Replacement of Animal Procedures: Alternatives in Testing, Research, and Education - The Dermatology Review

Replacement of Animal Procedures: Alternatives in Testing, Research, and Education

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01.22.21DISCLAIMER

Vivisection, animal experimentation, in vivo (in a living being) testing, animal testing, animal research. Whatever name it goes by, the use of animals for testing, research and, education is a controversial topic. Public opinion and indeed opinions in the scientific community are split between thinking it should cease entirely and thinking that it is necessary for safety and scientific progress. The estimated number of animals used in experiments worldwide is unknowable, due to differences in different counties regulations and reporting procedures. However, it is estimated that between 50 and 120 million (vertebrate) animals are used annually in tests and procedures including mice, fish, rats, rabbits, cats, dogs, and monkeys.

History of Animal Testing

Evidence of animals being used in experiments goes back to the 1500s. However, it was not until 1959 that thoughts about the ethics of using animals in this way became a legitimate discussion point within scientific circles. This was due to Russell and Burch, who came up with the idea of an aim to meet the 3 Rs as an ethical code regarding using animals in tests:

  • Replacement; where possible a non-animal test should be implemented.
  • Reduction; the number of tests carried out and the number of animals used in tests should be reduced as far as possible.
  • Refinement; the humane treatment of animals used in testing such as conditions they are kept in and the use of anesthesia.

    Even after this idea was promoted progress was slow. Years later public support, stemming from movements such as the environmental and animal welfare movements helped create a culture ripe for the setting up of the Fund For the Replacement of Animals in Medical Experiments (FRAME) in 1969.

    It took until the 1980s before the 3 R’s became more widely accepted and began to be more wholly incorporated into testing, research and education. In some places, such as the UK, this was even enshrined, somewhat, into law such as the UK’s Animal (Scientific) Procedures Act 1986.

    In 1987 the US teenager Jennifer Graham made the news and made many people question the necessity of animal testing in education, including the rule makers, by suing her school for making the dissection of animals a compulsory part of learning anatomy.

    However, although using animals for testing, research and educational purposes may have, in some cases, become more humane and in some areas decreased, particularly in the cosmetic testing and educational spheres. It can also be countered that the numbers of animals used particularly for medical research have increased exponentially in line with the advancement of science, increases in funding and more generally increases in population, product manufacture, and consumerism.

    Animal Testing and the Law

    The EU banned animal testing of finished cosmetic products in 2004. In 2009 this was increased to include ingredients shortly before a few years later introducing an import and sales ban on new cosmetics that have been tested on animals.

    Quite a few other countries have followed suit in either implementing complete or partial bans on cosmetic testing on animals. These include; Norway, Israel, New Zealand, Colombia, Turkey, Guatemala, and a smattering of US states namely California, Nevada, and Illinois while other states are still deliberating the change.

    However, when it comes to chemical testing, that is toxicology and drug research, the law is very much for animal testing rather than against it. That is to say, the regulatory bodies which oversee the safety of all products, including the FDA (Food and Drug Administration) and EPA (Environmental Protection Agency) in the US and the FSA (Food Standards Agency) and the MHRA (Medicines and Healthcare Products Regulatory Agency) in the UK, for example, require that thorough tests are carried out to assess their safety and these, invariably, include rigorous testing on animals.

    Arguments Against Animal Testing

    The arguments against animal testing fall into four main categories

    • Ethics
      Animals do have moral status. That is they can feel – both pain and pleasure. There are some arguments over whether animals feel pain in the same way that humans do. There is also debate over the level of emotion that animals feel. However, in the US and many other countries, there are laws in place to protect animals from abuse and harm which demonstrates the consensus that animals are capable of feeling pain and suffering. This being the case the use of animals in experimentation at all is ethically dubious and relies on the presumption/belief that humans have a higher moral status than that animals.
    • Cost
      The cost of using animals in testing, education, and research is huge. For manufacturers such as pharmaceutical companies, it is this consideration that is the driver for alternatives to animal testing. It is also a cause of frustration among many scientists and researchers who are bound by regulations to complete animal tests that use up funding that could be better spent on developing more reliable and relevant alternatives.
    • Speed
      Animal testing is time-consuming sometimes taking up to 10 years to complete a study for a single chemical or drug. This is another source of frustration for researchers and scientists when modern computer-based tests can be completed in a fraction of the time and, arguably, obtain better more reliable results.
    • Human Relevance
      This is, by far, the largest argument against animal testing as it renders virtually all testing redundant and therefore a waste of animal life, money, and time.

    There have been some high profile examples that human relevance should be paramount to testing. They show that despite following regulatory protocols, including rigorous and repeated testing on non-human animals, the human trials stages have had a catastrophic effect on the subjects.

    One in 1993 in the US was fialuridine; a potential treatment for hepatitis B. It had been approved for human testing after a 6 month trial on dogs. However, of the 15 of those who participated in the trial, 5 died, a further 2 people had to have liver transplants which saved their lives. The liver failure, multiple organ failure, and jaundice had been unexpected following the toxicity trials in animals.

    Another trial in London in 2006 was for a drug to treat rheumatoid arthritis and leukemia. All 6 participants suffered multiple organ failure and were told to expect serious and life-threatening auto-immune diseases and cancers for the rest of their lives. This was after animal trials, specifically trials in monkeys, which had shown no such effects even in a much higher dose.

    The third was in 2016 in France. This trial, for a drug to treat a plethora of health problems and pain relief, had been tested on various animal subjects from mice to monkeys with no adverse effects even in much higher doses than those given to the human volunteers. In the human trials, four people suffered serious neurological damage and one person died.

    These examples, among others, add substantial weight to the arguments against the relevance of animal testing for drug research and toxicology.

    It is not only the risk posed by drugs previously tested on animals that is an issue. There are also many chemicals and chemical compounds that are toxic to animals but are not toxic to humans. Aspirin is an example of one such chemical which – if it had been subject to the kinds of animal testing required by regulatory bodies today would not pass. The idea that many drugs may have not reached the human trial stage that could have saved many lives is disturbing.

    Even some drug companies and research organizations admit that the information gathered from animal experiments can be minimal. Rather than completing animal experiments because they are useful, they are completing them to fulfill the requirements set out by regulatory bodies, the Medicines, and Healthcare Products Regularity Agency, and the US Food and Drug Administration, for example.

    Education and Animal Testing

    The importance of replacing animal procedures in education cannot be underestimated. This is because it has a knock-on effect with regards to the replacement of animals in other spheres such as testing and research.

    This is because if the scientists and researchers as well as the politicians, decision-makers, and the consumers of the future are themselves participating in animal testing it:

      • Normalizes it
      • Desensitizes them to it
      • Might put people off a career in science or medicine
      • May cause trauma

    Students themselves have often been the initiators of not using animals in this way in education. From high school students refusing to dissect animals to learn anatomy to the group of medical students who knew that the killing of dogs was not going to help them to become doctors and so banded together to get their syllabus changed.

    There are many other suitable methods for teaching students at all levels without using animals. These include:

      • Films
      • Computer modeling
      • Internet-based learning
      • Virtual Reality
      • 3D Models

    Many medical schools in the US no longer have live animal laboratories including Yale, Harvard, Colombia, and Mayo and many states have laws that allow high school students a choice over participation in the dissection of animals.

    Replacements For Animal Testing

    Algorithms, Computer modeling or ‘In Silico’ Methods
    When it comes to toxicology – that is the testing of chemicals to assess their potentially harmful effects on humans and the wider environment – algorithms and computer modeling provide an alternative to animal testing that is not only as effective as animal testing but is more reliable.

    Scientists from the John Hopkins University have created an enormous database using known chemicals and their properties including, vitally, their toxicity. They used information from 800,000 animal tests that had already been completed for 10,000 chemical compounds. Computers can read this database and then predict the toxicity of new chemical compounds. By checking what similar chemicals do; do they cause skin irritation or cell damage for example. This mapping out of chemicals and chemical compounds has been used to replace animal testing before and is known as read-across. Previously it has relied on researchers to analyze and evaluate the chemicals which is time-consuming and, to some extent, subjective. The predictions from the computers were shown to be nearly 90% accurate. Repeating the same tests on animals would yield a significantly less accurate result; around 80%.

    This mapping tool will allow a larger number of chemical compounds to be tested for their toxicity, and therefore, their safety. This is good news for consumers. Currently of the approximately 100,000 chemicals in everyday products, such as food and medicine, a relatively small number have underdone robust testing. This is because of the costs; both ethical and financial. The latter of course is good for product manufacturers too.

    That this ‘in-silico’ testing method has performed better than the standard animal toxicology tests shows that it is a genuine contender for being a better, more cost-effective, safer, and more ethical way of testing the safety of chemicals and chemical compounds.

    Moreover, this may even mean that the safety of new chemicals can be predicted even before the chemical is created – this would mean that a huge amount of time and money could be saved by scientists and researchers only needing to create chemicals that have already been predicted to be safe.

    Human Studies

    The replacement of animal testing with testing on humans comes with its own set of ethical and technical issues.

    Technically the issues include differences in how different people react to different chemicals and processes. Scientists and researchers might test the same chemical in the same way on hundreds of different animals and across various species as well as among animals that have been inbred to ensure very similar genetic makeup. This would not be possible to replicate in human trials.

    There are also difficulties because regulatory bodies that control the way drugs and chemicals are testing insist upon much higher doses (often 500x or more) than would ever be safely used on humans to be tested.

    Regulatory bodies also insist upon animal testing after some types of testing such as micro-dosing.

    This suggests that until there are changes made to the regulation of chemical and drug testing that the replacements to animal testing that scientists and researchers are working so hard to improve upon cannot be fully implemented as replacements.

    There are also ethical issues with human studies. Considerations such as poverty pushing people to participate in testing and trials, and the potential for abuse. There are also consent issues; testing could not ethically go ahead on people who are unable to give informed consent such as children, or those with neurological impairments such as learning disabilities, or those with dementia.

    However, there are clear benefits of focusing on human biology. The terrible examples of drug trials going wrong show that even rigorous animal testing does not guarantee safety.

    Microdosing

    Microdosing is a viable alternative to animal testing particularly with regards to drug research. As the name suggests, this is when a human subject is given such a minute quantity of a drug that it does not have either a positive (i.e. what the drug is intended to do) effect or a negative one on the health of the subject. Instead reacts at a cellular or even molecular level.

    Researchers then use a combination of liquid chromatography and mass spectrometry to analyze what happens at a cellular and molecular level. Liquid chromatography is the technique whereby samples are separated into their individual parts to see their chemical makeup.

    Mass spectrometry is the process whereby when giving a human subject a microdose of a drug that is going to be tested the researchers will also add a tiny amount, also called a tracer element, of a radioactive element. The researchers then take a range of bodily samples from the participant which can then be put into a mass spectrometer. A mass spectrometer is a machine that combines a high voltage of electricity with magnets to see molecules and atoms and the presence of even tiny amounts of radioactivity. This machine can, therefore ‘see’ what these tiny doses of drugs do at a molecular level.

    In vitro Testing

    In vitro cell, culture techniques are a viable and human-relevant alternative to animal testing. Stem cell technology and bioengineering enable the creation of miniature and early stages of systems in vitro. The literal translation of ‘In Vitro’ is ‘in glass’ and is the opposite of ‘in vivo’ or ‘in body’. This refers to the containers used to create laboratory-grown human organs and organisms. There are already many examples of human body parts that have been grown in this way.

    • Laboratory-grown multi-layered human skin created from human epidermal and dermal skin cells has been in use for many years. It is commercially available as an alternative to animal testing for dermal toxicologists, researchers, and the pharmaceutical and cosmetic industries.Scientists at the
    • Ohio State University successfully created a mini-brain. The tiny brain is similar to that of a 5-week old human embryo and has working neurons complete with axons and dendrites (for signal sending and receiving).
    • Researchers used stem cells to create a heart complete with muscle, chambers, and a beat. This so-called mini-heart can be used to test for embryonic toxicology.
    • Lung organoids have also been created by developmental biologists from the University of Michigan. These lab-grown mini-lungs are complete with lung sacs and bronchi.
    • In Australia a team of scientists replicated, using stem cells, a mini kidney complete with the three different types of kidney cells or nephrons.
      Mini-stomachs, only 3 millimeters big have also been grown in vitro.

      Body on a Chip and 3D Printing

      This technology is the most advanced and most promising of the possible replacements for animal procedures in testing, research, and education.

      Scientists at Harvard’s Wyss Institute are leading the way in creating a miniature working version of the human body’s organs and systems attached to a microchip.

      These miniature organs and systems are created with cells created by a specially modified 3D printer.

      The body on a chip is the size of a memory stick. One side is home to organ-specific cells. The other houses replicated blood cells. Between them is a porous membrane allowing them to interact and behave as they would in a human body. The organ cells or mini-organs are linked with vascular channels and a pump can transfer the fluids and nutrients between the different types of replicated organs.

      This body on a chip can then show researchers the complete pharmacokinetic effects. That is how the body system affects, holds, and moves the drug through absorption, distribution, metabolism, and excretion.

      It also accurately shows the complete pharmacodynamics of a drug. That is the effect of the drug on the targeted organ as well as effects on other organs and the system as a whole.

      This technology is also applicable to toxicology and all other areas of biomedical research. It is faster and over time will prove more cost-effective than animal testing. Moreover, it is human-relevant.

      References:Archibald, Kathy, et al. “Replacing Animal Tests to Improve Safety for Humans.” Animal Experimentation: Working Towards a Paradigm Change, edited by Kathrin Herrmann and Kimberley Jayne, vol. 22, Brill, LEIDEN, BOSTON, 2019, pp. 417–442. JSTOR,
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