Research-Based argument essay

Overview

Ethical and Scientific Considerations Regarding Animal Testing and Research Hope R. Ferdowsian1,2*, Nancy Beck1

1 Physicians Committee for Responsible Medicine, Washington, D.C., United States of America, 2 Department of Medicine, The George Washington University,

Washington, D.C., United States of America

In 1959, William Russell and Rex

Burch published the seminal book, The

Principles of Humane Experimental Technique,

which emphasized reduction, refinement,

and replacement of animal use, principles

which have since been referred to as the

‘‘3 Rs’’. These principles encouraged

researchers to work to reduce the number

of animals used in experiments to the

minimum considered necessary, refine or

limit the pain and distress to which

animals are exposed, and replace the use

of animals with non-animal alternatives

when possible. Despite the attention

brought to this issue by Russell and Burch

and since, the number of animals used in

research and testing has continued to

increase, raising serious ethical and scien-

tific issues. Further, while the ‘‘3 Rs’’

capture crucially important concepts, they

do not adequately reflect the substantial

developments in our new knowledge about

the cognitive and emotional capabilities of

animals, the individual interests of ani-

mals, or an updated understanding of

potential harms associated with animal

research. This Overview provides a brief

summary of the ethical and scientific

considerations regarding the use of ani-

mals in research and testing, and accom-

panies a Collection entitled Animals, Re-

search, and Alternatives: Measuring Progress 50

Years Later, which aims to spur ethical and

scientific advancement.

Introduction

One of the most influential attempts to

examine and affect the use of animals in

research can be traced back to1959, with

the publication of The Principles of Humane

Experimental Technique [1]. William Russell

and Rex Burch published this seminal

book in response to marked growth in

medical and veterinary research and the

concomitant increase in the numbers of

animals used. Russell and Burch’s text

emphasized reduction, refinement, and

replacement of animal use, principles

which have since been referred to as the

‘‘3 Rs’’. These principles encouraged

researchers to work to reduce the number

of animals used in experiments to the

minimum considered necessary, refine or

limit the pain and distress to which

animals are exposed, and replace the use

of animals with non-animal alternatives

when possible.

Despite the attention brought to this

issue by Russell and Burch, the number of

animals used in research and testing has

continued to increase. Recent estimates

suggest that at least 100 million animals

are used each year worldwide [2]. How-

ever, this is likely an underestimate, and it

is impossible to accurately quantify the

number of animals used in or for exper-

imentation. Full reporting of all animal use

is not required or made public in most

countries. Nevertheless, based on available

information, it is clear that the number of

animals used in research has not signifi-

cantly declined over the past several

decades.

The ‘‘3 Rs’’ serve as the cornerstone for

current animal research guidelines, but

questions remain about the adequacy of

existing guidelines and whether research-

ers, review boards, and funders have fully

and adequately implemented the ‘‘3 Rs’’.

Further, while the ‘‘3 Rs’’ capture crucially

important concepts, they do not adequate-

ly reflect the substantial developments in

our new knowledge about the cognitive

and emotional capabilities of animals; an

updated understanding of the harms

inherent in animal research; and the

changing cultural perspectives about the

place of animals in society [3], [4]. In

addition, serious questions have been

raised about the effectiveness of animal

testing and research in predicting antici-

pated outcomes [5–13].

In August 2010, the Georgetown Uni-

versity Kennedy Institute of Ethics, the

Johns Hopkins University Center for Alter-

natives to Animal Testing, the Institute for

In Vitro Sciences, The George Washington

University, and the Physicians Committee

for Responsible Medicine jointly held a two

day multi-disciplinary, international confer-

ence in Washington, DC, to address the

scientific, legal, and political opportunities

and challenges to implementing alternatives

to animal research. This two-day sympo-

sium aimed to advance the study of the

ethical and scientific issues surrounding the

use of animals in testing and research, with

particular emphasis on the adequacy of

current protections and the promise and

challenges of developing alternatives to the

use of animals in basic research, pharma-

ceutical research and development, and

regulatory toxicology. Speakers who con-

tributed to the conference reviewed and

contributed new knowledge regarding the

cognitive and affective capabilities of ani-

mals, revealed through ethology, cognitive

psychology, neuroscience, and related dis-

ciplines. Speakers also explored the dimen-

sions of harm associated with animal

research, touching on the ethical implica-

tions regarding the use of animals in

research. Finally, several contributors pre-

sented the latest scientific advances in

Citation: Ferdowsian HR, Beck N (2011) Ethical and Scientific Considerations Regarding Animal Testing and Research. PLoS ONE 6(9): e24059. doi:10.1371/journal.pone.0024059

Editor: Catriona J. MacCallum, Public Library of Science, United Kingdom

Published September 7, 2011

Copyright: � 2011 Ferdowsian, Beck. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The authors are grateful to the National Science Foundation (grant SES-0957163) and the Arcus Foundation (grant 0902-34) for the financial support for the corresponding conference, Animals, Research, and Alternatives: Measuring Progress 50 Years Later. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: HRF and NB are employed by Physicians Committee for Responsible Medicine, which is a non-governmental organization which promotes higher ethical standards in research and alternatives to the use of animals in research, education, and training. Physicians Committee for Responsible Medicine is a nonprofit organization, and the authors adhered to PLoS ONE policies on sharing data and materials.

* E-mail: [email protected]

PLoS ONE | www.plosone.org 1 September 2011 | Volume 6 | Issue 9 | e24059

developing alternatives to the use of animals

in pharmaceutical research and develop-

ment and regulatory toxicity testing.

This Collection combines some papers

that were written following this conference

with an aim to highlight relevant progress

and research. This Overview provides a

brief summary of the ethical and scientific

considerations regarding the use of ani-

mals in research and testing, some of

which are highlighted in the accompany-

ing Collection.

Analysis and Discussion

Ethical Considerations and Advances in the Understanding of Animal Cognition

Apprehension around burgeoning med-

ical research in the late 1800s and the first

half of the 20 th

century sparked concerns

over the use of humans and animals in

research [14], [15]. Suspicions around the

use of humans were deepened with the

revelation of several exploitive research

projects, including a series of medical

experiments on large numbers of prisoners

by the Nazi German regime during World

War II and the Tuskegee syphilis study.

These abuses served as the impetus for the

establishment of the Nuremberg Code,

Declaration of Helsinki, and the National

Commission for the Protection of Human

Subjects of Biomedical and Behavioral

Research (1974) and the resulting Belmont

Report [16–18]. Today, these guidelines

provide a platform for the protection of

human research subjects, including the

principles of respect, beneficence, and

justice, as well as special protections for

vulnerable populations.

Laws to protect animals in research

have also been established. The British

Parliament passed the first set of protec-

tions for animals in 1876, with the Cruelty

to Animals Act [19]. Approximately ninety

years later, the U.S. adopted regulations

for animals used in research, with the

passage of the Laboratory Animal Welfare

Act of 1966 [20]. Subsequent national and

international laws and guidelines have

provided basic protections, but there are

some significant inconsistencies among

current regulations [21]. For example,

the U.S. Animal Welfare Act excludes

purpose-bred birds, rats, or mice, which

comprise more than 90% of animals used

in research [20]. In contrast, certain dogs

and cats have received special attention

and protections. Whereas the U.S. Animal

Welfare Act excludes birds, rats and mice,

the U.S. guidelines overseeing research

conducted with federal funding includes

protections for all vertebrates [22], [23].

The lack of consistency is further illustrat-

ed by the ‘‘U.S. Government Principles for

the Utilization and Care of Vertebrate

Animals Used in Testing, Research and

Training’’ which stress compliance with

the U.S. Animal Welfare Act and ‘‘other

applicable Federal laws, guidelines, and

policies’’ [24].

While strides have been made in the

protection of both human and animal

research subjects, the nature of these

protections is markedly different. Human

research protections emphasize specific

principles aimed at protecting the interests

of individuals and populations, sometimes

to the detriment of the scientific question.

This differs significantly from animal

research guidelines, where the importance

of the scientific question being researched

commonly takes precedence over the

interests of individual animals. Although

scientists and ethicists have published

numerous articles relevant to the ethics

of animal research, current animal re-

search guidelines do not articulate the

rationale for the central differences be-

tween human and animal research guide-

lines. Currently, the majority of guidelines

operate on the presumption that animal

research should proceed based on broad,

perceived benefits to humans. These

guidelines are generally permissive of

animal research independent of the costs

to the individual animal as long as benefits

seem achievable.

The concept of costs to individual

animals can be further examined through

the growing body of research on animal

emotion and cognition. Studies published

in the last few decades have dramatically

increased our understanding of animal

sentience, suggesting that animals’ poten-

tial for experiencing harm is greater than

has been appreciated and that current

protections need to be reconsidered. It is

now widely acknowledged by scientists

and ethicists that animals can experience

pain and distress [25–29]. Potential causes

of harm include invasive procedures,

disease, and deprivation of basic physio-

logical needs. Other sources of harm for

many animals include social deprivation

and loss of the ability to fulfill natural

behaviors, among other factors. Numerous

studies have demonstrated that, even in

response to gentle handling, animals can

show marked changes in physiological and

hormonal markers of stress [30].

Although pain and suffering are subjec-

tive experiences, studies from multiple

disciplines provide objective evidence of

animals’ abilities to experience pain.

Animals demonstrate coordinated re-

sponses to pain and many emotional states

that are similar to those exhibited by

humans [25], [26]. Animals share genetic,

neuroanatomical, and physiological simi-

larities with humans, and many animals

express pain in ways similar to humans.

Animals also share similarities with hu-

mans in genetic, developmental, and

environmental risk factors for psychopa-

thology [25], [26]. For example, fear

operates in a less organized subcortical

neural circuit than pain, and it has been

described in a wide variety of species [31].

More complex markers of psychological

distress have also been described in

animals. Varying forms of depression have

been repeatedly reported in animals,

including nonhuman primates, dogs, pigs,

cats, birds and rodents, among others [32–

34]. Anxiety disorders, such as post-

traumatic stress disorder, have been de-

scribed in animals including chimpanzees

and elephants [35], [36], [37].

In addition to the capacity to experience

physical and psychological pain or distress,

animals also display many language-like

abilities, complex problem-solving skills,

tool related cognition and pleasure-seek-

ing, with empathy and self-awareness also

suggested by some research. [38–44]. Play

behavior, an indicator of pleasure, is

widespread in mammals, and has also

been described in birds [45], [46]. Behav-

ior suggestive of play has been observed in

other taxa, including reptiles, fishes and

cephalopods [43]. Self-awareness, assessed

through mirror self-recognition, has been

reported for chimpanzees and other great

apes, magpies, and some cetaceans. More

recent studies have shown that crows are

capable of creating and using tools that

require access to episodic-like memory

formation and retrieval [47]. These find-

ings suggest that crows and related species

display evidence of causal reasoning,

flexible learning strategies, imagination

and prospection, similar to findings in

great apes. These findings also challenge

our assumptions about species similarities

and differences and their relevance in

solving ethical dilemmas regarding the use

of animals in research.

Predictive Value of Animal Data and the Impact of Technical Innovations on Animal Use

In the last decade, concerns have

mounted about how relevant animal

experiments are to human health out-

comes. Several papers have examined the

concordance between animal and human

data, demonstrating that findings in ani-

mals were not reliably replicated in human

clinical research [5–13]. Recent systematic

reviews of treatments for various clinical

Revisiting the Ethics and Science of Animal Use

PLoS ONE | www.plosone.org 2 September 2011 | Volume 6 | Issue 9 | e24059

conditions demonstrated that animal stud-

ies have been poorly predictive of human

outcomes in the fields of neurology and

vascular disease, among others [7], [48].

These reviews have raised questions about

whether human diseases inflicted upon

animals sufficiently mimic the disease

processes and treatment responses seen in

humans.

The value of animal use for predicting

human outcomes has also been questioned

in the regulatory toxicology field, which

relies on a codified set of highly standard-

ized animal experiments for assessing

various types of toxicity. Despite serious

shortcomings for many of these assays,

most of which are 50 to 60 years old, the

field has been slow to adopt newer

methods. The year 2007 marked a turning

point in the toxicology field, with publica-

tion of a landmark report by the U.S.

National Research Council (NRC), high-

lighting the need to embrace in vitro and

computational methods in order to obtain

data that more accurately predicts toxic

effects in humans. The report, ‘‘Toxicity

Testing in the 21 st

Century: A Vision and

a Strategy,’’ was commissioned by the

U.S. Environmental Protection Agency,

partially due to the recognition of weak-

nesses in existing approaches to toxicity

testing [49]. The NRC vision calls for a

shift away from animal use in chemical

testing toward computational models and

high-throughput and high-content in vitro

methods. The report emphasized that

these methods can provide more predic-

tive data, more quickly and affordably

than traditional in vivo methods. Subse-

quently published articles address the

implementation of this vision for improv-

ing the current system of chemical testing

and assessment [50], [51].

While a sea change is underway in

regulatory toxicology, there has been

much less dialogue surrounding the re-

placement of animals in research, despite

the fact that far more animals are used in

basic and applied research than in regu-

latory toxicology. The use of animals in

research is inherently more difficult to

approach systematically because research

questions are much more diverse and less

proscribed than in regulatory toxicology

[52]. Because researchers often use very

specialized assays and systems to address

their hypotheses, replacement of animals

in this area is a more individualized

endeavour. Researchers and oversight

boards have to evaluate the relevance of

the research question and whether the

tools of modern molecular and cell

biology, genetics, biochemistry, and com-

putational biology can be used in lieu of

animals. While none of these tools on their

own are capable of replicating a whole

organism, they do provide a mechanistic

understanding of molecular events. It is

important for researchers and reviewers to

assess differences in the clinical presenta-

tion and manifestation of diseases among

species, as well as anatomical, physiolog-

ical, and genetic differences that could

impact the transferability of findings.

Another relevant consideration is how

well animal data can mirror relevant

epigenetic effects and human genetic

variability.

Examples of existing and promising

non-animal methods have been reviewed

recently by Langley and colleagues, who

highlighted advances in fields including

orthodontics, neurology, immunology, in-

fectious diseases, pulmonology, endocrine

and metabolism, cardiology, and obstetrics

[52].

Many researchers have also begun to

rely solely on human data and cell and

tissue assays to address large areas of

therapeutic research and development. In

the area of vaccine testing and develop-

ment, a surrogate in-vitro human immune

system has been developed to help predict

an individual’s immune response to a

particular drug or vaccine [53], [54]. This

system includes a blood-donor base of

hundreds of individuals from diverse

populations and offers many benefits,

including predictive high-throughput in

vitro immunology to assess novel drug

and vaccine candidates, measurement of

immune responses in diverse human

populations, faster cycle time for discov-

ery, better selection of drug candidates for

clinical evaluation, and reductions in the

time and costs to bring drugs and vaccines

to the market. In the case of vaccines, this

system can be used at every stage,

including in vitro disease models, antigen

selection and adjuvant effects, safety

testing, clinical trials, manufacturing, and

potency assays. When compared with data

from animal experiments, this system has

produced more accurate pre-clinical data.

The examples above illustrate how

innovative applications of technology can

generate data more meaningful to hu-

mans, and reduce or replace animal use,

but advances in medicine may also require

novel approaches to setting research

priorities. The Dr. Susan Love Research

Foundation, which focuses on eradicating

breast cancer, has challenged research

scientists to move from animal research

to breast cancer prevention research

involving women. If researchers could

better understand the factors that increase

the risk for breast cancer, as well as

methods for effective prevention, fewer

women would require treatment for breast

cancer. Whereas animal research is largely

investigator-initiated, this model tries to

address the questions that are central to

the care of women at risk for or affected by

breast cancer. This approach has facilitat-

ed the recruitment of women for studies

including a national project funded by the

National Institutes of Health and the

National Institute of Environmental

Health to examine how environment and

genes affect breast cancer risk. This study,

which began in 2002, could not have been

accomplished with animal research [55].

Similarly, any approach that emphasiz-

es evidence-based prevention would pro-

vide benefits to both animals and humans.

Resource limitations might require a

strategic approach that emphasizes diseas-

es with the greatest public health threats,

which increasingly fall within the scope of

preventable diseases.

Conclusion It is clear that there have been many

scientific and ethical advances since the

first publication of Russell and Burch’s

book. However, some in the scientific

community are beginning to question

how well data from animals translates into

germane knowledge and treatment of

human conditions. Efforts to objectively

evaluate the value of animal research for

understanding and treating human disease

are particularly relevant in the modern

era, considering the availability of increas-

ingly sophisticated technologies to address

research questions [9]. Ethical objections

to the use of animals have been publically

voiced for more than a century, well

before there was a firm scientific under-

standing of animal emotion and cognition

[15]. Now, a better understanding of

animals’ capacity for pain and suffering

is prompting many to take a closer look at

the human use of animals [56].

Articles in the accompanying Collection

only briefly touch on the many scientific

and ethical issues surrounding the use of

animals in testing and research. While it is

important to acknowledge limitations to

non-animal methods remain, recent de-

velopments demonstrate that these limita-

tions should be viewed as rousing chal-

lenges rather than insurmountable

obstacles. Although discussion of these

issues can be difficult, progress is most

likely to occur through an ethically

consistent, evidence-based approach. This

collection aims to spur further steps

forward toward a more coherent ethical

framework for scientific advancement.

Revisiting the Ethics and Science of Animal Use

PLoS ONE | www.plosone.org 3 September 2011 | Volume 6 | Issue 9 | e24059

Acknowledgments

The authors thank the conference speakers and

participants for their participation.

Author Contributions

Conceived and designed the experiments:

HRF NB. Contributed reagents/materials/

analysis tools: HRF NB. Wrote the paper:

HRF NB.

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Revisiting the Ethics and Science of Animal Use

PLoS ONE | www.plosone.org 4 September 2011 | Volume 6 | Issue 9 | e24059