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INTERNATIONAL APPROACHES AND
PRINCIPLES FOR HUMANE ENDPOINTS
Humane Endpoints in Cancer Research
Fraser Darling
The vision of the Institute of Cancer Research is that people may live their
lives free from the threat of cancer as a life-threatening disease.
Cancer or malignant neoplasm refers to a class of diseases in which a
group of cells display uncontrolled growth (in other words division beyond the
normal limits), invasion (intrusion on and destruction of adjacent tissues), and
sometimes metastasis (spreading to other locations in the body via lymph or
blood). These three malignant properties of cancers differentiate them from be-
nign tumors, which are self-limiting and do not invade or metastasize. Most can-
cers form a tumor but some, like leukemia, do not. Cancer may affect people at
all ages, even fetuses, but the risk for most varieties increases with age; and can-
cers can affect all animals.
Cancer causes about 13% of all deaths and, according to the American
Cancer Society, 7.6 million people died from cancer in the world during 2007.
Where effective anticancer treatments do exist they can be very demanding on
the patient.
The objective of using live animals in cancer research is to develop rapid
diagnosis, better treatments for existing cancers, and an improved prognosis for
patients. With this in mind, scientists engaged in experimental cancer research
follow four main areas of investigation, some of which use laboratory animals.
Cancer research scientists attempt to discern, detect, identify, and develop.
To discern the biological mechanisms, scientists investigate different
sites of origin in the body, why particular cancers are more prevalent in some
tissues and not others, and the rate of growth and metastases of cancers.
The detection of potential carcinogens is an important chain in the link
to identify agents in the environment such as chemicals, potential carcinogenic
materials, exhaust fumes from motor vehicles, and other agents that may be re-
sponsible for carcinogenesis.
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154 Animal Research in a Global Environment: Meeting the Challenges
Identification of individuals at particular risk looks at epidemiological
studies and historical data to determine who in the general population may be at
greater risk of developing certain types of cancer. This particular area of investi-
gation has taken an important step forward in recent years since the advent of
genetic testing. Investigations may involve the examination of particular risk
factors, including lifestyle (tobacco use, alcohol consumption, obesity, lack of
physical activity) or genetic predisposition.
Developing ways to cure or control clinical disease is usually achieved
by improving the prognosis for patients through the use of drugs, chemo-
therapeutic agents, radiation therapy, and/or surgical intervention.
Laboratory rodents, usually mice and rats, have assisted scientists in the
field of cancer research and it is clear that they will continue to do so. They are
used as experimental models in cancer research studies only where there is a
justified need and only if absolutely necessary. The Institute of Cancer Research
does not use animals for research if nonanimal alternatives are available, and
endeavors to set humane endpoints for all research involving laboratory animals.
Because we need to use live animals in some research programs, it is es-
sential that these living creatures be afforded the best care at all times. Staff
tasked with caring for animals in the laboratory are continually striving to im-
prove and enhance animal husbandry and welfare. An important part of this
process is the use of humane endpoints in our animal experiments.
[According to] the OECD, a humane endpoint can be defined as “the ear-
liest indicator in an animal experiment of severe pain, severe distress, suffering,
or impending death.” Investigators make use of different humane endpoints de-
pending on the tumor model being studied in any particular animal, and try
wherever possible to determine accurate, predictive, and reproducible humane
endpoints.
Humane endpoints should be a consideration for all experiments involving
animals, but are essential in situations that may involve suffering or death (e.g.,
acute toxicology, infection, cancer, or inflammatory disease). They are just one
manifestation in the process of refinement of animal experiments. Humane end-
points are best used with prospective planning for their use, not ad hoc to ad-
dress specific welfare concerns as they might arise.
There are several considerations in arriving at the objective assessment of
pain and suffering and translating this into the appropriate endpoint in a given
experiment. An important point is the requirement to continually improve our
skills at observing the animals and assigning some objective values to the obser-
vations we make (usually these are based on animal behavior and physiology).
We also need to know, in any given study, which observations are the most sig-
nificant indicators of animal pain and suffering, and have scientific acceptance
of these measurements; otherwise they become invalid and unworkable. It fol-
lows, therefore, that validation and monitoring of other study parameters are
required to ensure robust predictability of the endpoint and minimal interference
with the scientific objectives.
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Humane Endpoints in Cancer Research 155
All personnel contribute to the care and welfare of the animals, and it’s
important that these individuals be provided with the correct training and knowl-
edge in order to develop their required skills, and for each to progress to a level
of competency. It is impossible to recognize signs of pain, suffering, or distress
in any animal if you do not, or are unable to, recognize (and have not received
training to be able to do so) normal signs of good health in an animal. Training
and competency are very important attributes, especially when dealing with hu-
mane endpoints. Staff development of skills is an evolving process, and a clear
program of training and mentoring enhances animal welfare and staff morale.
Biomedical research encompasses all types of research including research
into cancer. All research can be viewed as a giant puzzle. Humane endpoints are
an important and essential part of the discovery process. Everyone in the world-
wide research community has an individual role to play in creating parts of the
puzzle in order to find new treatments, enhanced therapies, and ultimately at-
tempts to cure some of our more difficult and challenging diseases, not just in
the field of cancer research but in all areas.
It’s important that if we continue to use animals for experimental purposes
we do this in the most humane manner at all times. All who are involved in ani-
mal research must have a clear sense of responsibility, but more importantly a
strong sense of compassion for the animals in their care. By the correct use and
validation of appropriate humane endpoints we will help to add important parts
to the puzzle.
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Humane Endpoints in Infectious Disease
Carol Eisenhauer
The topic of my presentation is humane endpoints in infectious disease.
This is a very sensitive and difficult topic, which I deal with almost every day as
the IACUC chair at the United States Army Medical Research Institute for In-
fectious Diseases (USAMRIID). The opinions I am expressing today are my
own and not those of my employer, the US Army.
USAMRIID does infectious disease research on some of the most danger-
ous viruses and bacteria in the world, and we do this under biocontainment con-
ditions, generally ABSL-3 and -4 conditions. USAMRIID is AAALAC accred-
ited and, as IACUC chair I can avow emphatically, does everything under an
approved animal protocol.
The study of infectious disease generally involves studies of disease
pathogenesis, immune response to infection, and development of therapeutics
and vaccines. Because it is ethically and morally wrong to perform clinical effi-
cacy studies with humans, the FDA has developed the animal rule, which allows
new drugs and biologic products to be tested in animals as a means to getting
approval for human use. Safety testing must still occur in humans, and the ani-
mal model is critical to the success of the FDA approval process. It is necessary
to understand that the animal study endpoints must be clearly related to the de-
sired benefit in the human; generally these are related to enhancement of sur-
vival or prevention of major morbidity.
The animal welfare regulations require that procedures involving animals
avoid or minimize discomfort, distress, and pain to the animals. The Public
Health Service Policy states that animals undergoing chronic pain or distress
should be euthanized as soon as feasible and appropriate, which leads to a dis-
cussion of humane endpoints. Death as an endpoint has always been a difficult
issue in infectious disease research. Lack of reproducible animal models often
leads to the use of death as an endpoint. The argument to support death as an
endpoint is that euthanasia and termination of the study before scientific objec-
tives are met compromise study results. On the other hand, the counterpoint is
that progression of infectious diseases to death allows unnecessary suffering,
which compromises research results.
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Humane Endpoints in Infectious Disease 157
Simply put, many animal models of infectious diseases are not clearly de-
fined and it is difficult to reliably differentiate animals that will die from those
that will recover despite showing severe clinical signs. There have been many
instances in which a severely ill animal recovered from its experimentally in-
duced infectious disease. Death of the animal is the final proof that the challenge
was lethal and that the vaccine failed to protect. Therefore some investigators
are reluctant to euthanize early or to use anything but death as an endpoint. An
argument may be made, however, that actual physiological events are missed
when death is the only criterion evaluated. The data gathered from monitoring
these events can be used to develop early and humane endpoints. Additionally,
for a variety of reasons including tissue autolysis, death of the animal diminishes
sample collection. Therefore, it is important to consider requirements for the
development of early and humane endpoints.
For an early endpoint to be acceptable, it must meet the following criteria:
it must be indicative of inevitable progression to death; it must reliably differen-
tiate the animals that will die from those that will recover despite showing se-
vere signs of toxicity; and it must adequately mimic the death endpoint.
The benefits of humane endpoints are many and should be emphasized
during the planning meetings with investigators. Specifically, the development
of uniform methods to assess endpoint criteria contributes to the validity and the
uniformity of the experimental data. Detailed observations of clinical signs may
lead to increased discriminatory experimental power. Last but most importantly,
use of humane endpoints avoids or terminates unnecessary pain and distress for
the research animal.
It is very important to tailor the endpoints to each animal protocol. Differ-
ent animal species react differently to the same viral or bacterial challenge. For
instance, Ebola Zaire is lethal in five to seven days in cynomolgus monkeys,
whereas it is lethal in seven to ten days in rhesus macaques. And in Mauritius-
origin cynos, monkeypox is 100% fatal while in Chinese-origin cynos there may
be only a 43% fatality. This emphasizes the importance of picking the right
species and understanding the course of that disease in that species. Outcomes
must also be defined; will morbidity suffice or must you go to the moribund
condition?
The route of the challenge is very important. The exposure route must be
similar to that anticipated in humans per the FDA. This affects the time course
and pathogenesis of the disease. It may be important to challenge at two or more
doses, because this can help differentiate physiological changes between survi-
vors and nonsurvivors. The viral and bacterial strain to be used should also be
considered when developing endpoints. Ebola Zaire is uniformly lethal and has a
shorter time course than Ebola Reston, which is also lethal but with a prolonged
time course. Finally, it is important to consider human safety when dealing with
infectious diseases.
When planning endpoints, one must consider observation frequency. It is
critical to set reasonable observation frequencies to ensure human safety, the
least stress to the animal, and investigator compliance. The frequency should be
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158 Animal Research in a Global Environment: Meeting the Challenges
set to minimize stress but allow for euthanasia, sample collection, and avoidance
of progression to death. It is necessary to know whether the animal is nocturnal
or diurnal and whether disruption of sleep will adversely affect the study. It is
also necessary to determine when to increase your observation frequencies so as
not to miss critical events.
As mentioned, human safety must always be considered when dealing
with infectious diseases. Promoting animal welfare by increased monitoring of
animals after exposure can jeopardize human safety. Therefore, investigators
and the IACUC should be encouraged to look for other, less intrusive and safer
methods of monitoring the animals, such as telemetry and in-room cameras.
Rodent species present their own challenges when developing humane
endpoints. Rodents are generally group housed and they are not always indi-
vidually identified, making their observation difficult. Additionally, clinical
signs of illness in rodents can be subtle and nondiscriminatory in nature.
It may be necessary to consider objective versus subjective endpoint crite-
ria. It is important to use a mixture of both, but when using subjective criteria
with three different people observing the animals throughout the day, they must
be very adequately trained on exactly what these criteria mean—e.g., “What is
ruffled fur in a mouse and should it be added to my score sheet?” The IACUC
must work with investigators in the development and use of humane endpoints.
In many institutions, the IACUCs have developed strong policies stating that
death as an endpoint is not acceptable. The IACUC should also require the use
of intervention criteria or score sheets that clearly define when the animal is to
be euthanized.
As I have already stated, the IACUC should work with the investigator to
determine the best schedule of animal monitoring. Personnel that monitor the
animals must understand normal species behavior as well as the clinical signs
expected during the course of the disease. Observation frequencies should in-
crease as the clinical signs become more severe and these observations need to
be documented.
The IACUCs must ensure that there is an available point of contact for
euthanasia so that when the time comes the animal will be euthanized promptly.
In fact, it may be wise to have an alternate point of contact to ensure that when
the score is met and it is time for euthanasia, this happens promptly.
When the clinical course of the infectious disease is not clearly defined for
the animal species, the IACUC should consider the use of a pilot study to allow
for criteria development. The IACUC should use subject matter experts to assist
in developing the criteria and should consider the use of analgesics for each in-
fectious disease, animal study, or protocol.
The IACUC should review the use of observation documentation as part
of its postapproval compliance monitoring. Another issue that the IACUC must
discuss is whether the humane endpoints should be the moribund or morbid
condition. This is a difficult issue and there is no right answer. Each study must
be considered separately. Often in assessing the effectiveness of the treatment or
vaccine, the moribund state is used, while the morbid state would be used if it is
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Humane Endpoints in Infectious Disease 159
not necessary to know if the animal will die as a result of the treatment or vac-
cine failure.
In a score sheet that we use at USAMRIID with filovirus research done in
macaques, if the score is equal to or greater than 10, the animal is administered
pain alleviation. If it is greater than 20 the animal is considered terminally ill
and is euthanized. Exceptions require consultations with the attending vet. The
use of score sheets has progressed over the years and with each experiment re-
finements are made to improve them.
In conjunction with the investigator we have been able to add some objec-
tive criteria; e.g., if liver enzymes double, a score of 1 is assigned, and if they
triple a score of 3 is given. The hope is to avoid the moribund end state and
euthanize when we see liver enzymes increase.
So these are the kinds of things going on at USAMRIID in infectious dis-
ease research. Everyone has a score sheet, and every investigator is encouraged
to define criteria or do a pilot study within that protocol so that future score
sheets may be developed based on these criteria.
In summary, it must be the goal of all infectious disease researchers
using animals and of the IACUCs that provide oversight for these animals to
develop humane early endpoints. Good science and humane animal care require
nothing less.
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Humane Endpoints and Genetically Modified
Animal Models: Opportunities and Challenges
Margaret Rose
Technologies that enable the targeted manipulation of the genome have
created new opportunities to study the role and interplay of specific genes in
both the regulation and function of physiological and behavioral processes and
the development of pathological conditions. Through the development of new or
novel animal models, these techniques enable new insights into the molecular
basis of disease processes and provide opportunities to develop targeted thera-
peutic approaches.
Despite the potential benefits from the use of these technologies, there are
ethical issues in relation to their application, some of which relate to the impact
on the welfare of the animals involved. The establishment of humane endpoints
is a key strategy in achieving the goal of refinement; when the use of animals is
scientifically justified but where there is a risk of those animals experiencing
pain or distress, applying the process by which humane endpoints are imple-
mented and reviewed underpins an informed and strategic approach to managing
such risks.
Genetically modified (GM) animal models present particular challenges
when developing criteria to set humane endpoints. I will provide an overview of
the animal welfare issues presented in the application of GM technologies and
discuss the opportunities and challenges to applying humane endpoints when
GM animal models are developed.
Introduction
The development of technologies that permit the targeted manipulation of
genetic material—be that by transgenesis or targeted mutagenesis—has created
opportunities to explore the organization, regulation, and function of molecular
processes in both normal and pathological states in ways previously not possi-
ble. Further, the application of these methods has expanded the availability of
160
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Humane Endpoints and Genetically Modified Animal Models 161
animal models that are more accurate analogues of the underlying disease proc-
esses and hence can be used to better understand disease processes and to de-
velop new, targeted therapies.
While the potential benefits of the use of these technologies are recog-
nized (Royal Society 2001; NRC 2002; Nuffield Council 2005), there is continu-
ing public disquiet about their use (Einsiedel 2005). A range of issues are being
raised, including fundamental ethical questions about the use of genetic modifi-
cation (GM) technologies and notions of the sanctity of life and the autonomy of
the individual as well as concerns about risks to human health and the environ-
ment. The welfare of the animals involved also has been a recurring issue and
has been addressed in a number of reports and guidelines (for example, Royal
Society 2001; Animal Procedures Committee 2001; Dennis 2002; Robinson et
al. 2003; Brown and Murray 2006; Wells et al. 2006; NHMRC 2007; CCAC
2008).
The process by which humane endpoints are developed, validated, and re-
viewed is a key platform in making progress toward the goal of refinement when
animals are used for scientific purposes (Morton 2000; Stokes 2000). Humane
endpoints are used for two complementary purposes: identifying the onset of a
disease process so that early intervention is possible either to initiate treatment
or to enable an early, defined endpoint in a study; or, alternatively, to determine
the point when an animal’s condition has deteriorated such that its involvement
in the study should be terminated.
Setting humane endpoints involves identifying potential risks and validat-
ing criteria to, first, identify specific physiological or behavioral changes associ-
ated with the animal model and, second, assess the impact on the animal in rela-
tion to both the predicted effects of the experimental treatment and general
criteria to assess the occurrence of pain and distress. Thus criteria are estab-
lished upon which decisions can be based and outcomes reviewed. This is an
iterative process that underpins informed decision making and validates the on-
going refinement of experimental procedures. Although the same processes ap-
ply to establish humane endpoints with GM animal models, as highlighted by
Dennis (2000) there are particular difficulties in these circumstances brought
about primarily by the unpredictability of the effects of GM technologies on
phenotypic expression.
In recent years there has been a rapid escalation in the development of
new GM models. In the biomedical sciences mice are by far the species most
often used, but a range of species can be involved, including zebrafish, pigs, and
nonhuman primates. Further, the pace and scope of the development of new GM
animal models are likely to continue for the foreseeable future, which presents
logistical challenges for the effective management of these animals, especially
when this involves significant numbers of animals and many lines with differing
phenotypes (Comber and Griffin 2007).
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162 Animal Research in a Global Environment: Meeting the Challenges
Welfare issues have been identified in relation to both the methods used to
produce GM animals and the resulting phenotype.
Production of GM Animals
GM animal models are produced by a number of different methods that re-
sult in reduced or enhanced expression or inactivation of a gene. The most
common methods used involve (1) transgenesis, where exogenous genetic mate-
rial from either the same or another species is inserted in a fertilized blastocyst
by microinjection, electroporation, or a nonpathogenic viral vector and then im-
planted in surrogate mothers; (2) targeted mutagenesis, which results in the
presence or absence of a specific gene (“knock-in” or “knockout”), which is
achieved by inserting modified genetic material in cultured embryonic stem cells
that are injected into a blastocyst and implanted in surrogate mothers; or (3) ran-
dom or chemical mutagenesis, where animals or their gametes are exposed to
mutagens that increase the rate of mutations, resulting in the production of novel
single gene mutations. Only a small percentage of animals produced will carry
the modified genome and significant numbers of animals may be required to
produce and maintain each GM line. Consequently, relative to the number of
GM animals created, significantly more are produced and culled.
A July 2003 report by a Joint Working Party on Refinement in the United
Kingdom reviewed the relative advantages and disadvantages of the production
of GM animals by either pronuclear injection or embryonic stem cell techniques
and recommended strategies to promote both reduction in the numbers of ani-
mals involved and refinement of procedures to minimize impact (Robinson et al.
2003). The report recommended criteria to benchmark the efficacy of proce-
dures so as to ensure production methods to maximize the potential to produce
GM animals and management strategies to reduce surplus production. For each
step in the process, the report recommends performance benchmarks (indicators
when there is a need to review that process) and outlines possible causative fac-
tors that should be considered. Thus this report sets out current standards of
good practice and provides a process to benchmark animal welfare outcomes in
the context of the needs and justification for current methods.
With both these technologies, donor animals undergo various, and some-
times multiple, procedures with the risk of associated pain or distress. Strategies
to manage and minimize the impact on the donors of surgical procedures, su-
perovulation of females, and tissue biopsy for genotyping are discussed in this
report. The recognition and uptake of opportunities to modify and refine these
procedures will continue to play an important role in the future development and
use of these methods.
While reports such as this highlight the need to be aware of the impact of
these procedures on the animals involved in the production of GM animals, in
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Humane Endpoints and Genetically Modified Animal Models 163
the one study to date these procedures were not shown to have a significant ef-
fect on the behavioral and physiological development of mouse progeny up to
30 weeks of age (Van der Meer et al. 2001).
GM Animal Models
GM animal models have been applied to the investigation of a range of
human diseases such as diabetes, obesity, atherosclerosis, chronic heart failure,
hypertension, cancer, autoimmune disease, and musculoskeletal and neurologi-
cal disorders. However, not all GM animals are bred as disease models. GM
animals may exhibit clinical disease but, given that the rationale behind the de-
velopment of GM technologies is to tease out the role and function of individual
genes or gene sequences, in many cases do not do so and that is not the intended
outcome.
Wells and colleagues (2006) observed that in only a minority of GM ani-
mals are animal welfare problems evident and that, with transgenic animals
where most often the purpose is to study the function of a DNA segment, ad-
verse effects are uncommon and that for GM models developed using targeted
mutagenesis (knock-in or knockout) where the purpose is to study the function
of a single gene, either embryonic death or animals with no evidence of adverse
effects are the most common outcomes. However, they noted that both targeted
and random mutagenesis can lead to neonatal mortality or animals with com-
promised health or welfare.
When adverse effects do occur they either are predicted on the basis of the
particular genetic modification or, notably, are not of a kind that was predicted
to occur or are seen in circumstances where adverse effects were not anticipated.
It is the uncertainty and low predictability of such events that present particular
challenges when managing GM animal colonies. Such unpredicted adverse ef-
fects may arise for a variety of reasons including the overexpression or the ab-
sence of the specific gene, interactions with collocated genes, or the influence of
the genetic background of donor animals or the background strain that may in-
teract with the targeted modification. Furthermore, adverse effects may not be
evident in the first generation and emerge only in subsequent generations (Den-
nis 2000).
Abnormalities in GM animals may affect the viability of offspring and
their long-term survival and welfare and may be linked to the specific gene
modification or reflect a peculiarity of the phenotype of the background strain.
A diverse range of abnormalities have been reported, including hydrocephalus,
cleft palate, malformed limbs, absence of teeth, poor mothering, absence of
milk, poor thermoregulatory ability, increased aggression and cannibalism, clot-
ting disorders, enhanced growth of tumors and development of metastases often
at atypical sites, diabetes, osteoporosis, degenerative joint disease, respiratory
disorders, inflammatory bowel disease, ulcerative colitis, liver and kidney
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174 Animal Research in a Global Environment: Meeting the Challenges
When I was trained in science in the ’60s I got that mantra. My students
are still getting it, although it is not quite as widespread as it was, fortunately,
because it really is a detriment to the thriving of science in our society, which
already is facing formidable obstacles.
Thus it is widely believed that animal welfare can be explicated without
reference to values, simply on the basis of objective biological fact. In reality,
the variation across cultures in views of animal welfare can be found historically
intraculturally. It is simply magnified by considerations of cultural variability.
Consider the following: In 1981 in response to burgeoning societal con-
cerns about animal welfare, the US agricultural community, represented by the
Council for Agricultural Science and Technology (CAST), published Scientific
Aspects of the Welfare of Food Animals. Reflecting a ubiquitous view among
producers, the CAST report spoke of welfare as follows: The principal criteria
used thus far as indices of the welfare of animals in production systems have
been rate of growth or production, efficiency of feed use, efficiency of reproduc-
tion, mortality, and morbidity. In other words, the welfare of an animal is de-
fined and determined by how well it fulfills the human purpose to which it is
put, with no reference to how it feels, whether or not it suffers pain, distress,
anxiety, boredom, loneliness, frustration, inability to move or be with con-
specifics, and so on.
Implicit in this definition are a set of values and a set of moral obligations
that are easily extracted: Humans are morally obliged to provide animals only
with a set of conditions that allows the animal to fulfill the purpose for which it
is kept by humans. In Kant’s terminology, then, animals are in no way ends in
themselves, they are strictly means to an end, a human end. Animal welfare is
based solely on these human ends. In metaphorical terms, welfare is to animals
as sharpness is to a saw, what is needed for both to be functional tools.
At roughly the same historical moment, the early 1980s, other definitions
of animal welfare were promulgated. In the writings of Marian Dawkins, Ian
Duncan, and myself, one essential feature of welfare was argued to rest in what
the animal experienced, its subjective states. The moral position implicit in such
views was that animals ought to be at least in some measure in Kantian terms
“ends in themselves” because they were conscious, and what they experienced
mattered to them. By the way, at that time much of the scientific community was
agnostic about the concept of animal consciousness. They overtly denied either
the existence or the knowability of animal consciousness; therefore what we did
to animals and how we forced them to live didn’t matter.
In my view of welfare, animals have intrinsic value rather than merely in-
strument value—that is, value merely as tools—because they are capable of
valuing in their subjective life what happens to them. There were other defini-
tions of welfare—e.g., the Farm Animal Welfare Council (FAWC) notion of the
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Cross-Cultural Ethical Perceptions and Ways to Resolve Challenges 175
Five Freedoms1 that grew out of the Brambell Commission, and so forth. The
point here is that even in British and American culture, one could find numerous
very obviously different and incompatible definitions of animal welfare, based
in radically differing views of the moral status of animals, separated irreconcila-
bly by disparate ethical values underlying them. Thus, the existence of divergent
views of animal welfare, differing across cultures, does not raise any new con-
ceptual problems that were not already present by virtue of the intracultural
value-based differences in views of what constitutes animal welfare.
It is in no way surprising that animal welfare should have emerged as a
moral issue in the latter part of the 20th century, because of the precipitous
changes in the nature of animal use that transpired in the mid-20th century. For
the entire history of civilization, the overwhelming use of animals in society was
in agriculture—food, fiber, locomotion, and power—and the key to success in
agriculture was good husbandry. Husbandry meant putting your animals in the
optimal conditions dictated by the animal’s biological natures and needs, and
augmenting their native ability to survive and thrive by provision of food during
famine, water during drought, help in birthing, medical attention, and protection
from predation.
This has been called the ancient contract. It was based on the insight that
producers did well if and only if animals did well, and vice versa. Thus, hus-
bandry was, in equal measure, a prudential and a moral imperative, sanctioned
by what is after all the ultimate motivation for human beings, self-interest. Thus
defining animal welfare and animal ethics was a nonissue.
In fact, the only animal ethic that was needed and can be found as early as
the Bible arose from the need to cover the case of the small number of psycho-
paths and sadists who were unmoved by self-interest. In other words, if you
were using animals in an agricultural way, which was the primary use of ani-
mals, you needed to put them in decent conditions and provide for their needs
during famine and drought and so forth and so on in order to be financially suc-
cessful.
Defining animal ethics and animal welfare became an issue when the na-
ture of agriculture changed from husbandry to industry. The values changed as
well. Primacy was now given to the values of efficiency and productivity.
Whereas one can characterize husbandry as putting square pegs in square holes,
round pegs in round holes, and creating as little friction as possible doing so, the
Industrial Revolution provided us with “technological sanders,” as it were, that
allowed us to force square pegs into round holes, round pegs into triangular
holes, while still keeping animals productive—things like air-handling systems,
antibiotics, vaccines, etc. If one had tried to develop these systems during the era
of animal husbandry, the animals would be dead in weeks of disease spreading
like wildfire, but with these sanders we can force square pegs into round holes.
1
These are freedom from thirst, hunger, and malnutrition; freedom from discomfort;
freedom from pain, injury, and disease; freedom to express normal behavior; and freedom
from fear and distress; available online (www.fawc.org.uk/freedoms.htm).
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176 Animal Research in a Global Environment: Meeting the Challenges
What was lost was the isomorphism between the animal well-being and
productivity that characterized husbandry, and thus animal welfare and animal
ethics became an issue instead of a presupposition of animal use. This was po-
tentiated by the advent at roughly the same time, the 1940s, of large amounts of
animal research and testing, again representing significant animal use that vio-
lated the symbiosis inherent in husbandry.
The research community typically deflected this issue by being agnostic
both about the relevance of ethics to science and about animal consciousness. I
was a principal architect of the 1985 federal laboratory animal laws in the
United States. In 1982 when I went before Congress to defend them, I was asked
to prove that there was a need for such a law. The research community claimed
they were already controlling pain in research animals.
So I went out and, with a colleague at the Library of Congress, did a litera-
ture search on laboratory animal analgesia. How many papers did I find? I found
none on laboratory animal analgesia. When I broadened it to animal analgesia, I
found two, one of which said there ought to be papers, and the other said here is
what we know: it was a one-pager in the Journal of the American Veterinary
Medical Association and it was very honest about not knowing anything and
how there was a moral imperative to know.
As public cognizance of the radical changes in animal use grew beginning
in the 1960s and 1970s, efforts in favor of restoring fairness to animal use began
to pervade Western society, beginning in Britain in the 1960s and resulting in
the view that animals were entitled to the famous five basic freedoms. The ensu-
ing years saw the emergence in Western society of “the new social ethic for
animals.”
As anyone attending to cultural history can easily determine, the issue of
animal treatment assumed major social prominence beginning about 1970.
Whereas 30 years ago in the United States one would have found no federal bills
pending in Congress pertaining to animal welfare, the last decade has witnessed
up to 50 and 60 per year. On a state level in 2004, there were well over 2,100
bills proposed in state legislatures pertaining to animal welfare; there were over
200 in California alone.
Most Western countries have recently adopted new laws protecting labora-
tory animals and ensuring control of their pain, often despite opposition from the
research community, which preferred a laissez-faire approach. Britain is of
course a notable exception, given the act of 1876.
Much of Northern Europe and the European Union have introduced major
restrictions on confinement agriculture, probably the most dramatic being the
Swedish law of 1988 that abolished confinement agriculture as taken for granted
in the US, and created what the New York Times very presciently called in 1988
a “bill of rights for farm animals.”
Although the US has been slow in developing its concern for agricultural
animals, in the last few years it has tended to accelerate, partially due to refer-
enda, legislative initiatives to abolish the most egregious of practices. The Pew
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Cross-Cultural Ethical Perceptions and Ways to Resolve Challenges 177
Commission report (PCIFAP.org) also educated a myriad of people who didn’t
really know about agriculture before.
Well, we can proffer evidence indefinitely, but I think enough has been
said and placed in evidence to buttress my claim regarding social concern. So
the question that arises is, if there is that much social concern, how is it express-
ing itself ethically?
Historically, both the laws protecting animals and the social ethic inform-
ing them were extremely minimalist, in essence forbidding—and this is lan-
guage from the legal system, from the cruelty laws as well as from judicial in-
terpretations of those laws—deliberate, willful, sadistic, deviant, extraordinary,
unnecessary cruelty not essential, as one judge put it, to ministering to the ne-
cessities of man, or completely outrageous neglect.
Those of you involved in animal welfare may well be aware that early ef-
forts to regulate animal research invoked the cruelty laws and tried to present in
evidence certain research that was “cruel,” and the universal judicial assessment
was that research is not the sort of thing that can be cruel. It is not deviant, it is
not sadistic, it does not betoken psychopathic behavior, etc. That is why it was
essential to develop, as one judge put it, a new ethic for animals, by going not to
the judiciary but to the legislature.
The ethic of anticruelty is found in the Bible and in the Middle Ages. St.
Thomas Aquinas, while affirming that although animals were not direct objects
of moral concern, nonetheless forbade cruelty to them on the grounds that those
who would be cruel to animals will inexorably graduate to people. This is an
insight that has subsequently been buttressed by decades of social scientific re-
search—our last dozen serial killers all had early histories of animal abuse.
Those involved with battered women’s shelters know that provisions must be
made for the woman’s animal or the husband who is a batterer will go back and
hurt the animal to get back at the woman. Psychiatrists acknowledge animal
abuse…as sentinel behavior for subsequent psychopathology.
Roughly beginning in 1800, anticruelty laws, reflecting the anticruelty
ethic, were codified in the legal systems of most Western societies. The key no-
tion explaining why there was a demand for a new ethic can be found in the fact
that the old ethic was so restricted in scope. If I draw a pie chart representing all
the suffering that animals experience at human hands, how much would you say
was the result of deliberate cruelty, a lot or a little? Every audience says a little.
One week I spoke to PETA at San Francisco State and the Billings Rodeo Asso-
ciation of Montana, and they both said 1%. Well, if only 1% is covered by the
cruelty ethic, then 99% is not. What that means is, as society has begun to con-
cern itself with the other 99%, it has sought a vocabulary, an ethic, of expressing
that concern in a manner that doesn’t invoke cruelty, which is essentially irrele-
vant.
Most animal suffering results from putatively reasonable and defensible
uses—industrial agriculture, which is meant to provide cheap and plentiful food;
scientific research, which advances knowledge, cures disease, and provides me-
dicaments.
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178 Animal Research in a Global Environment: Meeting the Challenges
In the 1970s when I was hired by a veterinary school to develop the field
of veterinary ethics, I realized pretty early that the moral status of animals was a
fundamental question in veterinary ethics. That led me to think about what sort
of ethics society was likely to develop if indeed it was to continue to be con-
cerned about animals. It dawned on me after about two years that ethics does not
come ex nihilo—it doesn’t come out of nothing. As Plato said, all ethics builds
on preestablished ethics. I surmised that society would look to the ethic we have
for people and modify it, change it—mutatis mutandis, as philosophers say—
appropriately change it to fit the animal situation.
What aspect of our ethics is in fact being extended? One that is applicable
to animal use is the fundamental problem of weighing the interests of the indi-
vidual human against the general public. Different societies have provided dif-
ferent answers to this problem. Totalitarian societies opt to devote little concern
to the individual, favoring instead the state or the Reich or the Volk or whatever
their version of the general welfare may be. At the other extreme, anarchical
groups such as communes give primacy to the individual and very little concern
to the group; hence they tend to enjoy a very transient existence, such as the
communes of the 1960s did.
In Western society, however, a balance is struck. Although most of our
decisions are made to benefit the general welfare, fences are built around indi-
viduals to protect the individual’s basic human interests from being sacrificed
for the majority. Thus we protect individuals from being silenced even if the
majority disapproves of what they say. We protect individuals from having their
property seized without compensation, even if such seizure benefits the general
welfare. We protect individuals from torture, even if they planted a bomb in an
elementary school and refuse to divulge its location.
What are these interests that we protect? We protect the interests of the in-
dividual that we consider essential to being human, to human nature, from being
submerged for the sake of the common good.
What are these fences around human individuals called? They are rights.
I’m not obviously going to be using the animal rights locution in the same way
as the animal rights people do. What they really mean is animal liberation. All
the legislative flurry of activity, the 2,400 bills proposed and similar acts, is an
attempt to provide societal guarantees of proper animal treatment since hus-
bandry no longer ensures it. It is absurd to suggest that these are the same rights
that humans have, because animals do not have the same natures that humans
have. I thought about not using the locution of rights, but I knew you would re-
alize that the concept was being invoked. However, it is the concept being in-
voked by the general public.
If you look at surveys (which I don’t really tend to trust but they are indi-
cators), close to 90% of the public will affirm that animals have rights. I have
lectured to 15,000 Western ranchers in every ranching state. What percentage of
them would say animals have rights? In my experience, well over 90% would.
An example of that occurred when the governor called a conference on the
effects of animal welfare and animal rights on Colorado agriculture about 18
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Cross-Cultural Ethical Perceptions and Ways to Resolve Challenges 179
years ago. The opening speaker was the head of the Colorado Cattlemen’s Asso-
ciation. He said, “If I had to raise animals like the chicken people do, I’d get the
hell out of the business.” I work very closely with these people. I just brokered a
deal between the Humane Society of the United States and Colorado agriculture
to avoid the costly referendum that took place in California, Proposition 2, ban-
ning veal crates and battery cages and gestation crates. It would have cost Colo-
rado agriculture $12 million to fight it and lose two to one, and they didn’t have
$12 million, so we were able to broker a compromise.
People are seeking to build fences around animals. There were two sur-
veys, one done by Gallup, one by Oklahoma State University, both of which had
almost identical results, although you would expect a discrepancy because Okla-
homa State is a very strong agricultural school and the poll was not particularly
agriculturally oriented. They both found that 80% of the general public wants to
see proper treatment of farm animals ensured by legislation.
People in society are seeking to build fences around animals to protect the
animals and their interests and their natures, which following Aristotle I have
called telos. Those of you who studied Aristotle know what he means by telos:
the biological and behavioral and psychological needs and interests that are con-
stitutive of a given type of animal—e.g., the pigness of the pig, as one of my
book reviewers once wrote, or the cowness of the cow. They are trying to pro-
tect that from being totally submerged in the quest for human general welfare,
and are trying to accomplish it by going to the legislature.
With good husbandry, respect for telos occurred automatically. In indus-
trial agriculture where it is no longer automatic, and also in animal testing, peo-
ple wish to see it legislated.
Very simply, the new ethic recognizes that fish must swim, birds must fly.
Clearly, then, the notion that animals ought to have legal protection for funda-
mental aspects of their natures, a notion actualized in the Swedish agricultural
law of 1988 and implicit in the Brambell Commission, is a mainstream phe-
nomenon.
One of the most extraordinary things about writing the laboratory animal
laws was the fact that the public did not divide on party lines. Support for con-
trolling pain and suffering in animals, for example, was invariant across Democ-
rats and Republicans.
People were not saying do not use animals in research. What they are say-
ing is, if you use animals in research, control the pain, control the distress. Dis-
tress is demarcated from pain in the US laws.
Conceptually speaking in terms of legal theory, animals cannot have rights
because they are property. The old slave decisions established that anything that
is property cannot have rights. This is a solecism, a legal oxymoron. However,
this could not be changed without a Constitutional amendment although a lot of
legal scholars are trying to do precisely that.
There was an animal law conference at Harvard Law School two years ago
where 350 people filled every space and 300 were turned away. Over 100 law
schools have courses in animal law, and a big thrust of most of those law profes-
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180 Animal Research in a Global Environment: Meeting the Challenges
sors is enfranchising animals and abolishing invasive animal use. But the same
functional goal can be accomplished by restricting how animal property is used,
which is exactly what the proliferation of laws attempts to do, including the
laboratory animal laws. The day they passed I was sitting with Tom Wolfle from
NIH and Dale Schwindaman from USDA, and they both shook my hand saying,
“Congratulations, you have established certain minimal rights for animals.”
These men were hardly radicals and essentially what they were saying was that
an animal now had the right to have its pain controlled if pain is inflicted in the
course of research, unless you were studying pain.
The good news is that we have gone from two published papers on analge-
sia to more than 11,000, with a correlative increase in its use, however deficient
that use may still be.
So with this analysis in mind, we can begin to answer the question of cul-
tural relativity of concepts of animal welfare. If our account is correct, there is
not great disparity across at least different Western societies: all believe morally
that animals should legally have their natures and interests protected and this
should be accomplished by the legal/regulatory system. This is perhaps truer in
Europe than in America.
Insofar as this notion seems to pervade Western democratic societies,
which dominate the world politically and economically, it appears that this
notion will dominate as the key notion of animal welfare, even as Western
democratic notions of human rights have dominated discourse regarding human
ethics.
People in other countries are beginning to realize that this notion will
dominate. For example, two years ago I addressed 300 Southeast Asian agricul-
ture animal producers who were greatly interested in what is happening in the
West because they knew that they would have to abide by those standards if they
were going to trade with the West. Recent announcements by Chinese govern-
ment officials explicitly state that pressures of globalization are forcing China to
consciously consider animal welfare and animal welfare legislation for the first
time in its history.
As more and more US research is being shipped to other countries for eco-
nomic reasons, we can be morally certain that public opinion will demand that it
be accompanied by the new ethic. Judy MacArthur Clark has a project to try to
bring Western ethical standards to these countries where the research will be
exported.
As we argued earlier, the concept of animal welfare is deeply value-laden,
both in what we choose to consider ingredient in an animal’s welfare and to
what extent we are willing to satisfy those welfare concerns. This in turn first
led to producers saying that welfare is what the animal requires to do the job we
expect of them. That has been turned around by the new ethic and placed the
locus of welfare in the animal, not in our generosity or largesse. That is the
source of the notion of rights, that they are entitled rather than simply being a
matter of our will.
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Cross-Cultural Ethical Perceptions and Ways to Resolve Challenges 181
We have argued that the new ethic is intended to restore the fair contract
inherent in husbandry, and it is primarily agricultural. It happened with research
first in the US because we are removed from agriculture. My average Columbia
PhD friend still thinks farms are Old McDonald’s farms. We have argued that
the new ethic is intended to restore the fair contract inherent in husbandry and to
ensure that animals lead decent lives. We have further argued that the source of
our primary obligation to animals is derived from attending to the animals’ na-
tures, even as the rights of humans are based in respecting the essentials of hu-
man nature. How does this notion transfer to animals?
In the US Constitution and in the foundational documents of other demo-
cratic societies, the relevant concept of human nature was derived from people’s
reaction to being denied certain things, from oppression. Having been denied
freedom of religion or belief, people demanded that such belief be protected
from governmental intrusion. Similarly, this is true of the seizure of property.
Philosophically, the notion of human nature is of course very problematic, with
many theories abounding about what human nature is and with some
philosophers, notably existentialists and Marxists, affirming that there is no such
thing. Interestingly enough, I would argue that whatever position you take on
human nature, the notion of animal nature is far less problematic than the notion
of human nature.
Animal life is far less plastic than human nature and is far less influenced
by culture, and is thus far easier to define. It is more obvious, for example, that
lions are predators than that humans are. Determining what animals are evolved
for is simpler than answering the same question about humans. So obvious is it
that animals have a nature that Aristotle, the greatest philosopher of common
sense in antiquity, made it the cornerstone of his biology, and correlatively made
biology based in telos the root metaphor for explaining everything in the uni-
verse. Whereas for Cartesian and post-Cartesian modern biology, biology is best
expressed in terms of physics and chemistry, for Aristotle physics and chemistry
were to be explained using functional biological categories. Physics was for
Aristotle the biology of dead matter, to put it paradoxically. Biological catego-
ries, functional categories, are the most appropriate categories for explanation
when it comes to living things.
So in De Anima, which is his biology, Aristotle lays out a functional tem-
plate for biology that still serves as the framework for the way biology is taught
in high school. Any living thing, says Aristotle, is a constellation of functions
constitutive of its nature, and all living things are to be described in terms of
how they fulfill these functions—locomotion, reproduction, nutrition, excretion,
sensation, and so on. We characterize living things in terms of how they fulfill
these functions. These functions, then, I would argue, constitute the telos of any
type of animal—the pigness of the pig, the dogness of the dog. Aristotle says,
tellingly, this nature is knowable simply by intelligent and repeated observation.
Respect for the animal’s nature was essential for traditional agriculture: the
greater the respect, the better the husbandry, the more productive was the ani-
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182 Animal Research in a Global Environment: Meeting the Challenges
mal. The fact of agricultural success attested to knowledge of animal telos. Un-
der extensive conditions, productivity did betoken good welfare.
Modern agricultural use circumvents respect for telos and forces square
pegs into round holes. Other animal uses ignore telos—for example, zoos and
maintenance of animals in research settings, where animals are housed in condi-
tions developed largely out of convenience for us but in violation of the needs
flowing from their natures, as when nocturnal burrowing creatures are kept in
polycarbonate cages under bright illumination or when social animals are kept in
isolation in zoos, or the most egregious example I ever experienced in my youth,
a giraffe cage in which the giraffe could not stand up. Such a situation would not
occur today, which in a weak way attests evidentially to the claim that society is
worried about animal telos.
Both Tom Wolfle and I in the early 1980s and David Morton today have
pointed out that the conditions under which we keep animals are probably more
invasive and more harmful to the animal than the number of overt invasive pro-
tocols. My understanding is that maybe 10-15% of protocols are seriously inva-
sive in research. But 100% of animals are kept under conditions that are inimical
to their basic natures.
I would thus argue that in today’s world, animal welfare is being defined
in terms of animal telos—that is, meeting the needs and interests that matter to
the animal by virtue of its biological and psychological nature. According to my
analysis, complete satisfaction of the animal’s telos would constitute what could
be legitimately called happiness for the animal. Thus, a happy lion would be a
lion kept under extensive conditions with other lions, allowing the full range of
lion behavior, including predatory behavior. A miserable lion would be one kept
alone in a small cage. The relevant ethical judgment for lions in captivity would
be to create a space that functionally approximates the ideal, as the research
community has done with primates. Thus, pigs in a straw-based pen system
would be happier than a sow in a sow stall, but not as happy as a sow with free
access to foraging and shelter from inclement weather. There is a huge body of
empirical data from Edinburgh on natural behavior in pigs, particularly sows. In
my view, part of the job of what is called animal welfare science is getting as
close as possible to happiness for the captive animal.
So there is more to being ethical to the research animals than simply mini-
mizing pain. There are all these other parameters. I find personally talking of
animal happiness unproblematic. Indeed, I would argue that animal happiness is
far clearer than human happiness, given the curse of human reflective con-
sciousness. A person may have every wish he or she ever wanted fulfilled, yet
not be happy for a multitude of reasons. Everyone has friends like this—for ex-
ample, people possessed of neurotic worry about losing it, neurotic worry about
whether they deserve it or not. We have no reason to believe that animals are
capable of such nonproductive navel-gazing. There are few human cases of hap-
piness as paradigmatic as the horse let out of the small corral after winter into a
large green pasture, after being fenced for months: the kicking up of the heels,
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Cross-Cultural Ethical Perceptions and Ways to Resolve Challenges 183
the breaking of wind, the exuberance of the gallop, and the whinny express joy
more clearly than any human affirmations. Typically, animals don’t lie.
In sum, we have argued that emerging social ethics for animals in
democratic societies will largely dictate the form animal welfare takes, and
particularly in the research area, since social and economic pressure will help
impose it on other societies. This emerging ethic emphasizes the rights animals
should have based on their biological and psychological natures or teloi. The
extent to which such telos can be accommodated will vary with circumstance,
but the ideal remains clearly demarcated. This idea was necessary to counter the
20th century tendency to see animal welfare as strictly determined by the human
purposes to which the animal is put.
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