Animal testing has been a controversial subject for a long time. We understand that animals suffer by our hands, but are mostly willing to accept it for the improvement of lives of humans. This can be explained by our evolutionary history - any species that would not value the life of itself and its comrades over the lives of other animals is bound for extinction. But we humans are trying to free ourselves from the purely Darwinistic outlook on the world. We possess empathy, even with other species. We contemplate ethics, morale and compassion.

The balance of the altruistic and pragmatic approach (we don't want to hurt animals but at the same time want to improve our lives) is why we spend a lot of time arguing ethics in animal testing. This gives rise to several important questions.

"Is it acceptable to test novel treatment methods on animals?", "Can we know the amount of suffering that an animal feels?", "What is the worth of a human and that of an animal?", "Are some animals worth more consideration than others?"

The answer to all these questions is: "It's up to your opinion." - no one can empirically measure ethics, we simply believe that given a specific situation, humans will try to act as ethically as possible. 

Keep in mind that our task is to provide arguments in support of animal testing, so the information on this page will be weighted in favor of testing on animals.

Irreplaceability of Animal Testing

As stated in an argument by Carey[1], animal studies are irreplaceable today. Releasing a chemical previously untested on animals (at least for toxicity) into human trials would be dangerous, unethical and the number of volunteers could be expected to be very low. 

An argument taken from [1]:

1. Chemicals can kill and injure humans and animals.

2. To develop efficiently a safe and effective medicine for humans, it is
logical, in order to protect humans as much as possible, to test a
chemical in a model which approximates most closely to the human.

3. A human being is made of interdependent organs and tissues as coded for
by that individual’s DNA.

4. It therefore follows that the best non-human models would also have
interdependent organs and tissues as coded for by DNA.

5. As a corollary of this, it follows that the more dissimilar the model,
the worse a model it will be. [If in a particular instance, this is not
the case, then good evidence needs to be produced to show that it is a
good model].

6. The best non-human models which have interdependent organs and tissues
as coded for by DNA are animals.

The argument continues to state that despite drastic phenomic differences between humans and commonly used lab animals, we do have a large portion of DNA in common and that there is no way to replace animal testing for toxicity of substances in humans.

The argument goes on to point out that If we regard it as unethical to test on animals because of the difference in DNA composition, we should take that logic to the extreme and say that we should not test on humans either because each individual (except identical twins) has a unique DNA. Therefore each drug should be tested anew on each person. This would clearly make drug testing impossible at all. This argument is a little far-fetched, as we can draw the line based on biological classification of animals and say that as long as the subject is homo sapiens the difference in DNA is within the margin of tolerance. 

Overall, we lack the models and techniques that could simulate the reaction of a human body to chemicals that could replace animal tests. They are in development, as mentioned in the review by Doke et al. [2], but in their current state, they cannot completely replace in vivo testing in animals.

Acknowledging and Overcoming Limitations

Humans are not the same as other animals. That is obvious and must be accounted for. Even the ~3% dissimilarity in DNA between non-human primates and humans goes a long way and animal tests can never substitute testing in humans. Nevertheless, our technological level doesn't allow us to eliminate them completely, so we must concentrate on improving the translatability of animal tests into humans.

For example, in her thesis [3], Martignoni reviews the differences in specific enzymes metabolizing drugs in the liver and intestine of various animals (mouse, rat, donkey, monkey, human). The conclusion is that it is necessary to select animals for study carefully, with specific enzymes being expressed more similarly in humans vs. different animals. This results in some animals being more useful in testing for specific kinds of drugs, while other animals for others. She also mentions that interpolating between animals is a viable method and can produce results better than single-species tests. The expression of genes was found to be sometimes independent on genetic similarities, with even small genetic differences resulting in completely different metabolical processes.  

The careful normalization of parameters of the animal is also necessary, with parameters such as body weight and liver weight as a percentage of body weight and hepatic hormone concentrations. As small animals have higher concentrations of hepatic enzymes per gram of body mass, they will eliminate drugs faster than humans in strictly weight-normalized doses.

An approach to overcome the non-translatability of animal studies into humans is the genetic engineering of animals that are more similar to humans in the relevant areas of study.

Animal tests are not the only possible toxicity tests and are always used in conjunction with other ways of testing, such as chemical tests, in vitro tests and so on.

Welfare of Animals

As animal studies are not replaceable today, treating the animals as ethically as possible is a priority. In the European Union, this process is guided by the three Rs approach. [2][4]

According to these guidelines, we should Reduce the number of animals used by all possible means, Refine the testing processes to minimize animal suffering and Replace animal testing by other methods whenever technologically possible.

This approach was first formulated in 1959, [5] and since then, found its way into legislature. The current legislature governing animal research in the European Union is the Directive 2010/63/EU [6]. It builds upon the three Rs principle and previous legislature and has been improved to accommodate for modern techniques, such as genetic modification of laboratory animals, stem cell modification and experiments on foetuses in later stages of development.

The directive requires not only compliance with the basic three Rs principle, but also specifies minimum standards for housing and care, regulates the use of animals through a project evaluation metric requiring inter alia (comparing to other studies) assessment of pain, distress and lasting harm caused to the animals. This is used to calculate an animal-cost-to-human-benefit ratio of the experiments. It requires regular inspections and improves accountability of researchers through measures such as public release of project summaries and retrospective assessment. It also promotes research of alternative methods that strive to replace animal tests.

Reduce

The reducing principle aims at reducing the number of animals used in tests to the lowest possible level - it can be summed up in 4 parts

• Eliminate unsuitable substances before beginning animal testing by using in vitro methods

• Share as much data as possible with the scientific community to avoid testing the same substance on animals multiple times - especially: share failures!

  • Failed experiments with new substances do not get published and the information gained in the experiment is lost

• Use as few animals as possible to get statistically significant results

  • Use statistical methods to decide how many animals need to be tested instead of going with "the more the better" approach

• Maximize information gained per animal per test

  • Measure as many aspects of the subject animal at once as possible to avoid unnecessary repetition of measurements and tests

Refine

The refinement principle tells us to provide the animals with the most humane conditions possible throughout their lives.

The main goal of refinement is to minimize the pain, suffering and stress of test animals. This is not only an ethical requirement, it is also a necessary scientific requirement. This is because stressed animals will display different physiology and the processes in their bodies will not be representative of healthy individuals.

This was shown by Hendriksen et al.[7], when mice provided with a complex cage system that allowed them freedom of exploration, movement and social interactions led to slower progression of a disease than in mice left in a bare cage.

This principle consists of providing animals with suitable hygienic conditions, sufficient food, natural sleep-cycle conditions and other things that constitute a "comfortable" life for the animals. It also requires that pain killers and sedatives be used in any trials where their use doesn't conflict with the goal of the experiment.

Replace

The replacement principle strives to reduce the number of animal tests in the long term by developing methods that replace animal testing. It also tells us to use alternative methods whenever technologically possible.

• Use modern analytical tools instead of animals - e.g. Chromatography for drug purity assessment instead of testing every batch on mice

• In sillico methods - Computer based simulations that simulate the chemical and biological processes in living tissue

  • Currently we lack the computing power and the precise chemical models at the quantum level to simulate chemical reactions properly, but great advances are being made in both fields, as shown by the 2013 Nobel Prize winners in their article [8]
  • Another step after being able to model chemistry is being able to integrate the physiology of living cells into the equation and complex inter-organ interactions

• In vitro - tissue and/or cell cultures mimicking human/animal physiology, albeit these are usually cultivated from animal tissue as well

• In chemico - synthetic molecules mimicking human enzyme action to assess how human enzymes will react with a given substance

  • The in vitro and in chemico tests lack the complex interactions between various organs and enzymes found in a human, so a combination of several tests is necessary to replace an animal trial

• Lower animals that feel less pain - discussion in next section

  • Moving from species that are considered more sentient to those less sentient, and non-sentient beings such as invertebrates and fungi

Extending three Rs to accommodate new developments

The three Rs have been conceived in the sixties and so did not consider many modern technologies and the ethical issues they bring. Most of these issues are already implemented in the mentioned EU directive. 

Genetically modified animals should be produced in an efficient way that does not require keeping of large colonies of breeder animals. GM animals are produced on a large-scale with relatively few having the desired mutation, which leads to a large population with unpredictable mutations, which may have a severely decreased quality of life. So, all animals used for production of test animals should be considered as part of the test, so that the overall cost to the animals can be better measured. 

Enhancing welfare through breeding and rearing should be employed as well as through the life in the laboratory through the experiment.

There are problems with enhancing living conditions of laboratory animals as old data may not be comparable to new data, since it has been proven that different living conditions result in different physiological processes.

Moral Arithmetic

Ethics are a field that is impossible to quantify, as every person gives different moral value to other human beings, animals, the environment and a different opinion on what constitutes harm, what constitutes a benefit, when is it immoral to cause harm and so on.

One thing is obvious, we are the product of evolution and so programmed to strive for survival and reproduction. Humans tend to place the highest value in the survival of themselves and their offspring.

The justification of animal experiments can be demonstrated by comparing the moral impact of doing versus not doing an experiment.

The arithmetic

When considering whether an experiment is justified, we should consider the moral cost of doing the experiment versus not doing it. [9]

The moral cost of not performing an experiment is the product of

• the moral value of a human being
• the value of the benefit that each human being won't get
• the number of human beings who would have benefited

The moral cost of the experiment is the product of

• the moral value of an experimental animal
• the negative value of the harm done to each animal
• the number of animals suffering in the experiment

But that's impossible to quantify, as we cannot agree on the moral value of a human being or the moral value of an animal. Also, the harm done by the experiment is not known beforehand as well as the benefit to humans cannot be foreseen until after the experiment.

Conclusion (subjective)

Animal testing is morally wrong. But it is less morally wrong than not doing animal testing as human life does have several orders of magnitude more value to me than the lives of animals. I am not a proponent of doing as much animal tests as possible, quite the opposite, the less the better.

But we need to accept that today, the choice is either "do animal testing" or "don't develop new drugs" and in this dilemma, the choice is clear. Animal testing is not all perfectly translatable to humans, but especially when modelling for toxicity in humans, animal trials are an indispensible tool today. If I had 3 different pills with an untested substance to choose from, knowing that the first one killed all tested animals when administered in micro-gram doses, another one killed half of them when administered in milligrams and the last one didn't kill any animals when administered in grams, other properties being equal, it's obvious to me which one to choose for human trials.

Animal testing has to be controlled and must meet strict standards for handling and care for animals in question. It should be abandoned if there ever is a model, or  combination of models, that will perform as well or better than animal models in the complex modelling of human toxicity or actual physiology impacts of chemicals. Until such time, we must try to abide by the extended 3R guidelines and try to reduce testing and provide good quality of life to the testing animals as technologically possible.

Bibliography

1) Carey W.D.H. (2002) A rationale for animal studies - response to "Animal studies in HIV research", 324:236

2) Doke S.K. et al. (2013) Alternatives to animal testing: A review, Saudi Pharmaceutical Journal

3) Martignoni M. (2006) Species and strain differences in drug metabolism in liver and intestine, Doctoral thesis - University of Birmingham

4) Workman P. et al. (2010) Guidelines for the welfare and use of animals in cancer research,  Br J Cancer. 25; 102(11): 1555–1577.

5) Russell W.M.S. and Burch, R. (1959) The Principles of Humane Experimental Technique

6) EU Directive 2010/63/EU (access 30/06/17)

7) Hendriksen C.F. (2009) Replacement, reduction and refinement alternatives to animal use in vaccine potency measurement, Expert Rev. Vaccines 8, 313–322.

8) Karplus M. (2014) Development of Multiscale Models for Complex Chemical Systems: From H+H2 to Biomolecules (Nobel Lecture)

9) Animal experimentation, http://www.bbc.co.uk/ethics/animals/using/experiments_1.shtml (access 03/07/17)