form of entertainment at the time. Galen also engaged in animal vivisection in order to develop theories on human anatomy, physiology, pathology, and pharmacology. In one of his experiments, he demonstrated that arteries, which were believed by earlier physicians to contain air, actually contained blood. Galen believed that animal physiology was very similar to that of human beings, but despite this similarity he had little sympathy for the animals on which he experimented. Galen recommended that his students vivisect animals “without pity or compassion” and warned that the “unpleasing expression of the ape when it is being vivisected” was to be expected. [ 80 ] [ 82 ] [ 81 ]

French philosopher René Descartes (1596-1650), who occasionally experimented on live animals, including at least one rabbit, as well as eels and fish, believed that animals were “automata” who could not experience pain or suffer the way that humans do. Descartes recognized that animals could feel, but because they could not think, he argued, they were unable to consciously experience those feelings. [ 66 ] [ 83 ]

English Physician William Harvey (1578-1657) discovered that the heart, and not the lungs, circulated blood throughout the body as a result of his experiments on living animals. [ 84 ] [ 85 ]

Animal Testing in the 1800s and Early 1900s

There was little public objection to animal experimentation until the 19th Century, when the increased adoption of domestic pets fueled interest in an anti-vivisection movement, primarily in England. This trend culminated in the founding of the Society for the Protection of Animals Liable to Vivisection in 1875, followed by the formation of similar groups. [ 79 ] [ 87 ]

One of the first proponents of animal testing to respond to the growing anti-testing movement was French physiologist Claude Bernard in his Introduction to the Study of Experimental Medicine (1865). Bernard argued that experimenting on animals was ethical because of the benefits to medicine and the extension of human life. [ 79 ]

Queen Victoria was an early opponent of animal testing in England, according to a letter written by her private secretary in 1875: “The Queen has been dreadfully shocked at the details of some of these [animal research] practices, and is most anxious to put a stop to them.” Soon the anti-vivisection campaign became strong enough to pressure lawmakers into establishing the first laws controlling the use of animals for research: Great Britain’s Cruelty to Animals Act of 1876 . [ 15 ] [ 88 ]

Russian physiologist Ivan Pavlov (1849-1936) demonstrated the “conditioned reflex” by training dogs to salivate upon hearing the sound of a bell or electric buzzer. In order to measure “the intensity of the salivary reflex,” wrote Pavlov, the dogs were subjected to a “minor operation, which consists in the transplantation of the opening of the salivary duct from its natural place on the mucous membrane of the mouth to the outside skin.” A “small glass funnel” was then attached to the salivary duct opening with a “special cement.” [ 86 ] [ 75 ]

In 1959, The Principles of Humane Experimental Technique by zoologist William Russell and microbiologist Rex Burch was published in England. The book laid out the principle of the “Three Rs” for using animals in research humanely: Replacement (replacing the use of animals with alternative research methods), Reduction (minimizing the use of animals whenever possible), and Refinement (reducing suffering and improving animals’ living conditions). The “Three Rs” were incorporated into the AWA and have formed the basis of many international animal welfare laws. [ 89 ] [ 90 ] [ 91 ]

Animals in Space and the Military

Since as early as 1948, animals have been used by the US space program for testing such aspects of space travel as the effects of prolonged weightlessness. After several monkeys died in unmanned space flights carried out during the 1940s, the first monkey to survive a space flight was Yorick, recovered from an Aerobee missile flight on Sep. 20, 1951. However, Yorick died several hours after landing, possibly due to heat stress. The first living creature to orbit the Earth was Laika , a stray dog sent into space on the Soviet spacecraft Sputnik 2 in Nov. 1957. Laika died of “overheating and panic” early in the mission, according to the BBC. The record for the most animals sent into space was set Apr. 17, 1998, when more than two thousand animals, including rats, mice, fish, crickets, and snails, were launched into space on the shuttle Columbia (along with the seven-member human crew) for neurological testing. [ 7 [ 8 ] [ 92 ] [ 116 ]

Since the Vietnam war , animals have also been used by the US military. The US Department of Defense used 488,237 animals for research and combat trauma training (“live tissue training”) in fiscal year 2007 (the latest year for which data are available), which included subjecting anesthetized goats and pigs to gunshot wounds, burns, and amputations for the training of military medics. In February 2013, after an escalation of opposition by animal rights groups such as People for the Ethical Treatments of Animals (PETA), Congress ordered the Pentagon to present a written plan to phase out live tissue training. The US Coast Guard, however, which was at the center of a 2012 scandal involving videotaped footage of goats being mutilated as part of its live tissue training program, said in May 2013 that the program will continue. [ 6 ] [ 93 ] [ 94 ] [ 95 ]

Regulations

A public outcry over animal testing and the treatment of animals in general broke out in the United States in the mid-1960s, leading to the passage of the AWA. An article in the November 29, 1965 issue of Sports Illustrated about Pepper, a farmer’s pet Dalmatian that was kidnapped and sold into experimentation, is believed to have been the initial catalyst for the rise in anti-testing sentiment. Pepper died after researchers attempted to implant an experimental cardiac pacemaker in her body. [ 74 ] [ 75 ]

Animal testing in the United States is regulated by the federal Animal Welfare Act (AWA), passed in 1966 and amended in 1970, 1976, and 1985. The AWA defines “animal” as “any live or dead dog, cat, monkey (nonhuman primate mammal), guinea pig, hamster, rabbit, or such other warm blooded animal.” The AWA excludes birds, rats and mice bred for research, cold-blooded animals, and farm animals used for food and other purposes. [ 3 ] [ 27 ]

The AWA requires that each research facility develop an internal Institutional Animal Committee (more commonly known as an Institutional Animal Care and Use Committee, or IACUC) to “represent society’s concerns regarding the welfare of animal subjects.” The Committee must be comprised of at least three members. One member must be a veterinarian and one must be unaffiliated with the institution. [ 3 ] [ 27 ]

While the AWA regulates the housing and transportation of animals used for research, it does not regulate the experiments themselves. The U.S. Congress Conference Committee stated at the time of the bill’s passage that it wanted “to provide protection for the researcher… by exempting from regulations all animals during actual research and experimentation… It is not the intention of the committee to interfere in any way with research or experimentation.” [ 66 ]

Animal studies funded by US Public Health Service (PHS) agencies, including the National Institutes of Health (NIH), are further regulated by the Public Health Service Policy on Humane Care and Use of Laboratory Animals. [ 27 ] All PHS funded institutions must base their animal care standards on the AWA and the Guide for the Care and Use of Laboratory Animals (also known as “the Guide “), prepared by the Institute for Laboratory Animal Research at the National Research Council. Unlike the AWA, the Policy on Humane Care and Use of Laboratory Animals and the Guide cover all vertebrate animals used for research, including birds, rats and mice. The Guide “establishes the minimum ethical, practice, and care standards for researchers and their institutions,” including environment and housing standards and required veterinary care. The Guide stipulates that “the avoidance or minimization of discomfort, distress, and pain when consistent with sound scientific practices, is imperative.” [ 71 ]

The US Department of Agriculture (USDA) Animal and Plant Health Inspection Service (APHIS) reports the number of animals used for research each year, though it excludes animals not covered by the AWA. For fiscal year 2010 (the latest year for which data are available as of Oct. 11, 2013), 1,134,693 animals were reported. Since the data excludes cold-blooded animals, farm animals used for food, and birds, rats, and mice bred for use in research, the total number of animals used for testing is unknown. Estimates of the number of animals not counted by APHIS range from 85%-96% of the total of all animals used for testing. [ 1 ] [ 2 ] [ 26 ] [ 65 ] [ 72 ]

The USDA breaks down its data by three categories of pain type: animals that experience pain during their use in research but are given drugs to alleviate it; animals who experience pain and are not given drugs; and animals who do not experience pain and are not given drugs. [ 26 ]

The U.S. Food and Drug Administration (FDA), which regulates the development of new medications, states that “At the preclinical stage, the FDA will generally ask, at a minimum, that sponsors… determine the acute toxicity of the drug in at least two species of animals.” [ 73 ]

On Dec. 29, 2022, President Joe Biden signed the FDA Modernization Act 2.0. Sponsored by Senator Rand Paul (R-KY), the law updates the U.S. Federal Food, Drug, and Cosmetic Act by eliminating the requirement that pharmaceutical companies test new drugs on animals before human trials. The amendment does not prevent companies from performing animals tests, but makes the tests the choice of the company. [ 151 ]

The Modern Debate

The 1975 publication of Animal Liberation by Australian philosopher Peter Singer galvanized the animal rights and anti-testing movements by popularizing the notion of “speciesism” as being analogous to racism, sexism, and other forms of prejudice. Addressing animal testing specifically, Singer predicted that “one day… our children’s children, reading about what was done in laboratories in the twentieth century, will feel the same sense of horror and incredulity… that we now feel when we read about the atrocities of the Roman gladiatorial arenas or the eighteenth-century slave trade.” [ 66 ]

In 1981, an early victory by then-fledgling animal rights group People for the Ethical Treatment of Animals (PETA) served to revitalize the anti-testing movement once again. A PETA activist working undercover at the Institute for Biological Research in Silver Spring, MD took photographs of monkeys in the facility that had engaged in self-mutilation due to stress. The laboratory’s director, Edward Taub, was charged with more than a dozen animal cruelty offenses, and an especially notorious photo of a monkey in a harness with all four limbs restrained became a symbolic image for the animal rights movement. [ 96 ]

In 2001, controversy erupted over animal experiments undertaken by a veterinarian at Ohio State University. Dr. Michael Podell infected cats with the feline AIDS virus in order to study why methamphetamine users deteriorate more quickly from the symptoms of AIDS. After receiving several death threats, Dr. Podell abandoned his academic career. Over 60% of biomedical scientists polled by Nature magazine say “animal-rights activists present a real threat to essential biomedical research.” [ 35 ] [ 97 ]

A 2007 report by the National Research Council of the National Academy of Sciences called for a reduction in the use of animal testing, recommending instead the increased use of in vitro methods using human cells. Though the report touted new technologies that could eventually eliminate the need for animal testing altogether, the authors acknowledged that “For the foreseeable future… targeted tests in animals would need to be used to complement the in vitro tests, because current methods cannot yet adequately mirror the metabolism of a whole animal.” [ 104 ]

In Mar. 2013, the European Union banned the import and sale of cosmetic products that use ingredients tested on animals. Some proponents of animal testing objected, arguing that some animal tests had no non-animal equivalents. A spokesman for the trade association Cosmetics Europe stated it is likely “that consumers in Europe won’t have access to new products because we can’t ensure that some ingredients will be safe without access to suitable and adequate testing.” India and Israel have also banned animal testing for cosmetic products, while the United States has no such ban in place. [ 98 ] [ 99 ]

China is the only major market where testing all cosmetics on animals is required by law, and foreign companies distributing their products to China must also have them tested on animals. China announced that its animal testing requirement will be waived for shampoo, perfume, and other so-called “non-special use cosmetics” manufactured by Chinese companies after June 2014. “Special use cosmetics,” including hair regrowth, hair removal, dye and permanent wave products, antiperspirant, and sunscreen, will continue to warrant mandatory animal testing. China’s National Medical Products Administration announced that animal testing for “ordinary” cosmetics (those that do not make claims such as “anti-aging”) will no longer be required as of May 2021. [ 43 ] [ 65 ] [ 114 ] [ 149 ]

After ceasing to breed chimpanzees for research in May 2007, the US National Institutes of Health announced in June 2013 that it would retire most of its chimpanzees (310 in total) over the next several years. While the decision was welcomed by animal rights groups, opponents said the decision would have a negative impact on the development of critical vaccines and treatments. The Texas Biomedical Research Institute released a statement claiming that the number of chimps to be retained (up to 50) was “not sufficient to enable the rapid development of better preventions and cures for hepatitis B and C, which kill a million people every year.” On Nov. 18, 2015 the US National Institutes of Health announced that its remaining 50 research chimpanzees will be retired to the Federal Chimpanzee Sanctuary System. Gabon remains the only country in the world that still experiments on chimpanzees. [ 4 ] [ 100 ] [ 117 ]

The Environmental Protection Agency (EPA) released a plan on Sep. 10, 2019 to reduce studies using mammal testing by 30% by 2025 and to eliminate the mammal testing altogether by 2035. In Nov. 2019, the FDA enacted a policy allowing some lab animals used for animal testing to be sent to shelters and sanctuaries for adoption. The National Institutes of Health (NIH) adopted a similar policy in Aug. 2019 and the Department of Veterans Affairs (VA) did so in 2018. [ 131 ] [ 146 ]

On Sep. 2, 2021, Mexico became the 41st country and first in North America to ban cosmetics testing on animals, according to the Humane Society International. [ 150 ]

Animal Testing and COVID-19

The COVID-19 (coronavirus) global pandemic brought attention to the debate about animal testing as researchers sought to develop a vaccine for the virus as quickly as possible. Vaccines are traditionally tested on animals to ensure their safety and effectiveness. News broke in Mar. 2020 that there was a shortage of the genetically modified mice that were needed to test coronavirus vaccines. [ 133 ]

Meanwhile, other companies tried new development techniques that allowed them to skip animal testing and start with human trials. Moderna Therapeutics used a synthetic copy of the virus genetic code instead of a weakened form of the virus. The FDA approved an application for Moderna to begin clinical trials on a coronavirus vaccine on Mar. 4, 2020, and the first participant was dosed on Mar. 16, 2020. [ 143 ] [ 147 ]

A shortage of monkeys, including pink-faced rhesus macaques, threatened vaccine development at the beginning of the pandemic and as variants of COVID-19 were found. The monkeys were previously flown in from China, but a ban on wildlife imports from China forced researchers to look elsewhere, a difficult task as China previously supplied over 60% of research monkeys in the United States. [ 148 ]

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University of Missouri

• Veterinary Health Center
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College of Veterinary Medicine

Research center for human-animal interaction, welcome to rechai.

People and animals have lived close to one another for centuries. The human animal bond is the strong connection that they feel toward one another. The MU College of Veterinary Medicine is proud of this exciting center based on the growing field of research showing how the human animal bond impacts health in people and animals.

Who we are:

The Research Center for Human-Animal Interaction (ReCHAI), founded in 2005, in College of Veterinary Medicine has a mission of education and conducting programs and studies about the benefits of human-animal interaction. ReCHAI is on the leading edge of programs and studies that explore how the human animal bond has an impact on the health of people and animals.

ReCHAI is designed to:

• Develop a program for research and education to study the health benefits of human-animal interaction (HAI).
• Promote the science of HAI.
• Document evidence demonstrating Animal Assisted Interventions (AAI) as a beneficial form of complementary therapy.
• Foster educational and research opportunities for MU students, as well as students from around the country and globe.
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Scientists are testing mRNA vaccines to protect cows and people against bird flu

FILE - Cows stand in the milking parlor of a dairy farm in New Vienna, Iowa, on Monday, July 24, 2023. The bird flu outbreak in U.S. dairy cows is prompting development of new, next-generation mRNA vaccines — akin to COVID-19 shots — that are being tested in both animals and people. In June 2024, the U.S. Agriculture Department is to begin testing a vaccine developed by University of Pennsylvania researchers by giving it to calves. (AP Photo/Charlie Neibergall, File)

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The bird flu outbreak in U.S. dairy cows is prompting development of new, next-generation mRNA vaccines — akin to COVID-19 shots — that are being tested in both animals and people.

Next month, the U.S. Agriculture Department is to begin testing a vaccine developed by University of Pennsylvania researchers by giving it to calves. The idea: If vaccinating cows protects dairy workers, that could mean fewer chances for the virus to jump into people and mutate in ways that could spur human-to-human spread.

Meanwhile. the U.S. Department of Health and Human Services has been talking to manufacturers about possible mRNA flu vaccines for people that, if needed, could supplement millions of bird flu vaccine doses already in government hands.

“If there’s a pandemic, there’s going to be a huge demand for vaccine,” said Richard Webby, a flu researcher at St. Jude Children’s Research Hospital in Memphis. “The more different (vaccine manufacturing) platforms that can respond to that, the better.”

The bird flu virus has been spreading among more animal species in scores of countries since 2020. It was detected in U.S. dairy herds in March, although investigators think it may have been in cows since December. This week, the USDA announced it had been found in alpacas for the first time.

At least three people — all workers at farms with infected cows — have been diagnosed with bird flu, although the illnesses were considered mild.

But earlier versions of the same H5N1 flu virus have been highly lethal to humans in other parts of the world. Officials are taking steps to be prepared if the virus mutates in a way to make it more deadly or enables it to spread more easily from person to person.

Traditionally, most flu vaccines are made via an egg-based manufacturing process that’s been used for more than 70 years. It involves injecting a candidate virus into fertilized chicken eggs, which are incubated for several days to allow the viruses to grow. Fluid is harvested from the eggs and is used as the basis for vaccines, with killed or weakened virus priming the body’s immune system.

Rather than eggs — also vulnerable to bird flu-caused supply constraints — some flu vaccine is made in giant vats of cells.

Officials say they already have two candidate vaccines for people that appear to be well-matched to the bird flu virus in U.S. dairy herds. The Centers for Disease Control and Prevention used the circulating bird flu virus as the seed strain for them.

The government has hundreds of thousands of vaccine doses in pre-filled syringes and vials that likely could go out in a matter of weeks, if needed, federal health officials say.

They also say they have bulk antigen that could generate nearly 10 million more doses that could be filled, finished and distributed in a matter of a few months. CSL Seqirus, which manufactures cell-based flu vaccine, this week announced that the government hired it to fill and finish about 4.8 million of those doses. The work could be done by late summer, U.S. health officials said this week.

But the production lines for flu vaccines are already working on this fall’s seasonal shots — work that would have to be interrupted to produce millions more doses of bird flu vaccine. So the government has been pursuing another, quicker approach: the mRNA technology used to produce the primary vaccines deployed against COVID-19.

These messenger RNA vaccines are made using a small section of genetic material from the virus. The genetic blueprint is designed to teach the body how to make a protein used to build immunity.

The pharmaceutical company Moderna already has a bird flu mRNA vaccine in very early-stage human testing. In a statement, Moderna confirmed that “we are in discussions with the U.S. government on advancing our pandemic flu candidate.”

Similar work has been going on at Pfizer. Company researchers in December gave human volunteers an mRNA vaccine against a bird flu strain that’s similar to — but not exactly the same as — the one in cows. Since then, researchers have performed a lab experiment exposing blood samples from those volunteers to the strain seen in dairy farms, and saw a “notable increases in antibody responses,” Pfizer said in a statement.

As for the vaccine for cows, Penn immunologist Scott Hensley worked with mRNA pioneer and Nobel laureate Drew Weissman to produce the experimental doses. Hensley said that vaccine is similar to the Moderna one for people.

In first-step testing, mice and ferrets produced high levels of bird flu virus-fighting antibodies after vaccination.

In another experiment, researchers vaccinated one group of ferrets and deliberately infected them, and then compared what happened to ferrets that hadn’t been vaccinated. All the vaccinated animals survived and the unvaccinated did not, Hensley said.

“The vaccine was really successful,” said Webby, whose lab did that work last year in collaboration with Hensley.

The cow study will be akin to the first-step testing initially done in smaller animals. The plan is for initially about 10 calves to be vaccinated, half with one dose and half with another. Then their blood will be drawn and examined to look for how much bird flu-fighting antibodies were produced.

The USDA study first will have to determine the right dose for such a large animal, Hensley said, before testing if it protects them like it did smaller animals.

What “scares me the most is the amount of interaction between cattle and humans,” Hensley said.

“We’re not talking about an animal that lives on a mountain top,” he said. “If this was a bobcat outbreak I’d feel bad for the bobcats, but that’s not a big human risk.”

If a vaccine reduces the amount of virus in the cow, “then ultimately we reduce the chance that a mutant virus that spreads in humans is going to emerge,” he said.

The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute’s Science and Educational Media Group. The AP is solely responsible for all content.

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Skin models as an alternative to animal testing

by Marie-Luise Righi, Fraunhofer-Gesellschaft

Animal testing has long been a fixture of medical and pharmaceutical research, but alternative methods are growing more and more important. Innovative methods allow for research aimed directly at humans—without using animal testing as an intermediate step.

TigerShark Science, a planned Fraunhofer start-up and spin-off of the Fraunhofer Translational Center for Regenerative Therapies TLC-RT at the Fraunhofer Institute for Silicate Research ISC, is taking this kind of approach. TigerShark Science hopes to use skin models grown from human stem cells to significantly reduce animal testing .

There are various methods that have the potential for minimizing or even eliminating animal testing. These methods include human stem cells that are grown in vitro and used to form miniature organs known as organoids.

Researchers at Fraunhofer ISC/TLC-RT in Würzburg are also working to develop these kinds of in-vitro tissue models with various areas of focus, including barrier organs like the skin. These lab-grown cell aggregates can be used to trace physiological processes and study them under controlled conditions—one way to replace or reduce animal testing.

The researchers involved in the TigerShark Science start-up project are taking the same approach: They have succeeded in culturing a skin model that can represent almost all of the structures present in human skin , making it a realistic skin model.

With their start-up idea, the team of researchers is now approaching the official spin-off stage. The founding team includes Dr. Florian Groeber-Becker, head of Fraunhofer TLC-RT at Fraunhofer ISC, Dr. Dieter Groneberg, group manager for in-vitro skin testing systems at the Fraunhofer TLC-RT, and Amelie Reigl, a project manager at the Fraunhofer TLC-RT and future managing director of TigerShark Science.

Complex models with three layers of skin

The start-up plans to begin by offering the pharmaceutical and cosmetics industries large unit volumes of healthy skin models simulating three layers of the skin—the epidermis, dermis, and hypodermis—with fat cells. These models are suitable for applications such as testing medications and their side effects or studying hair growth.

The organoids are complex skin models comprising various cell types. Like human skin, they have sebaceous glands and hairs. They can be used to study aspects such as how cells communicate with each other after an active ingredient is administered and whether active ingredients trigger irritation.

"There have been no skin models of this complexity on the market to date. They're one of a kind," Reigl says, explaining the technology's unique selling proposition and great potential.

An automated process is used to develop the organoids in large numbers inside a bioreactor. They are then applied to nanofibers using a special method. This creates what is known as an air–medium interface culture, in which the uppermost layer of the skin, the epidermis, is in contact with the air—unlike when the tissue is cultured in a Petri dish. The nanofibers are already patented, and there are also plans to patent the method itself.

The model enables fast testing, a huge advantage over animal tests, which can often be expensive and time-consuming. The skin organoid made from human stem cells can be used to achieve faster, more accurate results, in many cases with greater applicability in humans. It takes just one step to study the reactions of cells in all three layers of the skin, an option that has not been available on the market to date.

The skin model is currently undergoing further development. Future plans call for adding models with immune cells and blood vessels, and even models with tumor cells, which can be used to simulate and study diseases and conditions such as skin cancer. With the growing complexity of the model, further fields of application such as aspects of wound healing can be addressed or infection studies carried out.

"We plan to grow our portfolio in stages. As the first step, we're bringing the healthy skin model to market, but there will be others as well, such as a skin model to study skin fibrosis," Reigl explains.

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Animals and COVID-19

• The risk of animals spreading SARS-CoV-2, the virus that causes COVID-19, to people is low.
• The virus can spread from people to animals during close contact.
• More studies and surveillance are needed to understand how SARS-CoV-2 is spread between people and animals.
• People with suspected or confirmed COVID-19 should avoid contact with animals, including pets, livestock, and wildlife.

• Pet Owners and Others Handling Animals
• One Health Toolkit for Health Officials Managing Companion Animals with SARS-CoV-2

Coronaviruses are a large family of viruses. Some coronaviruses cause cold-like illnesses in people, while others cause illness in certain types of animals, such as cattle, camels, and bats. Some coronaviruses, such as canine and feline coronaviruses, infect only animals and do not infect people. Some coronaviruses that infect animals can be spread to people and then spread between people, but this is rare. This is what happened with SARS-CoV-2, which likely originated in bats.

Risk of people spreading SARS-CoV-2 to animals

People can spread SARS-CoV-2 to animals, especially during close contact.

Animals infected with SARS-CoV-2 have been documented around the world. Most of these animals became infected after contact with people with COVID-19, including owners, caretakers, or others who were in close contact. We don’t yet know all of the animals that can get infected. Animals reported infected worldwide include

• Companion animals, including pet cats, dogs, hamsters, and ferrets.
• Animals in zoos and sanctuaries, including several types of big cats (e.g., lions, tigers, snow leopards), otters, non-human primates, a binturong, a coatimundi, a fishing cat, hyenas, hippopotamuses, and manatees.
• Mink on mink farms.
• Wildlife, including white-tailed deer, mule deer, a black-tailed marmoset, a giant anteater, and wild mink near mink farms.

For information on how to protect pets and animals, visit

• What You Should Know about COVID-19 and Pets
• Companion Animals with COVID-19: Toolkit for Health Officials
• Reducing Risk of Spreading COVID-19 between People and Wildlife

Risk of animals spreading SARS-CoV-2 to people

The risk of animals spreading COVID-19 to people is considered low.

There is no evidence that animals play a significant role in spreading SARS-CoV-2, the virus that causes COVID-19, to people. There have been a few reports of infected mammalian animals spreading the virus to people during close contact, but this is rare. These cases include farmed mink in Europe and the United States, white-tailed deer in Canada, pet hamsters in Hong Kong, and a cat in Thailand. In most of these cases, the animals were known to be first infected by a person who had COVID-19.

It’s important to remember that people are much more likely to get COVID-19 from other people than from animals. There is no need to euthanize or otherwise harm animals infected with SARS-CoV-2.

There is a possibility that the virus could infect animals, mutate, and a new strain could spread back to people and then among people (called spillback). More studies and surveillance are needed to track variants and mutations and to understand how SARS-CoV-2 spreads between people and animals.

Mink and SARS-CoV-2

SARS-CoV-2 has been reported in farmed mink in multiple countries.  Currently, there is no evidence that mink are playing a significant role in the spread of COVID-19 to people.

In the United States, respiratory disease and increases in mink deaths have been seen on most affected mink farms. However, some infected mink might also appear healthy. Infected workers likely introduced SARS-CoV-2 to mink on the farms, and the virus then began to spread among the mink. Once the virus is introduced on a farm, spread can occur between mink, as well as from mink to other animals on the farm (dogs, cats). One wild mink and a small number of escaped farm mink trapped near affected farms in Utah and Oregon were found to be infected with SARS-CoV-2.

Although there is no evidence that mink are playing a significant role in the spread of SARS-CoV-2 to people, there is a possibility of mink spreading SARS-CoV-2 to people and other animals on mink farms. Mink-to-human spread of SARS-CoV-2 has been reported in the Netherlands, Denmark, and Poland, and data suggest it might have occurred in the United States.

• Investigations found that mink from a Michigan farm and a small number of people were infected with SARS-CoV-2 that contained unique mink-related mutations (changes in the virus’s genetic material). This suggests mink-to-human spread might have occurred.
• Finding these mutations in mink on the Michigan farm is not unexpected because they have been seen before in mink from farms in the Netherlands and Denmark, and also in people linked to mink farms worldwide.
• To confirm the spread of SARS-CoV-2 from mink to people, public health officials would need more information on the epidemiology and genetics of the virus in mink, mink farm workers, and the communities around mink farms.
• These results highlight the importance of routinely studying the genetic material of SARS-CoV-2 in susceptible animal populations like mink, as well as in people.

Guidance is available to protect worker and animal health, developed collaboratively by the U.S. Department of Agriculture (USDA), CDC, and state animal and public health partners using a One Health approach :

Prevent Introduction of SARS-CoV-2 on Mink Farms :  Interim SARS-CoV-2 Guidance and Recommendations for Farmed Mink and Other Mustelids

Response and Containment Guidelines :  Interim Guidance for Animal Health and Public Health Officials Managing Farmed Mink and other Farmed Mustelids with SARS-CoV-2

USDA maintains a list external icon  of all animals and mink farms in the United States with SARS-CoV-2 infections confirmed by their National Veterinary Services Laboratories.

Research on animals and COVID-19

More studies and surveillance are needed to understand if and how different animals could be affected by COVID-19.

Many studies have been done to learn more about how this virus can affect different animals, including if they are susceptible to infection and if they can spread infection to other animals. Studies on animals do not show whether animals can spread infection to people.

Based on these studies, we know that invertebrates, birds, reptiles, and amphibians are not susceptible to infection with SARS-CoV-2.

What CDC is doing

Since the beginning of the pandemic, CDC has been leading efforts to improve our understanding of how SARS-CoV-2 affects animals and how the virus might spread between people and animals. CDC has also worked to improve coordination of federal, state, and other One Health partners.

• CDC leads the One Health Federal Interagency COVID-19 Coordination (OH-FICC) Group, which brings together public health, animal health, and environmental health representatives from more than 20 federal agencies to collaborate and exchange information on the One Health aspects of COVID-19. For example, the group researches and develops guidance on the connection between people and pets, wildlife, zoo animals, and livestock; animal diagnostics and testing; and environmental health issues relevant to COVID-19.
• CDC leads the regular State-Federal One Health Update Call to bring local, state, tribal, and territorial partners together with OH-FICC members.
• CDC, USDA, state public health and animal health officials, and academic partners are working in some states to conduct active surveillance (proactive testing) of SARS-CoV-2 in pets, including cats, dogs, and other small mammals, that had contact with a person with COVID-19.
• CDC deployed One Health teams to multiple states to support state and local departments of health and agriculture, federal partners, and others in conducting on-farm investigations into SARS-CoV-2 in people, mink, and other animals (domestic and wildlife). The teams collected samples from animals on the farms and from people working on the farms and in surrounding communities.

Related Pages

• Reducing the Risk of SARS-CoV-2 Spreading between People and Wildlife
• Information on Bringing an Animal into the United States
• World Organisation for Animal Health: COVID-19 Events in Animals
• USDA: Confirmed cases of SARS-CoV-2 in Animals in the United States
• USDA: Coronavirus Disease 2019 external icon
• FDA: Coronavirus Disease 2019 external icon
• Confirmation of COVID-19 in a Canada Lynx at a Pennsylvania Zoo
• Confirmation of COVID-19 in Hyenas at a Colorado Zoo
• Confirmation of COVID-19 in a Coatimundi at an Illinois Zoo
• Confirmation of COVID-19 in a Binturong and a Fishing Cat at an Illinois Zoo
• Confirmation of COVID-19 in Ferret in Florida
• Confirmation of COVID-19 in Deer in Ohio
• Texas A&M Research Uncovers First Known COVID-19 UK Variant In Animals
• Confirmation of COVID-19 in a Snow Leopard at a Kentucky Zoo​
• USDA Confirms SARS-CoV-2 in Mink in Utah
• Confirmation of COVID-19 in Pet Dog in New York
• USDA Statement on the Confirmation of COVID-19 Infection in a Tiger in New York

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FDA and Cannabis: Research and Drug Approval Process

On this page:, fda supports sound scientific research.

• Cannabis Study Drugs Controlled Under Schedule I of the CSA
• Cannabis Study Drugs Containing Hemp

Additional Resources

The FDA understands that there is increasing interest in the potential utility of cannabis for a variety of medical conditions, as well as research on the potential adverse health effects from use of cannabis.

To date, the FDA has not approved a marketing application for cannabis for the treatment of any disease or condition. The agency has, however, approved one cannabis-derived drug product: Epidiolex (cannabidiol), and three synthetic cannabis-related drug products: Marinol (dronabinol), Syndros (dronabinol), and Cesamet (nabilone). These approved drug products are only available with a prescription from a licensed healthcare provider. Importantly, the FDA has not approved any other cannabis, cannabis-derived, or cannabidiol (CBD) products currently available on the market.

• Cannabis sativa L. is a plant that contains over 80 different naturally occurring compounds called “cannabinoids”
• Cannabidiol (CBD)
• Tetrahydrocannabinol (THC)
• Plants are grown to produce varying concentrations of cannabinoids – THC or CBD
• These plant variations are called cultivars

Cannabis-derived compounds

• Compounds occurring naturally in the plant – like CBD and THC
• These compounds are extracted directly from the plant
• Can be used to manufacture drug products
• Example: highly-purified CBD extracted from the plant

Cannabis-related compounds

• These synthetic compounds are created in a laboratory
• Can be used to manufacture drug products 
• Some synthetic compounds may also occur naturally in the plant and some may not
• Examples: synthetically-derived dronabinol (also naturally occurring) and nabilone (not naturally occurring) 

FDA has approved Epidiolex, which contains a purified form of the drug substance cannabidiol (CBD) for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age and older. That means FDA has concluded that this particular drug product is safe and effective for its intended use.

The agency also has approved Marinol and Syndros for therapeutic uses in the United States, including for nausea associated with cancer chemotherapy and for the treatment of anorexia associated with weight loss in AIDS patients. Marinol and Syndros include the active ingredient dronabinol, a synthetic delta-9- tetrahydrocannabinol (THC) which is considered the psychoactive intoxicating component of cannabis (i.e., the component responsible for the “high” people may experience from using cannabis). Another FDA-approved drug, Cesamet, contains the active ingredient nabilone, which has a chemical structure similar to THC and is synthetically derived. Cesamet, like dronabinol-containing products, is indicated for nausea associated with cancer chemotherapy.

FDA is aware that unapproved cannabis and/or unapproved cannabis-derived products are being used to treat a number of medical conditions including, AIDS wasting, epilepsy, neuropathic pain, spasticity associated with multiple sclerosis, and cancer and chemotherapy-induced nausea. Caregivers and patients can be confident that FDA-approved drugs have been carefully evaluated for safety, efficacy, and quality, and are monitored by the FDA once they are on the market. However, the use of unapproved cannabis and cannabis-derived products can have unpredictable and unintended consequences, including serious safety risks. Also, there has been no FDA review of data from rigorous clinical trials to support that these unapproved products are safe and efficacious for the various therapeutic uses for which they are being used.

FDA understands the need to develop therapies for patients with unmet medical needs, and does everything it can to facilitate this process. FDA has programs such as Fast Track, Breakthrough Therapy, Accelerated Approval and Priority Review that are designed to facilitate the development of and expedite the approval of drug products. In addition, the FDA’s expanded access (sometimes called “compassionate use”) statutory and regulatory provisions are designed to facilitate the availability of investigational products to patients with serious diseases or conditions when there is no comparable or satisfactory alternative therapy available, either because the patients have exhausted treatment with or are intolerant of approved therapies, or when the patients are not eligible for an ongoing clinical trial. Through these programs and the drug approval process, FDA supports sound, scientifically-based research into the medicinal uses of drug products containing cannabis or cannabis-derived compounds and will continue to work with companies interested in bringing safe, effective, and quality products to market.

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The FDA has an important role to play in supporting scientific research into the medical uses of cannabis and its constituents in scientifically valid investigations as part of the agency’s drug review and approval process. As a part of this role, the FDA supports those in the medical research community who intend to study cannabis by:

• Providing information on the process needed to conduct clinical research using cannabis.
• Providing information on the specific requirements needed to develop a human drug that is derived from a plant such as cannabis. In December 2016, the FDA updated its Guidance for Industry: Botanical Drug Development , which provides sponsors with guidance on submitting investigational new drug (IND) applications for botanical drug products. The FDA also has issued “ Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research, Draft Guidance for Industry .”
• Providing specific support for investigators interested in conducting clinical research using cannabis and its constituents as a part of the IND or investigational new animal drug (INAD) process through meetings and regular interactions throughout the drug development process.
• Providing general support to investigators to help them understand and follow the procedures to conduct clinical research through the FDA Center for Drug Evaluation and Research (CDER) Small Business and Industry Assistance group .

To conduct clinical research that can lead to an approved new drug, including research using materials from plants such as cannabis, researchers need to work with the FDA and submit an IND application to CDER. The IND application process gives researchers a path to follow that includes regular interactions with the FDA to support efficient drug development while protecting the patients who are enrolled in the trials. An IND includes protocols describing proposed studies, the qualifications of the investigators who will conduct the clinical studies, and assurances of informed consent and protection of the rights, safety, and welfare of the human subjects. The FDA reviews the IND to ensure that the proposed studies, generally referred to as “clinical trials,” do not place human subjects at an unreasonable risk of harm. The FDA also requires obtaining the informed consent of trial subjects and human subject protection in the conduct of the clinical trials. For research intending to develop an animal drug product, researchers would establish an INAD file with the Center for Veterinary Medicine (CVM) to conduct their research, rather than an IND with CDER.

FDA is committed to encouraging the development of cannabis-related drug products, including CBD. Those interested in cannabis-derived and cannabis-related drug development are encouraged to contact the relevant CDER review division and CDER’s Botanical Review Team (BRT) to answer questions related to their specific drug development program. The BRT serves as an expert resource on botanical issues and has developed the Botanical Drug Development Guidance for Industry to assist those pursuing drug development in this area. FDA encourages researchers to request a Pre-Investigational New Drug application (PIND) meeting to discuss questions related to the development of a specific cannabis-derived and cannabis-related drug product.

Please note that certain cultivars and parts of the Cannabis sativa L. plant are controlled under the Controlled Substances Act (CSA) since 1970 under the drug class "Marihuana" (commonly referred to as "marijuana") [21 U.S.C. 802(16)]. "Marihuana" is listed in Schedule I of the CSA due to its high potential for abuse, which is attributable in large part to the psychoactive intoxicating effects of THC, and the absence of a currently accepted medical use in the United States. From 1970 until December of 2018, the definition of “marihuana” included all types of Cannabis Sativa L. , regardless of THC content.  However, in December 2018, the Agriculture Improvement Act of 2018 (also known as the Farm Bill) removed hemp, a type of cannabis that is very low in THC (cannabis or cannabis derivatives containing no more than 0.3% THC on a dry weight basis), from controls under the CSA. This change in the law may result in a more streamlined process for researchers to study cannabis and its derivatives, including CBD, that fall under the definition of hemp, a result which could speed the development of new drugs containing hemp. 

Conducting clinical research using cannabis-derived substances that are considered controlled substances under the CSA often involves interactions with several federal agencies. For example:

• Protocols to conduct research with controlled substances listed in Schedule I are required to be conducted under a site-specific DEA investigator registration. For more information, see 21 CFR 1301.18 .
• National Institute on Drug Abuse (NIDA) Drug Supply Program provides research-grade marijuana for scientific study. Through registration issued by DEA, NIDA is responsible for overseeing the cultivation of marijuana for medical research and has contracted with the University of Mississippi to grow marijuana for research at a secure facility. Marijuana of varying potencies and compositions along with marijuana-derived compounds are available. DEA also may allow additional growers to register with the DEA to produce and distribute marijuana for research purposes. DEA that, as the result of a recent amendment to federal law, certain forms of cannabis no longer require DEA registration to grow or manufacture.
• Researchers work with the FDA and submit an IND or INAD application to the appropriate CDER divisions or other center offices depending on the therapeutic indication or population. If the research is intended to support the approval of an animal drug product, an INAD file should be established with CVM. Based on the results obtained in studies conducted at the IND or INAD stage, sponsors may submit a marketing application for formal approval of the drug.

Cannabis Study Drugs Controlled Under Schedule I of the CSA (greater than 0.3% THC on a dry weight basis)

Sponsor obtains pre-IND number through CDER review division to request a pre-IND meeting. For new animal drug research, a sponsor may engage with CVM to establish an INAD file. A pre-IND meeting with CDER is optional, and an opportunity to obtain FDA guidance on sponsor research plans and required content for an IND submission .

The sponsor contacts NIDA or another DEA-registered source of cannabis and/or cannabis-derived substances to obtain information on the specific cultivars available, so that all necessary chemistry, manufacturing, and controls (CMC) and botanical raw material (BRM) information can be included in the IND. Importation of products controlled under the CSA are subject to DEA authorization.

The sponsor may contact DEA to discuss Schedule I drug research plans that may require DEA inspection for an investigator and study site Schedule I license.

Step 4: If the selected BRM or drug substance manufacturer holds a Drug Master File (DMF) , the sponsor must obtain a Letter of Authorization (LOA) to reference CMC and BRM information. Alternatively, an IND submission would need to contain all necessary CMC data characterizing their study drug and ensuring it is safe for use in humans.

The sponsor sends a copy of the IND and clinical protocol, including a LOA (if applicable), to FDA.

FDA reviews the submitted IND. The sponsor must wait 30 calendar days following IND submission before initiating any clinical trials, unless FDA notifies the sponsor that the trials may proceed sooner. During this time, FDA has an opportunity to review the submission for safety to assure that research subjects will not be subjected to unreasonable risk.

If the IND is authorized by FDA as “safe to proceed” the sponsor may then submit their clinical protocol registration application, including referenced IND number, to DEA to obtain the protocol registration. Once this is received, the sponsor contacts NIDA or another DEA-registered source to obtain the cannabis and/or cannabis-derived substances and they can then begin the study.

For nonclinical research, including research conducted under an INAD file submitted established with CVM, there is no requirement of prior authorization of the protocol by FDA before the investigators may proceed with a protocol registration application submitted to DEA. For these nonclinical protocols, investigators may immediately pursue investigator and study site licensure, and protocol registration with DEA, so they may then obtain their Schedule I cannabis-derived study drug from supplier.

Cannabis Study Drugs Containing Hemp (no more than 0.3% THC on a dry weight basis)

Sponsor provides all applicable chemistry, manufacturing, and controls (CMC) and botanical raw material (BRM) information in the IND for review by FDA, including hemp cultivars.

If the selected hemp manufacturer holds a Drug Master File (DMF) , the sponsor must obtain a Letter of Authorization (LOA) to reference CMC and BRM information. Alternatively, an IND submission would need to contain all necessary CMC data characterizing their study drug and ensuring it is safe for use in humans.

FDA’s Role in the Drug Approval Process

The FDA’s role in the regulation of drugs, including cannabis and cannabis-derived products, also includes review of applications to market drugs to determine whether proposed drug products are safe and effective for their intended indications. The FDA’s drug approval process requires that clinical trials be designed and conducted in a way that provides the agency with the necessary scientific data upon which the FDA can make its approval decisions. Without this review, the FDA cannot determine whether a drug product is safe and effective. It also cannot ensure that a drug product meets appropriate quality standards. For certain drugs that have not been approved by the FDA, the lack of FDA approval and oversight means the safety, effectiveness, and quality of the drug – including how potent it is, how pure it is, and whether the labeling is accurate or false – may vary considerably.

• Product-Specific Guidance for Generic Drug Development: Draft Guidance on Cannabidiol Oral Solution (PDF - 42KB)
• Cannabis Clinical Research: Drug Master Files (DMFs) & Quality Considerations Webinar
• Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research, Draft Guidance for Industry
• FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD): Questions and Answers
• Development & Approval Process (Drugs)
• From an Idea to the Marketplace: The Journey of an Animal Drug through the Approval Process
• FDA Center for Drug Evaluation and Research Small Business and Industry Assistance group
• CVM Small Business Assistance
• National Institutes of Health (NIH): Guidance on Procedures for Provision of Marijuana for Medical Research
• National Institute on Drug Abuse's (NIDA) Role in Providing Marijuana for Research
• Drug Enforcement Administration - Registration of Manufacturers, Distributors, and Dispensers of Controlled Substances
• International Narcotics Control Board: Single Convention on Narcotic Drugs (1961)
• National Institute on Drug Abuse (NIDA): Ordering Guidelines for Marijuana and Marijuana Cigarettes

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Ethical considerations regarding animal experimentation

Aysha karim kiani.

1 Allama Iqbal Open University, Islamabad, Pakistan

2 MAGI EUREGIO, Bolzano, Italy

DEREK PHEBY

3 Society and Health, Buckinghamshire New University, High Wycombe, UK

GARY HENEHAN

4 School of Food Science and Environmental Health, Technological University of Dublin, Dublin, Ireland

RICHARD BROWN

5 Department of Psychology and Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada

PAUL SIEVING

6 Department of Ophthalmology, Center for Ocular Regenerative Therapy, School of Medicine, University of California at Davis, Sacramento, CA, USA

PETER SYKORA

7 Department of Philosophy and Applied Philosophy, University of St. Cyril and Methodius, Trnava, Slovakia

ROBERT MARKS

8 Department of Biotechnology Engineering, Ben-Gurion University of the Negev, Beer-Sheva, Israel

BENEDETTO FALSINI

9 Institute of Ophthalmology, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome, Italy

NATALE CAPODICASA

10 MAGI BALKANS, Tirana, Albania

STANISLAV MIERTUS

11 Department of Biotechnology, University of SS. Cyril and Methodius, Trnava, Slovakia

12 International Centre for Applied Research and Sustainable Technology, Bratislava, Slovakia

LORENZO LORUSSO

13 UOC Neurology and Stroke Unit, ASST Lecco, Merate, Italy

DANIELE DONDOSSOLA

14 Center for Preclincal Research and General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca‘ Granda Ospedale Maggiore Policlinico, Milan, Italy

15 Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy

GIANLUCA MARTINO TARTAGLIA

16 Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Milan, Italy

17 UOC Maxillo-Facial Surgery and Dentistry, Fondazione IRCCS Ca Granda, Ospedale Maggiore Policlinico, Milan, Italy

MAHMUT CERKEZ ERGOREN

18 Department of Medical Genetics, Faculty of Medicine, Near East University, Nicosia, Cyprus

MUNIS DUNDAR

19 Department of Medical Genetics, Erciyes University Medical Faculty, Kayseri, Turkey

SANDRO MICHELINI

20 Vascular Diagnostics and Rehabilitation Service, Marino Hospital, ASL Roma 6, Marino, Italy

DANIELE MALACARNE

21 MAGI’S LAB, Rovereto (TN), Italy

GABRIELE BONETTI

Astrit dautaj, kevin donato, maria chiara medori, tommaso beccari.

22 Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy

MICHELE SAMAJA

23 MAGI GROUP, San Felice del Benaco (BS), Italy

STEPHEN THADDEUS CONNELLY

24 San Francisco Veterans Affairs Health Care System, University of California, San Francisco, CA, USA

DONALD MARTIN

25 Univ. Grenoble Alpes, CNRS, Grenoble INP, TIMC-IMAG, SyNaBi, Grenoble, France

ASSUNTA MORRESI

26 Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy

ARIOLA BACU

27 Department of Biotechnology, University of Tirana, Tirana, Albania

KAREN L. HERBST

28 Total Lipedema Care, Beverly Hills California and Tucson Arizona, USA

MYKHAYLO KAPUSTIN

29 Federation of the Jewish Communities of Slovakia

LIBORIO STUPPIA

30 Department of Psychological, Health and Territorial Sciences, School of Medicine and Health Sciences, University "G. d'Annunzio", Chieti, Italy

LUDOVICA LUMER

31 Department of Anatomy and Developmental Biology, University College London, London, UK

GIAMPIETRO FARRONATO

Matteo bertelli.

32 MAGISNAT, Peachtree Corners (GA), USA

Animal experimentation is widely used around the world for the identification of the root causes of various diseases in humans and animals and for exploring treatment options. Among the several animal species, rats, mice and purpose-bred birds comprise almost 90% of the animals that are used for research purpose. However, growing awareness of the sentience of animals and their experience of pain and suffering has led to strong opposition to animal research among many scientists and the general public. In addition, the usefulness of extrapolating animal data to humans has been questioned. This has led to Ethical Committees’ adoption of the ‘four Rs’ principles (Reduction, Refinement, Replacement and Responsibility) as a guide when making decisions regarding animal experimentation. Some of the essential considerations for humane animal experimentation are presented in this review along with the requirement for investigator training. Due to the ethical issues surrounding the use of animals in experimentation, their use is declining in those research areas where alternative in vitro or in silico methods are available. However, so far it has not been possible to dispense with experimental animals completely and further research is needed to provide a road map to robust alternatives before their use can be fully discontinued.

How to cite this article: Kiani AK, Pheby D, Henehan G, Brown R, Sieving P, Sykora P, Marks R, Falsini B, Capodicasa N, Miertus S, Lorusso L, Dondossola D, Tartaglia GM, Ergoren MC, Dundar M, Michelini S, Malacarne D, Bonetti G, Dautaj A, Donato K, Medori MC, Beccari T, Samaja M, Connelly ST, Martin D, Morresi A, Bacu A, Herbst KL, Kapustin M, Stuppia L, Lumer L, Farronato G, Bertelli M. Ethical considerations regarding animal experimentation. J Prev Med Hyg 2022;63(suppl.3):E255-E266. https://doi.org/10.15167/2421-4248/jpmh2022.63.2S3.2768

Introduction

Animal model-based research has been performed for a very long time. Ever since the 5 th century B.C., reports of experiments involving animals have been documented, but an increase in the frequency of their utilization has been observed since the 19 th century [ 1 ]. Most institutions for medical research around the world use non-human animals as experimental subjects [ 2 ]. Such animals might be used for research experimentations to gain a better understanding of human diseases or for exploring potential treatment options [ 2 ]. Even those animals that are evolutionarily quite distant from humans, such as Drosophila melanogaster , Zebrafish ( Danio rerio ) and Caenorhabditis elegans , share physiological and genetic similarities with human beings [ 2 ]; therefore animal experimentation can be of great help for the advancement of medical science [ 2 ].

For animal experimentation, the major assumption is that the animal research will be of benefit to humans. There are many reasons that highlight the significance of animal use in biomedical research. One of the major reasons is that animals and humans share the same biological processes. In addition, vertebrates have many anatomical similarities (all vertebrates have lungs, a heart, kidneys, liver and other organs) [ 3 ]. Therefore, these similarities make certain animals more suitable for experiments and for providing basic training to young researchers and students in different fields of biological and biomedical sciences [ 3 ]. Certain animals are susceptible to various health problems that are similar to human diseases such as diabetes, cancer and heart disease [ 4 ]. Furthermore, there are genetically modified animals that are used to obtain pathological phenotypes [ 5 ]. A significant benefit of animal experimentation is that test species can be chosen that have a much shorter life cycle than humans. Therefore, animal models can be studied throughout their life span and for several successive generations, an essential element for the understanding of disease progression along with its interaction with the whole organism throughout its lifetime [ 6 ].

Animal models often play a critical role in helping researchers who are exploring the efficacy and safety of potential medical treatments and drugs. They help to identify any dangerous or undesired side effects, such as birth defects, infertility, toxicity, liver damage or any potential carcinogenic effects [ 7 ]. Currently, U.S. Federal law, for example, requires that non-human animal research is used to demonstrate the efficacy and safety of any new treatment options before proceeding to trials on humans [ 8 ]. Of course, it is not only humans benefit from this research and testing, since many of the drugs and treatments that are developed for humans are routinely used in veterinary clinics, which help animals live longer and healthier lives [ 4 ].

COVID-19 AND THE NEED FOR ANIMAL MODELS

When COVID-19 struck, there was a desperate need for research on the disease, its effects on the brain and body and on the development of new treatments for patients with the disease. Early in the disease it was noticed that those with the disease suffered a loss of smell and taste, as well as neurological and psychiatric symptoms, some of which lasted long after the patients had “survived” the disease [ 9-15 ]. As soon as the pandemic started, there was a search for appropriate animal models in which to study this unknown disease [ 16 , 17 ]. While genetically modified mice and rats are the basic animal models for neurological and immunological research [ 18 , 19 ] the need to understand COVID-19 led to a range of animal models; from fruit flies [ 20 ] and Zebrafish [ 21 ] to large mammals [ 22 , 23 ] and primates [ 24 , 25 ]. And it was just not one animal model that was needed, but many, because different aspects of the disease are best studied in different animal models [ 16 , 25 , 26 ]. There is also a need to study the transmission pathways of the zoonosis: where does it come from, what are the animal hosts and how is it transferred to humans [ 27 ]?

There has been a need for animal models for understanding the pathophysiology of COVID-19 [ 28 ], for studying the mechanisms of transmission of the disease [ 16 ], for studying its neurobiology [ 29 , 30 ] and for developing new vaccines [ 31 ]. The sudden onset of the COVID-19 pandemic has highlighted the fact that animal research is necessary, and that the curtailment of such research has serious consequences for the health of both humans and animals, both wild and domestic [ 32 ] As highlighted by Adhikary et al. [ 22 ] and Genzel et al. [ 33 ] the coronavirus has made clear the necessity for animal research and the danger in surviving future such pandemics if animal research is not fully supported. Genzel et al. [ 33 ], in particular, take issue with the proposal for a European ban on animal testing. Finally, there is a danger in bypassing animal research in developing new vaccines for diseases such as COVID-19 [ 34 ]. The purpose of this paper is to show that, while animal research is necessary for the health of both humans and animals, there is a need to carry out such experimentation in a controlled and humane manner. The use of alternatives to animal research such as cultured human cells and computer modeling may be a useful adjunct to animal studies but will require that such methods are more readily accessible to researchers and are not a replacement for animal experimentation.

Pros and cons of animal experimentation

Arguments against animal experimentation.

A fundamental question surrounding this debate is to ask whether it is appropriate to use animals for medical research. Is our acceptance that animals have a morally lower value or standard of life just a case of speciesism [ 35 ]? Nowadays, most people agree that animals have a moral status and that needlessly hurting or abusing pets or other animals is unacceptable. This represents something of a change from the historical point of view where animals did not have any moral status and the treatment of animals was mostly subservient to maintaining the health and dignity of humans [ 36 ].

Animal rights advocates strongly argue that the moral status of non-human animals is similar to that of humans, and that animals are entitled to equality of treatment. In this view, animals should be treated with the same level of respect as humans, and no one should have the right to force them into any service or to kill them or use them for their own goals. One aspect of this argument claims that moral status depends upon the capacity to suffer or enjoy life [ 37 ].

In terms of suffering and the capacity of enjoying life, many animals are not very different from human beings, as they can feel pain and experience pleasure [ 38 ]. Hence, they should be given the same moral status as humans and deserve equivalent treatment. Supporters of this argument point out that according animals a lower moral status than humans is a type of prejudice known as “speciesism” [ 38 ]. Among humans, it is widely accepted that being a part of a specific race or of a specific gender does not provide the right to ascribe a lower moral status to the outsiders. Many advocates of animal rights deploy the same argument, that being human does not give us sufficient grounds declare animals as being morally less significant [ 36 ].

ARGUMENTS IN FAVOR OF ANIMAL EXPERIMENTATION

Those who support animal experimentation have frequently made the argument that animals cannot be elevated to be seen as morally equal to humans [ 39 ]. Their main argument is that the use of the terms “moral status” or “morality” is debatable. They emphasize that we must not make the error of defining a quality or capacity associated with an animal by using the same adjectives used for humans [ 39 ]. Since, for the most part, animals do not possess humans’ cognitive capabilities and lack full autonomy (animals do not appear to rationally pursue specific goals in life), it is argued that therefore, they cannot be included in the moral community [ 39 ]. It follows from this line of argument that, if animals do not possess the same rights as human beings, their use in research experimentation can be considered appropriate [ 40 ]. The European and the American legislation support this kind of approach as much as their welfare is respected.

Another aspect of this argument is that the benefits to human beings of animal experimentation compensate for the harm caused to animals by these experiments.

In other words, animal harm is morally insignificant compared to the potential benefits to humans. Essentially, supporters of animal experimentation claim that human beings have a higher moral status than animals and that animals lack certain fundamental rights accorded to humans. The potential violations of animal rights during animal research are, in this way, justified by the greater benefits to mankind [ 40 , 41 ]. A way to evaluate when the experiments are morally justified was published in 1986 by Bateson, which developed the Bateson’s Cube [ 42 ]. The Cube has three axes: suffering, certainty of benefit and quality of research. If the research is high-quality, beneficial, and not inflicting suffering, it will be acceptable. At the contrary, painful, low-quality research with lower likelihood of success will not be acceptable [ 42 , 43 ].

Impact of experimentations on animals

Ability to feel pain and distress.

Like humans, animal have certain physical as well as psychological characteristics that make their use for experimentation controversial [ 44 ].

In the last few decades, many studies have increased knowledge of animal awareness and sentience: they indicate that animals have greater potential to experience damage than previously appreciated and that current rights and protections need to be reconsidered [ 45 ]. In recent times, scientists as well as ethicists have broadly acknowledged that animals can also experience distress and pain [ 46 ]. Potential sources of such harm arising from their use in research include disease, basic physiological needs deprivation and invasive procedures [ 46 ]. Moreover, social deprivation and lack of the ability to carry out their natural behaviors are other causes of animal harm [ 46 ]. Several studies have shown that, even in response to very gentle handling and management, animals can show marked alterations in their physiological and hormonal stress markers [ 47 ].

In spite of the fact that suffering and pain are personalized experiences, several multi-disciplinary studies have provided clear evidence of animals experiencing pain and distress. In particular, some animal species have the ability to express pain similarly to human due to common psychological, neuroanatomical and genetic characteristics [ 48 ]. Similarly, animals share a resemblance to humans in their developmental, genetic and environmental risk factors for psychopathology. For instance, in many species, it has been shown that fear operates within a less organized subcortical neural circuit than pain [ 49 , 50 ]. Various types of depression and anxiety disorders like posttraumatic stress disorder have also been reported in mammals [ 51 ].

PSYCHOLOGICAL CAPABILITIES OF ANIMALS

Some researchers have suggested that besides their ability to experience physical and psychological pain and distress, some animals also exhibit empathy, self-awareness and language-like capabilities. They also demonstrate tools-linked cognizance, pleasure-seeking and advanced problem-solving skills [ 52 ]. Moreover, mammals and birds exhibit playful behavior, an indicator of the capacity to experience pleasure. Other taxa such as reptiles, cephalopods and fishes have also been observed to display playful behavior, therefore the current legislation prescribes the use of environmental enrichers [ 53 ]. The presence of self-awareness ability, as assessed by mirror self-recognition, has been reported in magpies, chimpanzees and other apes, and certain cetaceans [ 54 ]. Recently, another study has revealed that crows have the ability to create and use tools that involve episodic-like memory formation and its retrieval. From these findings, it may be suggested that crows as well as related species show evidence of flexible learning strategies, causal reasoning, prospection and imagination that are similar to behavior observed in great apes [ 55 ]. In the context of resolving the ethical dilemmas about animal experimentation, these observations serve to highlight the challenges involved [ 56 , 57 ].

Ethics, principles and legislation in animal experimentation

Ethics in animal experimentation.

Legislation around animal research is based on the idea of the moral acceptability of the proposed experiments under specific conditions [ 58 ]. The significance of research ethics that ensures proper treatment of experimental animals [ 58 ]. To avoid undue suffering of animals, it is important to follow ethical considerations during animal studies [ 1 ]. It is important to provide best human care to these animals from the ethical and scientific point of view [ 1 ]. Poor animal care can lead to experimental outcomes [ 1 ]. Thus, if experimental animals mistreated, the scientific knowledge and conclusions obtained from experiments may be compromised and may be difficult to replicate, a hallmark of scientific research [ 1 ]. At present, most ethical guidelines work on the assumption that animal experimentation is justified because of the significant potential benefits to human beings. These guidelines are often permissive of animal experimentation regardless of the damage to the animal as long as human benefits are achieved [ 59 ].

PRINCIPLE OF THE 4 RS

Although animal experimentation has resulted in many discoveries and helped in the understanding numerous aspects of biological science, its use in various sectors is strictly controlled. In practice, the proposed set of animal experiments is usually considered by a multidisciplinary Ethics Committee before work can commence [ 60 ]. This committee will review the research protocol and make a judgment as to its sustainability. National and international laws govern the utilization of animal experimentation during research and these laws are mostly based on the universal doctrine presented by Russell and Burch (1959) known as principle of the 3 Rs. The 3Rs referred to are Reduction, Refinement and Replacement, and are applied to protocols surrounding the use of animals in research. Some researchers have proposed another “R”, of responsibility for the experimental animal as well as for the social and scientific status of the animal experiments [ 61 ]. Thus, animal ethics committees commonly review research projects with reference to the 4 Rs principles [ 62 ].

The first “R”, Reduction means that the experimental design is examined to ensure that researchers have reduced the number of experimental animals in a research project to the minimum required for reliable data [ 59 ]. Methods used for this purpose include improved experimental design, extensive literature search to avoid duplication of experiments [ 35 ], use of advanced imaging techniques, sharing resources and data, and appropriate statistical data analysis that reduce the number of animals needed for statistically significant results [ 2 , 63 ].

The second “R”, Refinement involves improvements in procedure that minimize the harmful effects of the proposed experiments on the animals involved, such as reducing pain, distress and suffering in a manner that leads to a general improvement in animal welfare. This might include for example improved living conditions for research animals, proper training of people handling animals, application of anesthesia and analgesia when required and the need for euthanasia of the animals at the end of the experiment to curtail their suffering [ 63 ].

The third “R”, Replacement refers to approaches that replace or avoid the use of experimental animals altogether. These approaches involve use of in silico methods/computerized techniques/software and in vitro methods like cell and tissue culture testing, as well as relative replacement methods by use of invertebrates like nematode worms, fruit flies and microorganisms in place of vertebrates and higher animals [ 1 ]. Examples of proper application of these first “3R2 principles are the use of alternative sources of blood, the exploitation of commercially used animals for scientific research, a proper training without use of animals and the use of specimen from previous experiments for further researches [ 64-67 ].

The fourth “R”, Responsibility refers to concerns around promoting animal welfare by improvements in experimental animals’ social life, development of advanced scientific methods for objectively determining sentience, consciousness, experience of pain and intelligence in the animal kingdom, as well as effective involvement in the professionalization of the public discussion on animal ethics [ 68 ].

OTHER ASPECTS OF ANIMAL RESEARCH ETHICS

Other research ethics considerations include having a clear rationale and reasoning for the use of animals in a research project. Researchers must have reasonable expectation of generating useful data from the proposed experiment. Moreover, the research study should be designed in such a way that it should involve the lowest possible sample size of experimental animals while producing statistically significant results [ 35 ].

All individual researchers that handle experimental animals should be properly trained for handling the particular species involved in the research study. The animal’s pain, suffering and discomfort should be minimized [ 69 ]. Animals should be given proper anesthesia when required and surgical procedures should not be repeated on same animal whenever possible [ 69 ]. The procedure of humane handling and care of experimental animals should be explicitly detailed in the research study protocol. Moreover, whenever required, aseptic techniques should be properly followed [ 70 ]. During the research, anesthetization and surgical procedures on experimental animals should only be performed by professionally skilled individuals [ 69 ].

The Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines that are issued by the National Center for the Replacement, Refinement, and Reduction of Animals in Research (NC3Rs) are designed to improve the documentation surrounding research involving experimental animals [ 70 ]. The checklist provided includes the information required in the various sections of the manuscript i.e. study design, ethical statements, experimental procedures, experimental animals and their housing and husbandry, and more [ 70 ].

It is critical to follow the highest ethical standards while performing animal experiments. Indeed, most of the journals refuse to publish any research data that lack proper ethical considerations [ 35 ].

INVESTIGATORS’ ETHICS

Since animals have sensitivity level similar to the human beings in terms of pain, anguish, survival instinct and memory, it is the responsibility of the investigator to closely monitor the animals that are used and identify any sign of distress [ 71 ]. No justification can rationalize the absence of anesthesia or analgesia in animals that undergo invasive surgery during the research [ 72 ]. Investigators are also responsible for giving high-quality care to the experimental animals, including the supply of a nutritious diet, easy water access, prevention of and relief from any pain, disease and injury, and appropriate housing facilities for the animal species [ 73 ]. A research experiment is not permitted if the damage caused to the animal exceeds the value of knowledge gained by that experiment. No scientific advancement based on the destruction and sufferings of another living being could be justified. Besides ensuring the welfare of animals involved, investigators must also follow the applicable legislation [ 74 , 75 ].

To promote the comfort of experimental animals in England, an animal protection society named: ‘The Society for the Preservation of Cruelty to Animals’ (now the Royal Society for the Prevention of Cruelty to Animals) was established (1824) that aims to prevent cruelty to animal [ 76 ].

ANIMAL WELFARE LAWS

Legislation for animal protection during research has long been established. In 1876 the British Parliament sanctioned the ‘Cruelty to Animals Act’ for animal protection. Russell and Burch (1959) presented the ‘3 Rs’ principles: Replacement, Reduction and Refinement, for use of animals during research [ 61 ]. Almost seven years later, the U.S.A also adopted regulations for the protection of experimental animals by enacting the Laboratory Animal Welfare Act of 1966 [ 60 ]. In Brazil, the Arouca Law (Law No. 11,794/08) regulates the animal use in scientific research experiments [ 76 ].

These laws define the breeding conditions, and regulate the use of animals for scientific research and teaching purposes. Such legal provisions control the use of anesthesia, analgesia or sedation in experiments that could cause distress or pain to experimental animals [ 59 , 76 ]. These laws also stress the need for euthanasia when an experiment is finished, or even during the experiment if there is any intense suffering for the experimental animal [ 76 ].

Several national and international organizations have been established to develop alternative techniques so that animal experimentation can be avoided, such as the UK-based National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) ( www.caat.jhsph.edu ), the European Centre for the Validation of Alternative Methods (ECVAM) [ 77 ], the Universities Federation for Animal Welfare (UFAW) ( www.ufaw.org.uk ), The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) [ 78 ], and The Center for Alternatives to Animal Testing (CAAT) ( www.caat.jhsph.edu ). The Brazilian ‘Arouca Law’ also constitutes a milestone, as it has created the ‘National Council for the Control of Animal Experimentation’ (CONCEA) that deals with the legal and ethical issues related to the use of experimental animals during scientific research [ 76 ].

Although national as well as international laws and guidelines have provided basic protections for experimental animals, the current regulations have some significant discrepancies. In the U.S., the Animal Welfare Act excludes rats, mice and purpose-bred birds, even though these species comprise almost 90% of the animals that are used for research purpose [ 79 ]. On the other hand, certain cats and dogs are getting special attention along with extra protection. While the U.S. Animal Welfare Act ignores birds, mice and rats, the U.S. guidelines that control research performed using federal funding ensure protections for all vertebrates [ 79 , 80 ].

Living conditions of animals

Choice of the animal model.

Based on all the above laws and regulations and in line with the deliberations of ethical committees, every researcher must follow certain rules when dealing with animal models.

Before starting any experimental work, thorough research should be carried out during the study design phase so that the unnecessary use of experimental animals is avoided. Nevertheless, certain research studies may have compelling reasons for the use of animal models, such as the investigation of human diseases and toxicity tests. Moreover, animals are also widely used in the training of health professionals as well as in training doctors in surgical skills [ 1 , 81 ].

Researcher should be well aware of the specific traits of the animal species they intend to use in the experiment, such as its developmental stages, physiology, nutritional needs, reproductive characteristics and specific behaviors. Animal models should be selected on the basis of the study design and the biological relevance of the animal [ 1 ].

Typically, in early research, non-mammalian models are used to get rapid insights into research problems such as the identification of gene function or the recognition of novel therapeutic options. Thus, in biomedical and biological research, among the most commonly used model organisms are the Zebrafish, the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans . The main advantage of these non-mammalian animal models is their prolific reproducibility along with their much shorter generation time. They can be easily grown in any laboratory setting, are less expensive than the murine animal models and are somewhat more powerful than the tissue and cell culture approaches [ 82 ].

Caenorhabditis elegans is a small-sized nematode with a short life cycle and that exists in large populations and is relatively inexpensive to cultivate. Scientists have gathered extensive knowledge of the genomics and genetics of Caenorhabditis elegans ; but Caenorhabditis elegans models, while very useful in some respects, are unable to represent all signaling pathways found in humans. Furthermore, due to its short life cycle, scientists are unable to investigate long term effects of test compounds or to analyze primary versus secondary effects [ 6 ].

Similarly, the fruit fly Drosophila melanogaster has played a key role in numerous biomedical discoveries. It is small in size, has a short life cycle and large population size, is relatively inexpensive to breed, and extensive genomics and genetics information is available [ 6 ]. However, its respiratory, cardiovascular and nervous systems differ considerably from human beings. In addition, its immune system is less developed when compared to vertebrates, which is why effectiveness of a drug in Drosophila melanogaster may not be easily extrapolated to humans [ 83 ].

The Zebrafish ( Danio rerio ) is a small freshwater teleost, with transparent embryos, providing easy access for the observation of organogenesis and its manipulation. Therefore, Zebrafish embryos are considered good animal models for different human diseases like tuberculosis and fetal alcohol syndrome and are useful as neurodevelopmental research models. However, Zebrafish has very few mutant strains available, and its genome has numerous duplicate genes making it impossible to create knockout strains, since disrupting one copy of the gene will not disrupt the second copy of that gene. This feature limits the use of Zebrafish as animal models to study human diseases. Additionally they are rather expensive, have long life cycle, and genomics and genetics studies are still in progress [ 82 , 84 ].

Thus, experimentation on these three animals might not be equivalent to experimentation on mammals. Mammalian animal model are most similar to human beings, so targeted gene replacement is possible. Traditionally, mammals like monkey and mice have been the preferred animal models for biomedical research because of their evolutionary closeness to humans. Rodents, particularly mice and rats, are the most frequently used animal models for scientific research. Rats are the most suitable animal model for the study of obesity, shock, peritonitis, sepsis, cancer, intestinal operations, spleen, gastric ulcers, mononuclear phagocytic system, organ transplantations and wound healing. Mice are more suitable for studying burns, megacolon, shock, cancer, obesity, and sepsis as mentioned previously [ 85 ].

Similarly, pigs are mostly used for stomach, liver and transplantation studies, while rabbits are suitable for the study of immunology, inflammation, vascular biology, shock, colitis and transplantations. Thus, the choice of experimental animal mainly depends upon the field of scientific research under consideration [ 1 ].

HOUSING AND ENVIRONMENTAL ENRICHMENT

Researchers should be aware of the environment and conditions in which laboratory animals are kept during research, and they also need to be familiar with the metabolism of the animals kept in vivarium, since their metabolism can easily be altered by different factors such as pain, stress, confinement, lack of sunlight, etc. Housing conditions alter animal behavior, and this can in turn affect experimental results. By contrast, handling procedures that feature environmental enrichment and enhancement help to decrease stress and positively affect the welfare of the animals and the reliability of research data [ 74 , 75 ].

In animals, distress- and agony-causing factors should be controlled or eliminated to overcome any interference with data collection as well as with interpretation of the results, since impaired animal welfare leads to more animal usage during experiment, decreased reliability and increased discrepancies in results along with the unnecessary consumption of animal lives [ 86 ].

To reduce the variation or discrepancies in experimental data caused by various environmental factors, experimental animals must be kept in an appropriate and safe place. In addition, it is necessary to keep all variables like humidity, airflow and temperature at levels suitable for those species, as any abrupt variation in these factors could cause stress, reduced resistance and increased susceptibility to infections [ 74 ].

The space allotted to experimental animals should permit them free movement, proper sleep and where feasible allow for interaction with other animals of the same species. Mice and rats are quite sociable animals and must, therefore, be housed in groups for the expression of their normal behavior. Usually, laboratory cages are not appropriate for the behavioral needs of the animals. Therefore, environmental enrichment is an important feature for the expression of their natural behavior that will subsequently affect their defense mechanisms and physiology [ 87 ].

The features of environmental enrichment must satisfy the animals’ sense of curiosity, offer them fun activities, and also permit them to fulfill their behavioral and physiological needs. These needs include exploring, hiding, building nests and gnawing. For this purpose, different things can be used in their environment, such as PVC tubes, cardboard, igloos, paper towel, cotton, disposable masks and paper strips [ 87 ].

The environment used for housing of animals must be continuously controlled by appropriate disinfection, hygiene protocols, sterilization and sanitation processes. These steps lead to a reduction in the occurrence of various infectious agents that often found in vivarium, such as Sendai virus, cestoda and Mycoplasma pulmonis [ 88 ].

Euthanasia is a term derived from Greek, and it means a death without any suffering. According to the Brazilian Arouca Law (Article 14, Chapter IV, Paragraphs 1 and 2), an animal should undergo euthanasia, in strict compliance with the requirements of each species, when the experiment ends or during any phase of the experiment, wherever this procedure is recommended and/or whenever serious suffering occurs. If the animal does not undergo euthanasia after the intervention it may leave the vivarium and be assigned to suitable people or to the animal protection bodies, duly legalized [ 1 ].

Euthanasia procedures must result in instant loss of consciousness which leads to respiratory or cardiac arrest as well as to complete brain function impairment. Another important aspect of this procedure is calm handling of the animal while taking it out of its enclosure, to reduce its distress, suffering, anxiety and fear. In every research project, the study design should include the details of the appropriate endpoints of these experimental animals, and also the methods that will be adopted. It is important to determine the appropriate method of euthanasia for the animal being used. Another important point is that, after completing the euthanasia procedure, the animal’s death should be absolutely confirmed before discarding their bodies [ 87 , 89 ].

Relevance of animal experimentations and possible alternatives

Relevance of animal experiments and their adverse effects on human health.

One important concern is whether human diseases, when inflicted on experimental animals, adequately mimic the progressions of the disease and the treatment responses observed in humans. Several research articles have made comparisons between human and animal data, and indicated that the results of animals’ research could not always be reliably replicated in clinical research among humans. The latest systematic reviews about the treatment of different clinical conditions including neurology, vascular diseases and others, have established that the results of animal studies cannot properly predict human outcomes [ 59 , 90 ].

At present, the reliability of animal experiments for extrapolation to human health is questionable. Harmful effects may occur in humans because of misleading results from research conducted on animals. For instance, during the late fifties, a sedative drug, thalidomide, was prescribed for pregnant women, but some of the women using that drug gave birth to babies lacking limbs or with foreshortened limbs, a condition called phocomelia. When thalidomide had been tested on almost all animal models such as rats, mice, rabbits, dogs, cats, hamsters, armadillos, ferrets, swine, guinea pig, etc., this teratogenic effect was observed only occasionally [ 91 ]. Similarly, in 2006, the compound TGN 1412 was designed as an immunomodulatory drug, but when it was injected into six human volunteer, serious adverse reactions were observed resulting from a deadly cytokine storm that in turn led to disastrous systemic organ failure. TGN 1412 had been tested successfully in rats, mice, rabbits, and non-human primates [ 92 ]. Moreover, Bailey (2008) reported 90 HIV vaccines that had successful trial results in animals but which failed in human beings [ 93 ]. Moreover, in Parkinson disease, many therapeutic options that have shown promising results in rats and non-human primate models have proved harmful in humans. Hence, to analyze the relevance of animal research to human health, the efficacy of animal experimentation should be examined systematically [ 94 , 95 ]. At the same time, the development of hyperoxaluria and renal failure (up to dialysis) after ileal-jejunal bypass was unexpected because this procedure was not preliminarily evaluated on an animal model [ 96 ].

Several factors play a role in the extrapolation of animal-derived data to humans, such as environmental conditions and physiological parameters related to stress, age of the experimental animals, etc. These factors could switch on or off genes in the animal models that are specific to species and/or strains. All these observations challenge the reliability and suitability of animal experimentation as well as its objectives with respect to human health [ 76 , 92 ].

ALTERNATIVE TO ANIMAL EXPERIMENTATION/DEVELOPMENT OF NEW PRODUCTS AND TECHNIQUES TO AVOID ANIMAL SACRIFICE IN RESEARCH

Certainly, in vivo animal experimentation has significantly contributed to the development of biological and biomedical research. However it has the limitations of strict ethical issues and high production cost. Some scientists consider animal testing an ineffective and immoral practice and therefore prefer alternative techniques to be used instead of animal experimentation. These alternative methods involve in vitro experiments and ex vivo models like cell and tissue cultures, use of plants and vegetables, non-invasive human clinical studies, use of corpses for studies, use of microorganisms or other simpler organism like shrimps and water flea larvae, physicochemical techniques, educational software, computer simulations, mathematical models and nanotechnology [ 97 ]. These methods and techniques are cost-effective and could efficiently replace animal models. They could therefore, contribute to animal welfare and to the development of new therapies that can identify the therapeutics and related complications at an early stage [ 1 ].

The National Research Council (UK) suggested a shift from the animal models toward computational models, as well as high-content and high-throughput in vitro methods. Their reports highlighted that these alternative methods could produce predictive data more affordably, accurately and quickly than the traditional in vivo or experimental animal methods [ 98 ].

Increasingly, scientists and the review boards have to assess whether addressing a research question using the applied techniques of advanced genetics, molecular, computational and cell biology, and biochemistry could be used to replace animal experiments [ 59 ]. It must be remembered that each alternative method must be first validated and then registered in dedicated databases.

An additional relevant concern is how precisely animal data can mirror relevant epigenetic changes and human genetic variability. Langley and his colleagues have highlighted some of the examples of existing and some emerging non-animal based research methods in the advanced fields of neurology, orthodontics, infectious diseases, immunology, endocrine, pulmonology, obstetrics, metabolism and cardiology [ 99 ].

IN SILICO SIMULATIONS AND INFORMATICS

Several computer models have been built to study cardiovascular risk and atherosclerotic plaque build-up, to model human metabolism, to evaluate drug toxicity and to address other questions that were previously approached by testing in animals [ 100 ].

Computer simulations can potentially decrease the number of experiments required for a research project, however simulations cannot completely replace laboratory experiments. Unfortunately, not all the principles regulating biological systems are known, and computer simulation provide only an estimation of possible effects due to the limitations of computer models in comparison with complex human tissues. However, simulation and bio-informatics are now considered essential in all fields of science for their efficiency in using the existing knowledge for further experimental designs [ 76 ].

At present, biological macromolecules are regularly simulated at various levels of detail, to predict their response and behavior under certain physical conditions, chemical exposures and stimulations. Computational and bioinformatic simulations have significantly reduced the number of animals sacrificed during drug discovery by short listing potential candidate molecules for a drug. Likewise, computer simulations have decreased the number of animal experiments required in other areas of biological science by efficiently using the existing knowledge. Moreover, the development of high definition 3D computer models for anatomy with enhanced level of detail, it may make it possible to reduce or eliminate the need for animal dissection during teaching [ 101 , 102 ].

3D CELL-CULTURE MODELS AND ORGANS-ON-CHIPS

In the current scenario of rapid advancement in the life sciences, certain tissue models can be built using 3D cell culture technology. Indeed, there are some organs on micro-scale chip models used for mimicking the human body environment. 3D models of multiple organ systems such as heart, liver, skin, muscle, testis, brain, gut, bone marrow, lungs and kidney, in addition to individual organs, have been created in microfluidic channels, re-creating the physiological chemical and physical microenvironments of the body [ 103 ]. These emerging techniques, such as the biomedical/biological microelectromechanical system (Bio-MEMS) or lab-on-a-chip (LOC) and micro total analysis systems (lTAS) will, in the future, be a useful substitute for animal experimentation in commercial laboratories in the biotechnology, environmental safety, chemistry and pharmaceutical industries. For 3D cell culture modeling, cells are grown in 3D spheroids or aggregates with the help of a scaffold or matrix, or sometimes using a scaffold-free method. The 3D cell culture modeling conditions can be altered to add proteins and other factors that are found in a tumor microenvironment, for example, or in particular tissues. These matrices contain extracellular matrix components such as proteins, glycoconjugates and glycosaminoglycans that allow for cell communication, cell to cell contact and the activation of signaling pathways in such a way that the morphological and functional differentiation of these cells can accurately mimic their environment in vivo . This methodology, in time, will bridge the gap between in vivo and in vitro drug screening, decreasing the utilization of animal models during research [ 104 ].

ALTERNATIVES TO MICROBIAL CULTURE MEDIA AND SERUM-FREE ANIMAL CELL CULTURES

There are moves to reduce the use of animal derived products in many areas of biotechnology. Microbial culture media peptones are mostly made by the proteolysis of farmed animal meat. However, nowadays, various suppliers provide peptones extracted from yeast and plants. Although the costs of these plant-extracted peptones are the same as those of animal peptones, plant peptones are more environmentally favorable since less plant material and water are required for them to grow, compared with the food grain and fodder needed for cattle that are slaughtered for animal peptone production [ 105 ].

Human cell culture is often carried out in a medium that contains fetal calf serum, the production of which involves animal (cow) sacrifice or suffering. In fact, living pregnant cows are used and their fetuses removed to harvest the serum from the fetal blood. Fetal calf serum is used because it is a natural medium rich in all the required nutrients and significantly increases the chances of successful cell growth in culture. Scientists are striving to identify the factors and nutrients required for the growth of various types of cells, with a view to eliminating the use of calf serum. At present, most cell lines could be cultured in a chemically-synthesized medium without using animal products. Furthermore, data from chemically-synthesized media experiments may have better reproducibility than those using animal serum media, since the composition of animal serum does change from batch to batch on the basis of animals’ gender, age, health and genetic background [ 76 ].

ALTERNATIVES TO ANIMAL-DERIVED ANTIBODIES

Animal friendly affinity reagents may act as an alternative to antibodies produced, thereby removing the need for animal immunization. Typically, these antibodies are obtained in vitro by yeast, phage or ribosome display. In a recent review, a comparative analysis between animal friendly affinity reagents and animal derived-antibodies showed that the affinity reagents have superior quality, are relatively less time consuming, have more reproducibility and are more reliable and are cost-effective [ 106 , 107 ].

Conclusions

Animal experimentation led to great advancement in biological and biomedical sciences and contributed to the discovery of many drugs and treatment options. However, such experimentation may cause harm, pain and distress to the animals involved. Therefore, to perform animal experimentations, certain ethical rules and laws must be strictly followed and there should be proper justification for using animals in research projects. Furthermore, during animal experimentation the 4 Rs principles of reduction, refinement, replacement and responsibility must be followed by the researchers. Moreover, before beginning a research project, experiments should be thoroughly planned and well-designed, and should avoid unnecessary use of animals. The reliability and reproducibility of animal experiments should also be considered. Whenever possible, alternative methods to animal experimentation should be adopted, such as in vitro experimentation, cadaveric studies, and computer simulations.

While much progress has been made on reducing animal experimentation there is a need for greater awareness of alternatives to animal experiments among scientists and easier access to advanced modeling technologies. Greater research is needed to define a roadmap that will lead to the elimination of all unnecessary animal experimentation and provide a framework for adoption of reliable alternative methodologies in biomedical research.

Acknowledgements

This research was funded by the Provincia Autonoma di Bolzano in the framework of LP 15/2020 (dgp 3174/2021).

Conflicts of interest statement

Authors declare no conflict of interest.

Author's contributions

MB: study conception, editing and critical revision of the manuscript; AKK, DP, GH, RB, Paul S, Peter S, RM, BF, NC, SM, LL, DD, GMT, MCE, MD, SM, Daniele M, GB, AD, KD, MCM, TB, MS, STC, Donald M, AM, AB, KLH, MK, LS, LL, GF: literature search, editing and critical revision of the manuscript. All authors have read and approved the final manuscript.

Contributor Information

INTERNATIONAL BIOETHICS STUDY GROUP : Derek Pheby , Gary Henehan , Richard Brown , Paul Sieving , Peter Sykora , Robert Marks , Benedetto Falsini , Natale Capodicasa , Stanislav Miertus , Lorenzo Lorusso , Gianluca Martino Tartaglia , Mahmut Cerkez Ergoren , Munis Dundar , Sandro Michelini , Daniele Malacarne , Tommaso Beccari , Michele Samaja , Matteo Bertelli , Donald Martin , Assunta Morresi , Ariola Bacu , Karen L. Herbst , Mykhaylo Kapustin , Liborio Stuppia , Ludovica Lumer , and Giampietro Farronato

• Patient Care & Health Information
• Diseases & Conditions
• Atopic dermatitis (eczema)

To diagnose atopic dermatitis, your health care provider will likely talk with you about your symptoms, examine your skin and review your medical history. You may need tests to identify allergies and rule out other skin diseases.

If you think a certain food caused your child's rash, ask your health care provider about potential food allergies.

Patch testing

Your doctor may recommend patch testing on your skin. In this test, small amounts of different substances are applied to your skin and then covered. During visits over the next few days, the doctor looks at your skin for signs of a reaction. Patch testing can help diagnose specific types of allergies causing your dermatitis.

Treatment of atopic dermatitis may start with regular moisturizing and other self-care habits. If these don't help, your health care provider might suggest medicated creams that control itching and help repair skin. These are sometimes combined with other treatments.

Atopic dermatitis can be persistent. You may need to try various treatments over months or years to control it. And even if treatment is successful, symptoms may return (flare).

Medications

Medicated products applied to the skin. Many options are available to help control itching and repair the skin. Products are available in various strengths and as creams, gels and ointments. Talk with your health care provider about the options and your preferences. Whatever you use, apply it as directed (often twice a day), before you moisturize. Overuse of a corticosteroid product applied to the skin may cause side effects, such as thinning skin.

Creams or ointments with a calcineurin inhibitor might be a good option for those over age 2. Examples include tacrolimus (Protopic) and pimecrolimus (Elidel). Apply it as directed, before you moisturize. Avoid strong sunlight when using these products.

The Food and Drug Administration requires that these products have a black box warning about the risk of lymphoma. This warning is based on rare cases of lymphoma among people using topical calcineurin inhibitors. After 10 years of study, no causal relationship between these products and lymphoma and no increased risk of cancer have been found.

• Drugs to fight infection. Your health care provider may prescribe antibiotic pills to treat an infection.
• Pills that control inflammation. For more-severe eczema, your health care provider may prescribe pills to help control your symptoms. Options might include cyclosporine, methotrexate, prednisone, mycophenolate and azathioprine. These pills are effective but can't be used long term because of potential serious side effects.
• Other options for severe eczema. The injectable biologics (monoclonal antibodies) dupilumab (Dupixent) and tralokinumab (Adbry) might be options for people with moderate to severe disease who don't respond well to other treatment. Studies show that it's safe and effective in easing the symptoms of atopic dermatitis. Dupilumab is for people over age 6. Tralokinumab is for adults.
• Wet dressings. An effective, intensive treatment for severe eczema involves applying a corticosteroid ointment and sealing in the medication with a wrap of wet gauze topped with a layer of dry gauze. Sometimes this is done in a hospital for people with widespread lesions because it's labor intensive and requires nursing expertise. Or ask your health care provider about learning how to use this technique at home safely.

Light therapy. This treatment is used for people who either don't get better with topical treatments or rapidly flare again after treatment. The simplest form of light therapy (phototherapy) involves exposing the affected area to controlled amounts of natural sunlight. Other forms use artificial ultraviolet A (UVA) and narrow band ultraviolet B (UVB) alone or with drugs.

Though effective, long-term light therapy has harmful effects, including premature skin aging, changes in skin color (hyperpigmentation) and an increased risk of skin cancer. For these reasons, phototherapy is less commonly used in young children and is not given to infants. Talk with your health care provider about the pros and cons of light therapy.

• Counseling. If you're embarrassed or frustrated by your skin condition, it can help to talk with a therapist or other counselor.
• Relaxation, behavior modification and biofeedback. These approaches may help people who scratch out of habit.

Baby eczema

Treatment for eczema in babies (infantile eczema) includes:

• Identifying and avoiding skin irritants
• Avoiding extreme temperatures
• Giving your baby a short bath in warm water and applying a cream or ointment while the skin is still damp

See your baby's health care provider if these steps don't improve the rash or it looks infected. Your baby might need a prescription medication to control the rash or treat an infection. Your health care provider might also recommend an oral antihistamine to help lessen the itch and cause drowsiness, which may be helpful for nighttime itching and discomfort. The type of antihistamine that causes drowsiness may negatively affect the school performance of some children.

More Information

• Biofeedback

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Clinical trials

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this condition.

Lifestyle and home remedies

Taking care of sensitive skin is the first step in treating atopic dermatitis and preventing flares. To help reduce itching and soothe inflamed skin, try these self-care measures:

• Moisturize your skin at least twice a day. Find a product or combination of products that works for you. You might try bath oils, creams, lotions, shea butter, ointments or sprays. For a child, the twice-a-day regimen might be an ointment before bedtime and a cream before school. Ointments are greasier and may sting less when applied. Choose products that are free of dyes, alcohols, fragrances and other ingredients that might irritate the skin. Allow the moisturizer to absorb into the skin before getting dressed.
• Apply an anti-itch cream to the affected area. A nonprescription cream containing at least 1% hydrocortisone can temporarily relieve the itch. Apply it no more than twice a day to the affected area before moisturizing. Once your reaction has improved, you may use this type of cream less often to prevent flares.
• Take an oral allergy or anti-itch medication. Options include nonprescription allergy medicines (antihistamines) — such as cetirizine (Zyrtec Allergy) or fexofenadine (Allegra Allergy). Also, diphenhydramine (Benadryl, others) may be helpful if itching is severe. But it causes drowsiness, so it's better for bedtime. The type of antihistamine that causes drowsiness may negatively affect the school performance of some children.
• Don't scratch. Rather than scratching when you itch, try pressing on or patting the skin. Cover the itchy area if you can't keep from scratching it. Keep your nails trimmed. For children, it might help to trim their nails and have them wear socks or gloves at night.
• Take a daily bath or shower. Use warm, rather than hot, water. If you're taking a bath, sprinkle the water with colloidal oatmeal, which is finely ground oatmeal made for bathing (Aveeno, others). Soak for less than 10 minutes, then pat dry. Apply moisturizer while the skin is still damp (within three minutes).
• Use a gentle, nonsoap cleanser. Choose one without dyes, alcohols or fragrances. Harsh soaps can wash away your skin's natural oils. Be sure to rinse off the cleanser completely.

Take a bleach bath. The American Academy of Dermatology recommends a bleach bath for relief from severe or frequent flares. Talk with your health care provider about whether this is a good option for you.

A diluted-bleach bath decreases bacteria on the skin and related infections. Add 1/2 cup (118 milliliters) of household bleach, not concentrated bleach, to a 40-gallon (151-liter) bathtub filled with warm water. Measurements are for a U.S.-standard-sized tub filled to the overflow drainage holes.

Soak from the neck down or just the affected areas for 5 to10 minutes. Don't put the head under water. Rinse off the bleach water with tap water. Take a bleach bath 2 to 3 times a week.

• Use a humidifier. Hot, dry indoor air can parch sensitive skin and worsen itching and flaking. A portable home humidifier or a humidifier attached to your furnace adds moisture to the air inside your home.
• Wear cool, smooth-textured clothing. Avoiding clothing that's rough, tight or scratchy. Also, in hot weather or while exercising, choose lightweight clothing that lets your skin breathe. When washing your clothing, avoid harsh detergents and fabric softeners added during the drying cycle.
• Treat stress and anxiety. Stress and other emotional disorders can worsen atopic dermatitis. Being aware of stress and anxiety and taking steps to improve your emotional health may help your skin too.
• Atopic dermatitis: Proper bathing can reduce itching
• Atopic dermatitis: Understand your triggers
• Ease stress to reduce eczema symptoms
• Can I exercise if I have atopic dermatitis?
• Eczema bleach bath: Can it improve my symptoms?
• How to treat baby eczema
• I have atopic dermatitis. How can I sleep better?

Alternative medicine

Many people with atopic dermatitis have tried alternative (integrative) medicine approaches to easing their symptoms. Some approaches are supported by clinical studies.

• Cannabinoids. When applied to skin, creams containing cannabinoids have been shown to ease itching and skin thickening. Several studies over more than 10 years showed some benefit.
• Natural oils. When added to bathwater, natural oils might help improve dry skin. Examples of such oils are soybean oil and mineral oil. Use caution with oils in a bathtub as they can make the tub slippery.
• Manuka honey. When applied to the skin, manuka honey has been shown to calm reactions on the skin. It has been used for centuries as an antimicrobial. Don't use in it on children under 1 year of age, as it carries the risk of infantile botulism.
• Acupuncture and acupressure. Several studies show that acupuncture and acupressure can reduce the itchiness of atopic dermatitis.

If you're considering alternative therapies, talk with your health care provider about their pros and cons.

Coping and support

Atopic dermatitis can make you feel uncomfortable and self-conscious. It can be especially stressful, frustrating or embarrassing for adolescents and young adults. It can disrupt their sleep and even lead to depression.

Some people may find it helpful to talk with a therapist or other counselor, a family member, or a friend. Or it can be helpful to find a support group for people with eczema, who know what it's like to live with the condition.

Preparing for your appointment

You're likely to start by seeing your primary care provider. Or you may see a doctor who specializes in the diagnosis and treatment of skin conditions (dermatologist) or allergies (allergist).

Here's some information to help you get ready for your appointment.

What you can do

• List your symptoms, when they occurred and how long they lasted. Also, it may help to list factors that triggered or worsened your symptoms — such as soaps or detergents, tobacco smoke, sweating, or long, hot showers.
• Make a list of all the medications, vitamins, supplements and herbs you're taking. Even better, take the original bottles and a list of the dosages and directions.
• List questions to ask your health care provider. Ask questions when you want something clarified.

For atopic dermatitis, some basic questions you might ask your health care provider include:

• What might be causing my symptoms?
• Are tests needed to confirm the diagnosis?
• What treatment do you recommend, if any?
• Is this condition temporary or chronic?
• Can I wait to see if the condition goes away on its own?
• What are the alternatives to the approach you're suggesting?
• What skin care routines do you recommend to improve my symptoms?

What to expect from your doctor

Your health care provider is likely to ask you a few questions. Being ready to answer them may free up time to go over any points you want to spend more time on. Your health care provider might ask:

• What are your symptoms and when did they start?
• Does anything seem to trigger your symptoms?
• Do you or any family members have allergies or asthma?
• Are you exposed to any possible irritants from your job or hobbies?
• Have you felt depressed or been under any unusual stress lately?
• Do you come in direct contact with pets or other animals?
• What products do you use on your skin, including soaps, lotions and cosmetics?
• What household cleaning products do you use?
• How much do your symptoms affect your quality of life, including your ability to sleep?
• What treatments have you tried so far? Has anything helped?
• How often do you shower or bathe?
• AskMayoExpert. Atopic dermatitis. Mayo Clinic; 2021.
• Chan LS, et al., eds. Complementary and alternative approaches II. In: Atopic Dermatitis: Inside Out or Outside In? Elsevier; 2023. https://www.clinicalkey.com. Accessed May 10, 2022.
• Eichenfield LF, et al. Current guidelines for the evaluation and management of atopic dermatitis: A comparison of the Joint Task Force Practice Parameter and American Academy of Dermatology guidelines. Journal of Allergy and Clinical Immunology; 2017; doi:10.1016/j.jaci.2017.01.009.
• Stander S. Atopic dermatitis. The New England Journal of Medicine. 2021; doi:10.1056/NEJMra2023911.
• American Academy of Dermatology Guidelines: Awareness of comorbidities associated with atopic dermatitis in adults. Journal of the American Academy of Dermatology. 2022; doi:10.1016/j.jaad.2022.01.009.
• Goldsmith LA, et al., eds. Atopic dermatitis. In: Fitzpatrick's Dermatology in General Medicine. 9th ed. McGraw-Hill Education; 2019. https://accessmedicine.mhmedical.com. Accessed May 9, 2022.
• Ash S, et al. Comparison of bleach, acetic acid, and other topical anti-infective treatments in pediatric atopic dermatitis: A retrospective cohort study on antibiotic exposure. Pediatric Dermatology. 2019; doi:10.1111/pde.13663.
• Eczema and bathing. National Eczema Association. https://nationaleczema.org/eczema/treatment/bathing. Accessed May 9, 2022.
• Lebwohl MG, et al. Atopic dermatitis. In: Treatment of Skin Disease: Comprehensive Therapeutic Strategies. 6th ed. Elsevier; 2022. https://www.clinicalkey.com. Accessed May 9, 2022.
• Eczema in skin of color: What you need to know. https://nationaleczema.org/eczema-in-skin-of-color. Accessed May 9, 2019.
• Kelly AP, et al. Atopic dermatitis and other eczemas. In: Taylor and Kelly's Dermatology for Skin of Color. 2nd ed. McGraw Hill; 2016. https://accessmedicine.mhmedical.com. Accessed May 9, 2022.
• Kelly AP, et al. Pediatrics. In: Taylor and Kelly's Dermatology for Skin of Color. 2nd ed. McGraw-Hill Education; 2016. https://accessmedicine.mhmedical.com. Accessed May 9, 2022.
• Chan LS, et al., eds. Complementary and alternative approaches I. In: Atopic Dermatitis: Inside Out or Outside In? Elsevier; 2023. https://www.clinicalkey.com. Accessed May 10, 2022.
• Chan LS, et al., eds. Topical therapies. In: Atopic Dermatitis: Inside Out or Outside In? Elsevier; 2023. https://www.clinicalkey.com. Accessed May 10, 2022.
• Schmitt BD. Eczema follow-up call. In: Pediatric Telephone Protocols: Office Version. 17th ed. American Academy of Pediatrics; 2021.
• Waldman RA, et al. Atopic dermatitis — Face. In: Dermatology for the Primary Care Provider. Elsevier; 2022. https://www.clinicalkey.com. Accessed May 9, 2022.
• Chan LS, et al., eds. Therapeutic guideline overview. In: Atopic Dermatitis: Inside Out or Outside In? Elsevier; 2023. https://www.clinicalkey.com. Accessed May 10, 2022.
• Chan LS, et al., eds. Clinical evidence: External factors. In: Atopic Dermatitis: Inside Out or Outside In? Elsevier; 2023. https://www.clinicalkey.com. Accessed May 10, 2022.
• Sokumbi O (expert opinion). Mayo Clinic. May 16, 2022.
• New drug for atopic dermatitis. AJN. 2022;122:18.
• Atopic dermatitis behind the knees
• Atopic dermatitis on the chest
• Atopic dermatitis: 6 ways to manage itchy skin
• Infantile eczema
• Mayo Clinic Minute: Eczema occurs in people of all ages

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