Rev. sci. tech. Off. int. Epiz., 2014, 33 (1), 265-272
Scientific uses of animals: harm–benefit analysis
and complementary approaches to implementing
the Three Rs
G. Griffin (1)*, J. MacArthur Clark (2), J. Zurlo (3) & M. Ritskes-Hoitinga (4)
(1) Canadian Council on Animal Care, 1510-130 Albert St, Ottawa, K1P 5G4, Canada
(2) Animals in Science Regulation Unit, Home Office, Marsham Street, London SW1P 4DF, United Kingdom
(3) The Johns Hopkins Center for Alternatives to Animal Testing, Bloomberg School of Public Health Sciences,
615 N. Wolfe St. W7032, Baltimore, MD 21205, United States of America
(4) SYRCLE (SYstematic Review Centre for Laboratory animal Experimentation), 231 CDL, Radboud University
Medical Center, P.O. Box 9101, NL6500 HB Nijmegen, the Netherlands
*Corresponding author: [email protected]
Summary
The principles of humane experimental technique, first described by Russell and
Burch in 1959, focus on minimising suffering to animals used for scientific purposes.
Internationally, as these principles became embedded in the various systems of
oversight for the use of animals in science, attention focused on how to minimise
pain, distress and lasting harm to animals while maximising the benefits to be
obtained from the work. Suffering can arise from the experimental procedures,
but it can also arise from the manner in which the animals are housed and cared
for. Increased attention is therefore being paid to the entire lifetime experience
of an animal, in order to afford it as good a quality of life as possible. Russell
and Burch were also concerned that animals should not be used if alternatives
to such use were available, and that animals were not wasted through poorquality science. This concept is being revisited through new efforts to ensure
that experiments are well designed and properly reported in the literature, that all
results – positive, negative or neutral – are made available to ensure a complete
research record, and that animal models are properly evaluated through periodic
systematic reviews. These efforts should ensure that animal use is truly reduced
as far as possible and that the benefits derived through the use of animals truly
outweigh the harms.
Keywords
Experimental design – Harm-benefit analysis – Meta-analysis – Publication standard –
Reduction – Refinement – Systematic review – Three Rs.
Introduction
When Russell and Burch wrote the Principles of Humane
Experimental Technique in 1959, espousing the tenet of
the Three Rs (Replacement, Reduction and Refinement)
(1), their primary focus was on minimising the harms
experienced by experimental animals. In the interim
fifty-plus years, the Three Rs have been interpreted and
re-interpreted by many. While there are researchers who
remain unclear about the definition of each of the Three Rs
(2, 3), the general concept, as part of a framework for the
ethics of animal experimentation, is now included in most
legislated and non-legislated systems of oversight (4).
Adherence to the Three Rs can ensure that animals are
used only when absolutely necessary, that the numbers of
animals used are kept to a minimum, and that suffering
is minimised. Other issues concerning the ethical use of
animals in science, not directly addressed by the Three Rs,
include: considerations of whether the use of an animal is
acceptable to the public; whether animal model data can
actually be translated to the end goal (for example, human
treatment, conservation, toxicity assessment); and whether
the suffering likely to be experienced by the animal during
the project is too great, irrespective of any potential gains.
While these concerns cannot be addressed directly by
considering the Three Rs, there may be potential for ‘Three
266
Rs thinking’ to inform a harm–benefit analysis of the
issues. This paper presents complementary approaches to
implementing the Three Rs within a harm–benefit analysis
of animal use, including: determining acceptable uses,
establishing limits on acceptable harms, and improving the
value of animal-based data.
Harm–benefit analysis
The concept of balancing harms against benefits finds its
roots in the utilitarian philosophy of Jeremy Bentham, who
said that, ‘it is the greatest happiness of the greatest number
that is the measure of right and wrong’ (5). The concept of
project review was first introduced in the United States in
the 1985 amendment of the Animal Welfare Act (6). Each
institution was to have an institutional animal care and use
committee (IACUC) to review and approve all proposed
animal experiments. However, the first utilitarian (harm–
benefit) approach appeared in the United Kingdom (UK) in
the Animals (Scientific Procedures) Act of 1986 (7), which
required weighing the ‘likely adverse effects on the animals’
against the ‘benefit likely to accrue’, an approach reflected
in parallel developments in other countries during the same
period, for example, in Australia, Canada, Finland, the
Netherlands and New Zealand (8).
Guidance on implementing this harm–benefit analysis
advanced over subsequent years (9, 10, 11) and it is now
explicitly included in the new European Union Directive
(12) which states that the harms should not only be
‘weighed’ against the likely benefits, but that the harms
must be ‘justified’ by the likely benefits. Furthermore, in
2011 both the Institute for Laboratory Animal Research
in the United States (13) and the World Organisation for
Animal Health (OIE), which has 178 Member Countries,
recognised the importance of the harm–benefit analysis
(14). Hence, over a period of some 25 years, the concept of
a harm–benefit analysis has become embedded globally into
common practice.
Determining acceptable uses
Assessing harms and benefits
Part of assessing whether the use of an animal is acceptable
is determining what the harms to the animal are likely to be.
The factors that should be considered include the following:
– the species and numbers of animals involved
– the type, frequency and duration of adverse effects
– the methods used to control adverse effects
Rev. sci. tech. Off. int. Epiz., 33 (1)
– the way in which the experiment will be terminated,
i.e. the ‘humane end-point’ (terminating an experiment as
early as possible to avoid unnecessary suffering, while still
reaching the scientific objectives [15])
– any expected mortality
– the type of housing (single or social) and environmental
enrichment
– the whole life experience of the animal, including any
significant transportation before, during or after procedures
and any prior use, or planned re-use.
The purpose of such assessments is to focus attention on
ways to implement the Three Rs to reduce harms as much
as possible.
Assessing the benefits is another critical part of determining
acceptable animal use. The benefits should be realistic and
relate to the project (16). Equally important is consideration
of the likelihood of success, which includes assessing the
expertise, resources and funding available, the novelty
of the proposed methods, and the record of success of
previous similar experiments. In addition, in assessing the
potential benefits it is useful to consider what the outputs
may be, who will use those outputs and how they will be
used. In general, benefits are achieved incrementally, each
small gain building on the previous knowledge base.
Balancing harms against benefits
Often the term ‘cost–benefit analysis’ is used to describe
this decision-making process, but this implies a more
formal mathematical calculation than is normally possible.
Therefore, the authors prefer the focus on a harm–benefit
analysis. In reality, the decision-making balance always
involves professional judgement. Applying a ‘severity limit’
(e.g. ‘mild’, ‘moderate’ or ‘severe’) restricts the maximum
permissible harm, which cannot be exceeded without
further assessment. At the end of each procedure, the actual
severity experienced by the animals can be recorded to
determine if the experiences of the animals were the same
as those predicted and if the severity assessment was valid.
It should be a responsibility of bodies such as IACUCs to
routinely monitor harms throughout a project, advise on
opportunities to implement Three Rs methods, and also
to review the benefits achieved. Sometimes the benefits
initially perceived are not realised, but other benefits, not
foreseen at the start, emerge.
A number of challenges remain in determining acceptable
uses. Some uses may be objectionable ethically, such as the
testing of tobacco or cosmetics, any benefits of which seem
unlikely to outweigh even the slightest harm. Also, as the
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Rev. sci. tech. Off. int. Epiz., 33 (1)
major benefit of basic research, by definition, is simply to
increase knowledge, any such research that involves highly
developed species and very invasive procedures should
always be regarded as questionable.
Opponents of animal research will argue that proposals are
rarely, if ever, rejected. This may be especially true where
studies are required by law, e.g. studies to test the safety of
products. Nevertheless, the discipline of considering harms
can help to identify potential refinements. In addition, the
authors believe that, in future, it will become increasingly
important to publish harm–benefit assessments alongside
project summaries, preferably in non-technical language.
This should support a culture of openness and also help to
improve the quality and consistency of such assessments.
Establishing limits on acceptable harms
In some cases the potential harms may be so great as to
exceed any possible benefit – for example, many uses (e.g.
chemical safety testing) of highly cognitive species such
as great apes, whose needs cannot be met in a laboratory
setting. In other cases, e.g. burn studies, even when the
use of an animal has been determined to be acceptable, the
harms may still be viewed as too great. For some of these
situations, careful consideration of refinement may permit
the potential harms to be decreased sufficiently to permit
the use to proceed.
resulting in the establishment of a number of organisations
focused on this goal (see Table I).
In parallel with the emergence of these organisations
and their focus on laboratory animal care, the concept of
refinement developed as one of the principles of humane
experimental technique, emphasising that, as Russell and
Burch stated, ‘Humane science is the best science’. In recent
years, refinement of housing and husbandry conditions
has been receiving increasing attention. Rather than merely
focusing on eliminating harms to animals in a laboratory
setting, a more proactive approach is being taken to improve
animal well-being by providing environments which enable
animals to meet their normal behavioural needs (e.g. through
appropriate social housing and inclusion of enrichment
devices) and reducing adverse conditions in animal rooms
(e.g. reducing noise and bright lights in rodent rooms) (18).
Nonetheless, more research is necessary to identify optimal
conditions for each species in a captive setting (19).
Refinement refers both to methods that alleviate, or minimise
the occurrence of, any pain and distress that may be caused,
and methods that enhance animal well-being (17). It has
the potential to improve the overall experience of animals
used in science by bringing the concept of animal welfare
in line with Three Rs alternatives, although it is perhaps the
least-well understood of the Three Rs (2, 3).
New techniques are also emerging that may improve the
welfare of animals under study. These include various noninvasive imaging technologies such as ultrasound, positive
emission tomography and nuclear magnetic resonance
(NMR) (e.g. 20), as well as the use of miniature implantable
devices that can monitor basic physiologic functions
(e.g. 21). Other refinements to be considered during
experimental procedures include the use of analgesics
and anaesthetics, the identification of humane end points
(15), and the use of behavioural methods to train animals
to cooperate in certain scientific procedures. The use of
positive reinforcement training, which provides animals
with rewards for voluntarily participating in a study, is
becoming more common (22). Trained animals experience
less distress and consequently are more reliable research
models.
Refinement considers the welfare of animals both under
normal husbandry conditions and during experimental
procedures. Recognising that diseased animals are not
good research models, both scientists and veterinarians
have realised the need to improve laboratory animal care,
From an ethical standpoint, the most difficult types of
animal research are those in which animal welfare is
severely compromised, such as when animals experience
unrelieved pain and/or distress in order to fulfil the scientific
requirements of the study. As described above, these are
Table I
Examples of international organisations focused on improving laboratory animal care
Organisation
Date of establishment
Website
Animal Care Panel (later to become the American Association for Laboratory Animal Science)
1950
www.aalas.org
Institute of Animal Resources (now ILAR), formed within the National Research Council
1953
http://dels.nas.edu/ilar
International Council for Laboratory Animal Science
1956
http://iclas.org
Association for Assessment and Accreditation of Laboratory Animal Care International
1965
www.aaalac.org
Federation of European Laboratory Animal Science Associations
1978
www.felasa.eu
ILAR: Institute for Laboratory Animal Research
268
cases in which the review of the harms and benefits of the
research is perhaps the most critical. Another important
ethical issue is the choice between focusing on reduction or
refinement. Is it better to use more animals that feel less pain
or fewer animals that feel more pain? While this must be
considered on a case-by-case basis, it is usually, considered
better to use more animals because they individually will
be subjected to less pain, discomfort or suffering (23). This
is particularly relevant to the use of the newer techniques
described above. Minimising the number of animals,
through the use of multiple NMRs for example, may impose
an additional burden on an individual animal, for example
through the need for repeated anaesthesia. It is therefore
important to consider the whole experience of the animal
from the time it is acquired and brought to the study facility,
throughout the study itself and subsequently until the very
end of its use in the laboratory or study environment.
Implementing the best refinement requires a team approach
among scientists, veterinarians and behaviourists, to make
certain that the science is exemplary. All aspects of animal
welfare are important to consider, e.g. it is vital to verify
that the animals are healthy subjects and that the conditions
in which they are kept allow them to meet their speciesspecific behavioural needs.
Improving the value
of animal-based data
Sometimes information derived from animal-based studies
does not ‘translate’ into benefits. For example, treatments
may appear not to ‘work’ in clinical trials, or serious sideeffects of drugs may emerge. This has raised the general
question of how we determine the usability of animal-based
data, particularly in medical research. It is essential that, as
part of harm–benefit analysis, biological scientists consider
how animal data will be applied: for example, for new drugs
and treatments for humans, in veterinary medicine or for
conservation purposes.
In addition to considering how the data will be used,
researchers must carry out a search for Three Rs alternatives
(in some jurisdictions this is a legal requirement).
Researchers can experience difficulties in searching for
potential alternatives (24) and, despite attempts by Three Rs
centres to provide support (25, 26, 27), searching relevant
databases can be a daunting task (28).
One innovative way to implement the Three Rs, i.e.
encouraging scrutiny of the literature, may be through a
synthesis of evidence, using systematic reviews (29). Sena
et al. (30) have convincingly argued that if meta-analysis
of data is used in conjunction with systematic reviews, for
Rev. sci. tech. Off. int. Epiz., 33 (1)
example, to determine the effectiveness of a drug, many
animal studies could be avoided (31, 32). This approach,
aimed at improving the quality of research data while
potentially reducing animal use further underlines Russell
and Burch’s emphasis on supporting the best science.
To be able to synthesise scientific evidence in a meaningful
way it is important that experimental details be published.
Unfortunately, many publications still include inappropriate
statistical methods (33), and fail to mention factors such
as ‘blinding’ and ‘randomisation’, which are two principles
that form the basis of good scientific practice. In an effort
to change this situation, at the 8th World Congress on
Alternatives and Animal Use in the Life Sciences, held in
2011, the Montréal Declaration was adopted, calling for an
improvement in the design of animal experiments (34).
To address the insufficiency of methodological details
currently reported in the literature, reporting guidelines have
been developed by several organisations (35, 36, 37, 38).
For example, the UK National Centre for the Replacement,
Refinement and Reduction of Animals in Research has
developed the ARRIVE guidelines (Animal Research:
Reporting of In Vivo Experiments). These guidelines have
been endorsed by over 300 journals. However, more needs
to be done to ensure implementation of good publication
standards. To this end, the International Council for
Laboratory Animal Science has recently established a
working group to define a set of harmonised international
principles.
The Dutch Parliament has already recognised the need for
systematic reviews to become the norm for animal studies, as
is the case for clinical studies. Moreover, the need to report
all animal data has been identified, including ‘negative’ and
‘neutral’ data, in order to prevent unnecessary duplication
and to provide an accurate research record (39). In time,
this move should also lead to an overall reduction in
animal use.
Translatability
and validity of animal models
The validity of animal models of human function continues
to be a challenge, as animal and human physiology are
not exactly the same. Systematic reviews provide a means
to review evidence on the potential usefulness of animal
models (e.g. 40), thus helping to select the appropriate
model for the research question, and prevent unnecessary
animal use. The current lack of experimental details
reported in scientific publications makes the evaluation of
the validity of animal models particularly difficult. In the
spirit of the Three Rs it is essential to understand why and
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Rev. sci. tech. Off. int. Epiz., 33 (1)
how animal models are currently used and how they might
be improved. This is a challenging but valuable task, which
requires the cooperation of all stakeholders involved (41).
Conclusions
Russell and Burch were clear that the suffering experienced
by individual animals should be the primary concern. The
order in which the Three Rs are generally considered –
Replacement, Reduction and Refinement – tends to focus
on minimising the numbers of animals used, rather than
minimising harms (23). A focus on how harms may be
minimised, by addressing both the procedures experienced
by the animals as well as the conditions under which they
are housed, provides a more holistic approach, aimed at
improving the quality of life for experimental animals.
At the same time as minimising harms to animals used
in science, it is equally important to ensure that their use
provides real benefits for humans, other animals and/
or the environment. Improving experimental design and
statistical analysis, reporting full details of experiments, and
making all data available, will help to ensure that animals
are not used needlessly and that their use contributes to the
advancement of science. Furthermore, the use of systematic
reviews and meta-analysis should add to the benefits
derived from the animals used, by ensuring that the animal
models are appropriate and that decisions made on the
basis of animal studies are fully informed.
L’utilisation d’animaux à des fins scientifiques :
analyse dommages-avantages et approches
complémentaires en application des « Trois R »
G. Griffin, J. MacArthur Clark, J. Zurlo & M. Ritskes-Hoitinga
Résumé
Les principes d’une expérimentation animale exempte de cruauté, tels
qu’énoncés pour la première fois par Russell et Burch en 1959, cherchent à
minimiser autant que possible les souffrances subies par les animaux utilisés à
des fins scientifiques. Au plan international, à mesure que ces principes servaient
de fondement aux diverses réglementations encadrant l’utilisation d’animaux à
des fins scientifiques, une réflexion s’est engagée sur les moyens de minimiser
la douleur, la détresse et les dommages persistants subis par ces animaux, tout
en maximisant les avantages apportés par l’expérimentation. Les souffrances
peuvent être provoquées par les procédures d’expérimentation, mais aussi par
la manière dont les animaux sont logés et traités. On s’intéresse donc de plus
en plus au ressenti des animaux tout au long de leur vie, afin de leur offrir la
meilleure qualité de vie possible. Russell et Burch se sont également prononcés
contre le recours à des animaux lorsqu’il existe une solution de remplacement,
et contre l’utilisation en pure perte d’animaux en cas de mauvaises conditions
d’expérimentation. Ce concept est aujourd’hui revisité grâce aux efforts déployés
pour s’assurer que les protocoles expérimentaux sont bien conçus et transcrits
fidèlement dans la littérature, que tous les résultats (positifs, négatifs ou non
concluants) sont rendus publics afin de consigner les travaux de recherche
de manière exhaustive, et que le recours aux modèles animaux fait l’objet
d’évaluations régulières et systématiques. Ces efforts devraient contribuer
à réduire véritablement l’utilisation des animaux de sorte que les avantages
obtenus soient supérieurs aux dommages.
Mots-clés
Analyse dommages-avantages – Conception d’une expérimentation – Examen
systématique – Méta-analyse – Norme de publication – Raffinement – Réduction – Règle
des « Trois R ».
270
Rev. sci. tech. Off. int. Epiz., 33 (1)
Utilización de animales con fines científicos:
análisis de daños-beneficios y métodos complementarios
para aplicar las «tres erres»
G. Griffin, J. MacArthur Clark, J. Zurlo & M. Ritskes-Hoitinga
Resumen
Los principios de las técnicas experimentales compasivas, enunciados por vez
primera por Russell y Burch en 1959, tienen por principal objetivo reducir al
mínimo el sufrimiento de los animales utilizados con fines científicos. A escala
internacional, a medida que esos principios se iban asentando en los diversos
sistemas de supervisión del uso de animales en la actividad científica, se empezó
a buscar sobre todo el modo de reducir al mínimo los niveles de dolor, ansiedad
y daños duraderos en los animales y a la vez extraer del trabajo el mayor
provecho posible. Aunque a veces el sufrimiento resulta de los procedimientos
experimentales, también puede provenir del modo en que están alojados o son
tratados los animales. Por ello cada vez se presta más atención al conjunto de
experiencias del animal a lo largo de su vida, con el fin de ofrecerle la mejor
calidad de vida posible. Russell y Burch abogaron también por evitar el uso de
animales cuando existan alternativas y por no desperdiciarlos con una praxis
científica de mala calidad. Estas ideas recobran ahora protagonismo gracias
a nuevas iniciativas destinadas a asegurar que los experimentos estén bien
concebidos y debidamente descritos en las publicaciones, que se expongan
todos los resultados (ya sean positivos, negativos o neutros), de forma que
quede constancia exhaustiva de la investigación, y que se evalúen debidamente,
mediante exámenes sistemáticos y periódicos, los modelos animales. Estos
esfuerzos deberían servir para reducir verdaderamente en lo posible el uso de
animales y para garantizar que los beneficios resultantes del uso de animales
compensen realmente los daños causados.
Palabras clave
Análisis de daños-beneficios – Concepción de experimentos – Examen sistemático –
Metaanálisis – Norma de publicación – Perfeccionamiento – Reducción – Tres erres.
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