Background
“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.”
- Queen Victoria, 1895
Animals have been used throughout history to better understand anatomy, physiology, and medicine; debates about the ethics of animal testing have been going on since the 17th Century.
Queen Victoria’s point of view was countered by Claude Bernard, a French physiologist, in 1865. He argued that experimenting on animals was ethical because of the benefits to medicine and human life. Barnard stated,
“experiments on animals are entirely conclusive for the toxicology and hygiene of man. The effects of these substances are the same on man as on animals, save for differences in degree.”
While we should respect Mr. Bernard as a pioneer in science, in the case of animal testing, he was utterly wrong.
In 1959, the “three R’s” for animal research were developed and are still used today:
- Replacement (replacing the use of animals with alternative research methods)
- Reduction (minimizing the use of animals whenever possible)
- Refinement (reducing suffering and improving animal’s living conditions)
In 2007, the National Research Council of the National Academy of Sciences called for animal testing to be further reduced and recommended using new technologies that could eventually eliminate the need for animal testing. Unfortunately, we are very far from reaching this goal.
Animal Research, a Necessary Evil?
The scientific establishment has touted animal testing as a necessary evil where the benefits to human health far outweigh ethical and other concerns.
There has been surprisingly little scientific scrutiny as to the efficacy of animal testing. It is generally supported without critical examination of its validity and a lack of data on how well experiments in animals predict human outcomes.
The answer is not very well. Although there are some very well-known cases where both animals and humans responded in the same way to drugs, such as penicillin, there are many more where species responses differed, for example,
- Isotretinoin (Accutane) caused congenital disabilities in rabbits, monkeys, and humans but not in rats and mice;
- Corticosteroids cause congenital disabilities in animals but not in humans, and
- Thalidomide did not cause congenital disabilities in many animal species but did in humans.
Why the discordance?
Laboratory procedures greatly affect the outcome of animal experiments: Animals are placed in cages for their lifetime, which causes distress and abnormal behavior. This can result in changes in neurochemistry, genetic expression, and elevation of blood pressure and heart rate. In other words, the animals are stressed, which can significantly affect test results.
Human diseases are not the same as animal diseases; the experimental animal model does not necessarily reflect the human condition. For example, a promising drug in stroke research in which a set of animal experiments was considered to meet the “gold standard” failed to work in clinical trials. This has been a recurring theme in drug research - promising drugs in animals fail to have any beneficial effect in humans, even after years, and sometimes decades, of testing.
A 2007 review examined the outcomes for treating several diseases, including osteoporosis and stroke, as they transitioned from animal to clinical studies. The results were only in accordance one-half of the time; in other words, the animal studies were no more likely to predict the benefit in humans than flipping a coin.
These differences are most likely due to differences between animals' and humans' physiology, behavior, genetics and pharmacokinetics (the transformation of chemicals or drugs within the body). And these differences are found within the same species. For example, studies have shown that the same strain of rats purchased from two suppliers can show different test results.
Why it Matters
The problem is not just that animal testing is not accurate; it also can be harmful to humans. On the one hand, investigators are misled by animal tests that show a drug is safe and effective, and clinical trial volunteers have their hopes dashed when this is not the case in humans.
Alternatively, drugs may be abandoned because of animal test results that do not apply to humans. An example is Gleevec, a very effective medication for treating chronic myelogenous leukemia that showed liver damage in dogs and serious adverse effects in 5 other species. The drug would have been abandoned based on the results of the animal tests. It was only allowed to continue to clinical trials because results in human cells did not show liver damage.
Better Approaches
There are three major alternatives to animal testing that have been developed over the last few decades:
- Human cell lines: Cells from inside the cheek or from the skin of people can be transformed back to stem cells, cells that are not fully developed. These stem cells can be grown and self-renew in Petri dishes and developed into any cell type that is under investigation. They also have the genetic imprint of the person from whom they were taken, allowing the ultimate in personalized medicine.
- Organoid systems: Human cell lines in Petri dishes do not fully model the diversity of cells and their 3-dimensional relationships in our organs. Organoid systems are closer models of organs that recreate complex cell diversity and the actual architecture of the organ. Presently, organoid systems have been developed for the human lungs, intestine, blood vessels, pancreas, and brain.
- Computational toxicology: Uses artificial intelligence to analyze chemical structures to predict toxicity, serving as a first pass to identify more promising or threatening chemical structures.
All three of these methods have shown results that outperform traditional animal tests. For example, a recent study used computational methods to define chemical similarity and showed better reproducibility than animal tests. Results from another study using an organoid intestinal model showed how inflammation can disrupt cellular metabolism and contribute to Crohn’s disease.
The Barriers to Acceptance
The two main barriers to acceptance of alternatives to animal testing are bureaucratic and scientific entrenchment. For scientific entrenchment, the good news is that eventually, scientists stuck in the old ways will move on and turn it over to a new generation of scientists. The bigger problem is how to accelerate regulatory change, moving the bureaucracy.
Animal testing is firmly embedded in our regulatory process. The FDA, EPA, and USDA have firm animal testing requirements that prove remarkably resistant to change. There are some steps in the right direction, but meaningful change has not occurred. In 2000, the National Toxicology Program set up the Interagency Center for the Evaluation of Alternative Toxicological Methods. In 2008 the EPA launched Toxicology in the 21st Century (Tox21), a research center touted as a pioneer in this area. Although both Centers have carried out numerous workshops and completed some interesting studies, the EPA is still very far from the goal set by its Administrator in 2019 of eliminating animal testing by 2035.
The EPA has not accepted alternatives to animal tests in the regulatory process, except for one change in 2021 that let researchers forgo testing chemicals on animal skin in certain circumstances. The FDA is not doing much better, allowing alternatives to animal testing in only a few cases in drug development and food safety.
Some scientists believe that we are entering a phase of scientific revolution where the old paradigm of animal experiments is not working, but science is not letting go, easily, of its older methods. This is due to the intransigence of those in positions of power at universities, federal agencies, and research centers who believe that the techniques they have used all their careers are the only correct ones and should continue to be used.
Accelerating change is critical for many reasons, including getting more accurate results in a timelier fashion. Remember, animal studies take a long time and are very costly. The new methods accelerate the time frame in which answers as to whether a drug is effective in humans or a chemical can harm humans can be reached. These faster answers will not only result in meaningful cost savings but also in saving lives for both animals and people.
Sources: The Flaws and Human Harms of Animal Experimentation
Why animal studies are often poor predictors of human reactions to exposure
