animal experimentation
TRANSCRIPT
0
Animal
Experimentation
Group members: Sofia Vrablova (56968), Alak Laz (57390), Naverawaheed Arshad (57389),
Tanya Cholakova (56977)
Supervisor: Lisa Samuelsen
Affiliation: Roskilde University, Third semester, NIB
Group no: 3
Date: 20/12/2016
1
Abstract
Animal experimentation is a crucial part of medical science. One of the ways to define it is
any scientific experiment conducted for research purposes that cause any kind of pain or
suffering to animals. Over the years, the new discovered drugs or treatments are first applied
on animals to test their positive outcomes to be later used by humans. There is a debate about
violating ethical considerations by exploiting animals for human benefits. However, different
ethical theories have been made to justify whether animal experimentation is morally right or
not. Laws and regulations have been enacted around the world to regulate the care and use of
animals in the laboratories. The results from animal experiments also lack reliability when
comparing them to humans. Animals and humans share some anatomical similarities but it is
difficult to completely generalize animal experiments to humans in a medical procedure. In
order to understand these issues closely, this paper focuses on the case study of thalidomide
tragedy. Thalidomide was a drug used to treat nausea in pregnant women but was banned as it
caused birth defects in many children. The aim of this paper is to analyse this case study to
evaluate how ethical it is to perform animal experiments and whether it is possible to abandon
it and excel in medical science with assistance of some promising alternatives of animal
experiments.
2
Table of Contents
ABSTRACT ................................................................................................................................ 1
INTRODUCTION: ..................................................................................................................... 3
HYPOTHESIS: ....................................................................................................................................... 5
SUB QUESTIONS: .................................................................................................................................. 5
RELATION TO SEMESTER THEMATIC CONSTRAINT ....................................................... 5
METHODOLOGY ...................................................................................................................... 6
LIMITATIONS: ...................................................................................................................................... 6
THE HISTORY OF ANIMAL EXPERIMENTATION .............................................................. 6
SOCIETY AND ANIMAL EXPERIMENTATION ..................................................................... 7
MORAL PHILOSOPHY THEORIES AND PRINCIPLES............................................................................... 9
Relativism ........................................................................................................................................ 9
Consequentialism ........................................................................................................................... 9
Deontology ...................................................................................................................................... 9
Speciesism ..................................................................................................................................... 10
LAWS AND REGULATIONS ................................................................................................................. 10
The 3Rs ......................................................................................................................................... 11
COMMON TECHNIQUES OF ANIMAL EXPERIMENTATION ........................................... 12
CHALLENGES WITH SPECIES GENERALIZATION .......................................................... 14
THE CASE STUDY OF THALIDOMIDE ................................................................................ 16
ANALYSIS ............................................................................................................................... 21
DISCUSSION............................................................................................................................ 26
CONCLUSION ......................................................................................................................... 31
BIBLIOGRAPHY ..................................................................................................................... 32
3
Introduction:
Animal testing is a very common practice performed for research purposes. It
refers to the procedure performed on non-human living animals with the purpose of
investigating into human diseases, assessing the effectiveness of medicinal products and
treatments, and testing surgical procedures before applying them on human patients [1][2].
Animal testing has also been used to refine the behavioural and psychological principles,
which is fundamental to understand the behavioural effects psychoactive drugs and
environmental toxicants [3]. There are many kinds of animal testing such as injecting toxic or
harmful substances, study their body parts after making them genetically modified or skin
corrosion tests [4]. Since the phenomena of animal testing is so broad there are different terms
defining it with different connotations. As it has also been entitled as animal experimentation
and vivisection [5], a Latin word which means exploratory surgery of live animals and this
term is usually used to describe animal testing in a very pejorative way [6]. The term used in
this paper for this procedure will be animal experimentation. Many people define animal
experimentation as any scientific experiment or test that can cause pain or suffering to living
animals [7]. This description for animal experimentation elucidates the parameters for the
main agenda of this paper. This paper will exclusively focus on the medical aspect of animal
experimentation, which means that it will focus on the usage and the effect of animal
experimentation during drug development.
Science has evolved by the use of animal experimentation [8]. Whether it is
treatment of infectious diseases or surgical procedures, pain relievers, medications for blood
pressure, insulin, nutrition supplements, organ transplants, treatments for shock trauma and
blood diseases, all of these have been developed and tested on animals before being used on
humans [8]. Hence, animal experimentation has had a huge contribution to medical science.
In ancient times, scientists used animals mainly in order to satisfy their
anatomical curiosity regarding any unfamiliar fact about the human body. Early Greeks such
as Aristotle (384 BC – 322 BC), Erasistratus (304 BC – 258 BC) and Galen (129 AD to 199
AD/217 AD) performed experiments on animals to advance the understanding of anatomy,
physiology, pathology and pharmacology. Ibn Zuhr, an Arab physician in the twelfth century,
introduced animal experimentation as an experimental method for testing surgical procedures
before applying them to human patients [2]. After some tragic drug catastrophe on humans, a
4
Federal Food, Drug and Cosmetic Act was passed in 1938 in the USA that required safety
testing of drugs on animals before they could be marketed to be used by humans [2]. Another
fiasco occurred in 1961 with a drug called thalidomide. Initially, thalidomide was developed
and marketed to be used as an off-labeled sedative in 1957 [9]. Later it was a widely used
drug in late 1950s and early 1960s for treating nausea in pregnant women. However in 1960s
it became apparent that thalidomide treatment caused severe birth defects in thousands of
children. Though it was banned in most countries, thalidomide later proved to be useful
treatment for leprosy, multiple myeloma and advanced HIV infection [10]. This drug was
undoubtedly a turning point in toxicity testing as this tragedy questioned the results obtained
from the initial animal experiment conducted with thalidomide. It prompted US and
international regulatory agencies to develop systematic toxicity testing protocols [10]. Most of
the drugs discovered in the 19th and 20th century were evaluated and came into use for humans
because of experimenting on animals [11].
Currently, animal research is conducted all over the world. However, the
number of animals used depends on the particular country. The USA counts only warm-
blooded animals in research, while EU countries count all vertebrates. No country counts
invertebrates as living animals that undergo experiments [12]. In 2015, the number of animals
used in EU countries was about 11 to 25 million while in the USA the number was about 4
million [12]. The main concern for animals in the experiments is the physical pain and mental
stress [11]. Therefore, it is important to look into the ethical aspect of this practice as well.
Currently, there is an ongoing debate on the use of animals for experimental purposes [6].
Many activists protest again animal testing. Their arguments are mostly based on the principle
of speciesism under which animals are attributed to a lower moral value on the sole basis of
belonging to different species [6].
Results obtained from animal experimentation also raise a question about the
credibility when compared to humans, as their reliability and limitations have increasingly
been acknowledged [13]. It is known that human diseases and animal model diseases are
different from each other, therefore those are difficult to generalize based on animal research
[13]. However, it is questionable whether it should be stopped, as there are a lot of
unanswered questions that generally involve complex diseases and injuries that require
animals to be studied and tested such as cancer, Alzheimer’s disease, arthritis or other mental
traumatic diseases [8]. At this moment, animals are crucial for testing treatments and drugs in
order to adequately understand these diseases. Since, we have this dilemma, we are compelled
5
to ask:
To what extent can a medical paradigm be formed without using animal studies?
In order to answer this question we will focus on the medical case study about
thalidomide tragedy. We will look into the usage and effects of thalidomide over the years
and focus on how it contributes in understanding the significance of animal experiments in
medical science. This case will also provide insight to the generalization of animal
experiments to humans. The reason to use a case study is that it will narrow down the broad
area of medical science into a smaller frame. The aim is to evaluate on the issue of how
ethical it is to use animals for experimental research and if this process is discontinued would
it then be possible to advance further in medical science.
Hypothesis:
Treating animals in some experiments is morally questionable and the results
from these experiments, when generalizing to humans, also lack reliability. This paper will
analyze the case study by evaluating the generalization of animal experiments to humans and
the ethical considerations related to it. We hypothesize that this will lead us to not support
animal experimentation and propose some promising alternatives of animal experimentation.
Sub Questions:
What are the scientific challenges with generalizing animal experiments?
What are the ethical considerations of using animals in medical research?
What are the available alternatives to animal testing in medical research?
Relation to Semester Thematic Constraint
This paper reflects upon the possibilities of conducting medical research with
and without the use of animals. The theme for semester is to shed light upon natural science
as cultural, historical and ethical phenomena viewed from outside. Therefore, this paper will
particularly look at the ethical and historical aspects of animal experimentation. It will
demonstrate how animal experimentation has developed and how its significance has evolved
over the time and how social legislations retaliate on such notion. It is relevant to evince the
moral issues regarding using animals for human benefits, so the ethical aspects of it will also
6
be elucidated.
Methodology
This paper is a literature-review report where no experiments will be conducted.
Animal studies published in peer-reviewed journals have been analysed. Since medical
science is a vast area, this paper focuses on a specific case study of thalidomide. This drug has
been famous for the tragedy related to it. This case study has been chosen because of its
prominent effect on improving the drug testing protocols.
The paper has been built on three main parts, which has ensured that an answer
for the research question is achieved. The main constituents of this paper are theory, analysis
of the case study and a discussion of the ethical considerations and possible alternatives of
animal experiments.
Common databases used for the research purposes of this paper are NCBI,
PubMed, RUC library databases, American Journal of medicine. Some of the commonly used
research terms in these databases were thalidomide, ethical aspects of animal testing and
history of animal experiments.
Limitations:
Animal experimentation is a procedure including many different kinds of animal
testing and experiments and it has different terms to describe them. So in order to avoid any
confusion and to form a direct path of the paper the term used for this paper is animal
experimentation which stands for those scientific experiments that cause any suffering, pain
or torture to the animals. The paper will not advert to any religion or spiritual views about
animal experimentation.
The History of Animal Experimentation
The use of animals in medical field traces back to ancient Greece with the first
mentions 500 BC in philosophers’ writings [4]. Some of them are Aristotle and Erasistratus
who studied living animals and then Hippocrates and Alcmene of Crotona who took it a step
further and studied animal organ´s structure and function [4]. The first vivisection ever was
7
performed by Galen (130 – 200 BC), who is therefore also called "The Father of Experimental
Medicine" [4] [10]. After ancient times there was a pause in animal research due to the
influence of the church [4]. Vivisection comes back in 16th century and with William
Harvey´s work, in which he proved blood circulation in more than 80 animal species [4] [11].
Another notable mention of animal research is in Lavoisier´s work on anesthesia and
respiration, Pasteur´s vaccines and demonstration of diphtheria toxin effects on animals by
Behring [4]. With increasing number of animal experiments being carried out, the first animal
protection law was introduced in Britain in 1822, later followed by Cruelty to Animals Act in
1876 [4] [12]. Even Charles Darwin supported this initiation, as he wrote: “You ask about my
opinion on vivisection. I quite agree that it is justifiable for real investigations on physiology;
but not for mere damnable and detestable curiosity. It is a subject which makes me sick with
horror, so I will not say another word about it, else I shall not sleep tonight” [12]. Following
Great Britain, there were societies established in US such as American Society for the
Prevention of Cruelty to Animals (ASPCA) in 1860s and American Antivivisection Society
(AAVS) in 1883 [12]. During this time, law in US stated: “any procedure can be performed
on an animal if it is successfully proven that it is scientifically justified, as specified under the
provisions of the Animal Welfare Act and the guide for the care and use of laboratory
animals, published by the National Academy of Sciences” and special committees had to
make sure that animal research alternatives were discussed before the experiment, that
experiment is not a duplicate and that pain relief drug was administrated to animal in case it
doesn’t interfere with the research [12].
Society and Animal Experimentation
The history of the regulation of animal research is essentially the history of the
emergence of meaningful social ethics for animals in society [14]. Through the decades, the
increasing usage of animals in scientific research has drawn attention toward the moral status
of animals involved in the scientific procedures. The discussion of the ethics of animal
experimentation has emerged from the moral relationship between humans and animals,
which have been justified through philosophical theories and religious faiths. As religions
have played a role in determining the relationship between animal and human, the ancient
8
societies of Greece and Rome also played a vital role in determining the different views
toward this relationship [15].
Tracing back to that time, the Greek philosopher "Aristotle" (384 BC-322BC),
was one of the greatest thinkers who have regarded humans in a different light compared with
the rest of the animal Kingdom[16].He argued that animals are below humans because only
humans can reason and have "rational souls"[16] [17].Therefore, animals can be used without
giving them any of the considerations which would be given to humans. Aristotle was not the
only philosopher who valued human lives more than animals', others also did so. The French
Philosopher Descartes (1596-1650) was on an agreement with Aristotle with assessing that
animals cannot reason however he added that animals cannot feel pain nor distress and don’t
have minds and language. For that reason, he described animals as machines who don’t
deserve compassion[17]. Research on animals' emotion and cognition have shown through the
decades that animals' potential to experience pain and distress is greater than it has been
weighed [18] .The German philosopher Kant (1724-1804), was one of the philosophers who
believed that animals do suffer, however despite that, he insisted that they still lack their
moral statues since they lack moral autonomy[16]. However, Bentham (1748-1832), the
English philosopher, argued that their ability to suffer is what makes them subjected to equal
moral consideration[17]. Bentham was one of the earliest proponents of animal rights[19].
Several activists, circles and philosophers, including Singer, have referred to his famous
quote: “The question is not, Can they reason, nor Can they talk? but, Can they suffer? Why
should the law refuse its protection to any sensitive being?”, to defend animal right and
welfare in vivisection[20][21].
Several people think that animal rights and animal welfare mean the same thing,
but in reality they don’t. It is important to understand the difference between animal rights
and animal welfare, because these two concepts are the main reason behind criticising animal
experimentation as a moral issue. Animal right is based on the idea that animal and human
have the same rights, while animal welfare refers to the fair treatment of animals which
protect animal from any negative states such as pain, fear or distress[10]. As long as the
suffering of animals is eliminated or reduced to the minimum and as long as there are no
alternative ways for reaching the same results obtained from animal experimentation, animal
experimentations is seen as morally right according to animal welfare activists. However,
according to animal rights activists, such as Regan, animals cannot be used for
experimentation. The philosophical discussions around the morality of animal testing has
9
always involved defending against animal rights and welfare. However philosophers’ attitudes
had differed from one another, due to their different backgrounds and ways of perceiving the
world.
Moral Philosophy Theories and Principles
To defend whether using animals in any scientific procedure is morally right or
wrong, different theories have been formed to represent different ways of reasoning. This
section introduces the most relevant and commonly used ethical theories in the discussion of
animal experimentation's morality.
Relativism
According to the Relativism, there are no universal moral standards because
morality is dependent on one’s culture. The judgment of whether an individual action or
practice is right or wrong is based on the moral norms of the society where the action is
practiced [24] [20].
Consequentialism
According to the consequentialism, the moral standards are determined by the
cost-benefit analysis of an action's consequences[25]. When the total good consequences
outweigh the total bad consequences, then the action is considered morally right. Through
history, different forms of consequentialism have emerged. One of the most powerful
approaches in animal ethics is utilitarianism.
Utilitarianism
The consequentialism in utilitarianism is that an action should be judged for its
consequences on the happiness of the largest number. Where the pleasure of an action should
outweigh the pain to be considered morally right on one side, and the social benefits of the
action should outweigh the disbenefits on the other side [25]. Thus the action should be more
favourable than non-favourable to everyone.
Deontology
Deontologists base morality on specific, foundational principles of obligations
regardless of the outcomes. Even if the consequence of an action is more favourable than
unfavourable to everyone, the action might be considered morally wrong. Considering the
consequences might contribute in forming the duty but they aren’t what make an action a
10
duty[26]. When you do your duty you behave morally and when you fail to do your duty you
behave immorally[17]. Several theories have emerged to approach the duty theory but the
most well-known theory is Kantianism.
Kantianism
Kantianism is a logical-based theory which is based on the ability of humans to
reason[27] . It is known for its well-known principle Categorical Imperative. Categorical
imperative takes the form of "Do X" or "Don’t do X" [27]. It is a command which is good-in-
itself since it mandates an action irrespective of one’s personal desires and condition and is
applied for everyone. [25]. It has two versions:
For an action to be considered morally right, it has to be possible according to a
universal law that can apply to all people.
For an action to be considered morally right, it should not only treat a person as a
means, but always as an end in itself.
Speciesism
Speciesism is based on the idea of treating members of one species as morally
more important than members of other species[28]. This kind of discrimination is based on
justification. For example being human is a justified reason for having greater moral values
than other species since humans can reason and are conscious while others can’t.
Laws and Regulations
Due to the pressure from several animal protection groups and the public on the
maltreatment of animals in scientific laboratories, laws have been enacted to regulate the care
and use of animals in the laboratories[29].The Cruelty to Animals Act was the world’s first
legislation to regulate the use and treatment of live animals in scientific research [30] .It was
passed by the British Parliament in 1876 and was known as the vivisection act. The Act only
covered the non-human vertebrates. It imposed that experiments must be performed with a
view to the advancement by new discovery of physiological knowledge or knowledge which
will be useful for saving or prolonging life or alleviating suffering [31]. Due to the animal
rights movement this law remained in force until it was replaced by the Animal (Scientific
procedure) Act in 1986. By passing this act, UK have been criticised for having some of the
strictest regulations in the world[32]. Research on great apes have been banned and a greater
protection were given to vertebrate animal: dog, monkeys, cates and horses. The act required
11
that before any regulated procedure is carried out, the procedure must be of a programme
specified in a project licence and be carried out by a person holding appropriate personal
licence authorities [33]. In addition to that, it required that application for licences procedures
on animal be considered on a case by case basis[33].With relative to the experimental
procedure, a harm-benefit analysis should be carried out to assess whether the expected
benefits outweigh any possible adverse effects to the animal and as long as there are no
scientifically suitable alternatives which replace the animal use, reduce the number of animals
needed or refine the procedure used to cause less suffering the regulated procedures can be
authorised [33].The principles of 3Rs are implemented in this law.
The 3Rs
In order to examine how decisions should be made on the use of animals in
research, William Russell and Rex Burch proposed the concept of 3Rs in 1959 in the book
”The Principle of Human Experimental Technique[19].50 years from there release, they
became accepted guiding principles for the ethical evaluation of animal use and national and
international legislation for the use of animal in scientific Procedure[22]. The principles
stands for:
I. Replacement: This refers to considering the methods which avoid or replace
the use of animal before conducting any scientific procedure which involve
animals. As long as the alternative to animal use in scientific procedure exist
such as computer simulations, mathematical modelling or in-vitro biological
system, animal use should be avoided[34].
II. Reduction: This refers to any method that will result in decreasing the usage
of animals in scientific procedures resulting in saving more animal lives.
Where fewer number of animals should be able to produce sufficient and valid
results. This could be established by avoiding the repetition of unnecessary
experiments[24] [20].
III. Refinement: This refers to refining the experimental procedure and techniques
and the enhancement of the welfare of animal used in science from their birth
until their death[20].The enhancement in the experimental procedure can be
maintained through choosing the appropriate species taking into account the
physiological and biological properties[34].
12
When applying the 3Rs to an animal-based study, equal consideration to the 3
principles must occur to ensure that the 3Rs have been satisfied [22]. In the case where the 3rs
are partially implemented, an animal-based study will not be approved. The application of
these principles have resulted in producing good experimental designs and data with greater
scientific validity. The 3Rs didn’t receive ethical criticism, because they don’t reflect a
specific ethical point of view or reasoning but instead unites ethical views and concepts. This
justifies its widespread use in publications from humane organizations, policies of scientific
funding groups, and in regulations and law. As the Animal (Scientific Procedure) Act in UK
implemented the 3Rs the Animal Welfare act in US also implemented the 3Rs.
The Animal Welfare act is the only federal law in the United States which is
intended to ensure the humane treatment of animals that are intended for research, bred for
commercial sale, exhibited to the public, or commercially transported [35]. The act was first
passed in 1966, but at that time it was named by Laboratory animal welfare act. In 1970, the
act was renamed by The Animal welfare act due to several amendments[36]. At the start of its
inaction, the act covered guinea pigs, hamsters, rabbits and cates while in 1970 the act
covered a broader classes of animals. Due to this change, the definition of animal was
changed to cover all-warm blooded animals. In 1985. In order to strengthen the standards for
providing animal care and the training for those who handle animals, the act implemented The
Institutional Animal Care and Use Committee.
Common Techniques of Animal Experimentation
This part aims to present the techniques currently used in animal experiments,
because many companies continue testing their products on animals, even though a lot of
modern alternatives of animal experiments have been discovered. That aspect will be further
deliberated in the discussion part [37].
Some of the tests consist of procedures, which cause pain and discomfort to the
animals [38]. Most animal studies usually proceed the following way: the substance, which
will be tested is given orally or placed on the animal’s body for a certain period of time, the
reaction of the organism is monitored, usually at the end of the experiment the animal is
sacrificed and its body is studied in detailed. In these sort of tests, the most used animals are
rodents, specifically mice and rats [37].
Types of experimental techniques, which are currently performed on animals
include: tests for carcinogenicity, mutagenicity, eye irritation (Draize eye test), acute toxicity,
13
repeated dose toxicity, skin corrosion/irritation, skin sensitization, pharmacokinetics/toxic
kinetics and metabolism, dermal penetration, reproductive and developmental toxicity,
neurotoxicity, eco toxicity etc. [37].
In this section, only the techniques used in the chosen case study on
Thalidomide will be presented. Most of the animal experiments involve the test for
teratogenicity [39][40]. Teratogenic agent could be chemicals, infectious agent, physical
condition or deficiency, which can damage the foetus’s DNA and its development. Exposure
of pregnant women to such teratogenic agents, could cause serious anomalies – extra fingers
or toes, malformation of the organs and even death of the foetus [38][39][40].
After the results seen from the thalidomide in 1961, it is recommended that
newly discovered drugs should be tested for teratogenic activity [41] [42]. The species that are
most commonly used in such tests are rabbits, mice and rats. Before and during the test, the
animals have to receive the same nutritional diet and be kept under the same conditions.
Moreover, a strict report of the observed abnormalities should be kept for future reference
[41] [42].
During teratogenic screening, in UK, the pregnant animals are given three types
of doses: high dose that should be high enough but not lethal for the animals, low dose and
intermediate dose. The tested drug should be given the same way as it would be clinically
administered. However, there are disadvantages of administering the drug in the diet. Firstly,
if the drug tastes bad then the animal would perhaps refuse to eat the food. Secondly, it is hard
to estimate how much of the drug the animal has taken [41].
The drug dosing should continue during organogenesis, although some
authorities believe that the dosing should be extended during the whole pregnancy. However,
such a prolonged dosing could possibly alter the mother’s metabolism and that could mask the
teratogenic effect of the tested drug [40]. In this context, it should also be mentioned that the
pregnancy between species vary significantly. Mice, humans and rabbits are all placental
mammals, which means that the reproductive investment in these species is expressed in
longer gestation, rather than prolonged lactation. Even though, all the three species possess
the same reproductive pattern, the length of the gestation varies a lot. For instance, Order
Rodentia, to which mice belong have gestation period of 21 days and Order Lagomorpha,
where rabbits belong, has gestation period of 30 to 36 days. However, the gestation in human
is significantly higher, almost 280 days [43]. Due to such differences in the pregnancy of
14
animals and humans, an experiment for teratogenicity conducted on pregnant rodents may
eventually produce different results than if the drug is consumed by a human.
The amount of pregnant animals used in the experiment should be high enough
to cover the statistical needs. For instance, in UK 20 pregnant rodents and 8 pregnant non-
rodents are typically used per test [40].
At the end of the test, the animals are sacrificed. The method of killing the
mother vary from laboratory to laboratory and among species. The uterus of the mother is
then examined and number and placement of live foetuses is counted. Details about the
foetuses, such as weight are entered on a record sheet. Foetuses are observed for external
abnormalities and then dissected [41] [42].
If the compound tested appears to have teratogenic effect during the animal
experimentation, further tests might be performed, in order to determine when exactly the
teratogenic action takes place [40].
Challenges with Species Generalization
This part will focus on interpreting how species are selected for research
purposes. This will be done by taking into account the differences between species and their
comparison on genetic, physiological, anatomical and molecular level. More attention will be
paid to the species, which have been subjected to tests during the thalidomide research and
development.
Every year more than 100 million animals worldwide are subjected to tests that
determine the safety of cosmetic, household products and medicines, due to the assumption
that animals respond the same way that humans do, when exposed to these products [1]. Due
to the different response of human and other species, studies have showed that many animal
tests could be unreliable and can even lead to fatal consequences, as in the case of
thalidomide [2][3].
Humans and other animal species differ anatomically, physiologically, in drug
absorption, and mechanisms of DNA repair. Therefore, animal experimentation may provide
inadequate information when trying to apply animal data to human diseases and drug response
[2]. For example, mice, which are the most commonly used animal in research and usually
serve as a helpful tool to scientist, when determining complex mechanism and diseases in the
15
human body or developing new drugs [4]. Mice and humans differ in many ways and thus it is
important that the differences and similarities between them is to be understood correctly, so
mice could be used as a useful model. According to research performed by National Human
Genome Research Institute (NHGRI), there are many DNA variations and gene expression
patterns that the two species do not share [4]. Moreover, it has been discovered that some
metabolic processes, stress responses and the activity of some genes of the immune system
differ between mice and humans [4].
Differences between humans and mice often prevent them from serving as good
animal models. For instance, scientists have discovered that for more than 4000 genes in
humans and mice, the transcription factor binding sites differ between the two species. In a lot
of cases, mice models are used to mimic processes happening in the human body, when
researching for specific disease. However, not all physiological changes that occur in the
human body during the disease could be mimicked at the same time [3]. Even though mice are
often used in medical research, they could be poor models for some human diseases [3].
Other aspects that may influence the results from animal experiments involve
the laboratory environment - the data from the animal studies can be affected by the stress
caged animals are experiencing during the experiments [5].
On the other hand, similarities have been discovered as well, which indicated
that mouse models could perhaps be used when studying certain human diseases and make the
disease treatable. Some of those diseases include acute promyelocytic leukaemia (APL),
breast cancer, painkiller drugs, anti-obesity drugs, gene therapy to treat diabetes, genome-
wide association studies, etc [4]. For instance, certain gene expression patterns in humans and
mice are related and specific DNA sequence differences, which are linked to diseases in
humans usually have analogue in the mouse genome [6]. The genomes of all mammals are
comparably similar due to the common ancestor they share. The protein-coding regions of
mice and humans are evolutionary conserved and thus genomes are 85% identical. On the
other hand, the non-coding regions of mice and humans are only 50% or less similar [7].
It has recently been discovered that, unlike humans, mice have a second thymus
gland, which has impaired the entire field of immunology research [8]. Often, the traditional
mouse model has been discredited and claimed to produce inaccurate results in areas such as:
16
cancer research, HIV/AIDS vaccines, infant death syndrome (SIDS, crib death), neurological
diseases etc. [8].
Rabbits are, as well, commonly used species for scientific research purposes and
are also one of the species involved in the thalidomide research [9]. There are similarities
between rabbits and humans in certain aspects, such as airway anatomy and responses to
inflammations. This also make them a reliable animal model when lung disease are
investigated [10]. Moreover, rabbits are commonly used in studies of platelet function,
thrombosis and atherosclerosis due to their ability to produce high amount of blood, to handle
experiments involving surgery and their diet is easily cholesterol manipulated, so they can
develop atherosclerosis [10] [11].
All in all, both mice and rabbits are preferred by researchers due to the
similarities they share with humans and the fact that they are relatively inexpensive and easy
to handle [11].
The Case Study of Thalidomide
Thalidomide was first synthetized in 1953 by The Swiss pharmaceutical
company CIBA and later in 1956 introduced by German pharmaceutical company Chemi
Grunenthal [44]. It was available under the trade name Contergan as a strong and safe non-
barbiturate sedative in more than 40 countries worldwide [45][46]. According to the
manufacturers, the main benefit of thalidomide was its very low acute toxicity that was
documented in animal experiments, mostly in rodent models, and the ability to induce deep
sleep without leaving the patient addicted [44] [10] [47]. It quickly became popular as
a treatment for anxiety, gastritis, insomnia and predominantly as a cure for morning sickness
for pregnant women, as it was advertised as harmless even in large doses [46]. Figure 1 shows
the chemical structure of thalidomide C13H10N2O4, which is a glutamic acid derivative [48]
Figur 1 Thalidomide’s chemical structure
17
Just five years after being on the market, two physicians, doctor William
McBride from Australia and doctor Widukind Lenz from Germany, noticed a link between
consumption of this drug and large amount of infants born with deformities of arms, legs or
internal organs [10] [44]. It is said that close to 10 000 children worldwide suffered from
malformations (phocomelia) due to thalidomide effect [10]. 40 percent of these children died
within one year [44]. However it was later found out that thalidomide significantly increases
risk of miscarriage, so the final number of pregnancies affected by this drug might be much
higher [46]. Effects of the thalidomide can be seen in Figure 3 below.
Figur 2 a) Scan of arms of an infant exposed to thalidomide in utero. White arrow: missing figure and fused elbow joint,
yellow arrow: shortening of the bone. b) Infant suffering from phocomelia . Source [44]
Many doubted this connection between birth defects and thalidomide, as for
example Josef Warkany [10]. His argument was that this drug did not cause any deformities
in rat models during the experiments [10]. According to a later study in 2000, the drug indeed
did not cause any malformations in rats, however it did show embryonic lethality [49].
Nevertheless, the drug was taken from the market in most of the countries in 1961 [45]. This
tragedy lead to more thorough regulations of pharmaceuticals as well as it brought up the
question of reliability of animal experiments [10]. New system of testing pharmaceuticals for
developmental toxicity was added and also one of the regulations that were implemented after
this incident was the requirement for conducting the experiment of potential medications on at
least two different species, where one of them cannot be a rodent [10]. This tragedy also had
an effect on FDA, Food and Drug Administration processes, and inefficiencies in animal
18
experiments were taken into consideration in order to produce better regulation processes,
provide more thorough consent for patients and demanded more transparency from drug
manufacturers [44].
Continued research on thalidomide after its ban in 1961 discovered
thalidomide’s immunomodulatory effects in 1965 [50]. This indicated a new use for this drug
– possible treatment of cutaneous manifestation of leprosy, also known as erythema nodosum
leprous (ENL) which was later confirmed and in 1998 it was approved by FDA as ENL
treatment, although it is under strict monitoring due to its side effects [50].
Other studies also confirmed beneficial results of thalidomide use in humans with HIV and
other immunodeficiency viruses [50].
In 1994, a research on rabbit models thalidomide’s ability to inhibit formation of new blood
vessels (angiogenesis) which can act as a key mechanism to stop cell proliferation in cancer
cells [50]. These results were later confirmed in human studies - in patients with myeloma and
also in other animal species [50].
However, following the first incident with thalidomide, not every animal
experiment was later confirmed in clinical trials in humans. In another animal study using rat
models, thalidomide also proved to be effective against graft-versus-host disease (GVHD),
both acute and chronic type [51][47]. It showed the ability to down regulate lymphocyte
response typical for GVHD and help the organism accept foreign transplant [51]. However
clinical trials did not always confirm these results, in some of the studies patients using
thalidomide developed GVHD even more often than placebo group [51]. The homografts in
mice were received successfully [47].
Similar scenario occurred while researchers tried to treat toxic epidermal necrolysis (TEN).
The clinical trial was a double-blind placebo-controlled randomized study, where thalidomide
group’s mortality was 83 percent, whereas mortality in placebo group was only 30 percent
[51].
Other off-label uses of the thalidomide drug include treatments of skin disease
prurigo nodularis, ulcerative disease aphthous stomatitis, type of vasculitis called Behcet
syndrome, chronic lupus and many more [51]. The history of thalidomide drug is summarized
in Figure 4 below.
19
Figur 3 chronological history timeline of thalidomide research
Source [48]
Thalidomide’s mechanism of action remains to be understood, as well as its teratogenic
effects [51]. Only some of its properties are known – such as thalidomide being anti-
inflammatory and immunomodulatory [51]. Its immunomodulatory effects were discovered
by accident, when dermatologist Sheskin noticed a patient’s improvement of leprosy caused
skin lesions, while the patient was taking thalidomide for its sedative effects [51]. This drug
20
inhibits phagocytosis and decreases level of cytokines by increasing degradation rate of
cytokines’ mRNA, which helps with erythema nodosum leprosum [51]. Antiinflammatory
effects were confirmed in studies with baboons and rhesus monkeys [47]. Thalidomide is also
anti-angiogenic, which may be useful in treating some types of cancers [51]. In its intentional
use as a sedative, thalidomide was useful because it is targeting certain protein called cereblon
which is encoded by a gene most likely linked with mental retardation [52]. One of the two
thalidomide’s optical isomers, s-thalidomide, was also found to induce apoptosis [51] [52].
Figur 4 Chemical structures of thalidomide’s optical isomers [15]
Thalidomide is soluble in lipids and is able to cross the placenta and therefore
affect the unborn child [52]. How exactly the teratogenicity is caused is not known, as there
are 24 proposed mechanisms at the moment, the most probable scenario is linked with
thalidomide’s anti-angiogenic effects [52]. Looking at the thalidomide’s chemical structure in
Figure 1, phthalimide ring on the left side is supposed to be responsible for teratogenicity,
while the right part, glutarimide ring is typical for hypnotic drugs – hence it’s official name
alfa-phthalimidoglutarimide [51] [47].
Despite its strong teratogenic toxicity, thalidomide’s acute toxicity is very low,
making it almost impossible to overdose on this drug [52]. The most common side-effects
include tingling in hands and feet, limb weakness, muscle cramps, constipation,
hypersensitivity or somnolence [52]. In pregnant women, the side effect is phocomelia of the
fetus as mentioned above, which is typically characterized by shortened or defective limbs, in
some cases completely missing limbs, ear or eye abnormalities, hypoplastic or absent bones
and gastrointestinal or genitourinary tract malformations [51]. Experiments using animal
models (source doesn’t specify used animal model)indicate that thalidomide should be non-
mutagenic [51].
This substance is slowly absorbed from gastrointestinal tract and the absorption
should not be affected by any consumed food [51]. However, high-fat foods can delay the
time needed for thalidomide to reach its peak plasma concentration – which normally is about
21
2,9 to 5,7 hours after the drug was taken [51]. The drug spreads out through the body fluids
and tissues extensively [51]. The drug is hydrolyzed through non-enzymatic pathway within
the blood and tissues spontaneously [51].
In humans, thalidomide is only hydrolyzed and then excreted in urine, however in some
animals thalidomide might be metabolized by cytochrome enzyme system [52]. The average
elimination time is 5-7 hours [51].
At the time, when the “Thalidomide tragedy” happened in 1961, it was already
known that some chemical compounds have teratogenic effect. However, no one appeared to
screen drugs for teratogenicity before the effect of the thalidomide, even though techniques at
the time were adequate for such kind of experiments [53][9]. In the Thalidomide case, during
animal examination, the drug did not produce malformations, when tested on rats, although
fetal restoration was observed. However, when tested on rabbits, Thalidomide produced some
well-defined malformations of the fetus [53][9].
Analysis
Looking at the contrasting effect of thalidomide on humans compared to
animals, scientists agreed that thalidomide resistance is species-specific [54]. There are some
functions in animals that differ from the human body, which grant animals resistance to
thalidomide teratogenicity. As mentioned earlier, thalidomide was tested on a number of
animals and mice and rats showed resistance to the drug, however rabbits and primates
suffered certain malformation [55]. On observing the molecular basis of thalidomide for
animal resistance, it has been found that thalidomide resistance is based on the capacity of
glutathione-dependent antioxidant defence [56]. Mouse and rats possess superior antioxidants
compared to humans. These antioxidants protect animal embryos from the damaging free
radicals that thalidomide introduces in the embryos. This indicated that the presence of
glutathione might repress thalidomide harmful effects [56].
Thalidomide was also tested on rabbits, which exhibited malformation to some
extent. Some researchers looked into the pharmacokinetics of different species to form the
basis of thalidomide specie-specific effects. It was observed that metabolism of thalidomide
22
also varies in different species [54]. One of the in vivo studies performed in 2004 by Lu et al.
shows that the half-life of thalidomide in blood plasma of mice is shorter than in humans,
while the half-life of rabbits show intermediate values between mice and humans. They found
that the half-life of thalidomide in mouse embryos was approximately half an hour while that
of human embryos was 7.3 hours [57]. Lu et al. found high amount of hydroxylated
thalidomide metabolites in mice, lower number in rabbits and barely any in humans [9]. So
the presence of a minimum amount of hydroxylated metabolites in rabbits could be the cause
for their malformation on being tested by thalidomide. Meanwhile the half-life of thalidomide
in rabbits is also considerably greater than mice. Fundamentally, a greater half-life will mean
lower rate of metabolism of thalidomide in body and in turn greater metabolism rate would
facilitate more rapid elimination of thalidomide from the system [57].
Non-human primates also manifested malformation in response to thalidomide
and almost giving the same reaction from the drug as humans [55]. This made researchers
presume that non-human primates are perhaps anatomically closest to humans. However,
when these non-primates were tested for other drugs it was discovered that the drugs known
to damage human fetus were found to be safe in 70% of the cases when tested on non-human
primates [9]. Then Hendrickx et al. found that the low doses of thalidomide had varying
effects on non-primates. However, they were mostly affected by thalidomide on receiving 25
to 150 times higher doses than normal human dose [55]. Hence, there is a possibility that the
offspring of non-human primates may not exhibit malformation just like humans if they are
given doses of thalidomide similar to humans. Consequently, non-human primates also do not
provide a promising resemblance to human body. This indicates that drug interactions can
differ drastically among animals and humans. Hence, the conjecture that experiments on
animals provides similar results for humans, still needs further verification.
Animals are not perfect representation of humans but they can probably be
adequate substitutes. It also enables us to understand any possible similarity between humans
and animals anatomically. Tamoxifen is a drug used to treat breast cancer discovered in early
1970s. It emerged as a result of a research program where using dimethylbenzathracene
(DMBA) induced rat mammary carcinoma model it was found that it blocks the binding of
estradiol to human breast’s estrogen-receptor (ER) and rat mammary tumor ER and prevented
23
the induction and growth of ER positive breast cancer [58]. However, initial trials ran only for
one year. As it is known that a month in a rat’s life is about a year in a human’s life, so a
month’s treatment, with a regular dosage, on the rat model was equivalent to 1 year’s
treatment in humans and it only delayed the onset of tumor. Hence, scientists found that
increasing the dose in humans will in turn delay the formation of tumor further. As higher the
daily dose of tamoxifen, the longer will be the delay in tumor recurrence [59]. This
demonstrates that although the requirement of dosage differs from rats to humans, only testing
tamoxifen on a rat model determined its anti-tumor effects. However, 20 years later it was
discovered that tamoxifen causes liver cancer in rats but no such symptoms were found in
humans [59]. This also supports the argument that rats or mice possess some similarity to
humans only to some extent.
On the contrary, in 1993 during the clinical trials of another drug called
fialuridine, the effect of the drug was distinct. In the initial 13 weeks trial, seven of the fifteen
patients with hepatitis B developed hepatic failure, lactic acidosis and pancreatic failure in the
first 8 weeks [60]. This toxicity developed even after the treatment was ceased. Then in a
current study the research used a TK-NOG mice with a humanized liver compared to a normal
mice. Both the TK-NOG mice and the control mice were treated with varying doses of
fialuridine, which was given orally. It was found that the TK-NOG mice showed similar traits
as the trial patients in 1993 while the control mice displayed no toxicity [60]. As it was seen,
in this clinical trial the TK-NOG mice functioned as a human in regards to the liver while the
control mice were normal mice and the effect of fialuridine was drastically different on the
two. This propounds that despite having similarities human and mice have dissimilarities and
they have different anatomical and hormonal complexities. It is not possible to decide on a
particular animal for complete generalization to humans, as the results can distinguish from
one drug to another. Likewise, in the thalidomide tragedy all the animals involved in the drug
testing experiment had some traits similar to humans but there were other factors in their
bodies that distinguished the impact of thalidomide on them. This might also raise the
question that a certain level of anatomical resemblance is not enough for generalizing the
effects of drug from animals to humans. It is not possible to depend on a particular set of
animals in order to examine the human body. Preferably it would be better to perform drug
trials on more than one animal in order to clearly see the difference in reaction. Hence more
animal experimentations are necessary to be conducted while performing drug trials.
24
Besides the physical variances of animals and humans, it is also crucial to look
into the ethical consideration related to the thalidomide drug trial through animal
experimentation.
Scientists doing medical research have the obligations to save human live, as this
action is their duty. In order to save human's lives, researchers have performed animal
experimentation to discover and test drugs safety before they are passed to clinical trials. In
the thalidomide case, animals have been used as means to test the safety of the drug before it
was passed into the market. Since animals didn’t develop any teratogenic effects, it was
marketed as a completely safe sedative and sleeping pill to everyone and when Dr. William
discovered that the drug also alleviated morning sickness it started to be recommended for
pregnant woman as off-labeled drug against nausea and morning sickness. However by
relying on the animal experimentation results, thalidomide have caused 10,000 birth defects
and thousands of fatal death worldwide. This raises two main ethical dilemmas:
I. Are the preclinical tests of thalidomide on animals morally justified?
II. Should thalidomide even have been on the market?
In order to analyse whether the preclinical test of thalidomide on animals is morally
justified a utilitarian would ask: Does the end justify the mean? If the consequences is more
favorable than unfavorable to everyone then the mean is justified. The consequences of
thalidomide was more non-favorable than favorable to everyone as thalidomide have caused
thousands of defects and death. In retrospect, the preclinical trials on animals can be
considered unethical as they turned not to be able to serve as a model for the adverse effect
observed. However according to deontology the animal experimentation in this case is
morally justified since the intention of the researchers is to save human's lives no matter what
the consequences are.
According to the categorical imperative, we should not treat a person only as a mean,
but always as an end in itself. If this version of categorical imperative is applicable to animals
then it is wrong to do pre-clinical tests of thalidomide on animals because then researchers
simply treat animals as means to achieve their goal. However Kant believed that categorical
imperative is not applicable to animals, as they are non-autonomous. Since they have no wills,
they have no intrinsic value and their ends are man [61][62]. In position to that, he believed
that humans have indirect duty toward animals since cruelty to animals will lead to cruelty to
25
humans, so animals should be treated humanely. Combining these two believes, Kant would
agree with the consequentialism because humans have no direct obligation toward animals.
Thus according to Kantianism, the preclinical trial of thalidomide on animals is also unethical
since the harm caused to the pregnant patients outweigh the benefits. On the other hand, if an
animal right activist as Regan want to judge whether animal experimentation on thalidomide
is ethical, he would directly answer: it’s unethical. Animals should be afforded the same level
of respectful treatments as human, and since animal rights are violated in preclinical trail of
thalidomide, then the animal experimentation involved in testing the safety of thalidomide is
not justified in any ways according to animal right activists.
The intention behind marketing thalidomide for pregnant woman was not to
cause birth defects, but to alleviate morning sickness, so the intension was good, thus the
action is considered ethical, in regards to the deontology stand point. While according to
consequentialists, marketing thalidomide at that time was unethical since it causes harm to
countless babies. When the pregnant patients took the drug, they were not informed that the
safety and effectiveness was not obtained by human clinical trials. Therefore, prescribing the
drug to 20,000 pregnant women worldwide was in its self a clinical trial where patients were
not informed. Even if thalidomide was tested on pregnant animals before it was passed to the
market, the drug would still have been passed to the market since deformities were not
observed in several species, and in the animals who developed deformities they were given
much higher doses than what would be given to a human. If the mechanism of thalidomide
was well understood, and if it was tested on a smaller number of humans before it was passed
to the market, the tragedy wouldn’t have happened. At that time, an approval of a drug didn’t
requires passing the FDA, but if it was required thalidomide wouldn’t have been on the
market at the first place.
Marketing thalidomide can be considered unethical both based on the
consequences and the procedure of testing its safety. Considering the case in U.S, after the
tragedy the FDA tightened its regulations on the surveillance and approval process for the
drugs to be sold in the U.S. [15].This was maintained by the Kefauver-Harris Drug
Amendments which guides the ethical principles for medical research involving human
participants. Where now it is required that any medical research involving human participants
should be based on thorough knowledge of the scientific literature, other sources, laboratory
and animal experimentation [63]. Where human participant should be given an informed
26
consent and the welfare of animals used for research should be respected. In addition to that,
the drug approval today involving animal experiments can take 8-10 years[3].Because of the
strict regulations implemented by the Kefauver-Harris Drug Act, the FDA approved the use of
thalidomide for treating inflammation associated with Hansens disease( leprosy) and as a
chemotherapeutic agent for patients with multiple myeloma[15][64].Due to the teratogenic
effect of thalidomide, patients are strictly warned and guided through the prescription. For an
instant, in the prescription of the thalidomide drug "Pomalyst" the warning shown in figure 1
are given to the patients with myeloma.
Figur 5 warning of the tratogenic effect of thalidomide in Pomalyst prescription [7]
Discussion
Unfortunately, thalidomide tragedy wasn’t an isolated case where animal
experiments simply failed to predict severe adverse reactions in humans. Similar scenario
occurred also with drug vioxx, which was meant to treat arthritis [65]. Vioxx is an anti-
inflammatory drug, approved by the U.S. Food and Drug Administration (FDA) in 1999 [66].
However, five years
later, it has been voluntarily withdrawn from the market by its manufacturer
after it caused more 140 000 strokes and 60 000 deaths just in USA [65][67]. The drug has
killed thousands of people worldwide by inducing heart attacks and other cardiovascular
diseases [67]. Before launched on the market, Vioxx was tested on five different animal
species, including mice, rabbit and monkeys, and no abnormalities have been discovered [67].
In animal studies it appeared safe and even protecting the heart muscle [65]. Another example
is benoxaprofen (oraflex), which was studied for a year in rhesus monkeys before being
27
released [65]. Despite being on the market for only three months, the drug managed to case
several deaths and thousands of adverse reactions [65] To this day, there wasn’t found an
animal model in which benoxaprofen’s hepatotoxicity was observed [68] Zomepirac (zomex)
was tested on rabbits and guinea pigs and had to be withdrawn from the market in 1983
because it caused anaphylactic shocks that often resulted in death, however this reaction was
still not observed in animal models [68] [69] [70].
More recent case happenned in March 2006, when therapeutic antibody tgn1412
was administred to 6 healthy volunteers during clinical trial [71]. All 6 volunteers experienced
variety of adverse reactions which later lead to multi-organ failure in all of them [71] One of
the participants had to have all of his toes amputated, as well as some of his fingertips and he
spent 147 days in hospital in medical coma with heart, liver and kidney failure while his body
tripled in size due to the swelling [72] Interestingly, this antibody was prior to clinical trial
tested extensively on rabbits and also on monkeys, which received 500 fold larger dose than
volunteers in clinical trial, but during these test no serious side effects were observed [71]
[73].
These incidents question the reliability of animal testing even within scientific
community and these doubts are indeed based on facts – to quote ”Of 93 serious adverse
reactions related to 43 small molecule drugs, only 19% were identified in animal studies” and
from a study that looked into the sensitivity of animal models to detect toxicity in humans by
evaluating 150 therapeutics: ”In total, the concordance between human and animal toxicity
was 71% for rodent and non-rodent species, 63% for non-rodent species, and 43% for rodent
species” [74]
Even though, some animals and humans have similar genomes, in many cases
these animals fail to mimic the complexity of the human body, which may lead to misleading
results from the animal studies. An example of that is the thalidomide tragedy, where some
controversial results from the animal experiments have been observed – in some studies well-
defined abnormalities have been developed rabbits, but doubtful teratogenicity in mice [41].
Due to the many differences between mice, rabbits and humans, it might be hard
for the extracted information from animal studies to be applied to humans, since the reaction
in species may vary. A good example is that 9 out of 10 drugs tested in animals fail human
clinical trials and do not enter the market [75]. That is why the average rate of successful
translation of animal experiments to human clinical trials is only 8%, which supports the fact
that animals have limited ability to mimic the complex processes in the human body [37].
28
On the other hand, animal research has a vital role in drug development and
modern medicine. Animal models could be good substitutes for the human’s organism in
some cases. For instance, due to animal studies, researchers have been able to make certain
discoveries such as antibiotics for infections or vaccines [53].
However, no animal model could perfectly simulate all human features. That is
why the differences and similarities between species should be taken into consideration and
the choice of animal should be made based on the type of experiment that will be done. In
other words, animal studies should be specifically targeted. For example, mice may serve as
suitable tool, when researching gene therapy to treat diabetes or genome-wide association
studies, since mice and humans protein-coding genes are 85 % identical [76]. Not
surprisingly, chimpanzees and humans are also possess genetic seminaries – their genomes
are 90% identical [77].
The other most commonly used animal in research is the rabbit. Humans and
rabbits have similarities in the airway anatomy and inflammatory response [78]. That could
make them a potentially reliable animal model, when lung disease are investigated, for
instance [78]. Moreover, rabbits could be used in atherosclerosis studies, because their diet is
easily cholesterol manipulated, so they can develop atherosclerosis [79].
As it is important to question the reliability of generalising animal
experimentations' results to human upon answering the research question, it is important to
determine whether animal experimentation is considered ethically right. As presented
previously, philosophers’ justifications and theories are to a large extent dependent on their
beliefs that’s why according to relativism there is no universal answer on whether animal
experimentation is ethically right. However all the represented theories agrees on the principle
of avoiding cruelty to animal with regardless of whether animal experimentation is seen
ethical or not. That’s why today animal experimentations are guided with strict regulations to
maintain animal welfare during experiments. The reason why scientist doing medical research
use animals is because they need them. But why wouldn’t they directly test the drug on
humans if it will result in more reliable results? The answer is simply because of speciesism.
The basic reason why animal are given lower moral values than humans in medical research is
that human are autonomous and have the will to decide their ends while animals cant. As
long as animal experimentation will continue to be conducted speciesism will continue to be
addressed by antivivisectionist. Speciesism is not seen in research only between human and
animals but also between the animals’ species themselves. As animals who are more sentient
29
are giving higher moral values than those who are less sentient. According to Regan, the best
thing we can do in terms of not using animals is not to use them [80]. He opposes
utilitarianism by saying that a good end would not justify an evil mean. However today, the
utilitarian viewpoint is dominated in the legislation of animal experimentation in the western
countries. Where animal experiments, according to the laws and regulations, deserve major
ethical consideration and such considerations should be in balance with moral consideration
of humans[81]. Scientists doing biomedical research should maintain animal welfare by
insuring that the potential benefits from the use of animals outweigh the suffering and pain on
animals while maintaining an acceptable use of animals and that harm they are exposed to is
minimized to the minimum and the highest well-being is achieved where animal use is
necessary[81]. This procedure of weighing the benefits against the harm is known as harm-
benefit analysis. The benefit of the animal experiment is likely limited to the research project
meeting its specific aims in generating new scientific knowledge. Because these experiments
add new knowledge to previous knowledge obtained, it’s important to relate it to previous
work. In order to see the expected benefits it’s important to choose the right animal model,
plan a proper study design and work with an experienced team. Looking back to the
thalidomide tragedy we can easily see how the expected benefits was not seen, since the study
design was not good. However even if the drug didn’t favour the purpose, it added new
knowledge about its teratogenic effect and was a lesson in drug and regulations. On the other
hand, assessing the harm can involve the animal species, experimental procedures, source of
animals, transport, husbandry and care conditions, quality of the facilities involved, and
expertise of the researchers[81]. From the animal experimentation examples presented
previously, we can see how it is difficult to assess the benefits of animal experimentation on
human thus this assessment might not favour the purpose all the times. On the other hand, the
corner stone of the ethical assessment of animal experimentation is the 3Rs, which is
implemented in most of the legislation on animal welfare. The requirement for Replacement,
Reduction and Refinement, presented in the theory part, results in fewer animal being used in
total, preference for the use of non-animal method or less sentient animals, and in procedure
which minimize pain and distress for those animals that are used for science[22]. As long as
alternatives of animal experimentation exist animal experimentation should be avoided.
Animal research can be substituted by in silico and in vitro studies [82][11]. A
popular in silico method are tools from computer programs analysing Structure Activity
Relationship (SAR) [82]. They are able to predict the activity of the drug in the body by
30
looking at different chemical groups attached to parent molecule [82]. QSAR – Quantitative
Structure Activity Relationship is a mathematical description of the correlation between
properties of a drug and drug’s biological activity [82]. The computer database is able to
predict the outcomes of the drugs, such as carcinogenicity or mutagenicity, the simulation is
also able to model pharmacokinetics and toxicity endpoints [82][83]. Computer models are
very fast compared to conventional methods and often inexpensive [82]. National Center for
Biotechnology Information (NCBI) even offers some of the software packages for free, it can
be downloaded by anyone from their website [83].
There are entire ‘’virtual human’’ models that have been programmed by using
already known human’s drug reaction [11]. These models can simulate several processes from
human metabolism to cardiovascular risks [11]. For instance, based on these model, HIV
inhibitor drug was designed by a computer as the need for the drug was very urgent and it was
more convenient to skip the animal test due to the lack of time [11]. Again, some of these
models are available for free from educational institutions [11].
In vitro methods include tissue engineering, tissue slices, organ cultures, cell
cultures, cell lines or stem cells [11][84]. Cultured cells are already being used, they have
proven to be very useful in cancer research [11]. Cultured liver tissues can be used in order to
predict drug toxicity [11][84]. Skin cells culture already became more commercial and easier
to access – as they are human skin models available called EpiDerm or EpiSkin, in which a
synthetic protein is used to simulate skin barrier [11]. Cell lines of neuroblastoma and glioma
are currently replacing the teratogenic tests [11]. A centre in Finland -The Finnish Centre for
Alternative Methods (FICAM) introduced a test of detecting effects on blood vessels
formation and after running the test with already known drugs, it showed excellent correlation
with human clinical and very low with animal research data [84]. Most of these methods have
been validated and are already reducing the animal suffering [11].
Another possible alternative to vivisection is a method called micro-dosing [11].
This method consists of administrating only small dose to human volunteers and safety of the
drug is examined by ultra-sensitivity of accelerator mass spectrometry [11]. Considering that
the current human clinical trials have a failure rate of drugs 40 percent in their first phase,
micro-dosing consumes less time and is more cost-effective [11].
Even though these effective alternatives exist animal experimentation in medical
research is still taking place. As long as the current legislation that requires pre-clinical test of
31
drugs on animal is not amended, animal experimentation will continue to be a part of medical
science.
Conclusion
In conclusion, it can be deduced that in current times it might not be possible to form a
medical paradigm with using animal experimentation to test drugs and treatments. Even
though there are effective alternatives in use with promising outcomes, there are laws
enforcing the pre-clinical trials of drugs on animals. As long as these laws stays, animal
experimentation cannot be eradicated completely from medical research field.
32
Bibliography
[1] “About Animal Testing : Humane Society International.” .
[2] R. Hajar, “Animal testing and medicine.,” Heart Views, vol. 12, no. 1, p. 42, Jan. 2011.
[3] American Psychological Association, “Research with Animals in Psychology,” American Psychological Association. pp. 1–4, 2015.
[4] “Testing - American Anti-Vivisection Society.” .
[5] “What is Vivisection? | About NEAVS.” .
[6] N. Henrique Franco, “Animal experiments in biomedical research: A historical perspective,” Animals, vol. 3, no. 1, pp. 238–273, 2013.
[7] “What is animal testing? | Cruelty Free International.” .
[8] N. Academy, O. F. Sciences, N. Academy, and O. F. Engineering, “How Have Animals Contributed to Improving Human Health ?,” 1991.
[9] R. Greek, N. Shanks, and M. J. Rice, “The History and Implications of Testing Thalidomide on Animals,” J. Philos. Sci. Law, vol. 11, no. October 3, pp. 1–32, 2011.
[10] J. H. Kim and A. R. Scialli, “Thalidomide: The tragedy of birth defects and the effective treatment of disease,” Toxicol. Sci., vol. 122, no. 1, pp. 1–6, 2011.
[11] D. K. Badyal and C. Desai, “Animal use in pharmacology education and research: the changing scenario.,” Indian J. Pharmacol., vol. 46, no. 3, pp. 257–65, 2014.
[12] “Animal Research Statistics | Speaking of Research.” .
[13] A. Akhtar, “The flaws and human harms of animal experimentation.,” Camb. Q. Healthc. Ethics, vol. 24, no. 4, pp. 407–19, Oct. 2015.
[14] B. E. Rollin, “The regulation of animal research and the emergence of animal ethics: A conceptual history,” Theor. Med. Bioeth., vol. 27, no. 4, pp. 285–304, 2006.
[15] E. Szucs, R. Geers, T. Jezierski, E. N. Sossidou, and D. M. Broom, “Animal welfare in different human cultures, traditions and religious faiths,” Asian-Australasian J. Anim. Sci., vol. 25, no. 11, pp. 1499–1506, 2012.
[16] W. Lane-Petter, “The ethics of animal experimentation.,” J. Med. Ethics, vol. 2, no. 3, pp. 118–126, 1976.
[17] R. Panaman, How to Do Animal Rights, Second PDF. Oxford, 2008.
[18] H. R. Ferdowsian and N. Beck, “Ethical and Scientific Considerations Regarding Animal Testing and Research,” vol. 6, no. 9, 2011.
[19] V. Braithwaite, Do Fish Feel Pain? New York: OUP Oxford, 2010.
[20] “Animal Rights Philosophy,” Speaking of Research. [Online]. Available: https://speakingofresearch.com/extremism-undone/ar-beliefs/. [Accessed: 22-Nov-2016].
[21] J. Bentham, An Introduction To The Principles of Morals and Legislation. London, 1780.
[22] N. Fenwick, G. Griffin, and C. Gauthier, “The welfare of animals used in science: how the ‘Three Rs’ ethic guides improvements.,” Can. Vet. J., vol. 50, no. 5, pp. 523–30, 2009.
33
[23] J. Lu, K. Bayne, and J. Wang, “Current status of animal welfare and animal rights in China,” ATLA Altern. to Lab. Anim., vol. 41, no. 5, pp. 351–357, 2013.
[24] M. Velasquez, C. Andre, T. Shanks, S.J., and M. J. Meyer, “Ethical Relativism,” Markkula Center For Applied Ethics. [Online]. Available: https://www.scu.edu/ethics/ethics-resources/ethical-decision-making/ethical-relativism/. [Accessed: 30-Nov-2016].
[25] J. Fieser, “Ethics,” The Internet Encylopedia of Philosophy, 2013. [Online]. Available: http://www.iep.utm.edu. [Accessed: 30-Nov-2016].
[26] J. P. Moreland, “THE EUTHANASIA DEBATE : UNDERSTANDING THE ISSUES ( Part One in a Two-Part Series on Euthanasia ),” CRI, no. 704, pp. 1–11, 1991.
[27] P. Kain, “Kantian Ethics,” Philos. Rev., vol. 119, pp. 104–108, 2010.
[28] B. Duignan, “Speciesism,” Encyclopedia Britannica, 2013. [Online]. Available: https://global.britannica.com/topic/speciesism. [Accessed: 30-Nov-2016].
[29] National Research Council, Science, Medicine, and Animal. 2004.
[30] S. Hamilton, “Susan Hamilton , ‘ On the Cruelty to Animals Act , 15 August 1876 ,’” no. August, pp. 1–12, 1876.
[31] J. E. Hampson, “History of animal experimentation control in the U.K.,” Int. J. Study Anim. Probl., vol. 2, no. 5, pp. 237–241, 1981.
[32] “Animal Research Regulations in The UK,” Speaking of Research. [Online]. Available: https://speakingofresearch.com/facts/animal-research-regulations-in-the-uk/. [Accessed: 21-Oct-2016].
[33] Home Office, Guidance on the operation of the Animals (Scientific Procedures) Act 1986, no. March. London: The Stationary office, 2014.
[34] M. M. Naderi, A. Sarvari, A. Milanifar, and S. B. Boroujeni, “Regulations and Ethical Considerations in Animal Experiments : International Laws and Islamic Perspectives,” vol. 4, no. 3, pp. 114–120, 2012.
[35] T. Cowan, “The Animal Welfare Act : Background and Selected Legislation,” pp. 1–13, 2012.
[36] A. D. Cardon, M. R. Bailey, and B. T. Bennett, “The Animal Welfare Act: from enactment to enforcement.,” J. Am. Assoc. Lab. Anim. Sci., vol. 51, no. 3, pp. 301–5, 2012.
[37] The American Anti-Vivisection Society, “Animals in Science.” .
[38] W. Chung, “Teratogens and Their Effects,” pp. 1–8, 2004.
[39] M. M. H. J. van Gelder, I. A. L. M. van Rooij, R. K. Miller, G. A. Zielhuis, L. T. W. de Jong-van den Berg, and N. Roeleveld, “Teratogenic mechanisms of medical drugs,” Hum. Reprod. Update, vol. 16, no. 4, pp. 378–394, 2010.
[40] E. Gilbert-Barness, “Teratogenic causes of malformations,” Ann. Clin. Lab. Sci., vol. 40, no. 2, pp. 99–114, 2010.
[41] M. J. Cook and F. a. Fairweather, “Methods used in teratogenic testing,” Lab. Anim., vol. 2, pp. 219–228, 1968.
[42] J. Schumann, “Teratogen screening: State of the art,” Avicenna J. Med. Biotechnol., vol. 2, no. 3, pp. 115–121, 2010.
[43] A. Larson, C. Hickman, R. Larry S, and C. P Hickman Jr, Integrated principles of Zoology. 1955.
34
[44] W. Rehman, L. M. Arfons, and H. M. Lazarus, “The Rise, Fall and Subsequent Triumph of Thalidomide: Lessons Learned in Drug Development,” Ther. Adv. Hematol., vol. 2, no. 5, pp. 291–308, 2011.
[45] R. Von Moos, R. Stolz, T. Cerny, and S. Gillessen, “Thalidomide: From tragedy to promise,” Swiss Med. Wkly., vol. 133, no. 5–6, pp. 77–87, 2003.
[46] Marilyn T. Millera and Kerstin K. Strömlandb, “What can we learn from the thalidomide experience: an ophthalmologic perspective.”
[47] M. Stephanie Tseng, BA, Grace Pak, MD, Kenneth Washenik, MD, PhD, Miriam Keltz Pomeranz, MD, and Jerome L. Shupack, “Rediscovering thalidomide: A review of its mechanism of action, side effects, and potential uses.”
[48] H. Mujagic, B. A. Chabner, and Z. Mujagic, “Mechanisms of action and potential therapeutic uses of thalidomide.,” Croat. Med. J., vol. 43, no. 3, pp. 274–285, 2002.
[49] A. H. P. Gemma Janer , Wout Slob, Betty C. Hakkert, Theo Vermeire, “A retrospective analysis of developmental toxicity studies in rat and rabbit: What is the added value of the rabbit as an additional test species?”
[50] J. M. W. and E. W. Shuang Zhou, Fengfei Wang, Tze-Chen Hsieh, “Thalidomide–A Notorious Sedative to a Wonder Anticancer Drug.”
[51] and S. H. M. Anthony J Perri III and D. O. J. 9 (3): 5, “A review of thalidomide’s history and current dermatological applications.”
[52] T. M. Katsunori Nakamura, Naoki Matsuzawa, Shigeru Ohmori, Yuichi Ando, Hiroshi Yamazaki, “Clinical Evidence of Pharmacokinetic Changes in Thalidomide Therapy.”
[53] Kristina Cook, “Facts about Animal Research.” .
[54] F. Chung, J. Lu, B. D. Palmer, P. Kestell, P. Browett, B. C. Baguley, M. Tingle, and L.-M. Ching, “Thalidomide Pharmacokinetics and Metabolite Formation in Mice, Rabbits, and Multiple Myeloma Patients,” Clin. Cancer Res., vol. 10, no. 17, 2004.
[55] N. Shanks, R. Greek, and J. Greek, “Are animal models predictive for humans?,” Philos. Ethics. Humanit. Med., vol. 4, p. 2, 2009.
[56] J. Knobloch, K. Reimann, L.-O. Klotz, and U. Rüther, “Thalidomide Resistance Is Based on the Capacity of the Glutathione-Dependent Antioxidant Defense,” Mol. Pharm., vol. 5, no. 6, pp. 1138–1144, Dec. 2008.
[57] J. Lu, N. Helsby, B. D. Palmer, M. Tingle, B. C. Baguley, P. Kestell, and L.-M. Ching, “Metabolism of Thalidomide in Liver Microsomes of Mice, Rabbits, and Humans,” J. Pharmacol. Exp. Ther., vol. 310, no. 2, 2004.
[58] V. C. Jordan and A. M. H. Brodie, “Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer.,” Steroids, vol. 72, no. 1, pp. 7–25, Jan. 2007.
[59] V. C. Jordan, “Tamoxifen as the first targeted long-term adjuvant therapy for breast cancer,” Endocr. Relat. Cancer, vol. 21, no. 3, 2014.
[60] D. Xu, T. Nishimura, S. Nishimura, H. Zhang, M. Zheng, Y.-Y. Guo, M. Masek, S. A. Michie, J. Glenn, and G. Peltz, “Fialuridine induces acute liver failure in chimeric TK-NOG mice: a model for detecting hepatic drug toxicity prior to human testing.,” PLoS Med., vol. 11, no. 4, p. e1001628, Apr. 2014.
35
[61] O. Johansson-Stenman, “Should Animal Welfare Count ?,” Polit. Sci., no. 197, pp. 1–28, 2006.
[62] S. D. Wilson, “Animal and Ethics,” The Internet Encyclopedia of Philosophy. [Online]. Available: http://www.iep.utm.edu/anim-eth/. [Accessed: 18-Dec-2016].
[63] B. Fintel, A. T.Samaras, and E. Carias, “The Thalidomide Tragedy: Lesson for Drug safety and regulation,” Helix Magazine ,Connecting Science to You, 2009.
[64] M. Hamburg, “50 years after Thalidomide: Why Regulations Matter,” U.S FOOD & DRUG ADMINSTRATION. [Online]. Available: http://blogs.fda.gov/fdavoice/index.php/2012/02/50-years-after-thalidomide-why-regulation-matters/. [Accessed: 18-Dec-2016].
[65] Andrew Knight, “Systematic Reviews of Animal Experiments Demonstrate Poor Human Clinical and Toxicological Utility.”
[66] J. B. Ph.D., “Peter Singer, Vioxx, and the Future of Animal Testing.” .
[67] J. B. Ph.D., “‘Peter Singer, Vioxx, and the Future of Animal Testing.’” .
[68] S. C. Gad, “Model Selection in Toxicology: Principles and Practice.”
[69] A. F. M. and L. Z. Philip C. Smith, “Effect of Esterase Inhibition on the Disposition of Zomepirac Glucuronide and Its Covalent Binding to Plasma Proteins in the Guinea Pig.”
[70] A. F. M. and L. Z. B. P C Smith, “Effect of esterase inhibition on the disposition of zomepirac glucuronide and its covalent binding to plasma proteins in the guinea pig.”
[71] Z. W. Sabrina Weißmuller, Stefanie Kronhart, Dorothea Kreuz, Barbara Schnierle, Ulrich Kalinke, Jorg Kirberg, Kay-Martin Hanschmann, “TGN1412 Induces Lymphopenia and Human Cytokine Release in a Humanized Mouse Model.”
[72] ] M. Seamark, “‘’Elephant Man’ drug trial victim set to win £2m payout for horrific injuries’,.” .
[73] M. S. R.J. Walla, “Are animal models as good as we think?”
[74] H. S. Peter J.K. van Meer , Marlous Kooijman , Christine C. Gispen-de Wied , Ellen H.M. Moors, “The ability of animal studies to detect serious post marketing adverse events is limited.”
[75] The American Anti-Vivisection Society, “Scientific Problems.” .
[76] E. Summary, “Of mice and men – are mice relevant models for human disease ?,” Eur. Comm. Work., no. May, pp. 1–10, 2010.
[77] Carl Zimmer, “Genes Are Us. And Them.,” National geographic. .
[78] N. A. Kamaruzaman, E. Kardia, N. Kamaldin, A. Z. Latahir, and B. H. Yahaya, “The rabbit as a model for studying lung disease and stem cell therapy,” Biomed Res. Int., vol. 2013, 2013.
[79] M. A. Packham, M. L. Rand, and R. L. Kinlough-Rathbone, “Similarities and differences between rabbit and human platelet characteristics and functions,” Comp. Biochem. Physiol. -- Part A Physiol., vol. 103, no. 1, pp. 35–54, 1992.
[80] D. Guha, Practical And Professional Ethics (vol. 3 : Bio-Medical Ethics. Concept Publishing Company, 2007.
[81] M. L. Graham and M. J. Prescott, “The multifactorial role of the 3Rs in shifting the harm-benefit analysis in animal models of disease,” Eur. J. Pharmacol., vol. 759, pp. 19–29, 2015.
[82] S. K. Doke and S. C. Dhawale, “Alternatives to animal testing: A review.,” Saudi Pharm. J. SPJ Off. Publ. Saudi Pharm. Soc., vol. 23, no. 3, pp. 223–9, 2015.
36
[83] E. O. Kehinde, “They see a rat, we seek a cure for diseases: The current status of animal experimentation in medical practice,” Med. Princ. Pract., vol. 22, no. SUPPL.1, pp. 52–61, 2013.
[84] T. Heinonen, “Better Science with Human Cell-based Organ and Tissue Models,” 2014.